Paradoxical Association of Enhanced Cholesterol Efflux With Increased Incident Cardiovascular Risks

Abstract

Objective Diminished cholesterol efflux activity of apolipoprotein B (apoB)–depleted serum is associated with prevalent coronary artery disease, but its prognostic value for incident cardiovascular events is unclear. We investigated the relationship of cholesterol efflux activity with both prevalent coronary artery disease and incident development of major adverse cardiovascular events (death, myocardial infarction, or stroke). Approach and Results Cholesterol efflux activity from free cholesterol–enriched macrophages was measured in 2 case– control cohorts: (1) an angiographic cohort (n=1150) comprising stable subjects undergoing elective diagnostic coronary angiography and (2) an outpatient cohort (n=577). Analysis of media from cholesterol efflux assays revealed that the high-density lipoprotein fraction (1.063<d<1.21) contained only a minority (≈40%) of [14C]cholesterol released, with the majority found within the lipoprotein particle–depleted fraction, where ≈60% was recovered after apolipoprotein A1 immunoprecipitation. Albumin immunoprecipitation recovered another ≈30% of radiolabeled cholesterol within this fraction. Enhanced cholesterol efflux activity from ATP-binding cassette transporter A1–stimulated macrophages was associated with reduced risk of prevalent coronary artery disease in unadjusted models within both cohorts; however, the inverse risk relationship remained significant after adjustment for traditional coronary artery disease risk factors only within the outpatient cohort. Surprisingly, higher cholesterol efflux activity was associated with increase in prospective (3 years) risk of myocardial infarction/stroke (adjusted hazard ratio, 2.19; 95% confidence interval, 1.02–4.74) and major adverse cardiovascular events (adjusted hazard ratio, 1.85; 95% confidence interval, 1.11–3.06). Conclusions Heightened cholesterol efflux to apoB-depleted serum was paradoxically associated with increased prospective risk for myocardial infarction, stroke, and death. The majority of released radiolabeled cholesterol from macrophages in cholesterol efflux activity assays does not reside within a high-density lipoprotein particle.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…nonfatal myocardial infarction, nonfatal stroke, or death. 50 In contrast, Rohatgi et al, revealed in a biobank of 2924 participants from the multiethnic Dallas Heart Study that the risk for future atherosclerotic cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or death from cardiovascular causes) decreases with increasing quartiles of cholesterol efflux capacity. 51 In 2450 probands of the LURIC study who underwent diagnostic coronary angiography, cholesterol efflux capacity was also inversely associated with cardiovascular mortality during 10 years of follow-up.…”

“…49 Two case-control cohort studies supported these earlier observations regarding the inverse association between cholesterol efflux capacity and prevalent CAD. 50 Several studies have addressed the usefulness of cholesterol efflux capacity as a predictor for cardiovascular disease events and got inconsistent findings. The first prospective analysis on HDL function reported by Li et al unexpectedly showed a higher cell-derived cholesterol efflux capacity being associated with a higher rather than a lower incident risk for nonfatal myocardial infarction/stroke and major adverse cardiovascular events, i.e.…”

“…51 Vice versa, the capacity of serum to elicit cholesterol efflux from RAW 264.7 or J774 cells correlated rather strongly (r = 0.92), yet Li et al did not find any association of cholesterol efflux capacity with incident CHD. 50 Because of the conflicting results and methodological differences, the causal contribution of HDL dysfunction to cardiovascular diseases is as yet not proven. The proof will depend on the elaboration of the molecular basis of disturbed cholesterol efflux capacity.…”

“…[49][50][51]240 Accuracy is difficult to assess because there is no gold standard. Cholesterol efflux capacity appears to be strongly influenced by the method used.…”

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

“…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…”