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

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Biochemistry

Background:

• High-density lipoprotein (HDL) is crucial for reverse cholesterol transport (RCT) and cardiovascular protection.
• Low HDL-cholesterol (HDL-C) correlates with cardiovascular risk, but therapies raising HDL-C have failed to reduce events.
• A U-shaped relationship between HDL-C and mortality suggests functional impairment, not just concentration, is critical.

Purpose of the Study:

• To review evidence shifting focus from HDL-C levels to HDL functionality for cardiovascular risk assessment.
• To highlight key functional metrics of HDL, including cholesterol efflux capacity (CEC), particle number (HDL-P), and subclass heterogeneity.
• To advocate for research prioritizing the enhancement of HDL function over mere concentration increase.

Main Methods:

• Literature review synthesizing current evidence on HDL function and cardiovascular risk.
• Analysis of studies comparing HDL-C, CEC, HDL-P, and subclass distribution in predicting cardiovascular outcomes.
• Evaluation of therapeutic interventions targeting HDL.

Main Results:

• Cholesterol efflux capacity (CEC) shows a stronger inverse correlation with cardiovascular risk than HDL-C.
• HDL particle number (HDL-P) is a superior predictor of cardiovascular events compared to HDL-C.
• HDL subclass heterogeneity (HDL2, HDL3) influences the protective functions of HDL particles.

Conclusions:

• Comprehensive assessment of HDL functionality (quality, particle concentration, subclass distribution) offers superior cardiovascular risk stratification.
• Future research and therapies should focus on restoring or enhancing HDL function, not solely increasing HDL-C levels.
• Functional HDL assessment represents a paradigm shift in understanding and managing cardiovascular disease risk.