Atherosclerosis Alfrin

ATHEROSCLEROSIS Mr. ALFRIN ANTONY Asst. LECTURER DEPARTMENT OF PATHOLOGY +919738286092

General Comments  Arteriosclerosis – Thickening and loss of elasticity of arterial walls – Hardening of the arteries – Greatest morbidity and mortality of all human diseases via Narrowing Weakening

Three patterns of arteriosclerosis  Atherosclerosis – The dominant pattern of arteriosclerosis – Primarily affects the elastic (aorta, carotid, iliac) and large to medium sized muscular arteries (coronary, popliteal)

 Monckeberg medial calcific sclerosis  Arteriolosclerosis –small arteries and arterioles (hypertension and DM)

Non-Modifiable Risk Factors  Age – A dominant influence – Atherosclerosis begins in the young, but does not precipitate organ injury until later in life

 Gender – Men more prone than women, but by age 60-70 about equal frequency

 Family History – Familial cluster of risk factors – Genetic differences

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       

AHA Classification of atherosclerosis

Fig.  11.7

Pathogenesis of atherosclerosis

Normal Artery

Atherosclerosis   

A disease of the intima A disease of the intima A disease of the intima

 Atheromas, atheromatous/fibrofatty plaques, fibrous plaques  Narrowing/occlusion; weakness of wall

Major components of plaque  Cells (SMC, macrophages and other WBC)  ECM (collagen, elastin, and PGs)  Lipid = Cholesterol (Intra/extracellular)  (Often calcification)

Two major processes in plaque formation  Intimal thickening (SMC proliferation and ECM synthesis)  Lipid accumulation

Response to injury hypothesis * Injury to the endothelium (dysfunctional endothelium) * Chronic inflammatory response * Migration of SMC from media to intima * Proliferation of SMC in intima • Excess production of ECM • Enhanced lipid accumulation

Response to injury hypothesis (I) 1. Chronic EC injury (subtle?) – EC dysfunction – Increased permeability – Leukocyte adhesion (via VCAM-1) – Thrombotic potential

Response to injury hypothesis (II) 1. 2. 3.

Accumulation of LDL (cholesterol) Oxidation of lesional LDL Adhesion & migration of blood monocytes; transformation into macrophages and foam cells 4. Adhesion of platelets 5. Release of factors from platelets, macrophages and ECs

Response to injury hypothesis (III) 1. 2. 3. 4.

Migration of SMC from media to intima Proliferation of SMC ECM production by SMC Enhanced lipid accumulation Intracellular (SMC and macrophages) Extracellular

Response to Injury

Endothelial Dysfunction

Initiation of Fatty Streak

Fatty Streak

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

Consequences of plaque formation Generalized – Narrowing/Occlusion – Rupture – Emboli – Leading to specific problems:  Myocardial and cerebral infarcts  Aortic aneurysms  Peripheral vascular disease

Is Atherosclerosis Reversible  Primate experiments – High fat diet discontinued; atherosclerotic lesions regress

 Humans – Decrease fat and caloric intake (wars, famine, wasting disease), atheromas decrease. – Angiography after cholesterol lowering, plaque size decreases

 What has to happen for plaques to regress? – LDL lowered – Mac ingest lipids – Reverse cholesterol transport, depends on HDL

Fatty Streak-Coronary Artery

Consequences of Atherosclerosis

Altered Vessel Function  Vessel change – Plaque narrows lumen – Wall weakened – Thrombosis – Breaking loose of plaque – Loss of elasticity

 Consequence – Ischemia, turbulence – Aneurysms, vessel rupture – Narrowing, ischemia, embolization – Athero-embolization – Increase systolic blood pressure

Late Changes  Calcification – An example of dystrophic calcification

 Cracking, ulceration, rupture – Usually occurs at edge of plaque

 Thrombus formation – – –

Caused by endothelial injury,ulceration, turbulence Organization of thrombus More thrombus

 Encroachment – Weakens vessel wall

 Bleeding – Ulceration, cracking and angiogenesis

ATHEROSCLEROSIS: Pathology, Pathogenesis, Complications, Natural History

Fibrous Plaques

Complicated Lesions

Complicated Lesions

Fibrous cap Cholesterol clefts

Elastin membrane destroyed

Neovas. Calcification Inflam. cells

Hemorrhage into Plaque

Common Consequences of Atherosclerosis in Specific Vessels

Aorta  Aneurysm – Pulsatile abdominal mass – Abdominal pain – Bleeding

 Atheroembolization  Narrowing of lumen – Usually not a problem

Aortic Aneurysm

Aortic Aneurysm

Coronary Arteries  Consequences of coronary artery atherosclerosis discussed next lecture

Coronary Artery Atherosclerosis

Coronary Artery Atherosclerosis

Carotids and Cerebral Circulation  Atherosclerosis with thrombosis can lead to brain infarction  Red or white  Coagulative or liquefactive  Can lead to transient ischemic attacks (TIA), if narrowing is aggravated by mural thrombus or vasospasm

Celiac and Mesenteric Arteries  Narrowing primarily at aorta bifurcation  Ischemia uncommon because of collateral circulation  Ischemia can occur if more than 1 artery severely affected - ischemic entercolitis

Renal Artery  Progressive ischemic atrophy of kidney leads to gradual kidney failure (nephrosclerosis)  Renal hypertension due to decreased perfusion

Iliac and Femoral Arteries  Aneurysms  Vessel occlusion by plaque and thrombus – Ischemia of leg muscles, especially during exercise (intermittent claudication) – Ulcers of skin of legs and feet – Gangrene of feet

Atherosclerotic Disease  Prevalence – 6 million Americans with CAD – 3 million Americans have had strokes

 Mortality – 1.5 million deaths/yr in US due to myocardial infarction – 0.5 million deaths/yr in US due to strokes

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-fatty plaque, or atheromatous plaque