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Slide Source: Lipids Online www.lipidsonline.org Pathogenesis of Acute Coronary Syndromes Nathan Wong.

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Presentation on theme: "Slide Source: Lipids Online www.lipidsonline.org Pathogenesis of Acute Coronary Syndromes Nathan Wong."— Presentation transcript:

1 Slide Source: Lipids Online Pathogenesis of Acute Coronary Syndromes Nathan Wong

2 Slide Source: Lipids Online Schematic Time Course of Human Atherogenesis Transition from chronic to acute atheroma Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease

3 Slide Source: Lipids Online Normal Fatty Streak Fibrous Plaque Occlusive Atherosclerotic Plaque Plaque Rupture/ Fissure & Thrombosis MI Stroke Critical Leg Ischemia Clinically Silent CoronaryDeath Increasing Age Effort Angina Claudication UnstableAngina Atherosclerosis: A Progressive Process Courtesy of P Ganz.

4 Slide Source: Lipids Online Libby P. Lancet. 1996;348:S4-S7. Media – T lymphocyte – Macrophage foam cell (tissue factor + ) – “Activated” intimal SMC (HLA-DR + ) – Normal medial SMC Fibrous cap Intima Lipid core Lumen The Anatomy of Atherosclerotic Plaque

5 Slide Source: Lipids Online Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995. Angiographically Inapparent Atheroma

6 Slide Source: Lipids Online The Matrix Skeleton of Unstable Coronary Artery Plaque Davies MJ. Circulation. 1996;94: Fissures in the fibrous cap

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

8 Slide Source: Lipids Online Libby P. Circulation. 1995;91: 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

9 Slide Source: Lipids Online 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 Slide Source: Lipids Online Cell Types in the Human Atheroma Monocyte/ Macrophage T-lymphocytes Tunica Media Intima Smooth muscle cells Endothelium

11 Slide Source: Lipids Online No symptoms + Symptoms Schematic Time Course of Human Atherogenesis Time (y) Symptoms Lesion initiation Ischemic Heart Disease CerebrovascularDisease Peripheral Vascular Disease

12 Slide Source: Lipids Online Macrophage Functions in Atherogenesis Attachment

13 Slide Source: Lipids Online Leukocyte–Endothelial Adhesion Molecules Mono T B PMN

14 Slide Source: Lipids Online 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 Slide Source: Lipids Online 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:

16 Slide Source: Lipids Online VCAM-1 Expression in Rabbit Aorta Li H et al. Arterioscler Thromb 1993;13: weeks on atherogenic diet

17 Slide Source: Lipids Online Penetration Macrophage Functions in Atherogenesis

18 Slide Source: Lipids Online 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 Slide Source: Lipids Online Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor– deficient mice Gu L et al. Mol Cell 1998;2:

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

21 Slide Source: Lipids Online 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 = compared to +/+ **p = compared to +/+

22 Slide Source: Lipids Online Macrophage Functions in Atherogenesis Division

23 Slide Source: Lipids Online Molecular Mediators of Atherogenesis M-CSF MCP-1 VCAM-1

24 Slide Source: Lipids Online Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap Libby P. Circulation 1995;91: – Synthesis Breakdown Lipid core IL-1 TNF- MCP-1 M-CSF Fibrous cap IFN-  CD-40L Collagen-degradingProteinases Tissue Factor Procoagulant

25 Slide Source: Lipids Online 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:

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

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


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