Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study

Abstract

SummaryBackgroundAlthough HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity—a prototypical measure of HDL function—has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain.MethodsWe measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40–79 years, assessed in 1993–97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants.FindingsCholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=–0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51–0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70–0·90) for a per-SD change in cholesterol efflux capacity.InterpretationHDL cholesterol efflux capacity might provide an alternative mechanism for therapeutic modulation of the HDL pathway beyond HDL cholesterol concentration to help reduce risk of coronary heart disease.FundingUS National Institutes of Health, UK Medical Research Council, Cancer Research UK.

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…Population studies elucidated HDLs as an independent inverse predictor of cardiovascular disease 30, 31. These epidemiologic findings were confirmed in vitro and in animal models, as supported by promotion of cholesterol efflux from cells or tissues,32 inhibition of vascular inflammation33, and improved endothelial cell function 34.…”

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

“…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…”

Beneficial Effects of Exercise-Based Cardiac Rehabilitation on High-Density Lipoprotein-Mediated Cholesterol Efflux Capacity in Patients with Acute Coronary Syndrome

“…Rohatgi et al used fluorescently labeled cholesterol method to measure cholesterol efflux capacity in the Dallas Heart Study, a population-based cohort study, and demonstrated that lower levels of cholesterol efflux capacity at baseline was a significant predictor for the incidence of atherosclerotic cardiovascular disease (CVD) during a 9.4-year follow-up period, independently of traditional risk factors including HDL-C, whereas HDL-C was not associated with the incidence of CVD 15) . Saleheen et al used radiolabeled cholesterol method to measure cholesterol efflux capacity in the EPIC-Norfolk study, a population-based prospective case-control study, and demonstrated that cholesterol efflux capacity was significantly inversely associated with incident CAD independent of established cardiovascular risk factors even after adjusting for HDL-C or apolipoprotein A1 16) . These results, therefore indicate the not level of HDL-C but the HDL function would attract much attention as an important therapeutic target for CAD.…”