Pathogenesis of Acute Coronary Syndromes Nathan Wong

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Slide Source:Lipids Onlinewww.lipidsonline.org

Pathogenesis of AcuteCoronary Syndromes

Nathan Wong

Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis

Transition from chronic to acute atheromaTransition from chronic to acute atheroma

Ischemic HeartIschemic HeartDiseaseDisease

CerebrovascularCerebrovascularDiseaseDisease

Peripheral VascularPeripheral VascularDiseaseDisease

NormalNormalFattyFatty

StreakStreakFibrousFibrousPlaquePlaque

Occlusive Occlusive AtheroscleroticAtherosclerotic

PlaquePlaque

PlaquePlaqueRupture/Rupture/Fissure &Fissure &

ThrombosisThrombosis

StrokeStroke

Critical Leg Critical Leg IschemiaIschemia

Clinically SilentClinically Silent

Coronary Coronary DeathDeath

Increasing AgeIncreasing Age

Effort AnginaEffort AnginaClaudicationClaudication

UnstableUnstableAnginaAngina

Atherosclerosis: A Progressive ProcessAtherosclerosis: A Progressive Process

Courtesy of P Ganz.

Libby P. Lancet. 1996;348:S4-S7.

– T lymphocyte

– Macrophagefoam cell (tissue factor+)

– “Activated” intimal SMC (HLA-DR+)

– Normal medial SMC

Fibrouscap

IntimaLipidcore

The Anatomy of Atherosclerotic PlaqueThe Anatomy of Atherosclerotic Plaque

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

Angiographically Inapparent AtheromaAngiographically Inapparent Atheroma

The Matrix Skeleton of UnstableThe Matrix Skeleton of UnstableCoronary Artery PlaqueCoronary Artery Plaque

Davies MJ. Circulation. 1996;94:2013-2020.

Fissures inthe fibrous cap

Libby P. Circulation. 1995;91:2844-2850.

Characteristics of Plaques Prone to RuptureCharacteristics of Plaques Prone to Rupture

– T lymphocyte

– Macrophagefoam cell (tissue factor+)

– “Activated” intimal SMC (HLA-DR+)

– Normal medial SMC“Stable” plaque

“Vulnerable” plaque

area ofdetail

MediaFibrous cap

Lipidcore

Libby P. Circulation. 1995;91:2844-2850.

Proposed Mechanisms of Event Proposed Mechanisms of Event Reduction by Lipid-Lowering TherapyReduction 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, Atheroma are not merely filled with lipid, but contain cells whose functions critically but contain cells whose functions critically influence atherogenesis:influence atherogenesis:

Intrinsic Vascular Wall Cells:

Endothelium

Smooth Muscle Cells

Inflammatory Cells:

Macrophages

T Lymphocytes

Mast Cells

Cell Types in the Human AtheromaCell Types in the Human Atheroma

Monocyte/Monocyte/MacrophageMacrophage

T-lymphocytesT-lymphocytesTunicaMedia

Intima

Smooth musclecells

EndotheliumEndothelium

No No symptomssymptoms ++ Symptoms Symptoms

Schematic Time Course of Human Schematic Time Course of Human AtherogenesisAtherogenesis

Time (y)Time (y)

SymptomsSymptoms

Lesion initiationLesion initiation

Ischemic HeartIschemic HeartDiseaseDisease

CerebrovascularCerebrovascularDiseaseDisease

Peripheral VascularPeripheral VascularDiseaseDisease

Macrophage Functions in AtherogenesisMacrophage Functions in Atherogenesis

AttachmentAttachment

Leukocyte–Endothelial Adhesion MoleculesLeukocyte–Endothelial Adhesion Molecules

MonoMonoTT

BB PMNPMN

Vascular Cell Adhesion Molecule 1Vascular Cell Adhesion Molecule 1(VCAM-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 An atherogenic diet rapidly induces

VCAM-1, a cytokine-regulatable VCAM-1, a cytokine-regulatable

mononuclear leukocyte adhesion mononuclear leukocyte adhesion

molecule, in rabbit aortic endotheliummolecule, in rabbit aortic endothelium

Li H et al. Arterioscler Thromb 1993;13:197-204.

VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit Aorta

Li H et al. Arterioscler Thromb 1993;13:197-204.

3 weeks on atherogenic diet

PenetrationPenetration

Monocyte Chemoattractant Protein 1Monocyte Chemoattractant Protein 1(MCP-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 Absence of monocyte chemoattractant

protein-1 reduces atherosclerosis in protein-1 reduces atherosclerosis in

low-density lipoprotein receptor–low-density lipoprotein receptor–

deficient micedeficient mice

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

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

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

LDL-R –/–LDL-R –/–

MCP-1 +/+MCP-1 +/+

LDL-R –/–LDL-R –/–

MCP-1 –/–MCP-1 –/–

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

Time on Diet: 12 – 14 weeks

+/+ -/-

20 – 25 weeks

*P = 0.001 compared to +/+**p = 0.005 compared to +/+

Division

Molecular Mediators of AtherogenesisMolecular Mediators of Atherogenesis

M-CSFMCP-1

VCAM-1

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

Libby P. Circulation 1995;91:2844-2850.

+ + + +

Synthesis Breakdown

Lipid core

IL-1TNF-MCP-1M-CSF

FibrouscapIFN-IFN-

CD-40L

Collagen-degradingCollagen-degradingProteinasesProteinases

Tissue FactorTissue FactorProcoagulantProcoagulant

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

Galis ZS et al. J Clin Invest 1994;94:2493-2503.

Plaque Rupture with ThrombosisPlaque Rupture with Thrombosis

Thrombus Fibrous cap

1 mmLipid core

Illustration courtesy of Frederick J. Schoen, M.D., Ph.D.

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

Weakening of the fibrous cap

Thrombogenicity Thrombogenicity of the lipid coreof the lipid core

Illustration courtesy of Michael J. Davies, M.D.

Pathogenesis of Acute Coronary Syndromes Nathan Wong

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