Pathogenesis of Acute Coronary Syndromes Nathan Wong BIOGRAPHICAL SKETCH(../lec5081/sketch.htm)

Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease BIOGRAPHICAL SKETCH(../lec5081/sketch.htm) Transition from chronic to acute atheroma

Atherosclerosis: A Progressive Process Plaque Rupture/ Fissure & Thrombosis Occlusive Atherosclerotic Plaque Fatty Streak Fibrous Plaque Unstable Angina Normal MI Coronary Death Stroke Effort Angina Claudication Clinically Silent Critical Leg Ischemia Increasing Age Courtesy of P Ganz.

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

Angiographically Inapparent Atheroma Nissen et al. In: Topol. Interventional Cardiology Update. 14;1995.

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

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

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.

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

Cell Types in the Human Atheroma Monocyte/ Macrophage Intima Endothelium Tunica Media T-lymphocytes Smooth muscle cells

Schematic Time Course of Human Atherogenesis Ischemic Heart Disease Cerebrovascular Disease Peripheral Vascular Disease Lesion initiation No symptoms + Symptoms Symptoms Time (y)

Macrophage Functions in Atherogenesis Attachment

Leukocyte–Endothelial Adhesion Molecules Mono T PMN B

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

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.

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

Macrophage Functions in Atherogenesis Penetration

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

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.

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.

Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice % Aortic Surface Stained Oil Red Staining ** * Gu L et al. Mol Cell 1998;2:275-281. +/+ -/- +/+ -/- Time on Diet: 12 – 14 weeks 20 – 25 weeks *P = 0.001 compared to +/+ **p = 0.005 compared to +/+

Macrophage Functions in Atherogenesis Division

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

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

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.

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

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.