Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease?

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Atherosclerosis Research

Background:

• High-density lipoprotein (HDL) and HDL-cholesterol (HDL-C) are traditionally linked to reverse cholesterol transport and reduced atherosclerotic cardiovascular disease (ASCVD) risk.
• Therapeutic interventions aiming to increase HDL-C have failed to reduce ASCVD events in statin-treated patients.
• Mendelian randomization studies question HDL-C's direct causal role in ASCVD risk.

Purpose of the Study:

• To re-evaluate the contribution of HDL-C to ASCVD risk assessment.
• To examine the complex relationship between HDL-C levels and ASCVD.
• To discuss the future role of HDL-C in ASCVD risk assessment, treatment, and prevention.

Main Methods:

• Review of biological functions of HDL-C and normative values.
• Analysis of epidemiological studies on HDL-C and ASCVD risk.
• Examination of recent evidence on very high HDL-C levels and mortality.

Main Results:

• Traditional view of HDL-C as a protective factor is challenged by recent findings.
• A nonlinear U-shaped relationship exists between HDL-C and subclinical atherosclerosis.
• Very high HDL-C levels (≥80 mg/dL men, ≥100 mg/dL women) are paradoxically associated with increased all-cause and ASCVD mortality.

Conclusions:

• HDL-C is not a universally protective factor against atherosclerosis.
• The role of HDL-C in ASCVD risk assessment requires reframing.
• Further research is needed to clarify the precise role of HDL-C in atherosclerosis and clinical ASCVD.