The Holy Grail of Cardiology

Vulnerable PlaquesVulnerable Plaques

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

Blood

Myocardium

Plaque

Victim /Patient

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

Vulnerable Blood

Vulnerable Myocardium

Vulnerable Plaque

Vulnerable Patient

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

In vivo StudiesIn vivo Studies

Thermosensor Basket CatheterThermosensor Basket Catheter

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

Infrared angio-thermography Infrared angio-thermography catheter catheter

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;

Disclosure: Disclosure:

Volcano Therapeutics, Inc.Volcano Therapeutics, Inc.

ThermaStar® Catheter

Not cleared by the FDA and not available for commercial sale.

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