79. Pathogenesis and morphology of atherogenesis

Question 1

Atherosclerosis definition

Answer 1

Thickening of the intima by atherosclerotic plaque and weakening of the media.

Involves medium muscular arteries and large elastic arteries.

Question 2

Risk factors (non-modifiable)

Answer 2

1. Age
2. Genetic abnormalities: homozygous familial hypercholesterolemia (LDL receptor defect)
3. Gender: male and post-menopausal women

Question 3

Risk factors (modifiable)

Answer 3

1. Hypertension
2. Smoking
3. Hyperlipidemia (more specifically hypercholesterolemia)
   
   • high level of LDL: mobilize cholesterol to peripheral
     tissue; causes are diabetes and saturated fat diet
   • low level of HDL; mobilize cholesterol to liver
     normally; causes are obesity and smoking
4. Alcoholism: decreased levels of NAD+ –> decreased beta oxidation and it inhibits lipoprotein lipase which transports lipids into tissues
5. Diabetes mellitus: increased hormone sensitive lipase causing increased secretion of free fatty acids from adipose tissue into blood. Normally insulin blocks HSL.

Question 4

Pathogenesis

Answer 4

chronic inflammation of arterial wall in response to endothelial injury

1. Endothelial injury or dysfunction
   
   • can be due to hemodynamic disturbance at branch
     points where there is turbulent flow
   • increased cholesterol –> free radicals
2. Lipids and monocytes accumulate in intima
   
   • lipids are oxidized by free radicals
3. Oxidized lipids are ingested by macrophages (foam cells): fatty streaks = macrophages filled with lipids
   
   • oxidized LDL cannot be degraded by macrophage
     –> foam cell
4. Chronic inflammation-healing deposition of lipids in intima: atherosclerotic plaque
   
   • oxidized LDL damages endothelium and smooth
     muscle cells leading to inflammation
   • Macrophages and T cell mediate chronic
     inflammation (IFN-gamma secretion)
   • SMC proliferation in the intima and lay down of ECM
     (mediated by platelets, EC, and macrophages that
     lay down PDGF, FGF, TGF-alpha)
5. Can have a stable or vulnerable plaque
   
   • vulnerable plaque: thin fibrous cap and large lipid
     core; high risk for rupture.
     - decreased collagen due to plaque
     inflammation that decrease collagen synthesis
     and increases collagen degradation
     - decreased SMC synthesis due to damage
     caused by cholesterol leading to decreased
     collagen synthesis

Question 5

Complications

Answer 5

1. Stenosis of medium blood vessels (critical stenosis > 70% stenosis)
   mesenteric arteries: ischemic bowel disease
   coronary arteries: angina
2. Plaque rupture (neck of the plaque)
   - thrombosis –> infarction
   coronary arteries: MI
   middle cerebral artery: stroke
   
   • atheroembolism
3. Media weakening –> aneurysm
4. Hemorrhage into plaque