ATHEROSCLERO SIS

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Atherosclerosis

Chronic, progressive, multifocal disease of the vessel wall intima within large elastic arteries and large/medium sized muscular arteries
The term atherosclerosis is derived from athero (meaning porridge) referring to the soft lipid-rich material in the centre of atheroma, and sclerosis (scarring) referring to connective tissue in the plaques.

ATHEROSCLEROTIC PLAQUE

NORMAL ARTERY

ATHEROSCLEROTIC PLAQUE
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Non-Modifiable Risk Factors

Age

A dominant influence Atherosclerosis begins in the young, but does not precipitate organ injury until later in life Men more prone than women, but by age 60-70 about equal frequency Familial cluster of risk factors Genetic differences

Gender

Family History

Modifiable Risk Factors (potentially controllable)

Hyperlipidemia Hypertension Cigarette smoking Diabetes Mellitus Elevated Homocysteine Factors that affect hemostasis and thrombosis Infections: Herpes virus; Chlamydia pneumoniae Obesity, sedentary lifestyle, stress

Atheroma
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Hyperlipidaemia
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high plasma cholesterol associated with atheroma LDL most significant HDL protective

Atheroma - Lipid Metabolism

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Lipid in the blood is carried on lipoproteins Lipoproteins carry cholesterol and triglycerides (TG) Hydrophobic lipid core Hydrophilic outer layer of phospholipid and apolipoprotein (A-E)

Atheroma - Lipid Metabolism

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Chylomicrons
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LDL
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transport lipid from intestine to liver

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rich in cholesterol carry cholesterol to non-liver cells carry cholesterol from periphery back to liver

VLDL
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HDL
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carry cholesterol and TG from liver TG removed leaving LDL

Familial Hyperlipidaemia
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Genetically determined abnormalities of lipoproteins Lead to early development of atheroma Associated physical signs
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arcus tendon xanthomas xanthelasma

Xanthelasma

Atheroma - Cigarette Smoking

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Powerful risk factor for IHD Risk falls after giving up Mode of action uncertain
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coagulation system reduced PGI2 increased platelet aggregation

Atheroma - Hypertension
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Strong link between IHD and high systolic/diastolic blood pressure Mechanism uncertain ? endothelial damage caused by raised pressure

Atheroma - Diabetes Mellitus

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DM doubles IHD risk Protective effect in premenopausal women lost DM also associated with high risk of cerebrovascular and peripheral vascular disease ?related to hyperlipidaemia and hypertension

Atheroma-Infection
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Chlamydia pneumoniae Helicobacter pylori Cytomegalovirus

Postulated that infection ,may cause atherosclerosis Sero epidemiological studies implicate role of certain bacteria, notably chlamydia trachomatis & viruses like CMV Another theory says that infections may potentiate the action of traditional risk factors Acute infection might also produce hemodynamic alterations that could trigger coronary events

INFECTION & ATHEROSCLEROSIS

Atheroma - Genetic Predisposition

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Familial predisposition well known Possibly due to

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variations in apolipoprotein metabolism variations in apolipoprotein receptors

AHA Classification of atherosclerosis

Fig. 11.7

STRUCTURE OF NORMAL ARTERY

NORMAL ARTERY

Endothelial cells Imp in vascular hemostasis Maintain blood in liquid state during protrated contact Heparin sulphate,Thrombomodulin Potent fibrinolytic agents:- tissue & urokinase type plasminogen activators

Arterial Smooth Muscle cells

Contract & relax and thus control blood flow In large arteries involved in atherosclerosis, abnormal SMC contraction can cause vasospasm SMC secrete complex arterial ECM -> role in vascular hemostasis

TUNICA INTIMA

Normal artery has a well developed trilayer stucture in adults Intima has complex structure: Endothelial monolayer resides on a basement membrane containing non fibrillar collagen types as type IV,laminin,fibronectin & ECM molecules With ageing intima developes SMCs & fibrillar forms of interstitial collagen

TUNICA MEDIA

In large arteries:well developed concentric layers of SMC interleaved with ECM -> this structure is well adapted to the storage of kinetic energy of LV systole Lamellar structure contributes to integrity of arterial trunks

In smaller muscular arteries:SMC embedded in surrouning matrix in a more continous than lamellar array. SMCs in normal arteries seldom proliferate

Tunica Adventitia

Contains collagen fibrils in a looser array than in intima Vasa vasorum & nerve endings localize in this layer Cells include fibroblasts & mast cells

ATHEROSCLEROSIS PATHOGENESIS

Atheroma - Pathogenesis
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Thrombogenic theory Insudation theory Reaction to injury hypothesis

Atheroma - Thrombogenic Theory

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1852 Karl Rokitansky

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plaques formed by repeated thrombi lipid derived from thrombi overlying fibrous cap

Atheroma - Insudation Theory

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1856 Rudolf Virchow

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endothelial injury inflammation increased permeability to lipid from plasma

Pathogenesis of Atherosclerosis Cause? Current hypothesis: Response to Injury Initiated by endothelial dysfunction Disease of the intima Intimal thickening Intra-and extra-cellular lipid accumulation Chronic Inflammation Basic Lesion: is termed atheroma, fibro-

Response to Injury

Endothelial Injury

Chronic or repetitive endothelial injury is the cornerstone of the response-to-injury hypothesis. Endothelial loss due to any kind of injury results in intimal thickening; In the presence of high-lipid diets, typical atheromas ensue.

Etiologic culprits include toxins from cigarette smoke, homocysteine, Inflammatory cytokines The two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia.

Chronic hyperlipidemia, particularly hypercholesterolemia, can impair EC function by reactive oxygen species. oxygen free radicals accelerate NO decay, damping its vasodilator activity With chronic hyperlipidemia, lipoproteins accumulate in the intima.

Endothelial Dysfunction

Initiation of fatty streak

Oxidized LDL is ingested by macrophages through a scavenger receptor resulting in foam-cell formation. Oxidized LDL stimulates release of growth factors, cytokines by macrophages that increase monocyte recruitment .

Initiation of Fatty Streak

Fatty Streak

Foam Cells/Cholesterol Crystals

Leukocyte Recruitment

Monocytes transform into macrophages and engulf lipoproteins Monocyte recruitment and differentiation into macrophages is protective, since these cells remove potentially harmful lipid particles. Over time, however, progressive accumulation of oxidized LDL drives lesion progression. Thus, macrophage activation results in

Activated macrophages also produce reactive oxygen species, aggravating LDL oxidation. T lymphocytes recruited to the intima interact with macrophages and can generate a chronic immune inflammatory state. As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth

Fibro-fatty Atheroma

Smooth Muscle Proliferation

Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions. Several growth factors are implicated .

The recruited SMCs synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques. However, activated inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism, resulting in unstable plaques.

Fibro-fatty Atheroma

Summary of Atherosclerotic Process

Multifactorial process (risk factors) Initiated by endothelial dysfunction Up regulation of endothelial and leukocyte adhesion molecules Macrophage diapedesis LDL transcytosis LDL oxidation Foam cells Recruitment and proliferation of smooth muscle cells (synthesis of connective tissue proteins) Formation and organization of arterial thrombi

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ANGIOGENESIS IN PLAQUE Endothelial migration & replication also occur as plaques develop a microcirculation, characterised by plexi of newly formed vessels Angiogenic factors = FGF,VEGF,PIGF and oncostatin Functional significance=> Relatively large surface area of leukocyte trafficking Allows growth of plaque Plaque micravessels are friable & prone to rupture

PLAQUE MINERALISATION

Develop areas of calcification as they develop Factors promoting calcification includecytokines as bone morphogenic protein,homologues of TGF beta and gamma carboxylic acid residues specialised in sequestering calcium and thus promoting mineralisation

Calcification

THE FOCALITY OF LESION FORMATION Spatial heterogenity of atherosclerosis Proposed hypothesis:Multicentric origin hypothesis Hydrodynamic basis, since sites of predeliction are proximal portion of arteries after branch points or bifurcations at flow dividers. Locally disturbed flow could induce alterations that promote the steps of early atherogenesis

Atheroma - Common Sites

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Aorta - especially abdominal Coronary arteries Carotid arteries Cerebral arteries Leg arteries

THE EVOLUTION OF ATHEROMA

SMC DEATH DURING ATHEROGENESIS In addition to SMC replication,death of these cells may also participate in complication of atherosclerosis Apoptosis may occur in response to inflammatory cytokines present in evolving atheroma T-cells that express Fas ligand, engage fas on surface of SMC & in conjunction with soluble cytokines lead to death of the SMC

ARTERIAL Extra cellular matrix ECM makes up much of volume of an advanced atherosclerotic plaque Major ECM molecules include: Interstitial collagens(type 1 & 3) Proteoglycans as versican,biglycan,aggregan & decorin ECM is secreted by SMCs and hence its secretion also depends upon balance(biosynthesis vs breakdown by matrix metalloproteinases)

During first part of life history of plaque growth is outward,in an albuminal direction. This increase in lumen of artery, so called positive remodelling or compensatory enlargement must involve turnover of ECM molecules to accommodate the circumferential growth of the artery Luminal stenosis occur only after >40% of cross sectional area of artery

COMPLICATION OF ATHEROSCLEROSIS

ARTERIAL STENOSIS AND THEIR CLINICAL IMPLICATION The phases of atherosclerotic process generally last many years, during which the affected individual is unaffected Growth occurs discontinuously with periods of relative quiescence punctuated by episodes of rapid progression After the plaque burden exceeds the capacity of artery to remodel outside, encroachment on arterial lumen begins Stenosis of >60% causes chronic stable angina or intermittent claudication on

Stable angina. Eccentric coronary stenosis

In many cases of Myocardial Infarction is not preceded by H/O stable angina This implies that many MI occur by lesions that do not limit blood flow. It is now recognized that thrombosis, complicating a not necessarily occlusive plaque, most often causes episodes of Unstable angina & acute MI Thus the culprit lesion may be sizeable, but may not produce a critical lumen narrowing because of phenomenon of compensatory enlargement

Unstable angina with plaque disruption

The plaque cap is torn, projects into the lumen, exposing a mass of thrombus filling the lipid core

Thrombosis/Complicated Lesion

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THROMBOSIS & ATHEROMA COMPLICATION A physical disruption of atherosclerotic plaque commonly cause acute thrombosis Modes:Fracture of fibrous cap of plaque=> accounts for ~2/3rd of acuteMI Superficial erosion of intima=> 1/4th of MI in selected referral cases from medical examiners on individuals who have succumbed to sudden cardiac death

PLAQUE RUPTURE & THROMBOSIS

Rupture of fibrous cap reflects an imbalance between forces that impinge on plaques cap & the mechanical strength of the fibrous cap, provided by interstitial forms of collagen Metabolism of collagen participates in regulating the propensity of a plaque rupture

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Factors affecting strength of fibrous cap are: T cell derived cytokine interferon gamma increase collagen synthesis TGF beta & PDGF released from platelet granules increase collagen synthesis Increased catabolism of ECM macromolecules that comprise fibrous cap weaken it. Macrophages in advanced human atheroma overexpress matrix metalloproteinases & elastolytic cathepsins that breakdown the collagen & elastin of

Vulnerable vs Stable Atherosclerotic Plaques

Vulnerable Plaque Lumen
Fibrous Cap
Lipid Core

Thin fibrous cap Inflammatory cell infiltrates: proteolytic activity Lipid-rich plaque

Stable Plaque Lumen

Lipid Core

Fibrous Cap

Thick fibrous cap Smooth muscle cells: more extracellular matrix Lipid-poor plaque

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Relative lack of SMCs, due to programmed cell death of SMCs provoked by inflammatory mediators, make the plaque vulnerable A prominent accumulation of macrophages and a large lipid pool concentrates biomechanical forces on the shoulder regions of plaques which are common sites of plaque rupture, hence the success of lipid lowering agents

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THROMBOSIS CAUSED BY SUPERFICIAL EROSION OF PLAQUES

Pathophysiology is less well understood In humans these are more likely to cause fatal acute MI in women & individuals with hypertriglyceridemia and Diabetes Mellitus Apoptosis of endothelial cells could contribute to desquamation of endothelial cells in areas of superficial erosions

Complicated Lesion/Ulceration/Thrombosis

DIFFUSE & SYSTEMIC NATURE OF PLAQUE VULNERABILITY & INFLAMMATION IN ATHEROGENESIS

Studies at autopsy of plaques that cause fatal thrombosis, brought the notion of vulnerable high risk plaque to fore. Evidence suggest that more than one high risk plaque often resides in a given coronary artery Inflammation thought to characterize the vulnerable plaque is widespread

Analysis of angiograms reveal in individuals with acute coronary syndromes has demonstrated evidence of plaque ulceration or thrombosis in more than one lesion Systemic markers of inflammation as CRP increase in pts with acute coronary syndrome This recognition has important therapeutic implications

RESTENOSIS AFTER ARTERIAL INTERVENTION After balloon angioplasty luminal narrowing recurs in approx. 1/3rd pts within 6 months Pathophysio of restenosis:After balloon angioplasty there is loss of lumen caliber from constriction of the vessel from adventitial side, the so called Negative Remodeling This renewed interest in adventitial inflammation with scar formation & wound contraction as a mechanism of arterial

Widespread use of stents has changed face of restenosis problem, since they are very effectively increase luminal diameter Currently stents that elaborate antiproliferative & antiinflammatory substances have shown great benefit in terms of preventing in-stent stenosis, albeit with a potential for augmenting late stent thrombosis

ACCELERATED ARTERIOSCLEROSIS FOLLOWING TRANSPLANTATION

Is the major limitation to long term survival of cardiac allograft since advent of immunosuppressive therapy Patient may not experience typical anginal symptoms coz of interruption of cardiac denervation post transplantation Observations suggest that immunological differences between host & recepient vessels might contribute

Endothelial cells in transplanted coronary artery express histocompatibility antigens activate T- cell in host cells which then secrete CYTOKINES(IFN-GAMMA)

Augment histocompatibility antigen genes, recruit leukocytes & activate macrophages to

Late post cardiac transplantation.

Garvin M R et al. Cardiovasc Res 1997;35:241-249

Copyright 1997, European Society of Cardiology

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ANEURYSMAL DISEASE In particular, affects infrarenal abdominal aorta Theory implicated behind this are : Because of absence of vasa vasorum, there is relative lack of blood supply to the tunica media in this portion Lumbar lordosis of the biped human may alter the hydrodynamics of blood flow in distal aorta

Transmural destructionof the arterial architecture occurs in aneurysmal disease Widespread destruction of the elastic laminae suggests a role of degradation of elastin,collagen & other constituents of arterial ECM Other factors postulated to have a role in: MMP,Angiotensin 2,TGF beta,hightened elastolysis, apoptposis of SMC \, soluble cytokines stc

Atheroma - Prevention
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No smoking Reduce fat intake Treat hypertension Not too much alcohol Regular exercise/weight control BUT some people will still develop atheroma!

Atheroma - Intervention
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Stop smoking Modify diet Treat hypertension Treat diabetes Lipid lowering drugs

Thank you