Cholesterol Efflux Capacity, High-Density Lipoprotein Function, and Atherosclerosis

Abstract

BACKGROUND High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden. METHODS We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima–media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B–depleted serum from the study participants. RESULTS The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima–media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P = 0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P = 0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. CONCLUSIONS Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.)

Variants at the APOE/C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High‐Density Lipoprotein Cholesterol

“…Using unsupervised hierarchical clustering, we noted that the BHK‐stimulated assay clustered with the J774‐basal model in controls, but with the J774‐stimulated and J774‐ABCA1–dependent measures in cases (Figure 1). Finally, we confirmed that CECs were associated with reduced prevalent CAD events, thus replicating previous observations3 and validating our data set (Table 1). …”

“…Background cholesterol efflux (obtained in the absence of apolipoprotein B–depleted plasma) was subtracted from individual cholesterol efflux values. To correct for interassay variability, CEC was measured with the same pool of 40 healthy volunteers’ serum in each assay, and individual percentage CEC values were divided (normalized) by percentage CEC of control serum in each assay, as described previously 3, 5. Control serum CEC values were required to be within the limits defined by the historical mean of CEC for each model, plus or minus 2 SDs, to allow batch qualification.…”

“…Cholesterol efflux from macrophages occurs mainly toward HDL particles through multiple pathways, including passive diffusion, as well as facilitated ABCG1‐ and SR‐BI–dependent transport and active ABCA1‐dependent transport 2. CEC of HDL represents the fraction of radiolabeled cholesterol exiting macrophages typically after 4 hours of incubation, and higher CEC values have been shown to be associated with reductions of both prevalent and incident cardiovascular disease,3, 4, 5 although conflicting reports have been published 6…”

Polyunsaturated fatty acids supplementation impairs anti‐oxidant high‐density lipoprotein function in heart failure

“…As HDL cholesterol concentrations were found predictive for HF exacerbations independent of HF aetiology,5 increasing research has focused on HDL. It has become apparent that quality and function of HDL may relate more to outcome in CV diseases than serum levels 6. Particularly, the anti‐oxidant capacity of HDL was found associated with HF and clinical outcome,7 emphasizing the pivotal role of oxidative stress in the pathogenesis of HF.…”

Impact of Self-association on Function of Apolipoprotein A-I

“…Increasing our knowledge of this fundamental property of apoA-I has clinical significance because apoA-I plasma levels uniquely predict risk of cardiovascular disease (22)(23)(24). One pathway through which apoA-I exerts its beneficial lipid trafficking function involves the plasma membrane transporter ATP-* This work was supported by a new investigator award from the TobaccoRelated Disease Research Program of California (Grant 18KT-0021) and an International Atherosclerosis Society Visiting Fellowship Award.…”