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Amit V Khera,
Marina Cuchel,
Margarita de la Llera-Moya,
Amrith Rodrigues, Megan F Burke,
Kashif Jafri,
Benjamin C French,
Julie A Phillips,
Megan L Mucksavage,
Robert L Wilensky,
Emile R Mohler,
George H Rothblat,
Daniel J Rader
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ABSTRACT: 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.).
New England Journal of Medicine 01/2011; 364(2):127-35. · 53.30 Impact Factor
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ABSTRACT: Regular physical activity and especially aerobic exercise are associated with reduced risk of disease and enhanced longevity, but the molecular mechanisms of these health benefits remain obscure. A comprehensive metabolomic approach was used to characterize the changes in blood levels of >200 metabolites upon vigorous exercise and identified two dozen that changed substantially. One, niacinamide, is intimately related to the metabolism of nicotinamide adenine dinucleotide (NAD(+)) and its reduced form NADH, which is in turn linked with exercise capacity as well as health status. Intensive investigation of metabolic changes with exercise could lead to pharmacological attempts to mimic the beneficial effects of exercise, an approach we term "gymnomimetics."
Science translational medicine 07/2010; 2(41):41ps35. · 7.80 Impact Factor
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Circulation Research 03/2010; 106(4):627-9. · 9.49 Impact Factor
