Lecture 4.2 - Atherosclerosis

Atherosclerosis

• Atherosclerosis is a type of arteriosclerosis, characterized by the accumulation of intracellular and extracellular lipid in the intima and media of large and medium-sized arteries.
• Does not affect veins or capillaries.
• Slowly progressive, build-up of fat (cholesterol) within the artery wall, characterized by intimal lesions called atheroma, atheromatous, or fibro-fatty plaques.

Pathogenesis of Atherosclerosis

• Response to injury hypothesis:
  • Initiated by endothelial dysfunction
  • Chronic inflammatory response - presence of macrophages
  • Migration of smooth muscle cells (SMC) from media to intima
  • Proliferation of SMC in intima
  • Excess production of extracellular matrix (collagen and elastin)
  • Enhanced lipid accumulation
• Two most important causes of endothelial dysfunction are:
  • Hemodynamic disturbances (hypertension)
  • Hypercholesterolemia
• Inflammation is also an important contributor

Macroscopic Features

• Fatty streak: yellow discoloration with no bulging (small accumulation of macrophages with fat inside)
• Simple plaque: raised yellow legion with irregular outline, large plaque present
• Complicated plaque: can end up with calcification and hemorrhage

Microscopic Features

• Early changes:
  • Proliferation of smooth muscle cells
  • Accumulation of foam cells
  • Extracellular lipid
• Later changes:
  • Fibrosis
  • Necrosis
  • Cholesterol clefts
  • +/- inflammatory cells
  • Disruption of internal elastic lamina
  • Damage extends into media
  • Ingrowth of blood vessels
  • Plaque fissuring

Clinical Complications

• Progressive lumen narrowing due to high-grade plaque stenosis
• Acute atherothrombotic occlusion - due to the activation of the coagulation cascade
• Thrombus embolisation into the distal arterial bed
• Ruptured abdominal atherosclerotic aneurysm
• Myocardial infarction (heart attack), ischaemic heart disease (IHD)
• Cerebral infarction (stroke)
• Aortic aneurysms
• Mesenteric occlusion
• Peripheral vascular disease (gangrene of the legs)

Risk Factors

• Non-modifiable risk factors:
  • Age
  • Gender (women protected relatively before menopause)
  • Genetic predisposition
• Modifiable risk factors:
  • Hyperlipidaemia (high plasma cholesterol, LDL most significant, HDL protective)
  • Cigarette smoking
  • Alcohol (>5 units/day associated with increased risk of IHD)
  • Infection (Chlamydia pneumoniae, Helicobacter pylori, Cytomegalovirus)
  • Hypertension (mechanism uncertain, endothelial damage caused by raised pressure)
• Diabetes mellitus: associated with high risk of cerebrovascular and peripheral vascular disease
• Other risk factors:
  • Lack of exercise
  • Obesity
  • Oral contraceptives
  • Stress and personality type?

Prevention and Intervention

• Prevention:
  • No smoking
  • Reduce fat intake
  • Treat hypertension
  • Not too much alcohol
  • Regular exercise/weight control
• Intervention:
  • Stop smoking
  • Modify diet
  • Treat hypertension
  • Treat diabetes
  • Lipid-lowering drugs