Clinical meaning
Atherosclerosis is a chronic inflammatory disease of medium and large arteries progressing through distinct stages. Initiation occurs at sites of endothelial dysfunction — branch points, bifurcations, and areas of disturbed laminar flow — where endothelial cells express adhesion molecules (VCAM-1, ICAM-1, selectins) and become permeable to circulating LDL particles. Subendothelial LDL undergoes oxidative modification by reactive oxygen species, creating oxidized LDL (oxLDL) that is a potent pro-inflammatory stimulus. OxLDL activates endothelial cells to secrete MCP-1 (monocyte chemoattractant protein-1), recruiting circulating monocytes that transmigrate into the intima and differentiate into tissue macrophages. Macrophages express scavenger receptors (SR-A, CD36) that internalize oxLDL without negative feedback regulation, transforming macrophages into lipid-engorged foam cells — the hallmark of the fatty streak (earliest visible lesion). Foam cells secrete inflammatory cytokines (TNF-alpha, IL-1, IL-6) and matrix metalloproteinases (MMPs) that degrade extracellular matrix, perpetuating a cycle of inflammation and tissue remodeling. As the lesion progresses, vascular smooth muscle cells (VSMCs) migrate from the media to the intima, proliferate, and synthesize collagen and elastin forming a fibrous cap overlying the lipid-rich necrotic core (composed of dead foam cells, cholesterol crystals, and cellular debris). Plaque vulnerability — the propensity for acute rupture causing thrombotic events — depends on fibrous cap thickness and necrotic core size. Vulnerable (unstable) plaques have thin fibrous caps (< 65 micrometers), large necrotic cores (> 40% of plaque volume), extensive macrophage infiltration at the shoulder regions, decreased VSMC content, and increased MMP activity that degrades collagen. Plaque rupture exposes the thrombogenic necrotic core and tissue factor to flowing blood, triggering the coagulation cascade and platelet aggregation, forming an occlusive or non-occlusive thrombus that manifests clinically as acute coronary syndrome, ischemic stroke, or acute limb ischemia. Importantly, vulnerable plaques often cause minimal luminal stenosis (< 50%) and are angiographically silent — most MIs arise from non-flow-limiting plaques that rupture, not from severely stenotic stable plaques.