SHAPE Society

2. Introducing
The Vulnerable Patient Consensus Statement
Published in

3. Circulation Journal Vol108, No14; October 7, 2003

4. Abstract
Circulation Journal Vol108, No14; October 7, 2003

5. Naghavi et al. Circulation. 2003;108:1664

6. Naghavi et al. Circulation. 2003;108:1664

8. Underlying Pathologies of "Culprit" Coronary Lesions
Naghavi et al. Circulation. 2003;108:1664
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

9. 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
Naghavi et al. Circulation. 2003;108:1664
Plaque ruptureFriedman 1966

10. Plaque rupture illustrated in 1966

11. The Challenge of Terminology
• Culprit Plaque; A Retrospective Term
Naghavi et al. Circulation. 2003;108:1664
Vulnerable Plaque = Future Culprit Plaque
• Vulnerable Plaque; A Prospective Term

12. • 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
Naghavi et al. Circulation. 2003;108:1664

13. • 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
Naghavi et al. Circulation. 2003;108:1664

14. • 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
Naghavi et al. Circulation. 2003;108:1664

15. • 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
Naghavi et al. Circulation. 2003;108:1664

16. Naghavi et al. Circulation. 2003;108:1664
The most common type

17. Naghavi et al. Circulation. 2003;108:1664
The Most Common Type of Vulnerable Plaque

18. Naghavi et al. Circulation. 2003;108:1664

19. Writer and Director: Morteza Naghavi, MD
Design and Animation: Mark Johnson
Music: Eric Jarvis
Natural History of Atherosclerosis and Vulnerable Plaques

20. Naghavi et al. Circulation. 2003;108:1664
Both Morphology and Activity Assessments are Needed

22. Naghavi et al. 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)

23. • 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)
Naghavi et al. Circulation. 2003;108:1664

25. 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
Naghavi et al. Circulation. 2003;108:1664
Conditions and Markers Associated with Myocardial Vulnerability

26. 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
Naghavi et al. Circulation. 2003;108:1664
Conditions and Markers Associated with Myocardial Vulnerability

27. 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
Naghavi et al. Circulation. 2003;108:1664

28. Electrode vest
measures ECG
potentials
Instrumentation
setup
Transverse CT
Images
Body Surface
potentials
Heart-torso
geometry
224-channel ECG
CT provides
geometry
a
b c
d e
f
g
Electrode vest
measures ECG
potentials
Instrumentation
setup
Transverse CT
Images
Body Surface
potentials
Heart-torso
geometry
224-channel ECG
CT provides
geometry
a
b c
d e
f
g

29. Naghavi et al. Circulation. 2003;108:1664

30. the Vulnerable Plaque-Blood-Myocardium Movie

31. The VP Pyramid
Screening >> Diagnosis Treatment>>
Outlines for Annual

32. CVD Genotyping?
Naghavi et al. Circulation. 2003;108:1664

33. Out-of- hospital
screening (EF,
serum tests,
physician visit)
Non-Invasive Imaging
Diagnostic Cath
Drug-Eluting Stent
Statin and other
Drugs

34. Screening >> Treatment

35. Annual Cost of
Heart Attacks
in the USA