Atherosclerosis is a chronic lipid-driven + immune-driven arterial wall disease responsible for most cardiovascular mortality. Step 1: endothelial dysfunction — risk factors (LDL excess, hypertension, smoking, diabetes, oxidative stress) impair NO bioavailability + upregulate adhesion molecules (VCAM-1, ICAM-1, E-selectin). Step 2: LDL retention + oxidation — LDL particles transcytose into subendothelial space, retained by proteoglycans, oxidized (oxLDL) by ROS + myeloperoxidase. Step 3: monocyte recruitment + foam cell formation — monocytes adhere → migrate into intima → differentiate to macrophages → scavenger-receptor (CD36, SR-A1) uptake of oxLDL → cholesterol-laden "foam cells" → fatty streaks. Step 4: smooth-muscle migration + fibrous cap — VSMCs migrate from media to intima, proliferate, secrete collagen → fibrous cap encasing the lipid core. Step 5: plaque progression — necrotic core (apoptotic foam cells + cholesterol crystals + cellular debris); cholesterol crystals trigger NLRP3 inflammasome (cross-link pyroptosis gasdermin); ongoing inflammation drives expansion. Step 6: plaque rupture or erosion — thin-cap fibroatheroma (vulnerable plaque): inflammation thins the cap (MMP-9 degradation), shear stress + sustained inflammation rupture it → exposure of thrombogenic core → platelet activation + coagulation cascade → arterial thrombus → MI / stroke. Therapeutics: statin-driven LDL lowering is the dominant evidence base (CTT meta-analyses); PCSK9 inhibition (evolocumab, alirocumab, inclisiran); icosapent ethyl (REDUCE-IT); antiplatelet (aspirin, P2Y12 inhibitors); anti-inflammatory targeting (canakinumab CANTOS, colchicine LoDoCo2/COLCOT). Cross-links: ldl receptor pcsk9 axis (cholesterol delivery), platelet aggregation (thrombus), nfkb signaling (inflammation), ferroptosis gpx4 lipid peroxidation (oxLDL).
Organ Systems
cardiovascular
immune-hematologic
Pathway Steps
cardiovascular risk factors (LDL ↑, HTN, smoking, DM, ↓NO) → endothelial dysfunction — via ↓ eNOS activity + adhesion molecule upregulation (VCAM-1, ICAM-1, E-selectin). Atherosclerosis begins with endothelial dysfunction: risk factors (high LDL, hypertension, smoking, diabetes) reduce nitric-oxide bioavailability and make the endothelium pro-inflammatory and permeable. Disturbed flow at branch points explains why plaques form at characteristic sites — the earliest, still-reversible stage.
circulating LDL → subendothelial retention + oxidation (oxLDL) — via transcytosis → proteoglycan retention → ROS + myeloperoxidase oxidation. ApoB lipoproteins (LDL) cross the activated endothelium and are retained by binding arterial proteoglycans, then modified (oxidized) to oxLDL. This subendothelial LDL retention is the initiating causal event — the basis of the “lower LDL is better” principle behind statins and PCSK9 inhibitors.
monocyte adhesion + migration → macrophage foam cells (fatty streaks) — via CD36 + SR-A1 scavenger uptake of oxLDL → unregulated cholesterol accumulation. oxLDL activates the endothelium to recruit monocytes, which enter the intima as macrophages and ingest oxLDL via scavenger receptors — unregulated uptake that turns them into lipid-laden foam cells. Aggregated foam cells form the fatty streak, the first visible lesion and the engine of plaque inflammation.
VSMC migration from media → fibrous cap formation — via collagen + ECM secretion encases lipid core; cap thickness determines stability. Vascular smooth-muscle cells migrate from the media into the intima and switch to a synthetic phenotype, laying down collagen to form a fibrous cap over the lipid core. This cap is protective — its thickness and collagen content determine whether a plaque stays stable or becomes rupture-prone.
apoptotic foam cells + cholesterol crystals → necrotic core + NLRP3 inflammasome activation — via cross-link to pyroptosis pathway — cholesterol crystals are NLRP3 triggers. As foam cells die and efferocytosis fails, their debris and cholesterol crystals coalesce into a necrotic lipid core. The crystals activate the NLRP3 inflammasome (IL-1β), driving the sterile inflammation that destabilizes plaque — the rationale for anti-IL-1β therapy (canakinumab) in cardiovascular disease.
thin-cap fibroatheroma + sustained inflammation → plaque rupture / erosion — via MMP-9 degrades cap; shear stress + inflammation tip the balance. A thin-cap fibroatheroma — a large necrotic core under a thin, inflamed, collagen-poor cap — is the vulnerable plaque. Inflammatory proteases (MMPs) degrade the cap while smooth-muscle death limits repair. Most heart attacks arise from such lesions, often not the most stenotic ones.
rupture exposure of thrombogenic core → platelet activation + coagulation → arterial thrombus — via tissue factor + collagen → MI / ischemic stroke / acute limb ischemia. When the cap ruptures or erodes, the thrombogenic core meets blood: exposed tissue factor and collagen trigger platelet activation and the coagulation cascade, forming an occlusive thrombus. This acute thrombosis — not gradual narrowing — causes most infarctions and strokes, and is why antiplatelet therapy is central.