atherosclerosis - columbia university · 5 atherosclerosis: response-to-injury model...
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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