HDL: Fact, fiction, or function? HDL cholesterol and cardiovascular risk

Area of Science:

• Cardiovascular Disease Research
• Lipid Metabolism and Atherosclerosis
• Biomarkers for Cardiovascular Risk

Background:

• High-density lipoprotein cholesterol (HDL-C) is widely used for cardiovascular risk prediction.
• However, HDL-C levels lack a direct causal association with atherosclerotic cardiovascular disease (ASCVD) events.
• Mendelian randomization studies have shifted focus from HDL-C concentration to its functional roles.

Purpose of the Study:

• To explore the functional aspects of high-density lipoprotein (HDL) beyond its cholesterol concentration.
• To investigate novel HDL functionalities as potential predictors of cardiovascular events.
• To assess the clinical utility of emerging HDL functional measurements for risk stratification.

Main Methods:

• Review of Mendelian randomization studies.
• Analysis of HDL's physiological functions in atherosclerosis and other systems.
• Evaluation of novel HDL measurements like cholesterol efflux capacity and inflammatory index.

Main Results:

• HDL plays critical roles in reverse cholesterol transport, oxidation, inflammation, and endothelial function.
• HDL is involved in immune modulation, apoptosis, and endothelial progenitor cell homeostasis.
• Dysfunctional HDL may offer superior cardiovascular event prediction compared to HDL-C levels.

Conclusions:

• HDL functionality, not just concentration, is crucial for understanding cardiovascular risk.
• Emerging HDL functional assays show promise for enhanced clinical risk stratification.
• Barriers to clinical adoption include measurement validity and commercial availability.