Atherosclerosis

Atherosclerosis is a chronic, lipid-driven inflammatory disease of medium and large arteries in which ApoB-containing lipoproteins (primarily LDL) are retained within the subendothelial intima, triggering a self-amplifying immune response that progressively narrows and stiffens the vessel lumen. The initiating event, described by Williams and Tabas (1995) as the "response-to-retention" hypothesis, is the electrostatic binding of ApoB100 to arterial proteoglycans; retained LDL undergoes oxidative and enzymatic modification, attracting monocytes that differentiate into macrophages and engulf lipid-laden particles to become foam cells — the histological hallmark of early lesions called fatty streaks. Over decades, foam cell apoptosis releases a necrotic lipid core that, combined with smooth-muscle-cell migration and fibrous cap formation, constitutes a mature atherosclerotic plaque; rupture of an unstable plaque precipitates acute myocardial infarction and ischaemic stroke, making atherosclerosis the leading cause of mortality worldwide. The causal role of LDL is established by Mendelian randomisation and statin trials; the inflammatory axis was confirmed in humans by the CANTOS trial (Ridker et al., 2017), in which IL-1β inhibition with canakinumab reduced major cardiovascular events independently of LDL lowering, demonstrating that inflammation is a modifiable driver of residual risk rather than merely a bystander.