HDL cholesterol efflux capacity and incident cardiovascular events

Abstract

Background: It is unclear whether high-density lipoprotein (HDL) cholesterol concentration plays a causal role in atherosclerosis. A more important factor may be HDL cholesterol efflux capacity, the ability of HDL to accept cholesterol from macrophages, which is a key step in reverse cholesterol transport. We investigated the epidemiology of cholesterol efflux capacity and its association with incident atherosclerotic cardiovascular disease outcomes in a large, multiethnic population cohort.

Methods: We measured HDL cholesterol level, HDL particle concentration, and cholesterol efflux capacity at baseline in 2924 adults free from cardiovascular disease who were participants in the Dallas Heart Study, a probability-based population sample. The primary end point was atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization or death from cardiovascular causes. The median follow-up period was 9.4 years.

Results: In contrast to HDL cholesterol level, which was associated with multiple traditional risk factors and metabolic variables, cholesterol efflux capacity had minimal association with these factors. Baseline HDL cholesterol level was not associated with cardiovascular events in an adjusted analysis (hazard ratio, 1.08; 95% confidence interval [CI], 0.59 to 1.99). In a fully adjusted model that included traditional risk factors, HDL cholesterol level, and HDL particle concentration, there was a 67% reduction in cardiovascular risk in the highest quartile of cholesterol efflux capacity versus the lowest quartile (hazard ratio, 0.33; 95% CI, 0.19 to 0.55). Adding cholesterol efflux capacity to traditional risk factors was associated with improvement in discrimination and reclassification indexes.

Conclusions: Cholesterol efflux capacity, a new biomarker that characterizes a key step in reverse cholesterol transport, was inversely associated with the incidence of cardiovascular events in a population-based cohort. (Funded by the Donald W. Reynolds Foundation and others.).

Figure 1. Atherosclerotic Cardiovascular Disease Events, According to Models Based on High-Density Lipoprotein (HDL) Cholesterol Level and Cholesterol Efflux Capacity

Hazard ratios and 95% confidence intervals (CIs), derived from Cox proportional-hazards models, are shown for the comparisons of quartile 4 (highest) with quartile 1 (lowest) of cholesterol efflux capacity. A total of 132 participants had a primary end-point event of atherosclerotic cardiovascular disease, defined as a first nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (percutaneous coronary intervention or coronary-artery bypass grafting) or death from cardiovascular causes. Traditional risk factors included age, sex, race, presence or absence of diabetes, presence or absence of hypertension, status with regard to current smoking, body-mass index, total cholesterol level, log-transformed triglyceride level, and status with regard to a history of statin use.

Figure 2. Kaplan–Meier Curves and Hazard Ratios for Cardiovascular Events, According to Quartile of Cholesterol Efflux Capacity

Kaplan–Meier curves and hazard ratios and 95% confidence intervals are shown for quartiles (Q1 through Q4) of cholesterol efflux capacity, with the use of quartile 1 (lowest cholesterol efflux capacity) as the reference, derived from Cox proportional-hazards models. Each quartile had equal numbers of men and women, and equal numbers of blacks and nonblacks. A total of 132 participants had a primary end-point event of atherosclerotic cardiovascular disease (Panel A), and 172 had a secondary end-point event of total cardiovascular disease (Panel B). Total cardiovascular disease was defined as the composite of the end points related to atherosclerotic cardiovascular disease and peripheral revascularization or hospitalization for heart failure or atrial fibrillation. Adjusted models included traditional risk factors for atherosclerotic cardiovascular disease, HDL cholesterol level, and HDL particle concentration. The insets show the same data on enlarged y axes.