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Atherosclerosis is a chronic inflammatory disease of large arteries in which lipid accumulation, endothelial dysfunction, and smooth muscle proliferation form plaques that progressively narrow the lumen. Plaque rupture triggers acute thrombosis.
Study the pathologic sequence: endothelial injury, LDL oxidation, foam cell formation, lipid core accumulation, and fibrous cap development. Understand risk factors (hypertension, dyslipidemia, smoking) and their mechanistic contributions.
Atherosclerosis is not simply cholesterol deposition—it requires endothelial injury and inflammation. Angiography may miss significant disease; many high-grade stenoses have negative imaging before rupture.
From your study of lipoproteins, you know that LDL particles carry cholesterol through the bloodstream. From your study of the inflammatory response, you know how endothelial cells respond to injury signals by expressing adhesion molecules and recruiting immune cells. Atherosclerosis is what happens when these two systems collide — over decades, in the arterial wall — and the result is a chronic wound that never fully heals. Understanding it requires tracing the sequence of events from the first endothelial insult to plaque rupture and acute thrombosis.
The process begins with endothelial dysfunction. Normally, endothelial cells lining the arterial wall form a smooth, non-sticky surface and continuously produce nitric oxide, which relaxes vascular smooth muscle and inhibits platelet adhesion. Hypertension, turbulent blood flow at arterial bends, smoking, and hyperglycemia all damage this protective layer. Dysfunctional endothelium becomes permeable to circulating LDL particles, which enter the subendothelial space (the intima). Once there, LDL is exposed to reactive oxygen species and undergoes oxidative modification to become oxidized LDL (ox-LDL) — the form that triggers the inflammatory cascade. This is why LDL level alone doesn't fully predict atherosclerosis risk; particle size, oxidizability, and endothelial integrity all matter.
Ox-LDL triggers endothelial cells to express adhesion molecules that recruit monocytes from the blood. Monocytes enter the intima and differentiate into macrophages, which engulf ox-LDL via scavenger receptors. Unlike the regulated LDL receptor you learned about in cholesterol metabolism, scavenger receptors are not downregulated by intracellular cholesterol — macrophages keep consuming ox-LDL until they become foam cells, lipid-laden cells that form the characteristic fatty streak visible even in young arteries. Foam cells die, releasing their lipid contents into the growing lesion and further amplifying inflammation. Smooth muscle cells from the media migrate into the intima, proliferate, and lay down a fibrous cap of collagen and matrix proteins over the growing lipid core. This stabilizes the plaque structurally — but the cap is only as strong as the balance between collagen synthesis and matrix metalloproteinase activity. When inflammatory cells within the plaque degrade the fibrous cap faster than smooth muscle cells repair it, the cap thins and becomes vulnerable.
Plaque rupture is the event that converts a stable chronic lesion into an acute emergency. When a thin-capped, lipid-rich plaque ruptures, the thrombogenic lipid core is exposed to flowing blood. Tissue factor in the lipid core immediately activates the coagulation cascade, generating thrombin and depositing fibrin. Platelets adhere, activate, and aggregate. The resulting thrombus can occlude the lumen partially (causing unstable angina) or completely (causing myocardial infarction or stroke). This explains a counterintuitive clinical observation: the plaques most likely to cause heart attacks are not always the ones causing the tightest luminal narrowing — they are the ones with large lipid cores and thin fibrous caps. A patient with 40% stenosis but an unstable plaque is often at higher immediate risk than a patient with 70% stenosis covered by a thick, stable fibrous cap.