Pathogenesis of Atherosclerosis – Bullet-Point Exam Notes

Atherosclerosis = chronic, multifocal, immuno-inflammatory + fibro-proliferative disease of medium/large arteries, driven by lipids.
Clinical catastrophes (myocardial infarction, stroke) result from superimposed thrombosis, not from plaque burden per se.
Central question: why do only a few plaques become thrombosis-prone after years of silent growth?

Elevated LDL-cholesterol is sufficient to initiate disease; symptomatic disease rare if plasma cholesterol <150\,\text{mg/dl}.
Accelerators: hypertension, diabetes, smoking, male gender, inflammatory markers.
Hemodynamic factors (low / oscillatory shear, branch points) ↑ local susceptibility.

HDL / \text{apoA-I}, exercise, moderate alcohol: inhibit LDL modification + promote reverse cholesterol transport.

Endothelium: becomes leaky, activated; up-regulates VCAM-1, ICAM-1, E/P-selectins → recruits monocytes & T cells.
Monocytes → macrophages: ingest modified LDL via scavenger receptors (SR-A, CD36) → foam cells; secrete MCP-1, MMPs, tissue factor.
Smooth Muscle Cells (SMC): migrate/proliferate into intima, synthesize collagen → fibrous cap stability; loss/apoptosis weakens cap.
Other leukocytes: mast cells (culprit lesions), neutrophils (post-rupture), adventitial B cells / plasma cells.

Fatty streak: EC + macrophage foam cells.
Progression: lipid-rich necrotic core (avascular, collagen-poor) forms via foam-cell death.
Calcification common; coronary calcium score reflects total plaque burden.
Neovascularization from vasa vasorum → fragile, leaky microvessels → inflammation, possible intraplaque hemorrhage.

Expansive (outward) remodeling: preserves lumen; typical of thin-cap fibroatheroma & acute coronary syndrome (ACS) culprit plaques.
Constrictive remodeling: accentuates stenosis; often in stable angina; favored by smoking, diabetes.

Plaque rupture = physical gap in thin fibrous cap exposing thrombogenic core.
Features associated with rupture:
• Large, soft lipid core
• Thin, collagen-poor cap
• Few SMCs, many macrophages at rupture site
• High MMP activity → matrix breakdown
• Adventitial inflammation & angiogenesis
Epidemiology: worldwide review 1\,114/1\,460\,(76\%) fatal coronary thrombi due to rupture; men \approx80\% vs women \approx60\%.
Rupture frequency → multiple, clinically silent episodes → stepwise lesion growth.

Initial platelet aggregation; fibrin essential for stabilization.
Plaque rupture more thrombogenic than erosion; both platelets & fibrin accumulate.

Circulating progenitor cells can differentiate into ECs & SMCs; potential therapeutic target for plaque stabilization.

Control LDL; enhance HDL.
Address systemic risk factors to prevent endothelial activation.
Stabilize existing plaques by promoting SMC collagen synthesis, inhibiting macrophage MMPs, reducing inflammation.
Early identification of rupture-prone plaques could transform atherothrombosis into a manageable chronic condition.