Rethinking beyond low-density lipoprotein cholesterol: Emerging biomarkers for early identification of coronary artery disease

Abstract:

Low-density lipoprotein cholesterol (LDL-C) remains the cornerstone biomarker for the assessment and management of coronary artery disease (CAD), and robust evidence confirms that LDL-C lowering reduces cardiovascular events. However, LDL-C reflects only the cholesterol content within low-density lipoprotein (LDL) particles and does not account for critical determinants of atherogenicity such as particle number, size heterogeneity, oxidative modification, genetic risk and vascular inflammation. Consequently, a substantial proportion of patients continue to experience cardiovascular events despite achieving guideline-recommended LDL-C targets, highlighting the persistence of residual cardiovascular risk. Numerous evidence support the clinical relevance of advanced LDL-related biomarkers, including small dense LDL, oxidised LDL, apolipoprotein B and non-high-density lipoprotein cholesterol, which more accurately reflect atherogenic particle burden. In addition, genetically determined and inflammatory biomarkers such as lipoprotein(a) and high-sensitivity C-reactive protein provide complementary insights into key pathogenic pathways driving atherosclerosis beyond lipid accumulation alone. Large population-based cohorts, Mendelian randomisation studies and randomised clinical trials have consistently demonstrated the independent and incremental prognostic value of these biomarkers across diverse populations. This review critically examines the limitations of LDL-C-centric risk assessment and synthesises evidence supporting the integration of advanced lipid and inflammatory biomarkers into clinical practice. A comprehensive, multi-marker approach may improve cardiovascular risk stratification in individuals who experience cardiovascular events despite optimal LDL-C control, enabling more precise and personalised preventive strategies.