146. What are the four main steps in the development of the atherosclerotic plaque?

The pathophysiologic process by which atherosclerosis occurs is complex and somewhat controversial. The working theory includes four steps:

1. Endothelial cell injury
2. Lipoprotein deposition
3. Inflammatory reaction
4. Smooth muscle cell cap formation

Endothelial cell injury: This is likely the initial factor that begins the process of atherosclerotic plaque formation. Since the endothelium are constantly exposed to the circulation, any toxin present can result in damage (as occurs during tobacco use, diabetes and dyslipidemia). The continuous physical force exerted upon the endothelium also plays a role as commonly the greatest atherosclerotic plaque occurs at arterial bifurcations (i.e. the bifurcation of the left main coronary artery and the left anterior descending). Hypertension increases the physical force present.

Lipoprotein deposition: When the endothelium is injured or disrupted, lipoprotein molecules can gain entry where they are then modified by oxidation (via free radicals or oxidizing enzymes) or glycation (diabetics). This modified lipoprotein (modified LDL) is inflammatory and able to be ingested by macrophages creating “foam cells” causing a “fatty streak” in the arterial wall.

Inflammatory reaction: The modified LDL is antigenic and attracts inflammatory cells into the arterial wall. Also, after endothelial injury, inflammatory mediators are released further increasing leukocyte recruitment.

Smooth muscle cell cap formation: Smooth muscle cells migrate to the surface of the plaque creating a “fibrous cap”. When this cap is thick, the plaque is stable, however thin capped atherosclerotic plaques are thought to be more prone to rupture or erosion causing thrombosis.