Patients With Coronary Endothelial Dysfunction Have Impaired Cholesterol Efflux Capacity and Reduced HDL Particle Concentration

Abstract

Rationale Coronary endothelial dysfunction (ED)–an early marker of atherosclerosis–increases the risk of cardiovascular events. Objective We tested the hypothesis that cholesterol efflux capacity and HDL particle concentration predict coronary ED better than HDL-cholesterol (HDL-C). Methods and Results We studied 80 subjects with non-obstructive (<30% stenosis) coronary artery disease. ED was defined as <50% change in coronary blood flow in response to intra-coronary infusions of acetylcholine during diagnostic coronary angiography. Cholesterol efflux capacity and HDL particle concentration (HDL-PIMA) were assessed with validated assays. Cholesterol efflux capacity and HDL-PIMA were both strong, inverse predictors of ED (P<0.001 and 0.005, respectively). In contrast, HDL-C and other traditional lipid risk factors did not differ significantly between control and ED subjects. Large HDL particles were markedly decreased in ED subjects (33%; P=0.005). After correction for HDL-C, both efflux capacity and HDL-PIMA remained significant predictors of ED status. HDL-PIMA explained cholesterol efflux capacity more effectively than HDL-C (r=0.54 and 0.36, respectively). The efflux capacities of isolated HDL and serum HDL correlated strongly (r=0.49). Conclusions Cholesterol efflux capacity and HDL-PIMA are reduced in subjects with coronary ED, independently of HDL-C. Alterations in HDL-PIMA and HDL itself account for a much larger fraction of the variation in cholesterol efflux capacity than does HDL-C. A selective decrease in large HDL particles may contribute to impaired cholesterol efflux capacity in ED subjects. These observations support a role for HDL size, concentration and function as markers—and perhaps mediators—of coronary atherosclerosis in humans.

High-Density Lipoproteins, Endothelial Function, and Mendelian Randomization

“…2, 17 This generalization appears to be refuted by results of cholesterol efflux studies on HDL such as the present work by Monette et al , 5 earlier macrophage efflux studies, 4, 18, 19 as well as by numerous findings in preclinical models. 20 Moreover, a recent study identified a rare loss of function variant of SCARB1 , the gene encoding SR-BI.…”

“…3 Studies in humans have indicated that the macrophage cholesterol efflux capacity of HDL is a strong inverse predictor of subclinical atherosclerosis and CVD, and remains highly statistically significant after correction for HDL-cholesterol levels, 4 suggesting that HDL cholesterol levels may be a poor surrogate for key functions of HDL mediating anti-atherogenic effects. In this issue of Circulation Research , Monette et al 5 measured acetylcholine-induced coronary artery vasodilation, an indicator of endothelial 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 LDL cholesterol levels did not correlate with coronary ED.…”

“…In contrast, HDL and LDL cholesterol levels did not correlate with coronary ED. 5 However, the HDL particle concentration, as assessed by ion mobility analysis, did correlate with HDL’s 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 5 and further supporting that HDL-mediated cholesterol efflux is directly related to suppression of atherogenesis in humans.…”

“…6 The same cholesterol efflux pathways have been implicated in endothelial cells. 7 Interestingly, patients’ medium and large, but not small HDL particles correlated positively with cholesterol efflux capacity and inversely with ED, 5 suggesting that cholesterol efflux mediated by ABCG1 could be important in maintaining coronary endothelial function. ABCG1, but not ABCA1, is highly expressed in cultured human aortic endothelial cells, 7 and in mice, ABCG1 as well as Scavenger Receptor BI (SR-BI) have been shown to interact with HDL to maintain the activity of endothelial NO synthase (eNOS), preserving endothelial function.…”

Time to ditch HDL-C as a measure of HDL function?

“…In a small study, the concentration of medium-sized HDL particles was selectively lower in subjects with advanced carotid atherosclerotic disease, independent of HDL-C levels [21]. Also, altered HDL particle concentration—but not HDL-C levels—predicts endothelial dysfunction as assessed by coronary angiography, supporting the notion that the size and concentration of HDL particles is an independent predictor of CVD risk [50]. …”