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High-density lipoprotein (HDL) is the particle transporting cholesterol from peripheral tissues to liver and thus high-density lipoprotein-cholesterol (HDL-C) has been considered as a major negative risk factor for coronary heart disease.1) In Framingham study, 12 years of follow-up showed a significant HDL-C effect on total and cardiovascular (CV) mortality.2) Not only epidemiologic studies but also clinical trials such as the Veterans Affairs High-density lipoprotein Intervention Trial (VA-HIT) suggested the beneficial effect of raising HDL-C.3) Not only the direct effect, the role of HDL-C as a modifying factor of statin effect has been also reported.4) However, further studies has shown that the relationship between HDL-C and CV diseases is not that simple. Cholesteryl ester transfer protein (CETP) inhibitor is a powerful raiser of HDL-C. Several CETP inhibitors have underwent clinical trials and mostly showed negative results regarding CV risk reduction except Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) study. Even this result has met critique that it may be due to the reduction of non-HDL-C, not the increase in HDL-C.5) A meta-analysis showed that simply increasing the amount of HDL-C does not reduce the CV risk once adjusted to low-density lipoprotein cholesterol reduction.6) If HDL-C reduction is an inadequate solution, where do we go from here? The function of HDL particle is probably the next subject to dig into.
Khera et al.7) reported that HDL function, measured by cholesterol efflux capacity from macrophages, had strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL-C level. If the HDL function really influences clinical outcome, what should be done to make it clinically applicable? Probably we need a reliable biomarker for HDL function, which is standardized, accurate and easy to measure. And treatment target should be changed from simply increasing the HDL-C level to improving the HDL function. There are several ongoing (and stopped) projects to enhance reverse cholesterol transport function of HDL,8) but the hurdle to success seems to be quite high.
In the current issue of the Korean Circulation Journal, Choi et al.9) investigates the relationship between HDL functions and HDL-associated proteins. The authors used not only cholesterol efflux capacity but also endothelial nitric oxide production and vascular cell adhesion molecule expression as indices of HDL function. They reported 19 proteins were associated with the higher HDL function and seven proteins with the lower function. While the authors are rather prudent in suggesting its clinical implications, this work seems to provide an intriguing starting point for further research. As the authors commented, there are significant limitations that clinical settings of the patients were not adequately addressed in the analysis and we do not know how the heterogeneity of subjects influenced the results. Some of the proteins they reported might be merely ‘associated’ and not with a significant functional role. However, at least this study may provide a candidate list for biomarker for HDL function, or even better, a list of possible target molecules for treatment to enhance HDL function. We still suffer from inadequate knowledge for HDL and is looking forward to a breakthrough. A long and winding road is ahead of us.
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