Presentation on theme: "Pathogenesis of Acute Coronary Syndromes Nathan Wong"— Presentation transcript:
1 Pathogenesis of Acute Coronary Syndromes Nathan Wong BIOGRAPHICAL SKETCH(../lec5081/sketch.htm)
2 Schematic Time Course of Human Atherogenesis Ischemic Heart DiseaseCerebrovascular DiseasePeripheral Vascular DiseaseBIOGRAPHICAL SKETCH(../lec5081/sketch.htm)Transition from chronic to acute atheroma
3 Atherosclerosis: A Progressive Process Plaque Rupture/ Fissure & ThrombosisOcclusiveAtherosclerotic PlaqueFatty StreakFibrous PlaqueUnstableAnginaNormalMICoronaryDeathStrokeEffort AnginaClaudicationClinically SilentCritical Leg IschemiaIncreasing AgeCourtesy of P Ganz.
4 The Anatomy of Atherosclerotic Plaque IntimaLipid coreFibrous capLumenMedia– T lymphocyte– Macrophage foam cell (tissue factor+)– “Activated” intimal SMC (HLA-DR+)– Normal medial SMCLibby P. Lancet. 1996;348:S4-S7.
6 The Matrix Skeleton of Unstable Coronary Artery Plaque Fissures inthe fibrous capDavies MJ. Circulation. 1996;94:
7 Characteristics of Plaques Prone to Rupture Fibrous capMediaLumenLipidcorearea of detail“Vulnerable” plaqueLumen– T lymphocyte– Macrophage foam cell (tissue factor+)Lipidcore– “Activated” intimal SMC (HLA-DR+)– Normal medial SMC“Stable” plaqueLibby P. Circulation. 1995;91:
8 Proposed Mechanisms of Event Reduction by Lipid-Lowering Therapy Improved endothelium-dependent vasodilationStabilization of atherosclerotic lesionsespecially nonobstructive, vulnerable plaquesReduction in inflammatory stimulilipoproteins and modified lipoproteinsPrevention, slowed progression, or regression of atherosclerotic lesionsLibby P. Circulation. 1995;91:
9 Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis:Intrinsic Vascular Wall Cells:EndotheliumSmooth Muscle CellsInflammatory Cells:MacrophagesT LymphocytesMast Cells
10 Cell Types in the Human Atheroma Monocyte/ MacrophageIntimaEndotheliumTunica MediaT-lymphocytesSmooth muscle cells
11 Schematic Time Course of Human Atherogenesis Ischemic Heart DiseaseCerebrovascularDiseasePeripheral Vascular DiseaseLesion initiationNo symptoms+ SymptomsSymptomsTime (y)
12 Macrophage Functions in Atherogenesis Attachment
14 Vascular Cell Adhesion Molecule 1 (VCAM-1) Binds monocytes and lymphocytes - Cells found in atheromaExpressed by endothelium over nascent fatty streaksExpressed by microvessels of the mature atheroma
15 An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endotheliumLi H et al. Arterioscler Thromb 1993;13:
16 VCAM-1 Expression in Rabbit Aorta 3 weeks on atherogenic dietLi H et al. Arterioscler Thromb 1993;13:
17 Macrophage Functions in Atherogenesis Penetration
18 Monocyte Chemoattractant Protein 1 (MCP-1) A potent mononuclear cell chemoattractantProduced by endothelial and smooth muscle cellsLocalizes in human and experimental atheroma
19 Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor–deficient miceGu L et al. Mol Cell 1998;2:
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:
21 Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice % Aortic Surface StainedOil Red Staining***Gu L et al. Mol Cell 1998;2:+/+-/-+/+-/-Time on Diet:12 – 14 weeks20 – 25 weeks*P = compared to +/+ **p = compared to +/+
23 Molecular Mediators of Atherogenesis VCAM-1MCP-1M-CSF
24 Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap SynthesisBreakdownCollagen-degradingProteinasesFibrous capIFN-–CD-40L++++IL-1 TNF- MCP-1 M-CSF++Lipid coreTissue FactorProcoagulantLibby P. Circulation 1995;91:
25 Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M) in Human AtheromaGalis ZS et al. J Clin Invest 1994;94:
26 Plaque Rupture with Thrombosis Fibrous capThrombus1 mmLipid coreIllustration 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 capThrombogenicity of the lipid coreIllustration courtesy of Michael J. Davies, M.D.