Atherosclerosis

Endothelial dysfunction at sites of low or oscillatory shear stress allows LDL to enter the intima, where it is oxidized. Endothelium expresses adhesion molecules (VCAM-1, ICAM-1) that recruit monocytes; they enter the intima, differentiate into macrophages, and engulf oxidized LDL via scavenger receptors. The resulting foam cells secrete cytokines that recruit more inflammation. Smooth muscle cells migrate from the media, proliferate, and produce extracellular matrix forming a fibrous cap over a lipid-rich necrotic core. Over decades the plaque grows, calcifies, and may eventually rupture.

Vulnerable plaques have a thin fibrous cap, large lipid core, and abundant inflammation. Macrophage-derived matrix metalloproteinases (MMPs) degrade collagen in the cap; cap thinning culminates in rupture. Exposed tissue factor, lipid, and collagen activate platelets and the coagulation cascade, forming an occlusive thrombus within minutes. Most rupture-related events occur in plaques that were not flow-limiting before — the unstable plaque is not necessarily the largest. Erosion of plaques without rupture also causes events, particularly in women and smokers.

LDL cholesterol is causal — Mendelian randomization, lifelong genetic variants, and trial data converge. Hypertension drives mechanical stress and endothelial injury. Smoking accelerates oxidation, inflammation, and thrombosis. Diabetes glycates lipoproteins and impairs endothelial function. Family history captures uncaptured genetic risk. Chronic inflammation from rheumatoid arthritis or HIV elevates risk. Lipoprotein(a) is a partly heritable, prothrombotic LDL-like particle that is now actionable with siRNA therapy in trials.

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis. The cell upregulates LDL receptors, clearing more LDL from blood. Each ~38 mg/dL (~1 mmol/L) drop in LDL reduces cardiovascular events by about 22% per year of treatment. High-intensity atorvastatin or rosuvastatin lowers LDL by ~50%. Beyond LDL lowering, statins have anti-inflammatory and plaque-stabilizing effects (reduce hsCRP, increase fibrous cap thickness). The benefit is durable and the side effects often overstated.

PCSK9 is a hepatic protein that promotes LDL receptor degradation. Monoclonal antibodies (evolocumab, alirocumab) and the siRNA inclisiran block PCSK9, raising LDL receptor density and lowering LDL by an additional ~60% on top of statins. They reduce major cardiovascular events ~15-20% in high-risk patients. Cost has limited adoption but is falling. Genetic loss-of-function PCSK9 mutations confer lifelong low LDL and dramatically reduced CV risk — direct evidence for the LDL-causal hypothesis.

Stable angina is reproducible chest discomfort with exertion, relieved by rest or nitroglycerin, reflecting flow limitation across a fixed stenosis. Acute coronary syndromes — unstable angina, NSTEMI, STEMI — represent plaque rupture and partial or complete occlusion of a coronary artery. STEMI requires immediate reperfusion (PCI within 90 minutes when feasible). The line between stable and unstable plaque is biology, not stenosis severity — many MIs occur from plaques with under 50% angiographic stenosis.

Yes, partly. Aggressive LDL lowering (LDL < 70 mg/dL sustained for years) shrinks plaque volume modestly on intravascular imaging, increases fibrous cap thickness, and reduces lipid content. Combined with smoking cessation, blood pressure control, antiplatelet therapy, and exercise, regression translates into measurable event reduction. Calcified plaque does not reverse, but the unstable lipid components do. The earlier and more aggressive the intervention, the greater the benefit — primary prevention outperforms secondary.