definition of vulnerable plaque naghavi- thi

Vulnerable Vulnerable Plaques and Plaques and Vulnerable Vulnerable

PatientsPatientsThe 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, James E. Muller, Ward Casscells,

Renu Virmani, Valentin Fuster, James T. Willerson

Vulnerable plaques, vulnerable Vulnerable plaques, vulnerable myocardium, and hypercoagulable state of myocardium, and hypercoagulable state of

the blood lead to the blood lead to sudden cardiac death and acute myocardial sudden cardiac death and acute myocardial

infarction.infarction.

Vulnerable Blood

Vulnerable Myocardium

Vulnerable Plaque

Vulnerable Patient

Potential 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 Atherosclerosis 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(conductive disorders, …)

Erosion Calcified Nodule Others

With Critical Stenosis Without Critical Stenosis

With Expansive Remodeling

Without Expansive Remodeling

  Terminology:Terminology:

Culprit Plaque:Culprit Plaque: a a RetrospectiveRetrospective Terminology Terminology

Vulnerable PlaqueVulnerable Plaque: : a a ProspectiveProspective Terminology Terminology

Underlying Underlying pathologies of pathologies of

“culprit” coronary “culprit” coronary lesionslesions1.1. Ruptured Plaques (~70%) Ruptured Plaques (~70%)

Stenotic (~20%)Stenotic (~20%) Non-stenotic (~50%) Non-stenotic (~50%)

2.2. Non-Ruptured Plaques (~ Non-Ruptured Plaques (~ 30%)30%)

ErosionErosion Calcified NoduleCalcified Nodule Others / UnknownOthers / Unknown MJ Davies, Circ. 1990; Falk et al. Circ. 1995; Virmani et al. ATVB 2000

Interchangeable TerminologiesInterchangeable Terminologies YESYES NONO

Vulnerable Plaque =Vulnerable Plaque = Vulnerable Vulnerable Plaque=Plaque=

High-Risk PlaqueHigh-Risk Plaque Soft-PlaqueSoft-Plaque

Dangerous PlaqueDangerous Plaque Non-Calcified Non-Calcified Plaque Plaque AHA Type IV AHA Type IV PlaquePlaqueNon-Stenotic Non-Stenotic PlaquePlaque

Proposed Histopathological Proposed Histopathological and Clinical Criteria for and Clinical Criteria for Definition of Vulnerable Definition of Vulnerable

PlaquePlaque   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 Endothelial Denudation with

Superficial Platelet Aggregation Superficial Platelet Aggregation 4.4. Fissured / Wounded PlaqueFissured / Wounded Plaque

Proposed Histopathological Proposed Histopathological and Clinical Criteria for and Clinical Criteria for Definition of Vulnerable Definition of Vulnerable

PlaquePlaque   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

Diagnosis and Screening- Diagnosis and Screening- Plaque LevelPlaque Level

Plaque inflammation (macrophage density or rate of monocyte Plaque inflammation (macrophage density or rate of monocyte infiltration) infiltration)

Matrix digesting enzyme activity in the cap (MMP 2, 3,9, etc) Matrix digesting enzyme activity in the cap (MMP 2, 3,9, etc)

Endothelial denudation or dysfunction (local NO production, Endothelial denudation or dysfunction (local NO production, anti/pro-coagulation properties of the endothelium) anti/pro-coagulation properties of the endothelium)

Superficial platelet aggregation and fibrin deposition (residual Superficial platelet aggregation and fibrin deposition (residual mural thrombus)mural thrombus)

Plaque cap thickness with a resolution of <100 micron Plaque cap thickness with a resolution of <100 micron

Collagen content, lipid core size, mechanical stability (stiffness and Collagen content, lipid core size, mechanical stability (stiffness and elasticity)  elasticity)  

Diagnosis and Screening- Diagnosis and Screening- Plaque LevelPlaque Level

Calcification burden and pattern (nodule, scattered, Calcification burden and pattern (nodule, scattered, intimal, deep) intimal, deep)

Angiogenesis, leaking vasa vaserum, and intraplaque Angiogenesis, leaking vasa vaserum, and intraplaque hemorrhagehemorrhage

Presence of certain microbial antigensPresence of certain microbial antigens

Rate of apoptosis (apoptosis protein markers, coronary Rate of apoptosis (apoptosis protein markers, coronary microsatellite, etc) microsatellite, etc)

Shear stress imaging (flow pattern throughout coronary Shear stress imaging (flow pattern throughout coronary arteryartery

Diagnosis and Screening- Diagnosis and Screening- Systemic LevelSystemic Level

CRP, CD40L, ICAM-1, VCAM, and other CRP, CD40L, ICAM-1, VCAM, and other serological markers of inflammationserological markers of inflammation

MMPs and acidic digesting proteinases MMPs and acidic digesting proteinases and their inhibitors such as TIMMPs and and their inhibitors such as TIMMPs and cystatin cystatin

Circulating apoptosis marker(s)Circulating apoptosis marker(s)

Markers of blood hypercoagulabilityMarkers of blood hypercoagulability

Diagnosis and Screening- Diagnosis and Screening- Systemic LevelSystemic Level

Markers of blood fibrinolysisMarkers of blood fibrinolysis

Markers of lipid-peroxidation Markers of lipid-peroxidation

PAPP-A, pregnancy associated plasma PAPP-A, pregnancy associated plasma protein –Aprotein –A

Plaque specific markers of immune Plaque specific markers of immune activation activation (anti-LDL Ab)(anti-LDL Ab)

A composite risk score

Plaque vulnerability index

Patient vulnerability index (e.g. VP Score)

Screening

Diagnosis- Active Diagnosis- Active InflammationInflammation

Intravascular: Intravascular: Thermography, Thermography, CE-MRICE-MRI FDG-PETFDG-PET ImmunoscintigraphyImmunoscintigraphy

Non-invasive: Non-invasive: CE-MRI (SPIO)CE-MRI (SPIO) Targeted CE-MRI, (macrophage specific Targeted CE-MRI, (macrophage specific

Gd-labeled Ab)Gd-labeled Ab)

Dx- Thin cap and large Dx- Thin cap and large lipid corelipid core

  Intravascular: Intravascular: OCTOCT IVUSIVUS High-resolution IVUSHigh-resolution IVUS AngioscopyAngioscopy NIR SpectroscopyNIR Spectroscopy ElastographyElastography MRIMRI IVUS-RF analysisIVUS-RF analysis  

Non-invasiveNon-invasive MRIMRI

DX-Endothelial denudation DX-Endothelial denudation with superficial platelet with superficial platelet

aggregation aggregation Intravascular: Intravascular:

OCTOCT Angioscopy with dyeAngioscopy with dye Matrix-targeted / fibrin-targeted immune-Matrix-targeted / fibrin-targeted immune-

scintigraphy scintigraphy

Non-invasive:Non-invasive: Fibrin/Matrix-targeted CE MRIFibrin/Matrix-targeted CE MRI Platelet/fibrin-targeted SPECTPlatelet/fibrin-targeted SPECT

Fissured/Wounded Fissured/Wounded PlaquesPlaques

Intravascular:Intravascular: OCTOCT IVUSIVUS High-resolution IVUSHigh-resolution IVUS MRI MRI

   Non-invasive: Non-invasive:

Fibrin-targeted CE-MRI Fibrin-targeted CE-MRI

Dx-Superficial Calcified Dx-Superficial Calcified Nodule Nodule

Intravascular: Intravascular: OCTOCT High-resolution IVUSHigh-resolution IVUS IVUSIVUS

Non-invasive: Non-invasive: EBCTEBCT MSCTMSCT MRIMRI

Yellow Color (in Yellow Color (in Angioscopy)Angioscopy)

Intravascular: Intravascular: AngioscopyAngioscopy Transcatheter colorimetryTranscatheter colorimetry

Non-invasive: Non-invasive: Presently impossiblePresently impossible

Dx- Intraplaque Dx- Intraplaque HemorrhageHemorrhage

Intravascular: Intravascular: NIR SpectroscopyNIR Spectroscopy Tissue DopplerTissue Doppler

Non-invasive: Non-invasive: MRIMRI

Dx-Stenotic PlaquesDx-Stenotic Plaques Intravascular: Intravascular:

Invasive X-ray AngiographyInvasive X-ray Angiography

Non-invasive: Non-invasive: Non-invasive MS-CECTNon-invasive MS-CECT MRA w/wo contrastMRA w/wo contrast EBT AngiographyEBT Angiography

Blood FactorBlood Factor Antithrombin III deficiencyAntithrombin III deficiency Protein C or S deficiencyProtein C or S deficiency Resistance to activated protein C Resistance to activated protein C

(factor V Leiden) (factor V Leiden) Antiphospholipid syndromeAntiphospholipid syndrome Nephrotic syndrome Nephrotic syndrome Platelet polymorphisms Platelet polymorphisms

MyocardialMyocardial FactorFactor Different cardiomyopathies Different cardiomyopathies Valvular diseaseValvular disease Primary electric disturbances Primary electric disturbances Chest trauma Chest trauma Anomalous origin of coronary arteriesAnomalous origin of coronary arteries Myocarditis Myocarditis Myocardial bridging Myocardial bridging

Different Types of Vulnerable Plaque As underlying Cause of Acute Coronary Events

NormalRupture-prone

Fissured ErodedCritical Stenosis Hemorrhage

Rupture-Prone Inflamed Plaque

Vulnerable Plaque Type 1

Eroded Plaque with Exposed Proteoglycans Prone to Thrombosis

Vulnerable Plaque Type 2

Fissured Plaque with Old and Fresh Overlaying Thrombi

Vulnerable Plaque Type 3

Intra-Plaque Hemorrhage Prone to Thrombosis

Vulnerable Plaque Type 4

Vulnerable Plaque Type 5

Asymptomatic Significantly Stenotic Plaque Prone to Occlusion