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HDL re-examined
G Kees Hovingh1, Daniel J Rader, Robert A Hegele
1aDepartment of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands bDepartment of Medicine and Genetics, Institute for Translational Medicine and Therapeutics, and Cardiovascular Institute, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA cDepartment of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
Insights
High-density lipoprotein cholesterol (HDL-C) levels predict cardiovascular disease (CVD) risk, but its causal role is debated. Research now focuses on HDL functionality rather than just HDL-C levels for CVD risk assessment.
Area of Science:
- Cardiovascular Disease Research
- Lipid Metabolism
- Atherosclerosis
Background:
- Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular disease (CVD) risk.
- HDL-C is widely used in CVD risk estimation models.
- The causal role of HDL in CVD is increasingly questioned by recent studies.
Purpose of the Study:
- To review current evidence on HDL-C and associated parameters in CVD risk.
- To explore the shift in focus from HDL-C levels to HDL functionality.
- To assess the implications for CVD risk prediction and therapeutic targeting.
Main Methods:
- Review of population studies and clinical trials.
- Analysis of genetic studies.
- Evaluation of HDL functionality markers, such as HDL efflux capacity.
Main Results:
- Inverse association between HDL-C levels and CVD risk confirmed.
- Genetic and clinical trial data challenge the causal role of HDL-C in atherosclerosis.
- HDL efflux capacity shows potential as an independent predictor of CVD events.
- Numerous clinical trials investigating HDL-C-raising agents are ongoing.
Conclusions:
- The predictive value of HDL-C for CVD events is established, but its causal role is debated.
- A paradigm shift towards evaluating 'HDL functionality' is evident.
- Further prospective studies are needed to confirm if optimizing HDL functionality reduces CVD risk.
Purpose Of Review:
To summarize the current evidence concerning the role of HDL-C and HDL-associated parameters in the risk for cardiovascular disease (CVD).
Recent Findings:
Numerous population studies have shown that plasma levels of HDL-C are inversely associated with CVD risk; in patient care HDL-C levels are therefore widely implemented in risk estimation models. A number of antiatherogenic properties have been ascribed to the HDL particle, but the hypothesis that HDL is causally related to CVD has been seriously challenged by recent data obtained from both human genetic studies and clinical trials. The final word on HDL-C as a therapeutic target is pending, as a number of clinical endpoint trials specifically focusing on the effect(s) of HDL-C increasing agents are underway. Moreover, recent data show that HDL efflux capacity could hold independent predictive value for CVD events, which clearly highlights the potential need to focus on HDL functionality, rather than on HDL-C levels.
Summary:
The dogmatic concept that HDL-C levels predict future CVD events is undisputed, but the role of HDL-C as a causal factor in atherosclerosis has been challenged by a number of different types of studies. In recent years, a paradigm shift toward 'HDL functionality' is apparent. Whether or not optimizing these markers of HDL functionality actually does reduce CVD risk requires formal testing in prospective controlled studies.
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