HDL METABOLISM-ANATOMY OF A-PLAQE

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Anatomy of the Atherosclerotic Plaque : 

Anatomy of the Atherosclerotic Plaque Lumen Lipid Core Fibrous cap Shoulder Intima Media Elastic laminæ Internal External

Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from: : 

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.

Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap : 

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

Plaque Rupture with Thrombosis : 

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

Potential Time Course of Statin Effects : 

Potential Time Course of Statin Effects * Time course established Days Years LDL-C lowered* Inflammationreduced Vulnerableplaquesstabilized Endothelialfunctionrestored Ischemicepisodesreduced Cardiaceventsreduced*

HDL Metabolism and Reverse Cholesterol Transport : 

HDL Metabolism and Reverse Cholesterol Transport A-I Liver CE CE CE FC FC LCAT FC Bile SR-BI A-I ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI ABC1 Macrophage Mature HDL Nascent HDL

Role of CETP in HDL Metabolism : 

Role of CETP in HDL Metabolism A-I Liver CE CE FC FC LCAT FC Bile SR-BI A-I ABC1 Macrophage CE B CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein LDLR VLDL/LDL CETP Mature HDL Nascent HDL CE SRA Oxidation

CETP Deficiency : 

CETP Deficiency Autosomal co-dominant; due to mutations in both alleles of CETP gene Markedly elevated levels of HDL-C and apoA-I Delayed catabolism of HDL cholesteryl ester and apoA-I HDL particles enlarged and enriched in cholesteryl ester No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease

Summary : 

Summary HDL metabolism is complex HDL-C and apoA-I levels are determined by both production and catabolic rates Rates of reverse cholesterol transport cannot be determined solely by steady-state levels of HDL-C and apoA-I Effect of genetic defects or of interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL Genes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis

HDL as a Therapeutic Target: Potential Strategies : 

Increase apo A-I production Promote reverse cholesterol transport Delay catabolism of HDL HDL as a Therapeutic Target: Potential Strategies

HDL and Reverse Cholesterol Transport : 

HDL and Reverse Cholesterol Transport Liver CE CE FC LCAT FC Bile SR-BI ABCA1 Macrophage Mature HDL Nascent HDL FC

Mechanisms Other Than Reverse Cholesterol Transport by Which HDL May be Antiatherogenic : 

Antioxidant effects Inhibition of adhesion molecule expression Inhibition of platelet activation Prostacyclin stabilization Promotion of NO production Mechanisms Other Than Reverse Cholesterol Transport by Which HDL May be Antiatherogenic

ApoA-I Mutations : 

ApoA-I Mutations Modest to marked reduction in HDL-C and apoA-I Rapid catabolism of apoA-I Systemic amyloidosis Premature atherosclerotic disease (rare)

Approaches to Increasing Apo A-I Production : 

Small molecule upregulation of apo A-I gene transcription Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano) Administration of peptides based on apo A-I sequence Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells) Approaches to Increasing Apo A-I Production

CETP Deficiency : 

CETP Deficiency Autosomal co-dominant; due to mutations in both alleles of CETP gene Markedly elevated levels of HDL-C and apoA-I Delayed catabolism of HDL cholesteryl ester and apoA-I HDL particles enlarged and enriched in cholesteryl ester No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease

Genes Involved in HDL MetabolismPotential Targets for Development of Novel Therapies for Atherosclerosis : 

Genes Involved in HDL MetabolismPotential Targets for Development of Novel Therapies for Atherosclerosis HDL-associated apolipoproteins — ApoA-I — ApoE — ApoA-IV HDL-modifying plasma enzymes and transfer proteins — LCAT — Lipoprotein lipase — CETP — Hepatic lipase — PLTP — Endothelial lipase Cellular and cell-surface proteins that influence HDL metabolism — ABC1 — SR-BI

Gene Transfer of ApoA-I to Liver Induces Regression of Atherosclerosis in LDLR–/– Mice : 

Gene Transfer of ApoA-I to Liver Induces Regression of Atherosclerosis in LDLR–/– Mice 0 1 2 3 4 5 Baseline Adnull Aortic lesion (%) AdhapoA-I * * P ? 0.05 Tangirala R et al. Circulation 1999;100:1816–1822

Overexpression of LCAT Prevents Development of Atherosclerosis in Transgenic Rabbits : 

Overexpression of LCAT Prevents Development of Atherosclerosis in Transgenic Rabbits * P < 0.003 LCAT = lecithin-cholesterol acyltransferase; Tg = transgenic Hoeg JM et al. Proc Natl Acad Sci U S A. 1996;93:11448–11453 Copyright ©1996 National Academy of Sciences, USA. 0 10 20 30 40 50 Control LCAT Tg Atherosclerotic surface area (%) *

Inflammation and Atherosclerosis : 

Inflammation and Atherosclerosis Inflammation may determine plaque stability - Unstable plaques have increased leukocytic infiltrates - T cells, macrophages predominate rupture sites - Cytokines and metalloproteinases influence both stability and degradation of the fibrous cap Lipid lowering may reduce plaque inflammation - Decreased macrophage number - Decreased expression of collagenolytic enzymes (MMP-1) - Increased interstitial collagen - Decreased expression of E-selectin - Reduced calcium deposition Libby P. Circulation 1995;91:2844-2850. Ross R. N Engl J Med 1999;340:115-126.

Increased Apo A-I Production is Antiatherogenic in Animals : 

Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits Regression of pre-existing atherosclerosis in animals Increased Apo A-I Production is Antiatherogenic in Animals

Slide 21: 

Lipid Levels as the Target Atherosclerosis as the Target Treatment Approach Measure and treat levels Only patients with levels above normal benefit Start on low dose and titrate Goal is “normal” levels Benefit same regardless of Rx Based on epidemiologic and observational data Find patients with disease or at risk All patients benefit, regardless of lipid levels Start on clinical trial–proven doses Goal is getting on and staying on Rx Statins have independent benefits Based on randomized clinical trial evidence

Role of Lipoproteins in Inflammation : 

Role of Lipoproteins in Inflammation

Atherosclerosis is an Inflammatory Disease : 

Atherosclerosis is an Inflammatory Disease Ross R. N Engl J Med 1999;340:115-126. Endothelium Vessel Lumen Intima Foam Cell Monocyte Cytokines Growth Factors Metalloproteinases Cell ProliferationMatrix Degradation Macrophage

Lipoprotein Classes and Inflammation : 

Lipoprotein Classes and Inflammation Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. HDL LDL Chylomicrons,VLDL, and their catabolic remnants > 30 nm 20–22 nm Potentially proinflammatory 9–15 nm Potentially anti- inflammatory

Structure of LDL : 

Structure of LDL Murphy HC et al. Biochemistry 2000;39:9763-970. Hydrophobic Core of Triglyceride and Cholesteryl Esters apoB Surface Monolayer of Phospholipids and Free Cholesterol

Role of LDL in Inflammation : 

Role of LDL in Inflammation Steinberg D et al. N Engl J Med 1989;320:915-924. Endothelium Vessel Lumen LDL LDL Readily Enter the Artery Wall Where They May be Modified LDL Intima Modified LDL Modified LDL are Proinflammatory Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine Other Chemical Modifications Oxidation of Lipidsand ApoB Aggregation

Modified LDL Stimulate Expression of MCP-1 in Endothelial Cells : 

LDL LDL Modified LDL Stimulate Expression of MCP-1 in Endothelial Cells Navab M et al. J Clin Invest 1991;88:2039-2046. Endothelium Vessel Lumen Intima Monocyte Modified LDL MCP-1

Differentiation of Monocytes into Macrophages : 

LDL LDL Differentiation of Monocytes into Macrophages Steinberg D et al. N Engl J Med 1989;320:915-924. Endothelium Vessel Lumen Intima Monocyte Modified LDL Modified LDL PromoteDifferentiation ofMonocytes intoMacrophages MCP-1 Macrophage

Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in Endothelial Cells : 

LDL LDL Modified LDL Induces Macrophages to Release Cytokines That Stimulate Adhesion Molecule Expression in Endothelial Cells Nathan CF. J Clin Invest 1987;79:319-326. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 AdhesionMolecules Cytokines Intima

Macrophages Express Receptors That Take up Modified LDL : 

LDL LDL Endothelium Vessel Lumen Monocyte Macrophage MCP-1 AdhesionMolecules Steinberg D et al. N Engl J Med 1989;320:915-924. Macrophages Express Receptors That Take up Modified LDL Foam Cell Modified LDL Taken up by Macrophage Intima

Macrophages and Foam Cells Express Growth Factors and Proteinases : 

LDL LDL Endothelium Vessel Lumen Monocyte Macrophage AdhesionMolecules Macrophages and Foam Cells Express Growth Factors and Proteinases Foam Cell Intima Modified LDL Cytokines Cell ProliferationMatrix Degradation Growth FactorsMetalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1

Slide 32: 

Endothelium Vessel Lumen Monocyte Macrophage MCP-1 AdhesionMolecules The Remnants of VLDL and Chylomicrons are Also Proinflammatory Foam Cell Intima ModifiedRemnants Cytokines Cell ProliferationMatrix Degradation Doi H et al. Circulation 2000;102:670-676. Growth FactorsMetalloproteinases Remnant Lipoproteins Remnants

Structure of HDL Particle : 

Structure of HDL Particle A-I A-I A-II A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides CE TG

Structure of HDL : 

Structure of HDL Rye KA et al. Atherosclerosis 1999;145:227-238. Hydrophobic Core of Triglyceride and Cholesteryl Esters apoA-II Surface Monolayer of Phospholipids and Free Cholesterol apoA-I

Slide 35: 

LDL LDL Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 AdhesionMolecules Cytokines HDL Prevent Formation of Foam Cells Intima HDL Promote Cholesterol Efflux Foam Cell

Slide 36: 

LDL LDL Mackness MI et al. Biochem J 1993;294:829-834. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 AdhesionMolecules Cytokines HDL Inhibit the Oxidative Modification of LDL Foam Cell HDL Promote Cholesterol Efflux Intima HDL InhibitOxidationof LDL

Inhibition of LDL Oxidation by HDL:Role of Paraoxonase : 

Inhibition of LDL Oxidation by HDL:Role of Paraoxonase Paraoxonase is transported in plasma as a component of HDL Paraoxonase is known to inhibit the oxidative modification of LDL Thus, the presence of paraoxonase in HDL may account for a proportion of the antioxidant properties of these lipoproteins Mackness MI et al. FEBS Lett 1991;286:152-154.

Role of HDL Apolipoproteins in Removing Oxidized Lipids from LDL : 

Role of HDL Apolipoproteins in Removing Oxidized Lipids from LDL CETP transfers oxidized lipids from LDL to HDL The oxidized lipids in HDL are reduced by HDL apolipoproteins The liver takes up reduced lipids from HDL more rapidly than from LDL Christison JK et al. J Lipid Res 1995;36:2017-2026; Gardner B et al. J Biol Chem 1998;273:6088-6095.

Slide 39: 

LDL LDL Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 AdhesionMolecules Cytokines Inhibition of Adhesion Molecules Intima HDL InhibitOxidationof LDL HDL Inhibit Adhesion Molecule Expression Foam Cell HDL Promote Cholesterol Efflux

Recruitment of Blood Monocytes by Endothelial Cell Adhesion Molecules : 

Endothelium Vessel Lumen MCP-1 E-Selectin Charo IF. Curr Opin Lipidol 1992;3:335-343. Recruitment of Blood Monocytes by Endothelial Cell Adhesion Molecules Intima VCAM-1 ICAM-1 Sticking Monocyte Rolling Transmigration

HDL Inhibit Endothelial Cell Sphingosine Kinase : 

HDL Inhibit Endothelial Cell Sphingosine Kinase Xia P et al. J Biol Chem 1999;274:33143-33147. Sphingomyelin Ceramide Sphingosine Sph-1-P HDL NF-KB Adhesion Protein Synthesis SM-ase Sph Kinase + TNF? X

Heterogeneity of HDL : 

Heterogeneity of HDL Rye KA et al. Atherosclerosis 1999;145:227-238. Apolipoprotein Composition A-I HDL A-I/A-II HDL A-II HDL Particle Shape Discoidal Spherical Lipid Composition TG, CE, and PL Particle Size HDL2b HDL2a HDL3a HDL3b HDL3c

Inhibition of Endothelial Cell VCAM-1 Expression by HDL: Effect of HDL Composition : 

Inhibition of Endothelial Cell VCAM-1 Expression by HDL: Effect of HDL Composition Inhibition unaffected by replacing apoA-I with apoA-II Inhibition unaffected by replacing apoA-I with SAA Inhibition unaffected by varying the cholesteryl ester or triglyceride content of HDL Inhibition IS affected by varying HDL phospholipids Baker PW et al. J Lipid Res 1999;40:345-353.

Additional Anti-inflammatory Properties of HDL : 

Additional Anti-inflammatory Properties of HDL HDL bind and neutralize proinflammatory lipopolysaccharides The acute phase reactant SAA binds to plasma HDL, which possibly neutralizes the effects of SAA Baumberger C et al. Pathobiology 1991;59:378-383; Benditt EP et al. Proc Natl Acad Sci U S A 1977;74:4025-4028.

Animal Studies : 

Animal Studies Increasing the concentration of LDL or remnant particles in animal models results in expression of endothelial cell adhesion molecules at the sites where atherosclerotic lesions develop Infusion or overexpression of apoA-I in animal models reduces oxidation of LDL and reduces endothelial cell adhesion molecule expression Sakai A et al. Arterioscler Thromb Vasc Biol 1997;17:310-316; Dimayuga P et al. Biochem Biophys Res Commun 1999;264:465-468; Cockerill GW et al. Circulation 2001;103:108-112; Theilmeier G et al. FASEB J 2000;14:2032-2039.

Studies in Humans : 

Studies in Humans Treatments that reduce the level of LDL reduce the plasma levels of C-reactive protein and soluble adhesion molecules BUT These effects may represent pleiotropic effects of lipid-modifying agents and be unrelated to the changes in lipoprotein levels Ridker PM et al. Circulation 1998;98:839-844; Hackman A et al. Circulation 1996;93:1334-1338.

Summary : 

Summary The evidence that atherosclerosis is an inflammatory disorder is overwhelming LDL are subject to proinflammatory modifications that may account for their atherogenicity HDL have anti-inflammatory properties that may contribute to their ability to protect against atherosclerosis

Conclusions : 

Conclusions Strategies that reduce proinflammatory modifications to LDL may reduce atherosclerosis Strategies that increase the anti-inflammatory properties of HDL may also reduce atherosclerosis More research is needed to determine whether pharmacological increases in HDL are anti-inflammatory and reduce atherosclerosis

HDL as a Therapeutic Target : 

HDL as a Therapeutic Target

Is HDL-C Simply a Marker of Increased Cardiovascular Risk? : 

Is HDL-C Simply a Marker of Increased Cardiovascular Risk? Smoke Are sedentary Are obese Are insulin resistant or diabetic Have hypertriglyceridemia Have chronic inflammatory disorders Low HDL-C levels are commonly found in patients who:

Production of Apo A-I by Liver and Intestine : 

Production of Apo A-I by Liver and Intestine A-I A-II Liver Intestine HDL A-I HDL

Increased Apo A-I Production is Antiatherogenic in Animals : 

Reduced initiation and progression of atherosclerosis in transgenic mice and rabbits Regression of pre-existing atherosclerosis in animals Increased Apo A-I Production is Antiatherogenic in Animals

HDL Metabolism as a Therapeutic Target: Potential Strategies : 

Increase apo A-I production Promote reverse cholesterol transport Delay catabolism of HDL HDL Metabolism as a Therapeutic Target: Potential Strategies

Approaches to Increasing Apo A-I Production : 

Small molecule upregulation of apo A-I gene transcription Intravenous infusion of recombinant protein (wild-type apo A-I, apo A-IMilano) Administration of peptides based on apo A-I sequence Somatic gene transfer of apo A-I DNA (liver, intestine, muscle, hematopoetic cells) Approaches to Increasing Apo A-I Production

HDL as a Therapeutic Target: Potential Strategies : 

Increase apo A-I production Promote reverse cholesterol transport Delay catabolism of HDL HDL as a Therapeutic Target: Potential Strategies

HDL and Reverse Cholesterol Transport : 

HDL and Reverse Cholesterol Transport Liver CE CE FC LCAT FC Bile SR-BI ABCA1 Macrophage Mature HDL Nascent HDL FC

Regulation of Cholesterol Efflux in the Macrophage : 

Regulation of Cholesterol Efflux in the Macrophage FC FC oxysterols LXR/RXR ABCA1 PPARs

Pharmacologic Manipulation of Cholesterol Efflux : 

Pharmacologic Manipulation of Cholesterol Efflux LXR/RXR PPARs Fibrates, TZDs, new agents New agents FC ABCA1

HDL as a Therapeutic Target: Potential Strategies : 

Increase apo A-I production Promote reverse cholesterol transport Delay catabolism of HDL HDL as a Therapeutic Target: Potential Strategies

Mechanisms Other Than Reverse Cholesterol Transport by Which HDL May be Antiatherogenic : 

Antioxidant effects Inhibition of adhesion molecule expression Inhibition of platelet activation Prostacyclin stabilization Promotion of NO production Mechanisms Other Than Reverse Cholesterol Transport by Which HDL May be Antiatherogenic

HDL Metabolism: Intravascular Remodeling of HDL : 

Liver CE CE FC FC LCAT FC Bile SR-BI ABCA1 Macrophage A-I TG CE HDL Metabolism: Intravascular Remodeling of HDL Kidney PL FC PL

HDL Metabolism: Role of Hepatic Lipase : 

Liver HL A-I TG CE HDL Metabolism: Role of Hepatic Lipase Kidney PL HDL2

HDL Metabolism: Role of CETP : 

Liver CE CE FC FC LCAT FC Bile SR-BI ABCA1 Macrophage HDL Metabolism: Role of CETP FC Kidney LDLR CETG CETP B VLDL/LDL

HDL Metabolism in CETP Deficiency : 

HDL Metabolism in CETP Deficiency CE FC FC LCAT ABCA1 Macrophage A-I CE FC CETG CETP B VLDL/LDL Delayedcatabolism X

Inhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits Significantly Reduced Aortic Atherosclerosis : 

Okamoto H et al. Nature 2000;406:203-207. Inhibition of CETP by JTT-705 in Cholesterol-Fed Rabbits Significantly Reduced Aortic Atherosclerosis % Aortic Lesion Control Simvastatin JTT-705

HDL Metabolism: Influence of CETP Inhibition : 

HDL Metabolism: Influence of CETP Inhibition Liver CE CE FC FC LCAT FC Bile SR-BI ABCA1 Macrophage FC LDLR CETG CETP B VLDL/LDL X

Management of Low HDL-C : 

Weight reduction and increased physical activity LDL-C is primary target of therapy Non-HDL-C is secondary target of therapy (if triglycerides ?200 mg/dL) Consider nicotinic acid or fibrates Management of Low HDL-C Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

Management of Low HDL-C : 

Therapeutic lifestyle changes Smoking cessation Regular aerobic exercise Weight loss Alcohol use? Management of Low HDL-C

Management of Low HDL-C : 

Therapeutic lifestyle changes Pharmacologic therapy Statins Management of Low HDL-C

Management of Low HDL-C : 

Therapeutic lifestyle changes Pharmacologic therapy Statins Fibrates Management of Low HDL-C

Management of Low HDL-C : 

Therapeutic lifestyle changes Pharmacologic therapy Statins Fibrates Niacin Management of Low HDL-C

Management of Low HDL-C : 

Lifestyle changes and secondary causes Pharmacologic therapy If LDL-C elevated: statin If TG elevated: fibrate If isolated low HDL-C: niacin Combination therapy Management of Low HDL-C

Summary : 

LDL-C remains the primary target of lipid-altering therapies HDL-C is an important CHD risk factor Even small increases in HDL-C may confer substantial benefit Intervention to raise HDL-C levels should be considered in high-risk patients Summary

Approach to the Patient with Low HDL-C : 

48-year-old man with metabolic syndrome and CHD After therapeutic lifestyle changes and a starting dose of statin: Cholesterol 179 mg/dL Triglycerides 252 mg/dL LDL-C 97 mg/dL HDL-C 32 mg/dL Glucose 104 mg/dL Approach to the Patient with Low HDL-C

Slide 75: 

Check list of common cardiac drugs

Slide 76: 

Plaque with multiple breaks in the cap and both an intraplaque and an intraluminal mural component of thrombosis

Slide 77: 

An episode of plaque disruption in which the torn cap projects into the lumen of the artery and thrombus is contained within the plaque core

Slide 78: 

Diagrammatic representation of stages of development of thrombosis after disruption

Schematic Time Course of Human Atherogenesis : 

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

Atherosclerosis: A Progressive Process : 

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

The Anatomy of Atherosclerotic Plaque : 

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

Angiographically Inapparent Atheroma : 

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

The Matrix Skeleton of UnstableCoronary Artery Plaque : 

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

Characteristics of Plaques Prone to Rupture : 

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

Proposed Mechanisms of Event Reduction by Lipid-Lowering Therapy : 

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

Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis: : 

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 : 

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

Schematic Time Course of Human Atherogenesis : 

No symptoms + Symptoms Schematic Time Course of Human Atherogenesis Time (y) Symptoms Lesion initiation Ischemic HeartDisease CerebrovascularDisease Peripheral VascularDisease

Macrophage Functions in Atherogenesis : 

Macrophage Functions in Atherogenesis Attachment

Leukocyte–Endothelial Adhesion Molecules : 

Leukocyte–Endothelial Adhesion Molecules Mono T B PMN

Vascular Cell Adhesion Molecule 1(VCAM-1) : 

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 : 

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 : 

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

Macrophage Functions in Atherogenesis : 

Penetration Macrophage Functions in Atherogenesis

Monocyte Chemoattractant Protein 1(MCP-1) : 

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 : 

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 : 

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

Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic Mice : 

Gu L et al. Mol Cell 1998;2:275-281. 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 +/+

Macrophage Functions in Atherogenesis : 

Macrophage Functions in Atherogenesis Division

Molecular Mediators of Atherogenesis : 

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

Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap : 

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

Increased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M?) in Human Atheroma : 

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.