Category: disease_cascade
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).