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Current anti-anginal therapyCurrent anti-anginal therapy
Current antianginal strategiesCurrent antianginal strategies
Current anti-anginal strategiesCurrent anti-anginal strategies
Non pharmacologic
Pharmacologic
TrimetazidineTrimetazidine
FasudilFasudil NicorandilNicorandil
IvabradineIvabradine
RanolazineRanolazine
Exercise Exercise trainingtraining
EECPEECP ChelationChelationtherapytherapy
SCSSCS
TMRTMR
Exercise TrainingExercise Training Enhanced external Enhanced external
counterpulsation counterpulsation (EECP)(EECP) Endothelial functionEndothelial function Promotes coronary Promotes coronary
collateral formationcollateral formation Peripheral vascular Peripheral vascular
resistanceresistance Ventricular functionVentricular function Placebo effectPlacebo effect
Chelation therapyChelation therapy
Current nonpharmacologic Current nonpharmacologic antianginal strategiesantianginal strategies
Transmyocardial Transmyocardial revascularization (TMR)revascularization (TMR) Sympathetic denervationSympathetic denervation AngiogenesisAngiogenesis
Spinal cord stimulation Spinal cord stimulation (SCS)(SCS) Neurotransmission Neurotransmission
of painful stimuliof painful stimuli Release of Release of
endogenous opiatesendogenous opiates Redistributes myocardial Redistributes myocardial
blood flow to ischemic areasblood flow to ischemic areas
Allen KB et al. N Engl J Med. 1999;341:1029-36.Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-25.
Murray S et al. Heart. 2000;83:217-20.
Potential cardioprotective Potential cardioprotective benefits of exercisebenefits of exercise
Domenech R. Circulation. 2006;113:e1-3. Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72.
NO NO productionproduction
ROS ROS generationgeneration
ROS ROS scavengingscavenging
Other Other mechanismsmechanisms
VasculatureVasculature ThrombosisThrombosisMyocardiumMyocardium
EECP - Enhanced External EECP - Enhanced External CounterPulsationCounterPulsation
External, pneumatic compression of lower External, pneumatic compression of lower extremities in diastole.extremities in diastole.
EECP - Enhanced External EECP - Enhanced External CounterPulsationCounterPulsation
EECP - Enhanced External EECP - Enhanced External CounterPulsationCounterPulsation
Sequential Sequential inflation of inflation of
cuffscuffs Retrograde aortic Retrograde aortic
pressure wave pressure wave Increased Coronary Increased Coronary
perfusion pressureperfusion pressure Increased Venous Increased Venous
ReturnReturn Increased PreloadIncreased Preload Increased Cardiac Increased Cardiac
OutputOutput
Simultaneous Simultaneous deflation of deflation of cuffs in late cuffs in late
DiastoleDiastole Lowers Systemic Lowers Systemic
Vascular Resistance Vascular Resistance Reduced Preload Reduced Preload Decreased Cardiac Decreased Cardiac
workload workload Decreased Oxygen Decreased Oxygen
ConsumptionConsumption
EECP - Enhanced External EECP - Enhanced External CounterPulsationCounterPulsation
35 total treatments35 total treatments 5 days per week x 7 weeks5 days per week x 7 weeks 1 hour per day1 hour per day
Appears to reduce severity of Angina Appears to reduce severity of Angina Not shown to improve survival or reduce Not shown to improve survival or reduce
myocardial infarctionsmyocardial infarctions Indicated for CAD not amenable to Indicated for CAD not amenable to
revascularization revascularization Anatomy not amenable to proceduresAnatomy not amenable to procedures High risk co-morbidities with excessive riskHigh risk co-morbidities with excessive risk
May be beneficial in treatment of refractory CHF May be beneficial in treatment of refractory CHF too, but generally this is not an approved too, but generally this is not an approved indication.indication.
EECP – Contraindications & EECP – Contraindications & PrecautionsPrecautions
Arrhythmias that interfere with machine Arrhythmias that interfere with machine triggeringtriggering
Bleeding diathesisBleeding diathesis Active thrombophlebitis & severe lower Active thrombophlebitis & severe lower
extremity vaso-occlusive diseaseextremity vaso-occlusive disease Presence of significant AAAPresence of significant AAA PregnancyPregnancy
TMLR - Transmyocardial Laser TMLR - Transmyocardial Laser RevascularizationRevascularization
High power CO2 YAG High power CO2 YAG and excimer laser and excimer laser conduits in myocardial to conduits in myocardial to create new channels for create new channels for blood flowblood flow
Possible explanations for Possible explanations for effecteffect Myocardial angiogenesisMyocardial angiogenesis Myocardial denervationMyocardial denervation Myocardial fibrosis with Myocardial fibrosis with
secondary favorable secondary favorable remodelingremodeling
TMLR – Direct TrialTMLR – Direct Trial
Only major blinded studyOnly major blinded study 298 pts with low dose, 298 pts with low dose,
high dose, or no laser high dose, or no laser channelschannels
No benefit to TMLR vs No benefit to TMLR vs Med therapy to Med therapy to Patient survivalPatient survival Angina classAngina class Quality of life assessmentQuality of life assessment Exercise durationExercise duration Nuclear perfusion imagingNuclear perfusion imaging Leon MB, et al. JACC 2005; 46:1812Leon MB, et al. JACC 2005; 46:1812
High Surgical Risk High Surgical Risk (Mortality 5%)(Mortality 5%)
Mainly used as adjunct Mainly used as adjunct therapy during CABG to therapy during CABG to treat myocardial that treat myocardial that cannot be bypassed.cannot be bypassed.
Chelation TherapyChelation Therapy
IV EDTA infusionsIV EDTA infusions 30 treatments over 30 treatments over
about 3 monthsabout 3 months Cost – about $3,000Cost – about $3,000 Aggressive marketing Aggressive marketing
by 500 to 1000 by 500 to 1000 physicians offering this physicians offering this treatmenttreatment
PLACEBO effect onlyPLACEBO effect only
Claimed Claimed pathophysiologic effectspathophysiologic effects Liberation of Calcium Liberation of Calcium
in plaquein plaque Lower LDL, VLDL, and Lower LDL, VLDL, and
Iron storesIron stores Inhibit platelet Inhibit platelet
aggregationaggregation Relax vasomotor toneRelax vasomotor tone Scavenge “free Scavenge “free
radicals”radicals”
Spinal Cord StimulationSpinal Cord Stimulation
power source conducting wires electrodes atstimulation site
Stimulation typicallyadministered for 1-2 hrs tid
Therapeutic mechanism appears to be alteration of anginal pain perception
Long-term Outcomes Following Long-term Outcomes Following SCSSCS
02468
101214161820
TotalAngina
Angina atRest
ExertAngina
NTGUse/wk
CCSClass
# HospAdms
Days inHosp
BaselineSCS
Prospective Italian Registry: 104 Patients, Follow-up 13.2 Mo
Episodes/wk
* p<0.0001
* * ** * *
*
(DiPede, et al. AJC 2003;91:951)
Randomized Trial of SCS vs. CABG Randomized Trial of SCS vs. CABG For Patients with Refractory AnginaFor Patients with Refractory Angina
14.6 15.216.2
13.7
4.4 4.15.2
3.1
02468
1012141618
Anginal attacks NTGconsumption
Anginal attacks NTGconsumption
Mean number
perweek
Baseline
6 months
Spinal cord stimulation (n=53) CABG (n=51)
*P < 0.0001
****
(Mannheimer, et al. Circulation 1998;97:1157)
104 Patients with refractory angina, not suitable for PCI and high risk for re-op (3.2% of patients accepted for CABG)
No difference in symptom relief between SCS and CABG
Current pharmacologic Current pharmacologic antianginal strategiesantianginal strategies
New mechanistic approaches to anginaNew mechanistic approaches to angina Rho kinase inhibition (Rho kinase inhibition (fasudilfasudil)) Metabolic modulation (Metabolic modulation (trimetazidinetrimetazidine)) Preconditioning (Preconditioning (nicorandilnicorandil)) Sinus node inhibition (Sinus node inhibition (ivabradineivabradine)) Late Na+ current inhibition (Late Na+ current inhibition (ranolazineranolazine))
Rho kinase inhibition: FasudilRho kinase inhibition: Fasudil Rho kinase triggers vasoconstriction through Rho kinase triggers vasoconstriction through
accumulation of phosphorylated myosinaccumulation of phosphorylated myosin
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
Ca2+ Ca2+
PLC
SR Ca2+
Receptor
Agonist
Myosin
Myosin-P
Myosin phosphatase
PIP2
IP3
MLCK
VOC ROC
Ca2+
Calmodulin
Rho
Rho kinase
Fasudil
Metabolic modulation (pFOX): Metabolic modulation (pFOX): TrimetazidineTrimetazidine
O2 requirement of O2 requirement of glucose pathway is glucose pathway is lower than FFA lower than FFA pathwaypathway
During ischemia, During ischemia, oxidized FFA levels oxidized FFA levels rise, blunting the rise, blunting the glucose pathwayglucose pathway
FFA Glucose
Acyl-CoA
Acetyl-CoA
Pyruvate
Energy for contraction
Myocytes
β-oxidation
Trimetazidine
MacInnes A et al. Circ Res. 2003;93:e26-32.Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.
pFOX = partial fatty acid oxidationFFA = free fatty acid
Preconditioning: NicorandilPreconditioning: Nicorandil
Nitrate-associated effects• Vasodilation of coronary epicardial arteries
Activation of ATP-sensitive K+ channels• Ischemic preconditioning• Dilation of coronary resistance arterioles
IONA Study Group. Lancet. 2002;359:1269-75.Rahman N et al. AAPS J. 2004;6:e34.
N O
O NO2
HN
Sinus node inhibition: IvabradineSinus node inhibition: Ivabradine
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
SA = sinoatrial
Sinus node inhibition: IvabradineSinus node inhibition: Ivabradine
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
SA = sinoatrial
SA node
AV node Common bundle
Bundle branches
Purkinje fibers
Sinus node inhibition: IvabradineSinus node inhibition: Ivabradine
IIf f current is an inward current is an inward Na+/K+ current that Na+/K+ current that activates pacemaker activates pacemaker cells of the SA nodecells of the SA node
IvabradineIvabradine Selectively blocks ISelectively blocks Iff in in
a current-dependent a current-dependent fashionfashion
Reduces slope of Reduces slope of diastolic depolarization, diastolic depolarization, slowing HRslowing HR
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
40
20
0
–20
–40
–60
0.5
Potential (mV)
Control Ivabradine 0.3 µM
Time (seconds)
SA = sinoatrial
SodiumCurrent
0
Late
Peak
0
Late
Peak
SodiumCurrent
Na+
ImpairedImpairedInactivationInactivation
ImpairedImpairedInactivationInactivation
Na+
Ischemia
Myocardial ischemia causes Myocardial ischemia causes enhanced late INaenhanced late INa
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.
Late Na+ current inhibition: Late Na+ current inhibition: RanolazineRanolazine
Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.
Myocardial ischemia
Late INa
Na+ Overload
Ca2+ Overload
Mechanical dysfunction LV diastolic tension
Contractility
Electrical dysfunctionArrhythmias
Ranolazine
Understanding Angina at the Understanding Angina at the Cellular LevelCellular Level
Ischemia impairs cardiomyocyte Ischemia impairs cardiomyocyte sodium channel functionsodium channel function
Impaired sodium channel function Impaired sodium channel function leads to:leads to: Pathologic increased late sodium Pathologic increased late sodium
currentcurrent Sodium overloadSodium overload Sodium-induced calcium overloadSodium-induced calcium overload
Calcium overload causes diastolic Calcium overload causes diastolic relaxation failure, which:relaxation failure, which: Increases myocardial oxygen Increases myocardial oxygen
consumptionconsumption Reduces myocardial blood flow Reduces myocardial blood flow
and oxygen supplyand oxygen supply Worsens ischemia and anginaWorsens ischemia and angina
Ranolazine
Ischemia
↑ Late INa
Na+ Overload
Diastolic relaxation failureExtravascular compression
Ca++ Overload
Chaitman BR. Circulation. 2006;113:2462-2472
Na+/Ca2+ overload and Na+/Ca2+ overload and ischemiaischemia
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
Late Na+ current
Diastolic wall tension (stiffness)
Intramural small vessel compression( O2 supply)
O2 demand
Na+ overload
Ca2+ overload
Myocardial ischemia
Ischaemia( oxygen supply/ Demand)
late Na+ current
Na+/Ca++ exchange pump activation
[Ca2+] overload
Diastolic wall tension (stiffness)
Vascular compression
[Na+]i
RanolazineRanolazine
Ranolazine – hemodynamic Ranolazine – hemodynamic affects affects
No affect of Blood Pressure or Heart No affect of Blood Pressure or Heart RateRate
Can be added to Conventional Medical Can be added to Conventional Medical therapy, especially when BP and HR do therapy, especially when BP and HR do not allow further increase in dose of not allow further increase in dose of BetaBlockers, Ca Channel blockers, and BetaBlockers, Ca Channel blockers, and Long Acting Nitrates.Long Acting Nitrates.
Ranolazine has twin pronged action.Ranolazine has twin pronged action.1.1. pFOXpFOX
2.2. Late Na inward entry blockadeLate Na inward entry blockade
Metabolic modulation (pFOX) Metabolic modulation (pFOX) and ranolazineand ranolazine
Clinical trials showed ranolazine SR 500–Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina1000 mg bid (~2–6 µmol/L) reduced angina
Experimental studies demonstrated that Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% ranolazine 100 µmol/L achieved only 12% pFOX inhibitionpFOX inhibition Ranolazine does not inhibit pFOX substantially at Ranolazine does not inhibit pFOX substantially at
clinically relevant doses clinically relevant doses Fatty acid oxidation Inhibition is not a major Fatty acid oxidation Inhibition is not a major
antianginal mechanism for ranolazineantianginal mechanism for ranolazineMacInnes A et al. Circ Res. 2003;93:e26-32.
Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83.
Antzelevitch C et al. Circulation. 2004;110:904-10.
pFOX = partial fatty acid oxidation
Ranolazine: Key conceptsRanolazine: Key concepts
Ischemia is associated with ↑ Na+ entry into Ischemia is associated with ↑ Na+ entry into cardiac cells cardiac cells Na+ efflux by Na+/Ca2+ exchange results in ↑ Na+ efflux by Na+/Ca2+ exchange results in ↑
cellular [Ca2+]i and eventual Ca2+ overload cellular [Ca2+]i and eventual Ca2+ overload Ca2+ overload may cause electrical and Ca2+ overload may cause electrical and
mechanical mechanical dysfunctiondysfunction ↑ ↑ Late INa is an important contributor to the Late INa is an important contributor to the
[Na+]i - dependent Ca2+ overload[Na+]i - dependent Ca2+ overload Ranolazine reduces late INa Ranolazine reduces late INa
Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.
Na+ and Ca2+ during Na+ and Ca2+ during ischemia and reperfusionischemia and reperfusion
Tani M and Neely JR. Circ Res. 1989;65:1045-56.
Na+
(μmol/g dry)
Ca2+
(μmol/g dry)
Time (minutes)
Rat heart model
Ischemia Reperfusion90
60
30
0
12
8
4
00 10 20 30 40 50 60
Intracellular levels
Medication Medication ClassClass
Impact Impact on HRon HR
Impact Impact on BPon BP
Physiologic Physiologic MechanismMechanism
Beta Beta BlockersBlockers
Decrease pump Decrease pump functionfunction
Calc Calc Channel Channel BlockersBlockers
Decrease Pump Decrease Pump function + Vaso-function + Vaso-dilitationdilitation
NitratesNitrates Vaso-dilitationVaso-dilitation
RanolazineRanolazine OO OO Reduced Cardiac Reduced Cardiac StiffnessStiffness
Pharmacologic Classes for Treatment of Angina
Late Na+ accumulation Late Na+ accumulation causes LV dysfunctioncauses LV dysfunction
Fraser H et al. Eur Heart J. 2006.
Isolated rat hearts treated with ATX-II, an enhancer of late INa
LV dP/dt(mm Hg/sec, in thousands)
LV-dP/dt
LV+dP/dt
(-)
(+)
Time (minutes)
ATX-II 12 nM(n = 13)A
TX
-II
Ranolazine 8.6 µM(n = 6)
Ran
ola
zin
e
10 20 30 40 50
-4
-3
-2
-1
0
1
2
3
4
5
6
LV end diastolic pressure
Baseline 15 30 45 600
10
20
30
40
50
60
70
Vehicle (n = 10)Ranolazine 10 µM (n = 7)
*
*
Reperfusion time (minutes)
mm
Hg
LV -dP/dt (Relaxation)
Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.
*P < 0.05
Vehicle Ranolazine
Baseline 30 60 75 90
-1000
-800
-600
-400
-200
0
***
*
mm
Hg
/sec
Reperfusion time (minutes)
Vehicle (n = 12)Ranolazine 5.4 µM (n = 9)
Isolated rabbit hearts
Late INa blockade - Late INa blockade - blunts blunts experimental ischemic LV damageexperimental ischemic LV damage
Myocardial ischemia: Myocardial ischemia: Sites of Sites of action of anti-ischemic medicationaction of anti-ischemic medication
Consequences of ischemia
Ca2+ overloadElectrical instabilityMyocardial dysfunction(↓systolic function/ ↑diastolic stiffness)
Ischemia
↑ O2 DemandHeart rateBlood pressurePreloadContractility↓ O2 Supply
Development of ischemia
Traditionalanti-ischemicmedications:β-blockersNitratesCa2+ blockers
Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.
Ranolazine
SummarySummary
Ischemic heart disease is a prevalent clinical Ischemic heart disease is a prevalent clinical conditioncondition
Improved understanding of ischemia has Improved understanding of ischemia has prompted new therapeutic approachesprompted new therapeutic approaches Rho kinase inhibitionRho kinase inhibition Metabolic modulationMetabolic modulation PreconditioningPreconditioning Inhibition of IInhibition of Iff and late INa currents and late INa currents
SummarySummary
Late INa inhibition and metabolic modulation Late INa inhibition and metabolic modulation reduce angina with minimal or no reduce angina with minimal or no pathophysiologic effectspathophysiologic effects Mechanisms of action is complementary to Mechanisms of action is complementary to
traditional agentstraditional agents
Stable CAD: Multiple Stable CAD: Multiple treatment optionstreatment options
Reduce symptoms
Treat underlying
disease
PCI & CABG
Lifestyle intervention
Alternative TX
Medical
therapy
ECGECG
R
Q
T
UP
S
mV
+
-
PWave
SpaceQRS
ST
T
PQ
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