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PATHOGENIC MECHANISMS OF ATHEROSCLEROSIS
Dr.Hesham Rashid, MD
Ass.Professor of Cardiology
Benha University
Normal Artery
GENERAL 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
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)
PATHOGENESIS OF
ATHEROSCLEROSIS
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
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
• Two theories have been suggested to explain the onset & progression of atherosclerotic lesions:
1. The chronic endothelial theory2. The lipid hypothesis.
• Both theories are interrelated & included in a multifactor-based hypothesis
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
Response to injury hypothesis (I)
1. Chronic EC injury (subtle?)–EC dysfunction
–Increased permeability
–Leukocyte adhesion (via VCAM-1)
–Thrombotic potential
Response to injury hypothesis (II)
2. Accumulation of LDL (cholesterol)3. Oxidation of LDL4. Adhesion & migration of blood
monocytes; transformation into macrophages and foam cells
5. Adhesion of platelets6. Release of factors from platelets,
macrophages and ECs
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
Response to Injury
Endothelial Dysfunction
Initiation of Fatty Streak
Fatty Streak
Fibro-fatty Atheroma
Fig. 11.7
AHA Classification of atherosclerosis
Fig. 11.7
AHA Classification of atherosclerosis
Fatty Streak-Coronary Artery
Fibrous Plaques Complicated Lesions
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
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
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