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.
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.
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.
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.).
Although 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.
We 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.
Cholesterol 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.
HDL 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.
US National Institutes of Health, UK Medical Research Council, Cancer Research UK.
Objectives This study sought to examine the role of lipoprotein-associated phospholipase A2 (Lp-PLA2 / PLA2G7 ) in human inflammation and coronary atherosclerosis. Background Lp-PLA2 has emerged as a ...potential therapeutic target in coronary heart disease. Data supporting Lp-PLA2 are indirect and confounded by species differences; whether Lp-PLA2 is causal in coronary heart disease remains in question. Methods We examined inflammatory regulation of Lp-PLA2 during experimental endotoxemia in humans, probed the source of Lp-PLA2 in human leukocytes under inflammatory conditions, and assessed the relationship of variation in PLA2G7 , the gene encoding Lp-PLA2 , with coronary artery calcification. Results In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA2 messenger ribonucleic acid decreased transiently, and plasma Lp-PLA2 mass declined modestly during endotoxemia. In vitro, Lp-PLA2 expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms in PLA2G7 with Lp-PLA2 activity or mass, numerous PLA2G7 single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms in CRP were significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification. Conclusions Circulating Lp-PLA2 did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA2 . Common genetic variation in PLA2G7 is associated with subclinical coronary atherosclerosis. These data link Lp-PLA2 to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA2 as a biomarker of Lp-PLA2 actions in the vasculature.
Objectives This study sought to examine the role of lipoprotein-associated phospholipase A2(Lp-PLA2/PLA2G7) in human inflammation and coronary atherosclerosis. Background Lp-PLA2has emerged as a ...potential therapeutic target in coronary heart disease. Data supporting Lp-PLA2are indirect and confounded by species differences; whether Lp-PLA2is causal in coronary heart disease remains in question. Methods We examined inflammatory regulation of Lp-PLA2during experimental endotoxemia in humans, probed the source of Lp-PLA2in human leukocytes under inflammatory conditions, and assessed the relationship of variation inPLA2G7, the gene encoding Lp-PLA2, with coronary artery calcification. Results In contrast to circulating tumor necrosis factor-alpha and C-reactive protein, blood and monocyte Lp-PLA2messenger ribonucleic acid decreased transiently, and plasma Lp-PLA2mass declined modestly during endotoxemia. In vitro, Lp-PLA2expression increased dramatically during human monocyte to macrophage differentiation and further in inflammatory macrophages and foamlike cells. Despite only a marginal association of single nucleotide polymorphisms inPLA2G7with Lp-PLA2activity or mass, numerousPLA2G7single nucleotide polymorphisms were associated with coronary artery calcification. In contrast, several single nucleotide polymorphisms inCRPwere significantly associated with plasma C-reactive protein levels but had no relation with coronary artery calcification. Conclusions Circulating Lp-PLA2did not increase during acute phase response in humans, whereas inflammatory macrophages and foam cells, but not circulating monocytes, are major leukocyte sources of Lp-PLA2. Common genetic variation inPLA2G7is associated with subclinical coronary atherosclerosis. These data link Lp-PLA2to atherosclerosis in humans while highlighting the challenge in using circulating Lp-PLA2as a biomarker of Lp-PLA2actions in the vasculature.
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