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Pathogenesis of Acute Coronary Syndromes Nathan Wong. Schematic Time Course of Human Atherogenesis. Ischemic Heart Disease. Cerebrovascular Disease. Peripheral Vascular Disease. Transition from chronic to acute atheroma. Atherosclerosis: A Progressive Process.

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Pathogenesis of Acute Coronary Syndromes Nathan Wong

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Pathogenesis of Acute

Coronary Syndromes

Nathan Wong


Schematic Time Course of Human Atherogenesis

Ischemic HeartDisease

CerebrovascularDisease

Peripheral VascularDisease

Transition from chronic to acute atheroma


Atherosclerosis: A Progressive Process

PlaqueRupture/Fissure &Thrombosis

Occlusive

AtheroscleroticPlaque

FattyStreak

FibrousPlaque

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

Lipidcore

Fibrouscap

Lumen

Media

–T lymphocyte

– Macrophagefoam 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 CardiologyUpdate. 14;1995.


The Matrix Skeleton of UnstableCoronary 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 ofdetail

“Vulnerable” plaque

–T lymphocyte

Lumen

– Macrophagefoam 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

Endothelium

Intima

TunicaMedia

T-lymphocytes

Smooth musclecells


Schematic Time Course of Human Atherogenesis

Ischemic HeartDisease

Cerebrovascular

Disease

Peripheral VascularDisease

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

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

Division


Molecular Mediators of Atherogenesis

VCAM-1

MCP-1

M-CSF


Matrix Metabolism and Integrity of the Plaque’s Fibrous Cap

Synthesis

Breakdown

Fibrouscap

Collagen-degrading

Proteinases

IFN-

CD-40L

+

+

IL-1TNF-MCP-1M-CSF

+

+

+

+

Tissue Factor

Procoagulant

Lipid core

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.


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