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From Vulnerable Plaques to From Vulnerable Plaques to Vulnerable PatientsVulnerable Patients
The 1The 1stst Guideline of Guideline of Association for Association for Eradication of Heart Attack (AEHA) Eradication of Heart Attack (AEHA) for Definition of Vulnerable Plaque and for Definition of Vulnerable Plaque and
Vulnerable PatientVulnerable Patient(VP.org)(VP.org)
Morteza Naghavi, Erling Falk, Mohammad Madjid, Silvio Litovsky, Ward Casscells, Renu Virmani,
James T. Willerson
Underlying Cause of All (fatal and non-fatal) Heart Attacks(Sudden Cardiac Death + Acute Coronary Syndrome)
With Occlusive Thrombi
With Rupture
>70% Stenosis
With Significant Atherosclerotic or Ischemic Heart
<70% Stenosis
Without Significant Atherosclerosis or Atherosclerosis-Derived Myocardial Damage
Without Occlusive Thrombi
Without Rupture With Old Myocardial Damage
WithoutOld Myocardial Damage
Only Myocardial-Derived Factors(primary conductive disorders, …)
Erosion Calcified Nodule Others
With Critical Stenosis Without Critical Stenosis
With Expansive Remodeling
Without Expansive Remodeling
~1.5 millions in the US
Underlying pathologies of Underlying pathologies of “culprit” coronary lesions“culprit” coronary lesions
1.1. Ruptured Plaques (~70%) Ruptured Plaques (~70%) Stenotic (~20%)Stenotic (~20%) Non-stenotic (~50%) Non-stenotic (~50%)
2.2. Non-Ruptured Plaques (~ 30%)Non-Ruptured Plaques (~ 30%) ErosionErosion Calcified NoduleCalcified Nodule Others / UnknownOthers / Unknown
MJ Davies, Circ. 1990; Falk et al. Circ. 1995; Virmani et al. ATVB 2000
Terminology:Terminology:
Culprit Plaque:Culprit Plaque: a a RetrospectiveRetrospective Terminology Terminology
Vulnerable PlaqueVulnerable Plaque: : a a ProspectiveProspective Terminology Terminology
Vulnerable Plaque:Vulnerable Plaque:
Plaques with high Plaques with high likelihood of likelihood of thrombosis or rapid thrombosis or rapid progressprogress
Interchangeable TerminologiesInterchangeable Terminologies YESYES NONO
Vulnerable Plaque =Vulnerable Plaque = Vulnerable Plaque=Vulnerable Plaque=
High-Risk PlaqueHigh-Risk Plaque Soft-PlaqueSoft-Plaque
Dangerous PlaqueDangerous Plaque Non-Calcified Plaque Non-Calcified Plaque
AHA Type IV PlaqueAHA Type IV Plaque
Non-Stenotic PlaqueNon-Stenotic Plaque
Proposed Histopathological and Proposed Histopathological and Clinical Criteria for Definition of Clinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque MajorMajor Criteria: Criteria:1.1. Active Inflammation (monocyte/ Active Inflammation (monocyte/
macrophage infiltration)macrophage infiltration) 2.2. Thin Cap with Large Lipid Core Thin Cap with Large Lipid Core 3.3. Endothelial Denudation with Superficial Endothelial Denudation with Superficial
Platelet Aggregation Platelet Aggregation 4.4. Fissured / Wounded PlaqueFissured / Wounded Plaque
Proposed Histopathological and Proposed Histopathological and Clinical Criteria for Definition of Clinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque MinorMinor Criteria: Criteria:1.1. Superficial Calcified nodule Superficial Calcified nodule 2.2. Glistening Yellow Glistening Yellow 3.3. Intraplaque Hemorrhage Intraplaque Hemorrhage 4.4. Critical StenosisCritical Stenosis5.5. Positive Remodeling? Positive Remodeling?
Ideal method for Ideal method for screening vulnerable screening vulnerable
plaque/patientplaque/patient Non-invasiveNon-invasive InexpensiveInexpensive AccurateAccurate Widely Reproducible Widely Reproducible
Proposed Histopathological and Proposed Histopathological and Clinical Criteria for Definition of Clinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque MajorMajor Criteria: Criteria:1.1. Active Inflammation (monocyte/ Active Inflammation (monocyte/
macrophage infiltration) macrophage infiltration) 2.2. Thin Cap with Large Lipid Core Thin Cap with Large Lipid Core 3.3. Endothelial Denudation with Superficial Endothelial Denudation with Superficial
Platelet Aggregation Platelet Aggregation 4.4. Fissured / Wounded PlaqueFissured / Wounded Plaque
Thermography: a Novel Thermography: a Novel Approach for Identification of Approach for Identification of
Vulnerable PlaquesVulnerable Plaques
Mohammad Madjid, MD, Mohammad Madjid, MD, Ward Casscells, MD,Ward Casscells, MD,
James T. Willerson, MD, James T. Willerson, MD, Morteza Naghavi, MD Morteza Naghavi, MD
Cardinal Signs of InflammationCardinal Signs of Inflammation
Pain
Redness
HEAT
Swelling
Inflammation
HypothesisHypothesis
Vascular inflammation and plaque Vascular inflammation and plaque vulnerability can be identified by vulnerability can be identified by the heat released from activated the heat released from activated macrophages in the plaque.macrophages in the plaque.
Temperature heterogeneity over the surface Temperature heterogeneity over the surface of an endartherectomized carotid plaqueof an endartherectomized carotid plaque
Casscells W et al. Lancet. 1996;347:1447-51
While macrophage/monocytes (with high metabolic rate) density was While macrophage/monocytes (with high metabolic rate) density was related to higher temperature, such a relation wasn’t seen with smooth related to higher temperature, such a relation wasn’t seen with smooth
muscle cell density (with less metabolic activity) muscle cell density (with less metabolic activity)
Inverse relation between temperature Inverse relation between temperature difference and cap thicknessdifference and cap thickness
Infrared experiments show Infrared experiments show temperature heterogeneitytemperature heterogeneity
Our dog model of atherosclerosis develops marked lesions in its coronary arteries (left panel). We observed significant temperature heterogeneity along the coronary arteries of these dogs using an infrared camera (right panel).
An infrared camera image shows marked temperature heterogeneity over the surface of an atherosclerotic carotid plaque
Inverse correlation of pH and temperature (ºC) in Inverse correlation of pH and temperature (ºC) in endartherectomized human carotid artery plaques endartherectomized human carotid artery plaques
Naghavi et al. Atherosclerosis, 2002, in press
Dog Model of AtherosclerosisDog Model of Atherosclerosis
Femoral Artery
Atherosclerotic
With Temperature Heterogeneity
Carotid Artery
Non-Atherosclerotic
Without Temperature Heterogeneity
Higher absolute temperature as well as temperature heterogeneity in femoral arteries of atherosclerotic dogs compared to their carotid arteries which are free of disease.
P<0.05
Temperature heterogeneity in Temperature heterogeneity in atherosclerotic lesions of Watabae rabbitsatherosclerotic lesions of Watabae rabbits
Temperature heterogeneity
In aortae of atherosclerotic mice
No temperature heterogeneity
In aortae of normal mice
Human StudiesHuman Studies
Our findings have been confirmed Our findings have been confirmed in clinical settings by the Hellenic in clinical settings by the Hellenic group of Stefandis and group of Stefandis and colleagues, and also in Belgium colleagues, and also in Belgium and the Netherlands. and the Netherlands.
In vivo In vivo thermal heterogeneity within human thermal heterogeneity within human atherosclerotic coronary arteries atherosclerotic coronary arteries
Stefanadis et al. Circulation. 1999;99:1965-71
The risk of an adverse cardiac event in patients with high The risk of an adverse cardiac event in patients with high temperature difference is significantly higher than that in temperature difference is significantly higher than that in
ACS patients with low temperature difference ACS patients with low temperature difference
Stefanadis et al. J Am Coll Cardiol. 2001;37:1277-83Stefanadis et al. J Am Coll Cardiol. 2001;37:1277-83
Stefanadis et al. J Mol Cell Cardiol. 2000;32:43-52
Strong correlation between C-reactive protein (CRP) (and serum amyloid A (SAA) ) and the temperature differences
Administration of atorvastatin in patients with coronary artery Administration of atorvastatin in patients with coronary artery disease results in less heat production from the culprit lesion and disease results in less heat production from the culprit lesion and less temperature difference. less temperature difference.
Stefanadis et al. Eur Heart J (in press)
StatinsNo statin
Tem
pera
ture
diff
eren
ce
2.5
2.0
1.5
1.0
.5
0.0
-.5
P<0,001
Toutozas et al reported correlation between Toutozas et al reported correlation between temperature and expansive remodeling and temperature and expansive remodeling and MMP-9 concentration MMP-9 concentration
Verheye et al showed significant temperature Verheye et al showed significant temperature
heterogeneity in cholesterol fed rabbits which heterogeneity in cholesterol fed rabbits which was reduced after changing from high to low-was reduced after changing from high to low-cholesterol diet in rabbits.cholesterol diet in rabbits.
Toutouzas et al. Circulation. 2000;102:II-707; Toutouzas et al. J Am Coll Cardiol. 2001;37:356AVerheye et al. Circulation Supple Oct. 2001;
Center for Vulnerable Plaque ResearchCenter for Vulnerable Plaque ResearchHouston, TexasHouston, Texas
Khawar Gul, MDKhawar Gul, MDSaid Siadaty, MDSaid Siadaty, MDSameh Naguib, MDSameh Naguib, MDBujin Gu, PhDBujin Gu, PhDReji John, MDReji John, MDBasit Malik, MDBasit Malik, MDKC Courian, MD KC Courian, MD Roxana Grausu, MD Roxana Grausu, MD
Mohammad Madjid, MD, Ward Casscells, MD, James T. Willerson, MD, Morteza Naghavi, MDMohammad Madjid, MD, Ward Casscells, MD, James T. Willerson, MD, Morteza Naghavi, MD