Title: ATHEROSCLEROSIS
1ATHEROSCLEROSIS
MEDS 520, 2007
WWAMI Medical Program, MSU
2General Comments
- Arteriosclerosis
- Thickening and loss of elasticity of arterial
walls - Hardening of the arteries
- Greatest morbidity and mortality of all human
diseases via - Narrowing
- Weakening
3Three 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)
4Non-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
5Modifiable 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
6AHA Classification of atherosclerosis
Fig. 11.7
7Pathogenesis of atherosclerosis
8Normal Artery
9Atherosclerosis
- 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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12Major components of plaque
- Cells (SMC, macrophages and other WBC)
- ECM (collagen, elastin, and PGs)
- Lipid Cholesterol (Intra/extracellular)
- (Often calcification)
13Two major processes in plaque formation
-
- Intimal thickening (SMC proliferation and ECM
synthesis) - Lipid accumulation
14Response 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
15Response to injury hypothesis (I)
- 1. Chronic EC injury (subtle?)
- EC dysfunction
- Increased permeability
- Leukocyte adhesion (via VCAM-1)
- Thrombotic potential
16Response to injury hypothesis (II)
- Accumulation of LDL (cholesterol)
- Oxidation of lesional LDL
- Adhesion migration of blood monocytes
transformation into macrophages and foam cells - Adhesion of platelets
- Release of factors from platelets, macrophages
and ECs
17Response to injury hypothesis (III)
- Migration of SMC from media to intima
- Proliferation of SMC
- ECM production by SMC
- Enhanced lipid accumulation
- Intracellular (SMC and macrophages)
- Extracellular
18Response to Injury
19Endothelial Dysfunction
20Initiation of Fatty Streak
21Fatty Streak
22Fibro-fatty Atheroma
23Summary 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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25Consequences of plaque formation
- Generalized
- Narrowing/Occlusion
- Rupture
- Emboli
- Leading to specific problems
- Myocardial and cerebral infarcts
- Aortic aneurysms
- Peripheral vascular disease
26Is 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
27Fatty Streak-Aorta
28Fatty Streak-Coronary Artery
29Consequences of Atherosclerosis
30Altered 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
31Late 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
32 ATHEROSCLEROSIS Pathology, Pathogenesis,
Complications, Natural History
33Complicated Lesions
Fibrous Plaques
34Complicated Lesions
35Neovas. Calcification Inflam. cells
Fibrous cap Cholesterol clefts
Elastin membrane destroyed
36Hemorrhage into Plaque
37Ulceration/Hemorrhage/Cholesterol Crystals
38Complicated Lesion/Calcification
39Foam Cells/Cholesterol Crystals
40Cholesterol Crystals/Foam Cells
41Thrombosis/Complicated Lesion
42Complicated Lesion/Ulceration/Thrombosis
43Common Consequences of Atherosclerosis in
Specific Vessels
44Aorta
- Aneurysm
- Pulsatile abdominal mass
- Abdominal pain
- Bleeding
- Atheroembolization
- Narrowing of lumen
- Usually not a problem
45Aortic Aneurysm
46Aortic Aneurysm
47Coronary Arteries
- Consequences of coronary artery atherosclerosis
discussed next lecture
48Coronary Artery Atherosclerosis
49Coronary Artery Atherosclerosis
50Carotids 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
51Celiac 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
52Renal Artery
- Progressive ischemic atrophy of kidney leads to
gradual kidney failure (nephrosclerosis) - Renal hypertension due to decreased perfusion
53Iliac 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
54Atherosclerotic 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
55Normal Artery
56Pathogenesis 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