ATHEROSCLEROSIS

WWAMI Medical Program, MSU

General Comments

Arteriosclerosis Thickening and loss of elasticity of

arterial walls Hardening of the arteries Greatest morbidity and mortality of

all human diseases viaNarrowingWeakening

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

Fig. 11.7

                                                                         

                                               

AHA Classification of atherosclerosis

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 imflammatory 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)

2. Accumulation of LDL (cholesterol)3. Oxidation of lesional LDL4. Adhesion & migration of blood

monocytes; transformation into macrophages and foam cells

5. Adhesion of platelets6. Release of factors from platelets,

macrophages and ECs

Response to injury hypothesis (III)

7. Migration of SMC from media to intima

8. Proliferation of SMC

9. ECM production by SMC

10. Enhanced lipid accumulationIntracellular (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-Aorta

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 capCholesterol clefts

Elastin membranedestroyed

Neovas.CalcificationInflam. cells

Hemorrhage into Plaque

Ulceration/Hemorrhage/Cholesterol Crystals

Complicated Lesion/Calcification

Foam Cells/Cholesterol Crystals

Cholesterol Crystals/Foam Cells

Thrombosis/Complicated Lesion

Complicated Lesion/Ulceration/Thrombosis

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

Normal Artery

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