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2.9. Atherosclerosis.ppt
1. Introduction
• Atherosclerosis is the gradual clogging of the arteries by fatty, fibrous deposits.
• A tiny lump of fibrous tissue grows as the artery tries to repair the damage.
Cholesterol accumulates and more tissue builds up.
• The arteries are thickened and hardened making a loss of elasticity causing
congestion. Atherosclerosis has one of the longest incubation periods.
• Starts about 2nd decade and manifests clinical usually around 5th and 6th , even later.
• Very slow course and has discontinuous development.
• Commonly presents suddenly with sudden death, AMI and stroke.
• Arteriosclerosis
– Thickening and loss of elasticity of arterial walls
– Hardening of the arteries followed by:
Narrowing
Weakening
– Greatest morbidity and mortality of all human diseases.
2. Atherosclerotic Disease
prevalence
• 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
3. 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
6. Normal arteries
• Three layered structure consisting of the intima, media and
adventitia.
• The intima is the inner most layer lined with
mono-layer of endothelial cells.
• Major functions of endothelial cells
1. Maintaining vascular tone
2. Prevents leukocyte & platelet adhesion to
the endothelium
3. Provides barrier to LDL cholesterol entry in to the
vascular wall.
10. Atheroma
• Usually affects arteries only some distance from branching
points focally.
• Causes narrowing in some arteries and ectasia in others.
• Even a single lesion may undergo narrowing and dilatation
in the course of its development.
11. Consequences of plaque
formation
Generalized
– Narrowing/Occlusion
– Rupture
– Emboli
– Leading to specific problems:
• Myocardial and cerebral infarcts
• Aortic aneurysms
• Peripheral vascular disease
12. Major components of plaque
• Cells (SMC, macrophages and other WBC)
• ECM (collagen, elastin, and PGs)
• Lipid = Cholesterol (Intra/extracellular)
• (Often calcification)
13. Response to injury hypothesis
Injury to the endothelium
(dysfunctional endothelium)
Chronic inflammatory response
Migration of SMC from media to intima
Proliferation of SMC in intima
Excess production of ECM
Enhanced lipid accumulation
14. Endothelial cell Monocyte Macrophage Foam cell Smooth muscle cell
Internal elastic
lamina
Vessel lumen
1. Endothelial
permeability
4. SMC
migration
2. Monocyte
adhesion and
transmigration
Increased stiffness
3. Macrophage
transformation
into foam cells
The major cellular events in the
progression of atherosclerosis
16. Disruption of the plaque may be caused by
1. Hemodynamic stress
2. Erosion of the endothelial surface
3. Rupture of the cap and spilling of its content
17. Promotion of coagulation & thrombosis
• Interaction of blood components and sub-endothelial
tissue, tissue factor, and von willebrand factor
• Platelet activation and aggregation after exposure to the
thrombin and the above factors
• Contribution by inflammatory process involving
inflammatory factors
18. Consequences
When this occurs in different organs it has different
clinical manifestation and different names
• Angina
• AMI
• Sudden death
• Stroke
• Paraplegia
• Renal artery stenosis- hypertension, renal failure
• Atherosclerotic aortic disease
• Peripheral vascular disease
25. 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)
26. 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
27. Renal Artery
• Progressive ischemic atrophy of kidney
leads to gradual kidney failure
(nephrosclerosis)
• Renal hypertension due to decreased
perfusion
28. 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
29. 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
30. Revision
Intimal accumulation of LDL
▼
Oxidation of LDL
▼
ox-LDL Injury to vascular wall
▼
Inflammatory response-
▼
Foam cell formation
▼
Smooth muscle proliferation – fibrous tissue deposition
▼
Plaque formation
▼
Further inflammatory response- cytokines release
▼
Progressive narrowing
▼
Vascular dysfunction – inadequate nitric oxide release
▼
Lumen narrowing from plaque and vasoconstriction
▼
Plaque fissure and thrombus formation-
▼
Partial or complete occlusion
31. 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
– Reverse cholesterol transport, depends on HDL