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AtherosclerosisAtherosclerosisAtherosclerotic Cardiovascular Disease

(ASCVD)

Endothelialinjury

Lipids(cholesterol)

Smooth m.proliferation

Pathogenesis ofatherosclerosis

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Normal Artery Structure

Lipoprotein particle

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Robert Hamilton, Ph.D.Cardiovascular Research Inst., UCSFEM: Negative staining

x 180,000x 180,000X 60,000X 60,000

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©MedscapeThe cholesterol in LDL accounts forapprox. 70% of the plasma cholesterol

Arteriosclerosis(Hardening of the arteries)

Arterial wall thickening + loss of elasticityMonckeberg medialcalcific sclerosis

Age 50Radiologic calcif.Lumen intactClinically insignif.

Arteriolosclerosis

-small arteries/arterioles-hyaline type / hyperplastic-hypertension / diabetes

hyaline

hyper-plastic

Atherosclerosis

-aorta & branches +coronary arteries

-ASCVD causes 38% of all deaths in N. America

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ATHEROSCLEROSIS: response-to-injury model

Atherosclerosis is a chronic inflammatory response of thearterial wall to endothelial injury.

1. Chronic endothelial injury

2. Accumulation of lipoproteins (LDL mainly)

3. Monocyte adhesion to endothelium

4. Platelet adhesion5. Factors released SMC recruitment

6. SMC proliferation and ECM production7. Lipid accumulation: extracellular/mac-SMC

basictenets

Risk Factors for Atherosclerosis

•Hyperlipidemia

•Smoking

•Hypertension

•Turbulence

•Genetics

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Endothelial injury

Chronic—repetitive injuryEarlynon-denudingendothelialdysfunction

-cig. smoke toxins-homocysteine-?? Infectious agents-cytokines genes for

Endothelial injury

Chronic—repetitive injuryEarlynon-denudingendothelialdysfunction

-cig. smoke toxins-homocysteine-?? Infectious agents

1. Hemodynamicdisturbances

(turbulence)2. Hypercholesterolemia3. Inflammation

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Endothelial injury

Chronic—repetitive injuryEarlynon-denudingendothelialdysfunction

-cig. smoke toxins-homocysteine-?? Infectious agents

1. Hemodynamicdisturbances

(turbulence)2. Hypercholesterolemia3. Inflammation

IEM

Smooth muscle proliferation:- proliferative & synthetic phenotype

in intimal SMC’s (vs. SMC in media)- growth factors: PDGF, FGF, TGFα

Pathogenic sequence ofatherosclerotic lesions

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Normal aorta

Fatty streak

Atheromatous plaque(fibrofatty plaque)

Complicated plaque

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Fatty Streaks

Atheromatous plaque (fibrofatty atheroma; plaque; atheroma)

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Complicated plaque: ulcerated/thrombus

Aneurysm

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Thrombus in aneurysm

Ao

1 abd. aorta

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3popliteal a’s

4 internal carotid a’s

5circle ofWillis vessels

ATHEROSCLEROSIS: Vessel involvement: desc. order

Cor. A’s

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Development of the smooth muscle cap

Atherosclerostic Plaque Structure

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ECECECMM

IELIELAA

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Natural history of atherosclerosisRobbins 8/e

Atherosclerosis (AS): Summary

1. AS is an intima-based lesion with a fibrouscap and atheromatous (gruel-like) core

2. Constituents: SMC’s, ECM, inflamm., lipid,necrotic debris

3. Endothelial injury + inflammation drive AS:risk factors influence EC dysfunction,SMC recruitment and activation

4. AS plaque complications: rupture—thrombosis—hemorrhage—embolization

5. Rx: risk factor recognition + reduction