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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


Schematic time course of human atherogenesis
Schematic Time Course of Human Atherogenesis

Ischemic HeartDisease

CerebrovascularDisease

Peripheral VascularDisease

Transition from chronic to acute atheroma


Atherosclerosis a progressive process
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
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
Angiographically Inapparent Atheroma

Nissen et al. In: Topol. Interventional CardiologyUpdate. 14;1995.


The matrix skeleton of unstable coronary artery plaque
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
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
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
Cell Types in the Human Atheroma whose functions critically influence atherogenesis:

Monocyte/Macrophage

Endothelium

Intima

TunicaMedia

T-lymphocytes

Smooth musclecells


Schematic time course of human atherogenesis1
Schematic Time Course of Human Atherogenesis whose functions critically influence atherogenesis:

Ischemic HeartDisease

Cerebrovascular

Disease

Peripheral VascularDisease

Lesion initiation

No symptoms

+ Symptoms

Symptoms

Time (y)


Macrophage functions in atherogenesis
Macrophage Functions in Atherogenesis whose functions critically influence atherogenesis:

Attachment


Leukocyte endothelial adhesion molecules
Leukocyte–Endothelial Adhesion Molecules whose functions critically influence atherogenesis:

Mono

T

PMN

B


Vascular cell adhesion molecule 1 vcam 1
Vascular Cell Adhesion Molecule 1 whose functions critically influence atherogenesis:(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
VCAM-1 Expression in Rabbit Aorta cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium

3 weeks on atherogenic diet

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


Macrophage functions in atherogenesis1
Macrophage Functions in Atherogenesis cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium

Penetration


Monocyte chemoattractant protein 1 mcp 1
Monocyte Chemoattractant Protein 1 cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium(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
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 mice1
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 atherogenesis2
Macrophage Functions in Atherogenesis Atherosclerotic Mice

Division


Molecular mediators of atherogenesis
Molecular Mediators of Atherogenesis Atherosclerotic Mice

VCAM-1

MCP-1

M-CSF


Matrix metabolism and integrity of the plaque s fibrous cap
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
Plaque Rupture with Thrombosis Smooth Muscle Cells (SMC) and Macrophages (M

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
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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