High-Density Lipoproteins, Endothelial Function, and Mendelian Randomization.

Although plasma high-density lipoprotein (HDL) cholesterol levels correlate inversely with the incidence of cardiovascular disease, the causative nature of this relationship has been called into question by Mendelian randomization studies and several failed clinical trials involving HDL-raising drugs. Studies in humans have indicated that the macrophage cholesterol efflux capacity of HDL is a strong inverse predictor of subclinical atherosclerosis and cardiovascular disease and remains highly statistically significant after correction for HDL cholesterol levels, suggesting that HDL-C levels may be a poor surrogate for key functions of HDL mediating antiatherogenic effects. In this issue of Circulation Research, Monette et al measured acetylcholine-induced coronary artery vasodilation, an indicator of endothelial nitric oxide (NO) bioavailability, in subjects undergoing coronary angiography, and showed that the cholesterol efflux capacity of HDL correlated inversely with coronary endothelial dysfunction (ED), a key event in early atherogenesis. In contrast, HDL and lowdensity lipoprotein cholesterol levels did not correlate with coronary ED. However, the HDL particle concentration, as assessed by ion mobility analysis, did correlate with HDL cholesterol efflux capacity and inversely correlated with coronary ED, leading to the conclusion that both HDL cholesterol efflux capacity and HDL particle concentration might provide clinically useful information on ED and coronary risk and further supporting that HDL-mediated cholesterol efflux is directly related to suppression of atherogenesis in humans.