1

AtherosclerosisAtherosclerosis

Ath l ti C di l DiAtherosclerotic Cardiovascular Disease(ASCVD)

Endothelialinjury

Lipids(cholesterol)

Smooth m.proliferation

Pathogenesis ofPathogenesis ofatherosclerosis

Normal Artery Structure

Lipoprotein particle

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

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

2

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

Arteriosclerosis(Hardening of the arteries)

Arterial wall thickening + loss of elasticityMőnckeberg medialcalcific sclerosis Arteriolosclerosis Atherosclerosis

Age 50Radiologic calcif.Lumen intactClinically insignif.

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

hyaline

hyper-plastic

-aorta & branches +coronary arteries

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

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

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

3

Endothelial injury

Chronic—repetitive injuryEarlynon-denudingendothelialdysfunction

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

1. Hemodynamicdisturbances

(turbulence)2. Hypercholesterolemia3. Inflammation

Lipoprotein particleLDL 1600molecules170

molecules1 moleculeApoB-100

700 molecules

LDL

Oxidation of LDL-lipoxygenases-myeloperoxidase-ROS

Role of oxidized LDL & CD36 in foam cell formation

internal elastic membrane

oxLDL CD36

mac Foam cell(foamy macrophage)

CD 36 signalling

scavengerreceptor for LDL

CD36 also mediatesactin polymerization & firm adhesions-

immobility of foam cells in the plaque

Endothelial injury

Chronic—repetitive injuryEarlynon-denudingendothelialdysfunction

IEM

-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

Normal aorta

Fatty streak

Ath t lAtheromatous plaque(fibrofatty plaque)

Complicated plaque

4

Fatty Streaks

Atheromatous plaque (fibrofatty atheroma; plaque; atheroma)

Complicated plaque: ulcerated/thrombus

Aneurysm

Thrombus in aneurysm

5

Ao

2

4 internal carotid a’s

5circle ofWillis vessels

ATHEROSCLEROSIS: Vessel involvement: desc. order

1 abd. aorta

2

3popliteal a’s

Cor. A’s

Development of the smooth muscle cap

Atherosclerostic Plaque Structure

ECECECECMM

IELIELAA

6

7

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: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

8