atherosclerosis ppt
TRANSCRIPT
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ATHEROSCLEROSIS
WWAMI Medical Program, MSU
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General Comments
Arteriosclerosis Thickening and loss of elasticity of
arterial walls Hardening of the arteries Greatest morbidity and mortality of
all human diseases viaNarrowingWeakening
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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)
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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
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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
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Fig. 11.7
AHA Classification of atherosclerosis
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Pathogenesis of atherosclerosis
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Normal Artery
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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
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Major components of plaque
• Cells (SMC, macrophages and other WBC)
• ECM (collagen, elastin, and PGs)
• Lipid = Cholesterol (Intra/extracellular)
• (Often calcification)
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Two major processes in plaque formation
• Intimal thickening (SMC proliferation and ECM synthesis)
• Lipid accumulation
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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
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Response to injury hypothesis (I)
1. Chronic EC injury (subtle?)– EC dysfunction– Increased permeability– Leukocyte adhesion (via VCAM-1)– Thrombotic potential
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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
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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
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Response to Injury
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Endothelial Dysfunction
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Initiation of Fatty Streak
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Fatty Streak
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Fibro-fatty Atheroma
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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
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Consequences of plaque formation
Generalized
Narrowing/Occlusion Rupture Emboli
Leading to specific problems: Myocardial and cerebral infarcts Aortic aneurysms Peripheral vascular disease
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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
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Fatty Streak-Aorta
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Fatty Streak-Coronary Artery
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Consequences of Atherosclerosis
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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
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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
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ATHEROSCLEROSIS:Pathology, Pathogenesis, Complications, Natural History
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Fibrous Plaques Complicated Lesions
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Complicated Lesions
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Fibrous capCholesterol clefts
Elastin membranedestroyed
Neovas.CalcificationInflam. cells
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Hemorrhage into Plaque
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Ulceration/Hemorrhage/Cholesterol Crystals
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Complicated Lesion/Calcification
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Foam Cells/Cholesterol Crystals
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Cholesterol Crystals/Foam Cells
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Thrombosis/Complicated Lesion
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Complicated Lesion/Ulceration/Thrombosis
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Common Consequences of Atherosclerosis in
Specific Vessels
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Aorta
Aneurysm Pulsatile abdominal
mass Abdominal pain Bleeding
Atheroembolization Narrowing of lumen
Usually not a problem
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Aortic Aneurysm
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Aortic Aneurysm
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Coronary Arteries
Consequences of coronary artery atherosclerosis discussed next lecture
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Coronary Artery Atherosclerosis
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Coronary Artery Atherosclerosis
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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
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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
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Renal Artery
Progressive ischemic atrophy of kidney leads to gradual kidney failure (nephrosclerosis)
Renal hypertension due to decreased perfusion
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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
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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
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Normal Artery
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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