High-Density Lipoprotein: NO Failure in Heart Failure

Despite numerous epidemiological studies demonstrating that high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk,1–3 several lines of evidence now indicate that targeting HDL-C levels to reduce the risk of cardiovascular events is unlikely to be effective. Studies of pharmacological interventions to raise HDL-C, such as niacin4,5 and 2 cholesteryl ester transfer protein inhibitors,6,7 have shown no benefit in reducing cardiovascular events. In addition, data from a large Mendelian randomization study have shown that some genetic variants associated with HDL-C seem to have little relationship to coronary heart disease.8 As a result, there is currently skepticism about whether interventions specifically to raise HDL-C levels will decrease the risk of cardiovascular events. Article, see p 1345 This failure of the so-called HDL cholesterol hypothesis has been accompanied by a shift toward a more rigorous, basic understanding of HDL as a molecule with multiple functions that can be differentiated from simple measures of HDL cholesterol mass. One of the important functions of HDL is its role in promoting cellular cholesterol efflux and reverse cholesterol transport. Our group and others have shown that the capacity of HDL to promote cholesterol efflux from macrophages ex vivo is inversely related to the risk of coronary heart disease even after controlling for HDL-C levels.9,10 Furthermore, niacin therapy does not augment cholesterol efflux despite raising HDL levels in statin-treated patients,11 which could explain the lack of efficacy of niacin despite increased HDL-C levels. Although more studies are certainly warranted, one hypothesis is that therapies that improve cholesterol efflux capacity and reverse cholesterol transport, such as infusion of a reconstituted HDL12 composed of apolipoprotein A1 and phospholipids, may improve cardiovascular outcomes. Beyond promoting cholesterol efflux, HDL is known to have anti-inflammatory, …