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IntroducingThe Vulnerable Patient Consensus Statement

Published in

Circulation Journal Vol108, No14; October 7, 2003

http://circ.ahajournals.org/cgi/content/abstract/108/14/1664

Abstract

Circulation Journal Vol108, No14; October 7, 2003

http://circ.ahajournals.org/cgi/content/abstract/108/14/1664

Naghavi et al. Circulation. 2003;108:1664

Underlying Pathologies of "Culprit" Coronary Lesions


Ruptured plaques ( ~ 70%)

• Stenotic ( 20%)• Nonstenotic ( 50%)

Nonruptured plaques ( ~ 30%)

• Erosion• Calcified nodule• Others/Unknown

*Adapted from Falk and associates,6 Davies,7 and Virmani and colleagues.7

Plaque rupture1966Constantinides

Plaque rupture1966Chapman

Thrombogenic gruel1964Byers

Plaque ulceration1963Gore

Plaque thrombosis1961Crawford

Plaque erosion1957Helpern

Plaque fissure1940Horn

Rupture-induced occlusion1938Wartman

Rupture of atheromatous abscess1934Leary

Plaque rupture1931Olcott

Description UsedYearAuthor

Descriptions Used by Pioneers for Culprit Plaques


Plaque ruptureFriedman 1966

Plaque rupture illustrated in 1966

The Challenge of Terminology

• Culprit Plaque; A Retrospective Term


Vulnerable Plaque = Future Culprit Plaque

• Vulnerable Plaque; A Prospective Term

• Outward (positive) remodeling

• Endothelial dysfunction

• Intraplaque hemorrhage

• Glistening yellow

• Superficial calcified nodule

Minor criteria

• Critical Stenosis

• Fissured plaque

• Endothelial denudation with superficial platelet aggregation

• Thin cap with large lipid core

• Active inflammation (monocyte/macrophage and sometimes T-cell infiltration)

Major criteria

Criteria for Defining Vulnerable Plaque Based on the Study of Culprit Plaques


• Shear stress (flow pattern throughout the coronary artery)

• Calcification burden and pattern (nodule vs scattered, superficial vs deep, etc)

• Collagen content versus lipid content, mechanical stability (stiffness and elasticity)

• Color (yellow, glistening yellow, red, etc)

• Remodeling (expansive vs constrictive remodeling)

• Plaque stenosis (luminal narrowing)

• Plaque lipid core size

• Plaque cap thickness

Plaque Morphology / Structure

Markers of Vulnerability at the Plaque/Artery Level


• Certain microbial antigens (eg, HSP60, C. pneumoniae)

• Matrix-digesting enzyme activity in the cap (MMPs 2, 3, 9, etc)

• Angiogenesis, leaking vasa vasorum, and intraplaque hemorrhage

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

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

• Plaque oxidative stress

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

• Plaque inflammation (macrophage density, rate of monocyte infiltration and density of activated T cell)

Plaque Activity / Function



• Total arterial burden of plaque including peripheral (eg, carotid IMT)

• Total coronary vasoreactivity (endothelial function)

• Total coronary calcium burden

• Transcoronary gradient of serum markers of vulnerability

Pan-Arterial




The most common type


The Most Common Type of Vulnerable Plaque

Writer and Director: Morteza Naghavi, MDDesign and Animation: Mark JohnsonMusic: Eric Jarvis

Natural History of Atherosclerosis and Vulnerable Plaques


Both Morphology and Activity Assessments are Needed


• Abnormal lipoprotein profile (e.g. high LDL, low HDL, abnormal LDL and HDL size density, lipoprotein (a), Lp-PLA2 …)• Serum markers of insulin resistance syndrome (e.g. diabetes, hyper triglyceridemia ) • Non-specific markers of inflammation (e.g. hsCRP, CD40L, ICAM-1, VCAM-1, P-selectin, leukocytosis, and other serologic markers related to the immune system. These markers may not be specific for atherosclerosis or plaque inflammation) • Specific markers of immune activation (e.g. anti-LDL antibody, anti-HSP antibody) • Markers of lipid-peroxidation (e.g. ox-LDL and ox-HDL)• Homocysteine • Pregnancy-associated plasma protein A (PAPP-A)• Circulating apoptosis marker(s) (e.g., Fas/Fas ligand, not specific to plaque)• Asymmetric dimethylarginine (ADMA) / dimethylarginine dimethylaminohydrolase (DDAH)• Circulating nonesterified fatty acids (e.g. NEFA)

Serologic Markers of Vulnerability(Reflecting Metabolic and Immune Disorders)

• Markers of blood hypercoagulability (e.g. fibrinogen, D-dimer, and factor V Leiden)• Increased platelet activation and aggregation (e.g., gene polymorphisms of platelet glycoproteins IIb/IIIa, Ia/IIa, and Ib/IX) • Increased coagulation factors (e.g., clotting of factors V, VII, VIII, von Willebrand factor, XIII)• Decreased anticoagulation factors (e.g., proteins S, C, thrombomodulin, and antithrombin III) • Decreased endogenous fibrinolysis activity (e.g. reduced t-PA, increased PAI-1, certain PAI-1 polymorphisms) • Prothrombin mutation (e.g. G20210A)• Other thrombogenic factors (e.g., anticardiolipin antibodies, thrombocytosis, sickle cell disease, polycythemia, diabetes mellitus, hypercholesterolemia, hyperhomocysteinemia) • Increased viscosity • Transient hypercoagulability (e.g. smoking, dehydration, infection, adrenergic surge, cocaine, estrogens, postprandial, etc.)

Blood Markers of Vulnerability(Reflecting Hypercoagulability)


With atherosclerosis-derived myocardial ischemia as shown by:

ECG abnormalities:- During rest- During stress test- Silent ischemia (e.g. ST changes on Holter monitoring)

Perfusion and viability disorder:- PET scan- SPECT

Wall motion abnormalities:- Echocardiography- MR imaging- X-ray ventriculogram- MSCT


Conditions and Markers Associated with Myocardial Vulnerability

Without atherosclerosis-derived myocardial ischemia:

• Sympathetic hyperactivity• Impaired arterial baroreflex• Left ventricular hypertrophy• Cardiomyopathy (dilated, hypertrophic, restrictive, or right ventricular)• Valvular disease (aortic stenosis and mitral valve prolapse)• Electrophysiologic disorders:

- Long QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, sinus and atrioventricular conduction disturbances, catecholaminergic polymorphic ventricular tachycardia, T-wave alternans, drug-induced torsades de pointes• Commotio cordis • Anomalous origination of a coronary artery• Myocarditis • Myocardial bridging


Conditions and Markers Associated with Myocardial Vulnerability

Diagnostic Criteria: - Arrhythmia - QT dispersion - QT dynamics - T wave alternans - Ventricular late potentials - Heart rate variability

Diagnostic Techniques:Non-Invasive: Resting ECG Stress ECG Ambulatory ECG Signal averaged electrocardiogram (SAECG) Surface high-resolution ECG Invasive: Programmed ventricular stimulation (PVS) Real-time 3D magnetic-navigated activation map

Available Techniques for Electrophysiologic Risk Stratification of Vulnerable Myocardium


Electrode vestmeasures ECG

potentials

Instrumentation setup

Transverse CT Images

Body Surfacepotentials

Heart-torsogeometry

224-channel ECG

CT provides geometry

a

b c

d e

f

g

Electrode vestmeasures ECG

potentials

Instrumentation setup

Transverse CT Images

Body Surfacepotentials

Heart-torsogeometry

224-channel ECG

CT provides geometry

a

b c

d e

f

g

the Vulnerable Plaque-Blood-Myocardium Movie

The VP PyramidScreening >> Diagnosis Treatment>>

Outlines for Annual

CVD Genotyping?


Out-of- hospital screening (EF, serum tests, physician visit)

Non-Invasive Imaging

Diagnostic CathDrug-Eluting Stent

Statin and other Drugs

Screening >> Treatment

Annual Cost of Heart Attacks

in the USA

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