54. Atherosclerosis and its cellular and molecular pathophysiology

Pathogenesis of atherosclerosis

The most important risk factors for atherosclerosis are:

  • Smoking
  • Diabetes mellitus
  • Hypertension
  • Dyslipidaemia
  • Obesity
  • Homocystinuria
  • Alcohol consumption

Atherosclerosis involves multiple phases and processes:

  • Damage of endothelium
  • Endothelial dysfunction
  • Inflammation of vessel wall
  • Activation of macrophages
  • Activation of smooth muscle cells
  • Calcification of plaque

Damage of endothelium: The endothelium usually protects the rest of the vessel wall from the stress of turbulence and components in the blood. The endothelium may be damaged by multiple factors, like hypertension, which increases shear forces and smoking, which increases the level of reactive oxygen species.

Endothelial dysfunction: As the endothelial is damaged will it be dysfunctional and start to express different surface proteins and act differently. Here are the most important consequences:

  • The vasodilator mechanisms are impaired – decreased NO production, increased endothelin production
  • The endothelial cells begin to express adhesion molecules like selectins and integrins
  • The endothelial cells produce leukocyte chemokines that attract inflammatory cells
  • The endothelial cells produce inflammatory cytokines, like TNF-α, IL-1 and IL-6
  • The endothelial barrier is disrupted, allowing LDL to enter the vessel wall

Inflammation of the vessel wall: The aforementioned factors attract lymphocytes and macrophages and cause the vessel wall to become inflamed. The LDL inside the vessel wall is modified as it becomes oxidized and glycated. Macrophages recognize modified LDL with scavenger receptors and phagocytose the LDL, turning them into foam cells.

Activation of macrophages: Macrophages become activated as they phagocytose LDL. This causes them to produce reactive oxygen species and lysosomal enzyme, which further damages the vessel wall and further oxidizes LDL.

Activation of smooth muscle cells: Inflammatory cytokines and platelet derived growth factor, produced by the dysfunctional endothelium, attracts smooth muscle cells from the tunica media to the tunica intima and activates them into myofibroblasts. Activated myofibroblasts proliferate and produce extracellular matrix, forming fibrosis.

Calcification of plaque: Ca2+ will deposit into the plaque and cause it to become firm. At this point is the plaque comprised of a fibrous cap and a core containing necrotic cells, cholesterol and calcium.

Consequences of atherosclerosis

There are four possible consequences of plaque:

  • The plaque may grow so large that it occludes the artery enough to cause ischaemia
    • Stable angina
  • The plaque may rupture, exposing the thrombogenic core, causing a thrombus to form on the plaque which completely obstructs the vessel
    • AMI
  • The plaque may become loose, only occasionally and partially blocking the blood flow
    • Unstable angina
  • The plaque may loosen completely and cause an atheroembolism

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55. Disorders of the hypothalamo-pituitary system. Pituitary insufficiency

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