טרשת עורקים-מצגת מספר 2

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Pathogenesis of AtherosclerosisH.Cohen 04-2009 2

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Harrison's Principles of Internal Medicine 16th Edition / Harrison's OnlineChapter 224. The Pathogenesis of Atherosclerosis

Basic & Clinical Endocrinology Francis S. Greenspan, David G. Gardner 7th edition 2004 chapter 19

Immune and Inflammatory Mechanisms of Atherosclerosis. Annu. Rev. Immunol. 2009. 27:16597

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Atherosclerosis-definition

Atherosclerotic plaqueH.Cohen 04-2009 4

AtherosclerosisDyslipidemia Diabetes HTN Smoking FHx

Risk Factors

clinical manifestationsCoronary Heart Disease

BiologyInflammation Coagulation Endothelial function T cell Macrophages

Cerebro Vascular Disease PVD

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Major Vascular Manifestations of AtherothrombosisIschemic stroke Carotid vertebral

coronary Myocardial infarction Angina pectoris mesenteric ischemia

renal artery stenosis splanchnic circulation

Femoral iliac

Peripheral arterial disease: Gangrene Necrosis

H.Cohen 04-2009Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 16

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Atherothrombosis is the Leading Cause of Death WorldwideAtherothrombosis*Cancer Infectious Disease Pulmonary disease Violent death AIDS 05% 14% 12% 19% 24% 52%

Mortality (%) 10 20 30 40 50 60

Cardiovascular disease is a leading cause of global mortality, accounting for almost 17 million deaths annually or 30% of all global mortality . 2007Cardiovascular disease, ischemic heart disease and cerebrovascular disease

World Health Organization. The World Health Report 2001. Geneva: WHO; 2001.

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??? Atherothrombosis and Cause of Death in Israel" -8991 4002

-000,001 041 311 63 34 63 249002-40 H.Cohen

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911

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smooth muscle

Slide 20. The arterial wall consists of three functionally separate layers: 1) the intima (composed of a single monolayer of endothelial cells, in contact with circulating blood), 2) the media (composed mainly of smooth muscle cells, embedded in extracellular matrix), and 3) the 9 adventitia (harbours nutrient vessels, nerves and dense fibroelastic H.Cohen 04-2009 tissue). Reproduced with permission from Ross R, Glomset JA. The pathogenesis of atherosclerosis (part 1). N Engl J Med 1976; 295:369-377. 1976 Massachusetts Medical Society. All rights reserved.

Cross section of an artery

sub-intimal space

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Atherosclerosis TimelineFoam Cells Fatty Streak Intermediate Atheroma Lesion Fibrous Complicated Plaque Lesion/Rupture

Endothelial DysfunctionFrom first decade From third decade From fourth decadeSmooth muscle and collagen

Growth mainly by inflammation and lipid accumulation H.Cohen 04-2009Adapted from Stary HC et al. Circulation. 1995;92:1355-1374.

Thrombosis,11

inflammation

Atherogenesis in autopsy of young and healthy individuals

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Cross section of an coronary atherosclerotic artery

Initiation of AtherosclerosisH.Cohen 04-2009 14

Localization of atherosclerosis

hemodynamic forces may influence cellular events provide an explanation for the localization of atherosclerotic lesions

at sites of disturbance to laminar shear stress.

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Fatty streak initial lesion of atherosclerosis arise from increases in the content of lipoproteins inside the intima

Fatty streaksInflammation

Endothelial cells

Foam cells

Adventitia

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Endothelial cells Inflammation

Foam cells

Adventitia

Fatty streaks

- ) (LPextracellular matrix

1

-

- )(ox LP ox 9002-40 H.Cohen 81

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Endothelial cells Inflammation

Foam cells

Adventitia

Fatty streaks LEUKOCYTE RECRUITMENT

ADHESION PENETRATION Chemoattractant- cytokines : monocyte chemoattractant protein 1

3

4

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Intercellular adhesion molecule-1 (ICAM-1) vascular cell adhesion molecule1(VCAM-1

chemoattractant factorsmonocyte chemotactic protein : produced by vascular wall cells in response to modified lipoproteins

ADHESION PENETRATION

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Endothelial cells Inflammation

Foam cells

Adventitia

Accumulation of leukocytes characterizes the formation of early atherosclerotic lesions

macrophage

ACCUMULATION

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NON REGULATED

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6

7

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) tumor necrosis factor (TNF- ) interleukin-1 (IL-1

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(1)

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The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56

(2) .

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The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56

(3)

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The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56

(4)

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The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56

(5)

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The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56

(6)

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The Postprandial State and Risk of Cardiovascular Disease. Diabetic Medicine. 1997;14: s50-s56

Foam Cellsmononuclear phagocytes ingest lipids and become foam cells, represented by a cytoplasm filled with lipid droplets

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FATTY STREAK

Not all fatty streaks progress to form complex atheromata Some lipid-laden macrophages leave the artery wall, exporting lipid in the process. Reverse cholesterol transport mediated by high-density lipoproteins (HDL),H.Cohen 04-2009

provides an30

independent pathway for lipid removal from atheroma

Stable atherosclerotic plaque Fibrous plaque evolves from the fatty streak accumulation of connective tissue increased number of smooth muscle cells deeper extracellular lipid pool.

Characteristics of the stable atherosclerotic plaqueEndothelial cellsInflammationLipid core

Fibrous cap(VSMCs and matrix)

Intimal VSMCs

Cytokines induce local production of growth factors

growth factors and cytokines produced locally -stimulate the proliferation of smooth-muscle cells in the intima +media and stimulates interstitial collagen production by smooth-muscle cells

Adventitia

Vascular Smooth Muscle Cells

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Medial VSMCs

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A stable atherosclerotic plaque is at low risk of ruptureH.Cohen 04-2009 33

Features of stable plaquesI. II.

thick fibrous cap of uniform density confers mechanical stability. high VSMC and collagen content in the lipid-rich core that occupies less than 40% fibrous cap. of the total volume of the plaque

III. IV.

low infiltration of inflammatory cells (macrophages and T-lymphocytes)

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The stable atherosclerotic plaquevascular remodellingNo reduction in the dimensions of the lumen

Thick, VSMC-rich fibrous cap

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Vulnerable atherosclerotic plaquePlaques that are considered vulnerable are at high risk of rupture

PLAQUE EVOLUTION during the evolution of the atherosclerotic plaque there is a complex balance between : entry and way out of lipoproteins and leukocytes cell proliferation and cell death extracellular matrix production and remodelingH.Cohen 04-2009 37

The vulnerable atherosclerotic plaque Fibrous cap

InflammationT cellderived cytokine IFN-inhibit collagen synthesis of vsmc proteolytic enzymesdegrade the extracellular matrix.

Intimal VSMCs

Lipid core

Adventitia inflammatory mediators processes that weaken the plaque's fibrous cap + enhance its vulnerability to ruptureH.Cohen 04-2009 38

Characteristics of vulnerable Plaques1.

lipid core that exceeds 40% of the total volume of the plaque high infiltration of macrophage and cells. T-lymphocyte

2.

3.

thin, friable fibrous cap with a reduced collagen and VSMC content. increased circumferential wall stress on the fibrous cap.

4.

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Characteristics of Vulnerable and Stable PlaquesFibrous cap MediaLumenArea of detail

Lipid core

Vulnerable PlaqueLumen Lipid core

T lymphocyte Macrophage foam cell (tissue factor+) Activated intimal SMC

Stable Plaque

Normal medial SMCH.Cohen 04-2009

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Libby. Circulation. 1995;91:28442850.

Unstable Plaque

Thin Fibrous Cap Lipid Core

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The relation between atherosclerosis and acute cardiac events

Vulnerable plaques are believed to account for only 1020% of all coronary lesions. Responsible for the majority of acute clinical events !H.Cohen 04-2009 42

Plaque Rupture

Disruption or erosion of an atherosclerotic plaque:Allows circulating blood to contact the lesion and its

highly thrombogenic, lipid-rich core.Adhesion and aggregation of platelets at the site of

rupture.Formation of a partially occlusive, platelet-rich

thrombus.

H.Coh