Biological Consequences of Dysfunctional HDL

Area of Science:

• Cardiovascular Science
• Biochemistry
• Molecular Medicine

Background:

• Epidemiological studies suggest an inverse correlation between high-density lipoprotein (HDL) cholesterol and cardiovascular disease (CVD) risk.
• HDL particles are involved in reverse cholesterol transport (RCT) and possess atheroprotective functions, including anti-inflammatory, anti-thrombotic, and antioxidant properties.
• Clinical trials and Mendelian randomization studies question the benefit of simply increasing HDL cholesterol (HDL-C) levels for CVD outcomes.

Purpose of the Study:

• To review the pathological conditions that lead to the formation of dysfunctional HDL.
• To discuss the role of dysfunctional HDL in atherosclerosis and other conditions.
• To highlight the shift in focus from HDL-C levels to HDL functional properties for potential therapeutic strategies.

Main Methods:

• Review of epidemiological studies.
• Analysis of clinical trial data.
• Examination of Mendelian randomization studies.
• Discussion of pathological mechanisms leading to HDL dysfunction.

Main Results:

• HDL-C-raising therapies have not consistently improved cardiovascular outcomes.
• Genetic studies show that increased HDL-C levels do not always decrease myocardial infarction risk.
• HDL from atherosclerotic patients can exhibit impaired atheroprotective functions and acquire pro-atherogenic properties, termed 'dysfunctional HDL'.

Conclusions:

• Focusing on HDL functional properties, rather than just HDL-C levels, is crucial for understanding and treating CVD.
• Dysfunctional HDL, even with normal or high HDL-C levels, plays a role in atherosclerosis.
• Pharmacological strategies aimed at restoring HDL functions may offer a more significant impact on CVD outcomes.