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Pathogenesis of Acute Coronary Syndromes Nathan Wong

Pathogenesis of Acute Coronary Syndromes Nathan Wong. Schematic Time Course of Human Atherogenesis. Ischemic Heart Disease. Cerebrovascular Disease. Peripheral Vascular Disease. Transition from chronic to acute atheroma. Atherosclerosis: A Progressive Process.

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Pathogenesis of Acute Coronary Syndromes Nathan Wong

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  1. Pathogenesis of Acute Coronary Syndromes Nathan Wong

  2. Schematic Time Course of Human Atherogenesis Ischemic HeartDisease CerebrovascularDisease Peripheral VascularDisease Transition from chronic to acute atheroma

  3. Atherosclerosis: A Progressive Process PlaqueRupture/Fissure &Thrombosis Occlusive AtheroscleroticPlaque FattyStreak FibrousPlaque Unstable Angina Normal MI Coronary Death Stroke Effort Angina Claudication Clinically Silent Critical Leg Ischemia Increasing Age Courtesy of P Ganz.

  4. The Anatomy of Atherosclerotic Plaque Intima Lipidcore Fibrouscap Lumen Media – T lymphocyte – Macrophagefoam cell (tissue factor+) – “Activated” intimal SMC (HLA-DR+) – Normal medial SMC Libby P. Lancet.1996;348:S4-S7.

  5. Angiographically Inapparent Atheroma Nissen et al. In: Topol. Interventional CardiologyUpdate. 14;1995.

  6. The Matrix Skeleton of UnstableCoronary Artery Plaque Fissures in the fibrous cap Davies MJ. Circulation. 1996;94:2013-2020.

  7. Characteristics of Plaques Prone to Rupture Fibrous cap Media Lumen Lipid core area ofdetail “Vulnerable” plaque – T lymphocyte Lumen – Macrophagefoam cell (tissue factor+) Lipid core – “Activated” intimal SMC (HLA-DR+) – Normal medial SMC “Stable” plaque Libby P. Circulation. 1995;91:2844-2850.

  8. Proposed Mechanisms of Event Reduction by Lipid-Lowering Therapy • Improved endothelium-dependent vasodilation • Stabilization of atherosclerotic lesions • especially nonobstructive, vulnerable plaques • Reduction in inflammatory stimuli • lipoproteins and modified lipoproteins • Prevention, slowed progression, or regression of atherosclerotic lesions Libby P. Circulation. 1995;91:2844-2850.

  9. Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: Intrinsic Vascular Wall Cells: • Endothelium • Smooth Muscle Cells Inflammatory Cells: • Macrophages • T Lymphocytes • Mast Cells

  10. Cell Types in the Human Atheroma Monocyte/Macrophage Endothelium Intima TunicaMedia T-lymphocytes Smooth musclecells

  11. Schematic Time Course of Human Atherogenesis Ischemic HeartDisease Cerebrovascular Disease Peripheral VascularDisease Lesion initiation No symptoms + Symptoms Symptoms Time (y)

  12. Macrophage Functions in Atherogenesis Attachment

  13. Leukocyte–Endothelial Adhesion Molecules Mono T PMN B

  14. Vascular Cell Adhesion Molecule 1(VCAM-1) • Binds monocytes and lymphocytes- Cells found in atheroma • Expressed by endothelium over nascent fatty streaks • Expressed by microvessels of the mature atheroma

  15. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium Li H et al. Arterioscler Thromb 1993;13:197-204.

  16. VCAM-1 Expression in Rabbit Aorta 3 weeks on atherogenic diet Li H et al. Arterioscler Thromb 1993;13:197-204.

  17. Macrophage Functions in Atherogenesis Penetration

  18. Monocyte Chemoattractant Protein 1(MCP-1) • A potent mononuclear cell chemoattractant • Produced by endothelial and smooth muscle cells • Localizes in human and experimental atheroma

  19. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor–deficient mice Gu L et al. Mol Cell 1998;2:275-281.

  20. Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice LDL-R –/–MCP-1 +/+ LDL-R –/–MCP-1 –/– Gu L et al. Mol Cell 1998;2:275-281.

  21. Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice Oil Red Staining % Aortic Surface Stained ** * +/+ -/- +/+ -/- Time on Diet: 12 – 14 weeks 20 – 25 weeks *P = 0.001 compared to +/+**p = 0.005 compared to +/+

  22. Macrophage Functions in Atherogenesis Division

  23. Molecular Mediators of Atherogenesis VCAM-1 MCP-1 M-CSF

  24. Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap Synthesis Breakdown Fibrouscap Collagen-degrading Proteinases IFN- – CD-40L + + IL-1TNF-MCP-1M-CSF + + + + Tissue Factor Procoagulant Lipid core Libby P. Circulation 1995;91:2844-2850.

  25. Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M) in Human Atheroma Galis ZS et al. J Clin Invest 1994;94:2493-2503.

  26. Plaque Rupture with Thrombosis Fibrous cap Thrombus 1 mm Lipid core Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.

  27. Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: • Weakening of the fibrous cap • Thrombogenicity of the lipid core Illustration courtesy of Michael J. Davies, M.D.

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