This document contains a summary of a presentation on vulnerable patient syndrome. It includes PowerPoint slides and videos on defining and identifying vulnerable plaques and patients. It thanks sponsors for their support of the educational event. The slides define vulnerable plaques as those likely to rupture in the future, causing heart attacks, and provide criteria for identifying them based on morphology and activity. Biomarkers and conditions that increase plaque and myocardial vulnerability are also summarized. The presentation outlines a pyramid approach for screening, diagnosing, and treating vulnerable patients annually to help reduce heart attacks and their high costs.

2. Dear Member of AEHA
Thank you for participating in the First Vulnerable
Patient Symposium. This educational CD contains
multiple PowerPoint slide presentations along with
animated movies. Also included the Part I and II of
the Vulnerable Patient Manuscript.
AEHA would like to thank the generous support
of :
Amersham Health, CV Therapeutics, diaDexus, and
American Heart Technologies.

3. Introducing
The Vulnerable Patient Consensus Statement
Published in

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

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

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

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

9. 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

10. 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
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Plaque ruptureFriedman 1966

11. Plaque rupture illustrated in 1966

12. 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

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

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

19. Naghavi et al. Circulation. 2003;108:1664
Non-Stenotic Vulnerable Plaques overall are More Dangerous
Since they are far More Frequent than Stenotic Ones

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

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

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

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

32. Annual Cost of
Heart Attacks
in the USA

33. Stay Tuned for the Guidelines
Screening >> Diagnosis Treatment>>
in Part III and IV

34. HELP AEHA SAVE VULNERABLE PATIENTS