High-density lipoprotein in cardiovascular diseases: From high quantity to high quality.

High-density lipoprotein (HDL) plays a key role in reverse cholesterol transport (RCT), traditionally associated with cardiovascular protection. However, while low HDL-cholesterol (HDL-C) levels correlate with increased cardiovascular risk, therapeutic interventions raising HDL-C (e.g., niacin, fibrates) have failed to reduce cardiovascular events. Recent evidence reveals a U-shaped relationship between HDL-C and mortality, with both excessively high and low levels conferring risk-indicating functional impairment as the critical determinant. Consequently, focus has shifted from HDL-C quantification to functional assessment: (1) Cholesterol efflux capacity (CEC) exhibits a stronger inverse correlation with cardiovascular risk than HDL-C; (2) HDL particle number (HDL-P) outperforms HDL-C in predicting cardiovascular events; (3) HDL subclass heterogeneity (e.g., HDL2, HDL3), where composition and distribution determine the protective functions of HDL particles. This review synthesizes evidence demonstrating that comprehensively assessing HDL functionality-including quality metrics, particle concentration, and subclass distribution-provides superior cardiovascular risk assessment. Future research must prioritize restoring or enhancing HDL function rather than merely increasing its concentration.