5091 - Pathogenesis of Acute Coronary Syndromes Nathan Wong Slide Source Lipids Online www.lipidsonline.org Schematic Time Course of Human

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Unformatted text preview: Pathogenesis of Acute Coronary Syndromes Nathan Wong Slide Source: Lipids Online www.lipidsonline.org Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease Transition from chronic to acute atheroma Slide Source: Lipids Online www.lipidsonline.org Atherosclerosis: A Progressive Process Normal Fatty Streak Plaque Occlusive Rupture/ Fibrous Atherosclerotic Fissure & Plaque Plaque Thrombosis Unstable Angina MI Coronary Death Stroke Critical Leg Ischemia Slide Source: Lipids Online www.lipidsonline.org Clinically Silent Effort Angina Claudication Increasing Age Courtesy of P Ganz. The Anatomy of Atherosclerotic Plaque Intima Fibrous cap Lipid core Lumen Media T lymphocyte Macrophage foam cell (tissue factor+) "Activated" intimal SMC (HLA-DR+) Normal medial SMC Libby P. Lancet. 1996;348:S4-S7. Slide Source: Lipids Online www.lipidsonline.org Angiographically Inapparent Atheroma Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995. Slide Source: Lipids Online www.lipidsonline.org The Matrix Skeleton of Unstable Coronary Artery Plaque Fissures in the fibrous cap Davies MJ. Circulation. 1996;94:2013-2020. Slide Source: Lipids Online www.lipidsonline.org Characteristics of Plaques Prone to Rupture Fibrous cap Media Lumen area of detail Lipid core "Vulnerable" plaque Lumen Lipid core T lymphocyte Macrophage "Stable" plaque Libby P. Circulation. 1995;91:2844-2850. foam cell (tissue factor+) "Activated" intimal SMC (HLA-DR+) Normal medial SMC Slide Source: Lipids Online www.lipidsonline.org Proposed Mechanisms of Event Reduction by LipidLowering Therapy Improved endotheliumdependent 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. Slide Source: Lipids Online www.lipidsonline.org 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 Slide Source: Lipids Online www.lipidsonline.org Cell Types in the Human Atheroma Monocyte/ Macrophage Intima Tunica Media Tlymphocytes Smooth muscle cells Slide Source: Lipids Online www.lipidsonline.org Endothelium Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Lesion initiation No symptoms + Symptoms Time (y) Peripheral Vascular Disease Symptoms Slide Source: Lipids Online www.lipidsonline.org Macrophage Functions in Atherogenesis Attachment Slide Source: Lipids Online www.lipidsonline.org LeukocyteEndothelial Adhesion Molecules Mono T B PMN Slide Source: Lipids Online www.lipidsonline.org Vascular Cell Adhesion Molecule 1 (VCAM1) Binds monocytes and lymphocytes Cells found in atheroma Expressed by endothelium over nascent fatty streaks Expressed by microvessels of the mature atheroma Slide Source: Lipids Online www.lipidsonline.org An atherogenic diet rapidly induces VCAM1, a cytokineregulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium Li H et al. Arterioscler Thromb 1993;13:197204. Slide Source: Lipids Online www.lipidsonline.org VCAM1 Expression in Rabbit Aorta 3 weeks on atherogenic diet Li H et al. Arterioscler Thromb 1993;13:197204. Slide Source: Lipids Online www.lipidsonline.org Macrophage Functions in Atherogenesis Penetration Slide Source: Lipids Online www.lipidsonline.org Monocyte Chemoattractant Protein 1 (MCP1) A potent mononuclear cell chemoattractant Produced by endothelial and smooth muscle cells Localizes in human and experimental atheroma Slide Source: Lipids Online www.lipidsonline.org Absence of monocyte chemoattractant protein1 reduces atherosclerosis in lowdensity lipoprotein receptordeficient mice Gu L et al. Mol Cell 1998;2:275281. Slide Source: Lipids Online www.lipidsonline.org Reduced Lipid Deposition in MCP1Deficient Atherosclerotic Mice LDLR / MCP1 +/+ LDLR / MCP1 / Gu L et al. Mol Cell 1998;2:275281. Slide Source: Lipids Online www.lipidsonline.org Reduced Lipid Deposition in MCP1Deficient Atherosclerotic Mice 30 % Aortic Surface Stained Oil Red Staining 25 20 15 10 5 0 Time on Diet: * +/+ / 12 14 weeks **p = 0.005 compared to +/+ ** +/+ / 20 25 weeks Slide Source: Lipids Online www.lipidsonline.org *P = 0.001 compared to +/+ Macrophage Functions in Atherogenesis Division Slide Source: Lipids Online www.lipidsonline.org Molecular Mediators of Atherogenesis VCAM1 MCP1 MCSF Slide Source: Lipids Online www.lipidsonline.org Matrix Metabolism and Integrity of the Plaque's Fibrous Cap sis Synthe Break do wn IFN CD40L + Collagendegrading Proteinases + + + + + IL1 TNF MCP1 MCSF Fibrous cap Lipid core Libby P. Circulation 1995;91:28442850. Tissue Factor Procoagulant Slide Source: Lipids Online www.lipidsonline.org 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;94:24932503. Slide Source: Lipids Online www.lipidsonline.org Plaque Rupture with Thrombosis Thrombus Fibrous cap 1 mm Illustration courtesy of Frederick J. Schoen, M.D., Ph.D. Lipid core Slide Source: Lipids Online www.lipidsonline.org Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: Weakening of the fibrous cap the lipid core Thrombogenicity of Illustration courtesy of Michael J. Davies, M.D. Slide Source: Lipids Online www.lipidsonline.org ...
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This note was uploaded on 02/23/2012 for the course PHARM 290 taught by Professor Staff during the Fall '10 term at Rutgers.

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