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Kounis Syndrome
From Bedside to Bench
Nicholas Kounis Iatros MD PhD FESC FACCNicholas Kounis Iatros MD PhD FESC FACC
ldquoA hypersensitivity blow up inside the coronariesrdquo
Hypersensitivity inflammation
Acute coronary syndrome+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
ldquo helliphellipeven ordinary allergic reactions could promote plaque disruptionhelliphelliphelliprdquo Circulation 1995 92 1083
Mast cells
From bone marrow enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid (mRNA) for stem cell factor and have KIT receptors for the SCF They migrate into all the tissues including the brain which does not suffer from allergic reactions because IgE does not cross the blood-brain barrier and they
differentiate and mature there This takes several days to weeks
Basophils develop in bone marrow from granulocyte precursors and entering the circulation only when fully mature They are not normally found in extravascular tissues compartments only migrating there during late-phase allergic responses
Named by Paul Erlich in 1887 (German=mastzellen=well fed)
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity inflammation
Acute coronary syndrome+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
ldquo helliphellipeven ordinary allergic reactions could promote plaque disruptionhelliphelliphelliprdquo Circulation 1995 92 1083
Mast cells
From bone marrow enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid (mRNA) for stem cell factor and have KIT receptors for the SCF They migrate into all the tissues including the brain which does not suffer from allergic reactions because IgE does not cross the blood-brain barrier and they
differentiate and mature there This takes several days to weeks
Basophils develop in bone marrow from granulocyte precursors and entering the circulation only when fully mature They are not normally found in extravascular tissues compartments only migrating there during late-phase allergic responses
Named by Paul Erlich in 1887 (German=mastzellen=well fed)
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
ldquo helliphellipeven ordinary allergic reactions could promote plaque disruptionhelliphelliphelliprdquo Circulation 1995 92 1083
Mast cells
From bone marrow enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid (mRNA) for stem cell factor and have KIT receptors for the SCF They migrate into all the tissues including the brain which does not suffer from allergic reactions because IgE does not cross the blood-brain barrier and they
differentiate and mature there This takes several days to weeks
Basophils develop in bone marrow from granulocyte precursors and entering the circulation only when fully mature They are not normally found in extravascular tissues compartments only migrating there during late-phase allergic responses
Named by Paul Erlich in 1887 (German=mastzellen=well fed)
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity inflammation
Acute coronary syndrome
Hypersensitivity coronary syndrome (Kounis syndrome)
+
ldquo helliphellipeven ordinary allergic reactions could promote plaque disruptionhelliphelliphelliprdquo Circulation 1995 92 1083
Mast cells
From bone marrow enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid (mRNA) for stem cell factor and have KIT receptors for the SCF They migrate into all the tissues including the brain which does not suffer from allergic reactions because IgE does not cross the blood-brain barrier and they
differentiate and mature there This takes several days to weeks
Basophils develop in bone marrow from granulocyte precursors and entering the circulation only when fully mature They are not normally found in extravascular tissues compartments only migrating there during late-phase allergic responses
Named by Paul Erlich in 1887 (German=mastzellen=well fed)
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquo helliphellipeven ordinary allergic reactions could promote plaque disruptionhelliphelliphelliprdquo Circulation 1995 92 1083
Mast cells
From bone marrow enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid (mRNA) for stem cell factor and have KIT receptors for the SCF They migrate into all the tissues including the brain which does not suffer from allergic reactions because IgE does not cross the blood-brain barrier and they
differentiate and mature there This takes several days to weeks
Basophils develop in bone marrow from granulocyte precursors and entering the circulation only when fully mature They are not normally found in extravascular tissues compartments only migrating there during late-phase allergic responses
Named by Paul Erlich in 1887 (German=mastzellen=well fed)
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Mast cells
From bone marrow enter the circulation as mononuclear cell precursors that express messenger ribonucleic acid (mRNA) for stem cell factor and have KIT receptors for the SCF They migrate into all the tissues including the brain which does not suffer from allergic reactions because IgE does not cross the blood-brain barrier and they
differentiate and mature there This takes several days to weeks
Basophils develop in bone marrow from granulocyte precursors and entering the circulation only when fully mature They are not normally found in extravascular tissues compartments only migrating there during late-phase allergic responses
Named by Paul Erlich in 1887 (German=mastzellen=well fed)
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis syndrome the hypersensitivity coronary syndrome
What isldquoThe concurrence of acute coronary syndromes with conditions associated with mast cell activation involving interrelated and
interacting inflammatory cells and including allergic or hypersensitivity and anaphylactic or anaphylactoid insultsrdquo ldquoIt is caused by inflammatory mediators such as histamine neutral proteases arachidonic acid products platelet activating factor and a variety of cytokines and chemokines released during the activation processrdquo ldquoA subset of platelets bearing FCεRI and FCεRII receptors are also involved in the activation cascaderdquo
Mast cells
Macrophages T-cells
Mast cells
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
The cytokine network Image of the global network of cytokine interactions between the 4 immune cells (red nodes) and the 15 non-immune body cells (blue nodes) The black edges represent mutual connections the grey edges represent one-way connections
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
The vicious cycle of inflammatory cells
Macrophages
Mast cells
Macrophages
T-cells
Macrophages
All these inflammatory cells participate in a vicious inflammatory cycle and via multidirectional signals
1 Mast cells can enhance T cell activation1
2 T cells can mediate mast cell activation and proliferation2
3 Inducible macrophage protein-1α can activate mast cells3
4 mast cells can activate macrophages4
5 T cells can regulate macrophage activity5
1 Nakae S et al J Immunol 2006 176 2238 2 Mecori YA et al Clin Immunol 1999 104 517 3 Miyazaki D et al J Clin Invest 2005 115 434 4 Salari H et al J Immunol 1989 142 2821 5 Doherty TM Curr Opin Immunol 1995 7 400
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Mast cell the pleiotropocyte andits Inflammatory mediatorsbull PREFORMED MEDIATORS
bull Biogenic amines
bull -histaminebull -Renin bull -angiotensin IIbull -serotonin
bull Chemokines
bull -IL-8 MCP-1 MCP-3 MCP-4 RANTES
bull Enzymes
bull -arysulfatasesbull -carbopeptidase Abull -Chymasebull -kinogenasesbull -phospholipasesbull -tryptase Cathepsin Gbull bull Peptides
bull -bradykininbull -corticotropin-releasing hormonebull -endorphinsbull -endothelinbull -somatostatinbull -substance Bbull -vasoactive intestinal peptidebull -urocortinbull -vascular endothelial growth factorbull -vascular factor
bull Proteoglycans
bull -chondroitin -heparin -hyaluronic acid
bull NEWLY SYNTHESIZED MEDIATORSbull Cytokines
bull -interleukins (IL)- 1234569101316
bull -interferon-γbull -macrophagebull activating factorbull bull bull -tumor necrosis factor-α
bull Growth factors
bull -granulocyte monocyte-colony stimulating factor
bull -fibroblast growth factorbull -nerve growth factorbull -stem cell factorbull -vascular endothelial growth
factor bull bull Arachidonic acid products
bull -leukotrienesbull -platelet activating factorbull -prostaglandins (thromboxane)
Theoharides TC J Clin Psychopharmacol 200222103
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis syndrome main actions of main mediators
Cardiac effects of histamine1Coronary vasoconstriction (histamine test)2 Induces tissue factor expression and activity3 Activates platelets and potentiates the
aggregatory response of agonists eg adrenaline 5-hydroxytryptamine and thrombin
4 Intimal thickening5 Inflammatory cell modulation6 Modulates the activity of neutrophils
monocytes and eosinophils7 Proinflammatory cytokine production8 P-selectine upregulation9 Sensitizites nerve endings in coronary plaques
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis syndrome cardiac actions of main mediators Proteases
Tryptase
1 Activates the zymogen forms of metalloproteinases such as interstitial collagenase gelatinase and stromelysin and can promote plaque disruption or rupture
2 Degrates the pericellular matrix components fibronectin and vitronectin and neuropeptides such as vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP)
3 Tryptase can degrade HDL 4 Activates neighboring cells by
cleaving and activating protease-activated receptor (PAR)-2 and thrombin receptors
Chymase
1 Converts angiotensin I to angiotensin II and angiotensin II receptors are found in the medial muscle cells of human coronary arteries Thus angiotensin II generated by chymase could act synergistically with histamine and aggravate the local spasm of the infarcted coronary artery Chymase also can remove cholesterol from HDL
2 Activates MMP-1-2-9 and plays a major role in the physiologic degradation of fibronectin and thrombin
Cathepsin D
1 Angiotensin II-forming protease
2Degrates both fibronectin and VE-cadherin which are necessary for
adhesion of endothelial cells to their basement membrane and to each other
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Leukotrienes Powerful arterial vasoconstrictors and their biosynthesis is enhanced in the acute phase of
unstable angina
Thromboxane A potent mediator of platelet aggregation with vasoconstricting properties
Platelet activating factor In myocardial ischemia acts as proadhesive signalling molecule or via activation of leucocytes and platelets to release other
mediators It can act either through the release of leukotrienes or as a direct vasoconstrictor
Kounis syndrome cardiac actions of the main mediators
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis syndrome variants Type I variant includes patients with normal coronary arteries
without predisposing factors for coronary artery disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm without increase of cardiac enzymes and troponins or coronary artery spasm progressing to acute myocardial infarction with raised cardiac enzymes and troponin Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Type II variant includes patients with culprit but quiescent pre-existing atheromatous disease in whom the acute release of inflammatory mediators can induce either coronary artery spasm with normal cardiac enzymes and troponins or plaque erosion or rupture manifesting as acute myocardial infarction
Type III variant includes patients with coronary artery stent thrombosis in whom aspirated thrombus specimens stained with hematoxylin-eosin and Giemsa demonstrate the presence of eosinophils and mast cells respectively
Biteker M Expert Rev Clin Immunol 2010 6 777-88
Nikolaidis LA et al Can J Cardiol 2002 18 508Nikolaidis LA et al Can J Cardiol 2002 18 508
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis (MMAS)NicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Analgesics (eg aspirin and dipyrone)
Anesthetics (eg etomidate isoflurane midazolam propofol remifentanil rocuronium bromide
succinylcholine suxamethonium and trimethaphan)
Antibiotics (eg ampicillin ampicillinsulfactam amoxicillin amikacin cefazolin cefoxitin
cefuroxime cephradine cinoxacin lincomycin penicillin sulbactamcefoperazone
piperacillintazobactam trimethoprimndashsulfamethoxazole sulperazon and vancomycin)
Anticoagulants (eg heparin and lepirudin)
Antineoplastics (eg 5-fluorouracil capecitabine carboplatin denileukin interferons paclitaxel
and vinca alkaloids)
Contrast media (eg Iohexone loxagate diatrizoate meglumine and sodium indigotindisulfonate)
Glucocorticoids (eg b-methasone and hydrocortisone)
Nonsteroidal anti-inflammatory drugs (eg alclofenac diclofenac and naproxen)
Proton pump inhibitors (eg lansoprazole pantoprazole)
Skin disinfectants (eg chlorhexidine and povidone-iodine)
Thrombolytics (eg streptokinase tissue plasminogen activator and urokinase)
Others (eg allopurinol enalapril esmolol dextran bupropion fructose insulin iodine protaminetetanus antitoxin glaphenine and mesalamine Losartan gelofusin)
2 ConditionsAngioedemaBronchial asthmaChurgndashStrauss syndromeExercise-induced anaphylaxisFood allergyHay feverIdiopathic anaphylaxisIntracoronary stentingMastocytosis-MMASNicotineSerum sickness UrticariaScombroid syndrome
3 Environmental exposuresDog lickingGrass cuttingHymenoptera stingsJellyfish stingsLatex contactMillet allergyPoison ivyShellfish eating (kiss of death)Viper venom
Causes capable of inducing Kounis syndrome1 Drugs
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Clinical and Electrocardiographic Features of Kounis Syndrome
Clinical Symptoms
bull Chest discomfortbull Acute chest painbull Dyspneabull Faintnessbull Nauseabull Vomitingbull Syncopebull Pruritusbull Urticaria
Clinical sings
bull Hypotentionbull Diaphoresisbull Pallorbull Palpitationsbull Bradycardiabull Tachycardia
Electrocardiographic sings
T-wave flattering T-wave inversionST segment elevation (STEMI)ST segment depression (non-STEMI)QRS complex prolongationQT segment prolongationSinus tachycardiaSinus bradycardiaNodal rhythm Atrial fibrillationVentricular ectopicsBigeminal rhythm
Kounis NG Zavras GM Br J Clin Pract 1991 45 121
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
The challenging treatment of Kounis syndrome
bull Τype I Treatment of the allergic event alone can abolish it so give corticosteroids H1 and H2 blockers Ca-blockers nitrates
bull Τype ΙΙ The acute coronary event protocol plus the type I treatment
bull Τype ΙΙΙ The type I and type II treatment plus thrombus aspiration Histological examination of thrombus and staining for eosinophils (hematoxylin-eosin) and mast cells (Giemsa) Allergic symptoms following stent implantation need anti allergic treatment if they insist desensitization for the guilty component and finally Stent extraction
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
One shoud bear in mind-Nitroglycerin can cause hypotension and tachycardia
-B-blockers can exaggerate coronary spasm due to unopposed a- adrenergic receptors action
-Epinephrine can aggravate ischemia and worsen coronary spasm in Kounis syndrome In severe cases sulfide free epinephrine is preferable (02-05mg 11000 aqueous solution) In patients on b-blockers may be ineffective Glucagon may be considered
-Opiates such as morphine codeine and meperidine should be given with extreme caution because can induce massive mast cell degranulation and aggravate allergic reaction Fentanyl and its derivatives show slight mast cell activation and should be preferable
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis Syndrome
helliphelliphelliphelliphelliphellip ldquoAllergic angina and allergic myocardial infarction represent a magnificent natural paradigm that might have profound clinical and therapeutic implications This is based on clinical and laboratory findingsrdquohelliphelliphelliphelliphellip
Kounis NG et al Circulation 1999 10 e156
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES they are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plt0001
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Plasma histamine in the great cardiac vein in 11 patients with variant angina (group A) and in 8 with normal
angiogram or with fixed coronary stenosis (group B)
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Overnight histamine levels in the same patient in two different dates
with and without anginal attack
Sakata Y et al Am J Cardiol 1996 77 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Plasma histamine did not raise during or after acetylcholine-induced vasospasm in
any of patients with variant angina
Sakata Y et al Am J Cardiol 199677 1121-1126
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kovanen PT et al Circulation 1995921084
First question Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES
Densities of activated mast cells in 20 patientsdied from acute myocardial infarction in the previous 24 hours
Circulating blood contains only mast cell precursors and these take several days or weeks to mature and filled with cytoplasmic secretory granulesThereforethe mast cells must have been present at the site of rupture before the acute event
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during anaphylactic insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Question 2 Is ischemic myocardial damage a primary event during anaphylactic insults I think yes
Before infusion
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
2 min after ovalbumin infusion was started (guinea pigs)
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Question 2Anaphylaxis affects the heart directly
a LVSP c LVdPdt d mean BP (rapid increase in contractile papameters) bLVEDP(cardiac pump failure) e cardiac output fstroke
volume
ldquoThe present data showed a significant rise in BP concurrent myocardial ischemia and incipient LV pump failure during the early stages of anaphylaxis Thus the idea that the registered anaphylactic cardiac damage might be due to peripheral vasodilation can be definitely excludedrdquo
Felix SB et al Exper Med 1990 190 2439Felix SB et al Exper Med 1990 190 2439
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoTakotsubo and Kounis syndrome following intravenous adrenaline injections for
anaphylactic reactionrdquo Kajander OA et al Int J Cardiol 2012 in press
Intravenous fluids administration and
corticosteroids did not revert anaphylactic shock but the patient recovered with the
current myocardial infarction therapy protocol (ACE-
inhibitor ASA thrombolysis etc)
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Τhree important questions concerning Kounis syndrome
(ldquoΤhere are more more questions than answersrdquo top 20 song of 70nties perfomed by Jony Nash)
1 Does inflammatory cell activation precede acute coronary events
Are the released inflammatory mediators the cause or are the result of the acute coronary syndrome I believe YES that are the cause
2 Is ischemic
myocardial damage a primary event during hypersensitivity insults I THINK YES (It is believed that systemic vasodilatation reduced venous return leakage of plasma and volume loss due to increase vascular perneability and the ensuing depression of cardiac output contribute to coronary hypoperfusion with subsequent myocardial damage)
3 Why Kounis syndrome occurs less often while allergic reactions are so common Letrsquos see
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Question 3
Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene
thromboxane PAF and chemokines) exists above which it can provoke coronary artery spasm andor
plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Question 3Why Kounis syndrome occurs less often while allergic reactions are so common
-A threshold level of mast cell content (histaminetryptasechymase leukotriene thromboxane PAF and chemokines) exists above which it can provoke coronary
artery spasm andor plaque erosion or rupture Kounis NG et al Int J Cardiol 2006 110 7-14
-Patients with increased baseline tryptase are prone to develop immediate and severe allergic reaction to hymenoptera sting Such patients have clonal mast cell
disorder either systemic mastocytosis or monoclonal mast cell activationAkin C et al Blood 2007 110 2331-3
Are there any KITmutations that lower the stimulus threshold
for anaphylaxis and ldquothese patients have hyper-responsive mastcell phenotype resulting in the development of severe allergic reactionsrdquo
Metcalfe DD et al J Allergy Clin Immunol 2009 123 687-688
and why not of Kounis syndrome
KIT is the mast cell transmembrane receptor for the stem cell factor (cytokine)that is essential for mast cell growth differentiation development
proliferationsurvival adhesion and homing
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoKounis syndrome a cause of chest pain to keep in mind may be associated with E148Q mutationrdquo Saylan b et al Hong Kong J Emerg Med 2012 19 278-282
Coincidence
Letrsquos seehelliphellip
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Frequency of stent thrombosis up to 35 Death 20 to 40)
-ldquoOf 5842 STEMI
patients treated
with primary PCI
201 (35)
presented with
definite early ST 97
(17) were acute
and 104(18)
were subacute STrdquoHeestermans AA et al J Thromb Haemost 2010 8 2385-93
-Thereafter 05 to 1Holmes DR et al JACC White Paper 2010 56 1357
The incidence of stroke in untreated atrial fibrillation is approximately 2-10 per year and 26-29 in treated
Friberg L et al Eur Heart J 2010 31 967-75
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Clinical implications of Kounis syndrome Kounis syndrome seems to be the main cause of
stent and other intracardiac device thrombosis Less restenosis but more thrombosis
Contrasting mechanisms of obstruction of bare-metal and drug-eluting stents
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
THE FACTS First generation Drug Eluting Stents (are still used)
components
1The metal itself is made from stainless steel which contains
nickel chromium titanium manganese and molybdenum
2The polymer coating
3The antineoplastic Paclitaxel or 3The antiproliferative Rapamycin
All these are strong allergens and constitute the ldquostent antigenic complexrdquo
Kounis NG et al Kounis NG et al J Am Coll Cardiol 2006 48 592
33
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome Hypersensitivity reactions to nickel
allergic contact dermatitis baboon syndrome bronchial asthma
dependent edema diffuse exanthema
fever flexural dermatitis itching erythema
pericarditis pompholyx formation
rosacea sarcoid granuloma (delayed hypersensitivity)
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314-323
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity to Drug Eluting stents components and Kounis
syndromeHypersensitivity reactions with the use of polymers
and Latex
-allergic conjunctivitis -allergic rhinitis
-allergic allergic stomatitis -facial angioedema
-generalized anaphylactic reaction -generalized urticaria
-interstitial asthma -neurodermatitis
-stomatitis venenada
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity to Drug Eluting Stents components and Kounis
syndromeHypersensitivity reactions with the use of paclitaxel
-angioedema -atrioventricular block
-bronchospasm -cutaneous flushing
-diaphoresis -Kounis syndrome
-left bundle branch block -ventricular tachycardia
-urticaria
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Hypersensitivity to Drug Eluting Stents components and Kounis
syndrome
Kounis NG Hahalis G Theoharides TC J Interven Cardiol 2007 20 314
Hypersensitivity reactions with the use of rapamycin
-acrocyanosis -angioedema
-flushing -pruritus
-interstitial pneumonitis -Schonlein-Henoch purpura
-localized eczematiform eruption -palpable purpura due to leucocytoplastic vasculitis
-paradoxic coronary vasoconstriction
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
SECOND GENERATION DES they are named cobalt-chromium or platinum
chromium stents (misleading term)1Xience (everolimus) stentThe information we have obtained from the manufacturer indicates that the alloy composition of the Xience stent is 55 cobalt 20 chromium 15 tungsten 10 nickel
Min Max Carbon 005 015
Manganese 100 200
Silicon -- 040
Phosphorus -- 0040
Sulfur -- 0030
Chromium 1900 2100
Nickel 900 1100
Tungsten 1400 1600
ron -- 300
Cobalt Balance Balancebull
2Endeavor (zotarolimus) stent
3The PROMUS platinum-chromium everolimus-eluting stent PROMUS (another misleading term)Contains also nickel
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Nickel sensitization (patch test)in North-Eastern Italy(Belluno Bolzano Padova Pordedone RoveretoRovigo Trento Trieste)
316 in women (9771)100 in men (4693)The overall prevalence 246
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
4 Clopidogrel-induced allergic skin rash
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
5 Kounis NG et al ldquoMyocardial infarction after aspirin treatment and the Kounis syndromerdquo J R Soc
Med 2005 98 296
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
The 6th inadvertent antigen6 Atopic stented individuals are under the risk of any additional
drug or environmentalexposure which may ldquojoin forcesrdquo with the previous 5
agents and trigger the cascade of intrastent thrombosis
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
More than 5 antigens are irreversibly implanted and some of them apply continuous persistent
chronic and repetitive allergic irritation A total of 1000 bridges are
necessary to trigger the cell out of maximal number of some 500 000 -1 000 000 IgE molecules on the cell surface It might be possible to accumulate the critical number of bridges by more than one noncross-reactive allergen and its corresponding IgE antibodyrdquo
ldquo IgE antibodies with different specificities can have an additive effect ie if mast cells are sensitized with small even subthreshold numbers of IgE antibodies of different specificities they can ldquojoin forcesrdquo and trigger the cells to release its mediatorsif the patient is simultaneously exposed to corresponding allergensrdquo
Nopp A et al Allergy 2006 61 1336
MacGlashan DW et al J Immunol 1997 158 1438
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Do Stents like magnet attract inflammatory cells
1 Stent thrombosis associated with allergic symptoms such as glottis edema cold sweat and tongue enlargement followed a flavonate-propyphenasone administration a week after stent implantation Int J Cardiol 2009 134 e45-6
2 Acute myocardial infarction in the stented area coincided with allergic reaction following intravenous administration of the non-anionic contrast material iopromide during a routine excretory urography Int J Cardiol 2010 139 206-9
3 Intrastent thromboses have also been reported following insect and larvae sting allergic reactions Cases J 2009 2 7800
4 Late drug eluting stent thrombosis due to acemetacine Type III Kounis syndrome - Kounis syndrome due to AcemetacineInt J Cardiol 2012 155 461-2
5 Recurrent acute stent thrombosis due to allergic reaction secondary to clopidogrel
Am J Therapeutics 2011 18 e119-e122
But clopidogrel is given to prevent stent thrombosis
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
-Localized Hypersensitivity and Late Coronary Thrombosis Secondary to a Sirolimus-Eluting Stent
Should We Be Cautious- Virmani et al Circulation 2004 109 701
Focal strut malapposition with aneurysmal dilatation (double arrows in D and F) and occlusive luminal thrombosis
E Extensive inflammation consisting primarily of eosinophils and lymphocytes with a focal giant cell reaction around stent strut () and surrounding polymer Marked inflammation is similarly present in intima media and adventitia in J (left box in E) K and L (Luna stains) show giant cells (arrowheads) around a polymer remnant that has separated from stent
strut and numerous eosinophils within arterial wall
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Figure 1 Aspirated thrombus from patient with type III variant of Kounis syndrome Whitestar shows thrombus infiltrated by numerous eosinophils black star shows fibrin deposition andblackndashwhite star shows red cells mixed with scattered eosinophils Kounis NG et al Future Cardiology 2011 7 805-824
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
It has been stated that ldquoeosinophilic infiltration of intrastent thrombus
seems to be a common finding in stented
patients and is not a peculiarityrdquo
Zavalloni D et al J Cardiovasc Med 200910 942 ldquoHumanitas Clinical Instituterdquo Milan
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Atherosclerosis 2011 215 166ndash169
Eosinophil cationic protein and clinical outcome after bare metal stent implantationGiampaolo Niccoli Gregory A Sguegliaa Micaela Contea Nicola CosentinoaSilvia Minellia Flavia Bellonia Carlo Trania Vito Sabatob Francesco BurzottaaItalo Portoa Antonio Maria Leonea Domenico Schiavinob Filippo Creaa
-
ldquoHistory of allergy is a predictor of adverse events in unstable angina treated with coronary angioplastyrdquo Brunneti et al Allergol Immunopathol 2012 in press
-Which means that allergic predispositionmay help in prediction of the risk for stentthrombosis therefore measuring of eosinophil cationic protein should be added in our work up- Kounis NG et al Atherosclerosis 2011 217 67-69
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Platelets play an important role in pathogenesis of Thrombosis
1 Platelet adhesion
2 Platelet activation
3 Platellet aggregation
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen))Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamine
Ticlopidin
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
ldquoallergic unitrdquo
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
serotonin
LMW Heparin
HIRUDIN
BIVALIRUDIN
epinephrine
TXA2
thrombin
ADP
Fibrinogen
GP IIb IIIa inhibitors
2 ACTIVATION
MediatorsAdhesive (vWF fibrinogen)Prothrombotic (VXI PAI-1)Proinflammatory (PDGF PF4)Aggregatory (ADP ATP Ca Mg)
Mast cell
MEDATORS
EosinophilAspirin
Mast cell
serotonin
Pl changes from discoid to spiculated form
Degranulation
PATHOPHYSIOLOGY OF STENT THROMBOSIS AND KOUNIS SYNDROME
ClopidogrelPrasugrell
(P2Y12)
Ticagrelor
Triflusal
GP IIb IIIa receptors
PAF histamineFCεRI-FCεRII
Ticlopidin
MAST CELL INHIBITORS
ldquoallergic unitrdquo
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
H1- antihistamines and activated blood plateletsM Petriacutekovaacute1 V Janˇc inovaacute1 R Nosaacutel1 M Maacutejekovaacute1 and D Holomaacuteˇn ovaacute2
1 Institute of Experimental Pharmacology SAS Duacutebravskaacute 9 841 04 Bratislava Slovak Republic 2 National Transfusion Service Bratislava Slovak Republic
Inflammation Res 2006 55 Suppl 1 S51-S52
a Whole human blood from healthy male donors b Platelets in plasma c Isolated plateletsAntihistamines Dithiaden Loratadine and Bromadyl inhibited platelet activation-aggregation in all 3 experimental systems
It was thought that this action was on cytosolic phospholipase A2 at arachidonate cascade rather than at specific histamine receptors ()
Platelets were stimulated with adenosine-5 diphosphate (ADP) in
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Fighting against device thrombosis
1Taking careful history of adverse drug reactions and allergies
2 Performing antibody and skin testing when and where appropriate
3 Measuring eosinophilic kationic protein
4 Monitoring of inflammatory mediators after stent or device insertion
5 Performing macrophage and T-cell activation studies
6 Considering desensitization strategies
7 Considering the use of mast cell stabilizers and steroids
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7 Measuring of acute phase reactans8 Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
ldquo In conjunction with the RADAR (Research on Adverse
Drug events And Reports) project we
have started protocol
that incorporates some of the suggestions
of Dr Kounis
This protocol includes skin tests to stent componentshelliprdquo
Nebeker JR et al JACC 200648 593
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
1Nickel free stainless steel with number of blood platelets attached to it and 316L stainless steel after
dipping in fresh human blood plasma for 25 min and 3 hours
Yang K Ren Y Sci Technol Adv Mater 2010 11 1-13
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
2 Bioabsorbable Stents A
self expanding drug-eluting non allergic poly-lactic acid stent
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis Syndrome Therapeutic implications
bull So far attempts have been made to counteract the actions of inflammatory mediators by using experimentally
bull Mediator antagonists
bull Mediator receptor blockers
bull Inhibitors of mediator biosynthesis
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoThe same mediators from the same cells are present in both acute allergic and in acute non allergic
coronary eventsrdquo
bull Histamine concentration is double than normal in ACS (Clejan S et al J Cell Mol Med 2002 6 583)
bull Histamine is elevated in attacks of variant angina (Sakata V et al Am J Cardiol 1996 771121)
bull Tryptase is elevated especially in the ST depression group and is potentially a new marker for the unstable plaque (Filipiak KJ et al Clin Cardiol 2003 26 366)
bull Tryptase elevation could be a novel biomarker identifying asymptomatic patients and for the treatment efficacy (Deliargyris EN et al Atherosclerosis 2005 178 381)
bull Tryptase is elevated in unstable angina (Cuculo A et al Cardiologia 1998 43 189)
bull
bull Arachidonic acid metabolites Thromboxane and leukotrienes are significantly increased than normal in ACS (Takase B et al Angiology 199647 649)
bull Arachidonic acid metabolites Thromboxane and leukotrienes are
elevated in unstable angina Stress test is not accompanied by elevation (Cipollone F et al Circulation 2003 107 55)
bull IL-6 is elevated in ACS (Deliargyris EN et al Am J Cardiol 2000 86 913)
bull Infiltrates of activated mast cells are in ratio 2001 in the erosion or ruptured plaque areas in patients died within 2 days after acute MI than in nearby healthy areas (Kovanen PT et al Circulation 1995 92 1083)
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Xiang M Sun J Lin Y et al Usefulness ofserum tryptase level as an independent
biomarker for coronary plaque instability in aChinese population Atherosclerosis 2011 215
494ndash499
Zdravkovic V Pantovic S Rosic G et al
Histamine blood concentration in ischemic
heart disease patients J Biomed Biotechnol
2011 2011 315709
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
common pathway for acute allergic and non allergic coronary
syndromes If it is so then
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
A new possibility emerges for the prevention of coronary plaques to
become unstable lesions prone to induce acute
myocardial infarction and that is
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoinhibition of mast cell
degranulationrdquo
bull Kaartinen M et al Circulation 1994 90 1669bull Kounis NG Int J Cardiol 2006 110 7bull Lindstedt KA et al J Cell Mol Med 2007 11 739bull Kounis et al Future Cardiology 2011 7 805-824
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
In medical armamentarium Drugs and natural molecules capable to
stabilize mast cellsbull Sodium nedocromil (intal)bull Sodium cromoglycate (lomuntal)bull Lodoxamidebull Ketotifen-H1-blocker (Zaditen)bull Flavonoid quercetin ( intacellular Ca)bull Flavone luteolin inhibits T-cells mast cells and mast cell-dependent T-cell activationbull Relaxin (hormone from corpus luteus and prostate generates NO)bull NO inhibits IL-6 production through TNF-α inhibitionbull Peptides from C3α C3α+ C3α9+ inhibit FcεRI-induced degranulation and TNF-α
releasebull Simultaneous inhibition of H1 and H2 bull Zaprinast (phosphodiesterase inhibitor)bull Stem cell factor (SCF) targeting drugs since SCF is essential for mast cell
development proliferation survival adhesion and homing (Jensen et al Inflamm Allergy Drug Targets 2007 6 57)
bull IgG1 humanized monoclonal antibodies recognizing and masking corresponding IgEs in mast cell membrane (Leung DYM et al N Engl J Med 2003 348 986)
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Nemmar et al have managed to abrogate late thrombotic events experimentally by stabilizing mast cell membrane with sodium cromoclycate and reducing inflammation with dexamethasone
Nemmar A et al Circulation 2004 110 1670-1677
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Is therefore Kounis syndrome a magnificent natural paradigm and naturersquos own experiment in a final trigger pathway implicated for coronary spasm and plaque erosion or rupture namely acute myocardial infarction
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoldquoImagination is more important than Imagination is more important than knowledgerdquoknowledgerdquo
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoThis is not the end it is not even the beginning of the end but perhaps it is the end of the beginningrdquo
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Grazie TanteGrazie Tante
My euharisties to all of youMy euharisties to all of you
THANK YOUTHANK YOU
Nicholas Kounis IatrosNicholas Kounis Iatros
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Clinical implications
2 MENTAL STRESS AND THE KOUNIS SYNDROME
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation Kounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Fighting against device thrombosis1Taking careful history of
adverse drug reactions and allergies
2Performing antibody and skin testing when and where appropriate
3Monitoring of inflammatory mediators after stent or device insertion
4Performing macrophage and T-cell activation studies
5Considering the use of mast cell stabilizers and steroids
6Considering desensitization strategies
Kounis NG et al J Am Coll Cardiol 2006 48 592Kounis NG et al N Engl J Med 2006 354 2076
7Measuring of acute phase reactans8Periprocedural antiinflammatory therapyGaspardone A Versaci F Am J Med 2005 96 65L
-
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
syndromeImpulses from high cortical centers (emotional and depressogenic stress)
Limbic system
Hypothalamus chemical mediator release -norepinephrine -serotonin -acetylcholine
activate cells of paraventricularnucleus of hypothalamus production of CRH (main coordinator of mental stress)
enters the portal venous system of hypothalamus stimulates the locus coeruleous ( a dense collection of autonomic cells in the midbrain) to secrete norepinephrine at the sympathetic nerve endings activation of corticotrophs of the anterior pituitary gland production of propiomelanocortin adrenal medulla to produce kidney to activate the large amounts of epinephrine renin-angiotensin system
cleaved to form ACTH adrenal cortex stimulation corticosteroid production
All above cascade induces -a heightened cardiovascular activity -cytokine IL-1 IL-6 TNF-α production-endothelial injury resulting in -macrophage activation-Induction of adhesion molecules on endothelial cells -MAST CELL ACTIVATION-recruiting inflammatory cells to arterial wall-Acute phase response with protein production such as in inflammation
KOUNIS SYNDROMEKounis NG et al Eur Heart J 2006 27 757 Kounis NG Filippatos GS Circulation J 2007 71 170
TheThe brainbrain thethe heartheart and the and the KounisKounis
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Acute stress and mast cell activation
bull Light photomicrographs of heart sections from C57BL mice stained with toluidine blue to show cardiac mast cells (A) in control (unstressed) (B C and D) stressed mice Empty granules stain pink (arrowhead) as compared to the dark blue color of intact granules (solid arrows) note almost totally activated mast cell in (D) Bar=10 μm
Huang M et al Cardiovascular Research
2002 55 150-160
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
3Kounis syndrome and sudden death
Maron BJ et al Circulation 2007 115 1643Maron BJ et al Circulation 2007 115 1643
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Schwartz HJ et al Is unrecognized
anaphylaxis a cause of sudden unexpected death Clin Exper Allergy 1995 25 866
ldquo We conclude that mast cell activation may accompany up to 13 of sudden unexpected deaths in adults Measurement of both tryptase and specific IgE antibody levels in post mortem sera from patients experiencing sudden unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis including those due to insect stingsrdquo
Zinka B et al Unexplained cases of sudden infant death shortly after hexavalent vaccination Vaccine 2006 31 5781
SIDS cases in Austria and general vaccination with HIB HBV and hexavalent vaccines in the vaccination schedule of the first 2 years of life
Unusual causes of sudden death
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ECG of a 13 year old girl with fatal allergic reaction following rubella vaccination-Colombo Sri Lanka
II
I
I
III
AVR AVL AVF
V1 V2 V3
V4 V5 V6
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
ldquoElevated serum concentrations of beta-tryptase but not alpha-tryptase in Sudden
Infant Death Syndrome (SIDS) An investigation
of anaphylactic mechanismsrdquo Buckley MG Variend S Walls AF Clin Exp Allergy 2001 31 1696-704
ldquoAnaphylactic deaths in Auckland New Zealand a review of coronial autopsies from 1985 to 2005rdquo
CONCLUSION Anaphylactic reaction is an uncommon cause of sudden death In many cases no specific macroscopic or microscopic findings were detected at autopsy In the presence of a typical clinical history postmortem measurement of serum tryptase levels can be a
useful diagnostic aid Low I Stables S Pathology 2006 38 328-332
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Kounis syndrome
bull Therapeutic implications
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
TREATMENT OF KOUNIS SYNDROME1 Treatment of type I variant Treatment of allergic event alone can abolish type I variant Give vasodilators e g nitrates and Ca-blockers
2 Treatment of type II variant a Apply acute coronary event protocol + corticosteroids and antihistamines b Give vasodilators e g nitrates and Ca-blockers when appropriate
One should bear in mind that
bullEpinephrine is life saving in anaphylaxis but in Kounis syndrome can aggravate ischemia and induce coronary vasospasm Sulfite free epinephrine is recommended IM 02-05 mg (11000) of aqueous solution is preferablebullIn patients on b-blockers epinephrine may be ineffective It may also promote more vasospasm due to unopposed alpha adrenergic effect Glucagon may be consideredbullAvoid opiates such as morphine codeine and meperidine since they can induce massive mast cell degranulation and aggravate allergic reactionbullFentanyl and its derivatives show a slight mast cell activation and should be the drugs of choice when narcotic analgesia is necessary
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Mast cell activation precedes acute coronary event
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Mast cell activation precedes acute coronary event
bull ldquoMast cells macrophages and T-cells infiltrate not only the sites of coronary arteries at which plaque rupture or erosion has occurred but also the sites of coronary plaques susceptible to erosion or rupture (shoulders autopsy findings) which means they invade before an actual coronary eventrdquo
bull Therefore they infiltrate the lesions and release their mediators before erosion or rupture and they are not part of inflammatory response to rupture initiated by other processes
Kaartinen Met al Circulation 1994
bull Shoulder the vulnerable part of atheroma
Shoulder the vulnerable part of coronary Shoulder the vulnerable part of coronary
atheromaatheroma
(In carotids the cap (In carotids the cap Karapanayiotides T Circulation Karapanayiotides T Circulation
2006 114 e598)2006 114 e598)))
90 1669
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Arachidonic acid products such as leukotrienes and thromboxane were significantly raised in patients with
unstable angina than with stable angina and with nonischemic chest pain
bull Eicosanoid metabolites did not increase as a result of effort-induced ischemia in stable angina up to 6 days after positive exercise test
bull ldquoThis can rule out a role of ischemia per se in the induction of eicosanoid increaserdquo
bull Circulation 2003 107 55 Cipollone F et al
l
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
Acute stress and mast cell activation
bull Transmission electron micrographs of cardiac mast cells from (A) control unstressed and (B) stressed C57BL mice showing numerous secretory granules that have released their contents (arrowheads) note tissue from both control and stressed mice have numerous intact granules (solid arrow) Bar=1 μm
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
The Brain and the Heart the twain have met
laquoΕχε τους πόδας σου ζεστούς την κεφαλήν σου κρύα τον στόμαχόν σου αδειανό (ελαφρύ) γιατρό δεν έχεις χρείαraquo
Axαική Λαική ελληνική σοφεία
(Keeping your legs warm your brain cool and your stomach (nearly) empty takes the doctor away)
ldquoSleep a lot Eat a little and walk a lotrdquo
Paul Dudley White
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
-Occlusion of metallic biliary stent related to nickel allergy-
Khan SF et al Gastrointestinal Endosc 2007 66 413
![CASE REPORT Open Access A case of Kounis syndrome ......spastic amines and phospholipase A [1]. Hornets protect their nests and any disturbance pro-vokes them to attack people in the](https://img.pdfslide.net/doc/110x75/60d419741d1fb06eee221543/case-report-open-access-a-case-of-kounis-syndrome-spastic-amines-and-phospholipase.jpg)
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