This review aims to provide an overview on the properties of high-density lipoproteins (HDLs) and their cardioprotective effects. Emergent HDL therapies will be presented in the context of the current understanding of HDL function, metabolism, and protective antiatherosclerotic properties. The epidemiological association between levels of HDL-C or its major apolipoprotein (apoA-I) is strong, graded, and coherent across populations. HDL particles mediate cellular cholesterol efflux, have antioxidant properties, and modulate vascular inflammation and vasomotor function and thrombosis. A link of causality has been cast into doubt with Mendelian randomization data suggesting that genes causing HDL-C deficiency are not associated with increased cardiovascular risk, nor are genes associated with increased HDL-C, with a protective effect. Despite encouraging data from small studies, drugs that increase HDL-C levels have not shown an effect on major cardiovascular end-points in large-scale clinical trials. It is likely that the cholesterol mass within HDL particles is a poor biomarker of therapeutic efficacy. In the present review, we will focus on novel therapeutic avenues and potential biomarkers of HDL function. A better understanding of HDL antiatherogenic functions including reverse cholesterol transport, vascular protective and antioxidation effects will allow novel insight on novel, emergent therapies for cardiovascular prevention. 1. Introduction An increasing body of literature emphasizes the concept that HDL functionality, rather than the absolute cholesterol mass (HDL-C), may be a more accurate indicator for risk of developing atherosclerosis [1]. This hypothesis has led to investigation of HDL as both a biomarker for cardiovascular risk and a therapeutic target to be functionally modulated [2]. Epidemiological studies consistently demonstrate that low plasma level of HDL-C is associated with increased risk of CVD, but this epidemiological association has not translated into evidence that raising HDL-C prevents CVD. Atherosclerosis remains the leading cause of death in developed countries and is a major health concern worldwide. While LDL cholesterol (LDL-C) is clearly established as the major lipoprotein risk factor [3], the residual risk in large-scale clinical trials raises concern that other lipoprotein fractions may be causal in this residual risk. Increasingly, questions have been raised around the hypothesis that raising HDL-C pharmacologically is necessary beneficial. In this regard, after the recent failure of the drugs torcetrapib,
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