HDL-C: Helpful, harmful, hopeful, or guilty by association

Area of Science:

• Cardiovascular Medicine
• Biochemistry
• Lipid Metabolism

Background:

• High-density lipoproteins (HDL) have historically been considered protective against atherosclerotic cardiovascular disease (ASCVD).
• The role of HDL cholesterol (HDL-C) in ASCVD risk has evolved from a simple inverse relationship to a more complex understanding.
• Recent therapeutic strategies targeting HDL functionality have not consistently yielded cardiovascular benefits.

Purpose of the Study:

• To review the intricate relationship between HDL-C and ASCVD.
• To explore the shift in perspective from HDL-C quantity to functionality in ASCVD prevention.
• To discuss emerging evidence on elevated HDL-C and ASCVD risk, and future therapeutic directions.

Main Methods:

• Literature review of studies investigating HDL-C and ASCVD.
• Analysis of recent clinical trials on HDL-modifying therapies.
• Discussion of biochemical functions of HDL and their impact on cardiovascular outcomes.

Main Results:

• A U-shaped curve characterizes the relationship between HDL-C levels and ASCVD risk.
• Enhancing HDL particle function has not reliably translated to reduced cardiovascular events.
• Evidence suggests elevated HDL-C may be associated with increased ASCVD risk in some contexts.

Conclusions:

• The utility of HDL-C as a direct therapeutic target for ASCVD prevention is increasingly questioned.
• HDL-C may serve as a biomarker reflecting complex pathological processes rather than a direct causal factor.
• Future research should focus on understanding the nuanced role of HDL and its associated factors in cardiovascular health.