Vulnerable Plaques and Vulnerable Patients

1. Vulnerable Plaques and Vulnerable Patients The 1stGuideline of Association for Eradication of Heart Attack AEHA for Definition of Vulnerable Plaque and Vulnerable Patient (VP.org) Morteza Naghavi, Erling Falk, Mohammad Madjid, Silvio Litovsky, James Muller, Ward Casscells, Renu Virmani, P.K. Shah, MD, Robert S. Schwartz, MD, Juan Jose Badimon, PhD, Valentin Fuster, James T. Willerson

2. Vulnerable plaques, vulnerable myocardium, and hypercoagulable state of the blood lead to sudden cardiac death and acute myocardial infarction.

3. Potential Underlying Cause of All (fatal and non-fatal) Heart Attacks (Sudden Cardiac Death + Acute Coronary Syndrome) Without Significant Atherosclerosis or Atherosclerosis-Derived Myocardial Damage WithSignificant Atherosclerosis or Ischemic Heart Only Myocardial-Derived Factors (conductive disorders, …) With Occlusive Thrombi Without Occlusive Thrombi With Rupture Without Rupture With Old Myocardial Damage Without Old Myocardial Damage >70% Stenosis <70% Stenosis Erosion Calcified Nodule Others Without Expansive Remodeling With Expansive Remodeling With Critical Stenosis Without Critical Stenosis

4. Terminology: • Culprit Plaque: a Retrospective Terminology • Vulnerable Plaque: a Prospective Terminology

5. Underlying pathologies of “culprit” coronary lesions Ruptured Plaques (~70%) Stenotic (~20%) Non-stenotic (~50%) Non-Ruptured Plaques (~ 30%) Erosion Calcified Nodule Others / Unknown MJ Davies, Circ. 1990; Falk et al. Circ. 1995; Virmani et al. ATVB 2000

6. Interchangeable Terminologies

7. Proposed Histopathological and Clinical Criteria for Definition of Vulnerable Plaque ·Major Criteria: • Active Inflammation (monocyte/ macrophage infiltration) • Thin Cap with Large Lipid Core • Endothelial Denudation with Superficial Platelet Aggregation • Fissured / Wounded Plaque

8. Proposed Histopathological and Clinical Criteria for Definition of Vulnerable Plaque ·Minor Criteria: • Superficial Calcified nodule • Glistening Yellow • Intraplaque Hemorrhage • Critical Stenosis • Positive Remodeling?

9. Ideal method for screening vulnerable plaque/patient • Non-invasive • Inexpensive • Accurate • Widely Reproducible

10. Diagnosis and Screening- Plaque Level • Plaque inflammation (macrophage density or rate of monocyte infiltration) • Matrix digesting enzyme activity in the cap (MMP 2, 3,9, etc) • Endothelial denudation or dysfunction (local NO production, anti/pro-coagulation properties of the endothelium) • Superficial platelet aggregation and fibrin deposition (residual mural thrombus) • Plaque cap thickness with a resolution of <100 micron • Collagen content, lipid core size, mechanical stability (stiffness and elasticity)  

11. Diagnosis and Screening- Plaque Level • Calcification burden and pattern (nodule, scattered, intimal, deep) • Angiogenesis, leaking vasa vaserum, and intraplaque hemorrhage • Presence of certain microbial antigens • Rate of apoptosis (apoptosis protein markers, coronary microsatellite, etc) • Shear stress imaging (flow pattern throughout coronary artery

12. Diagnosis and Screening- Systemic Level • CRP, CD40L, ICAM-1, VCAM, and other serological markers of inflammation • MMPs and acidic digesting proteinases and their inhibitors such as TIMMPs and cystatin • Circulating apoptosis marker(s) • Markers of blood hypercoagulability

13. Diagnosis and Screening- Systemic Level • Markers of blood fibrinolysis • Markers of lipid-peroxidation • PAPP-A, pregnancy associated plasma protein –A • Plaque specific markers of immune activation (anti-LDL Ab)

14. Screening • A composite risk score • Plaque vulnerability index • Patient vulnerability index (e.g. VP Score)

15. Diagnosis- Active Inflammation • Intravascular: • Thermography, • CE-MRI • FDG-PET • Immunoscintigraphy • Non-invasive: • CE-MRI (SPIO) • Targeted CE-MRI, (macrophage specific Gd-labeled Ab)

16. Dx- Thin cap and large lipid core • Intravascular: • OCT • IVUS • High-resolution IVUS • Angioscopy • NIR Spectroscopy • Elastography • MRI • IVUS-RF analysis • Non-invasive • MRI

17. DX-Endothelial denudation with superficial platelet aggregation • Intravascular: • OCT • Angioscopy with dye • Matrix-targeted / fibrin-targeted immune-scintigraphy • Non-invasive: • Fibrin/Matrix-targeted CE MRI • Platelet/fibrin-targeted SPECT

18. Fissured/Wounded Plaques • Intravascular: • OCT • IVUS • High-resolution IVUS • MRI • Non-invasive: • Fibrin-targeted CE-MRI

19. Dx-Superficial Calcified Nodule • Intravascular: • OCT • High-resolution IVUS • IVUS • Non-invasive: • EBCT • MSCT • MRI

20. Yellow Color (in Angioscopy) • Intravascular: • Angioscopy • Transcatheter colorimetry • Non-invasive: • Presently impossible

21. Dx- Intraplaque Hemorrhage • Intravascular: • NIR Spectroscopy • Tissue Doppler • Non-invasive: • MRI

22. Dx-Stenotic Plaques • Intravascular: • Invasive X-ray Angiography • Non-invasive: • Non-invasive MS-CECT • MRA w/wo contrast • EBT Angiography

23. Blood Factor • Antithrombin III deficiency • Protein C or S deficiency • Resistance to activated protein C (factor V Leiden) • Antiphospholipid syndrome • Nephrotic syndrome • Platelet polymorphisms

24. MyocardialFactor • Different cardiomyopathies • Valvular disease • Primary electric disturbances • Chest trauma • Anomalous origin of coronary arteries • Myocarditis • Myocardial bridging

25. Different Types of Vulnerable Plaque As underlying Cause of Acute Coronary Events Rupture-prone Critical Stenosis Hemorrhage Normal Fissured Eroded

26. Rupture-Prone Inflamed Plaque Vulnerable Plaque Type 1

27. Eroded Plaque with Exposed Proteoglycans Prone to Thrombosis Vulnerable Plaque Type 2

28. Fissured Plaque with Old and Fresh Overlaying Thrombi Vulnerable Plaque Type 3

29. Intra-Plaque Hemorrhage Prone to Thrombosis Vulnerable Plaque Type 4

30. Asymptomatic Significantly Stenotic Plaque Prone to Occlusion Vulnerable Plaque Type 5