This document summarizes a scientific paper published in Circulation in 2003 about vulnerable plaques and patients. It discusses what has been learned since prior conferences on this topic, including defining major and minor criteria for vulnerable plaques based on culprit plaques. It outlines markers of vulnerability at the plaque/artery level relating to plaque morphology/structure, activity/function, and pan-arterial assessments. Conditions and markers associated with myocardial vulnerability both with and without atherosclerosis-derived ischemia are also summarized. The challenges of terminology and techniques for risk stratification of vulnerable myocardium are briefly discussed.
2. From
The First Vulnerable Plaque Symposium
7-10pm Rosen Plaza Hotel
March 27, 2001– Orlando, FL
To
The First Vulnerable Patient Symposium
7-10pm Rosen Plaza Hotel
November 11, 2003 – Orlando, FL
What Have We Learned?
12. The Challenge of Terminology
• Culprit Plaque; A Retrospective Term
Circulation. 2003;108:1664
Vulnerable Plaque = Future Culprit Plaque
• Vulnerable Plaque; A Prospective Term
13. • 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
Circulation. 2003;108:1664
14. • 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
Circulation. 2003;108:1664
15. • 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
Markers of Vulnerability at the Plaque/Artery Level
Circulation. 2003;108:1664
16. • 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
Markers of Vulnerability at the Plaque/Artery Level
Circulation. 2003;108:1664
20. Writer and Director: Morteza Naghavi, MD
Design and Animation: Mark Johnson
Music: Eric Jarvis
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Vulnerable Plaques
23. Circulation. 2003;108:1664
• 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)
24. • 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)
Circulation. 2003;108:1664
25.
26. 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
Circulation. 2003;108:1664
Conditions and Markers Associated with Myocardial Vulnerability
27. 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
Circulation. 2003;108:1664
Conditions and Markers Associated with Myocardial Vulnerability
28. 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
Circulation. 2003;108:1664
29.
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