High-Density Lipoproteins: Biology, Epidemiology, and Clinical Management

Area of Science:

• Cardiovascular Science
• Lipid Metabolism
• Arteriosclerosis Research

Background:

• High-density lipoproteins (HDL) exhibit diverse protective effects against arteriosclerosis, often independent of their cholesterol content.
• HDL cholesterol (HDL-C) is a widely used biomarker for cardiovascular risk, despite conflicting evidence from Mendelian randomization studies and failed HDL-C-raising therapies.
• HDL particles are heterogeneous, with functionality potentially impaired by oxidation and inflammation, leading to proatherogenic effects.

Purpose of the Study:

• To review the complexities and controversies surrounding HDL and atherosclerotic cardiovascular disease.
• To explore the limitations of HDL cholesterol as a sole biomarker and therapeutic target.
• To highlight the potential of HDL functionality and intimal HDL processes for therapeutic development.

Main Methods:

• Review of epidemiological data and Mendelian randomization studies.
• Analysis of HDL particle heterogeneity, composition, and function.
• Examination of HDL's role in the arterial wall, including biogenesis, function, and egress.

Main Results:

• The association between HDL-C and cardiovascular risk is strong but potentially not causal.
• HDL-C-raising therapies have largely failed, questioning the HDL-C hypothesis.
• HDL functionality, rather than cholesterol content, may be a more relevant biomarker and therapeutic target.

Conclusions:

• HDL's beneficial effects are complex and not solely determined by plasma HDL-C levels.
• Therapeutic strategies targeting HDL functionality, especially within the arterial intima, hold promise for treating atherosclerotic cardiovascular disease.
• Further research into intimal HDL processes is crucial for unlocking HDL's full therapeutic potential.