Atherogenic lipoprotein particles and premature coronary artery disease: from molecular mechanisms to precision prevention

Premature coronary artery disease (PCAD), commonly defined as coronary disease before age 55 in men and 65 in women, reflects interactions among inherited susceptibility, metabolic dysfunction, environmental exposures, and vascular inflammation. This narrative review examines cumulative exposure to atherogenic apolipoprotein B (apoB)-containing particles as one major, modifiable pathway in atherosclerotic PCAD. Low-density lipoprotein cholesterol (LDL-C) measures cholesterol mass, whereas apoB provides an estimate of particle burden and may reveal discordance in insulin resistance, diabetes, obesity, and hypertriglyceridemia. Hepatic very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL, and lipoprotein(a) [Lp(a)] contain apoB-100; intestinal chylomicrons and their remnants contain apoB-48. Lp(a) adds a predominantly inherited exposure and carries oxidized phospholipids with inflammatory and calcific effects. Triglyceride-rich remnants connect impaired lipid metabolism to arterial cholesterol delivery. Epidemiological, genetic, and mechanistic evidence supports these pathways, but their clinical interpretation requires a distinction between association, lifelong genetic exposure, and treatment benefit. LDL-lowering therapies have established cardiovascular outcome efficacy. By contrast, company-reported topline results from Lp(a)HORIZON in September 2026 indicated that pelacarsen did not meet its prespecified primary composite cardiovascular endpoint; interpretation remains provisional pending a peer-reviewed report. Outcome benefits of other selective Lp(a)- and remnant-directed therapies remain under investigation. A proposed conceptual framework for prevention combines conventional risk-factor control, complementary apoB assessment, once-in-adulthood Lp(a) testing, metabolic and family assessment, and selected genetic evaluation. These elements may improve recognition of inherited and metabolic risk, but the framework has not been validated as a treatment-selection algorithm. Whether apoB-guided care or mechanism-specific interventions improve outcomes beyond established prevention remains an important research question.