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Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD.

ABSTRACT: BACKGROUND:Patients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implications for cardiovascular disease. METHODS:We recruited 120 CKD patients (eGFR<30mL/min/1.73m2) and 120 control subjects (eGFR ?60mL/min/1.73m2) in order to measure cholesterol efflux using either patients' HDL and THP-1 macrophages or patients' monocytes and a flow cytometry based cholesterol efflux assay. We also measured cell-surface levels of the common ? subunit of the IL-3/GM-CSF receptor (IL-3R?) which has been linked to defective cholesterol homeostasis and may promote monocytosis. In addition, we measured plasma inflammatory cytokines and plasma metabolite profiles. RESULTS:There was a strong positive correlation between cell-surface IL-3R? levels and monocyte counts in CKD (P<0.001). ABCA1 mRNA was reduced in CKD vs. control monocytes (P<0.05), across various etiologies of CKD. Cholesterol efflux to apolipoprotein A1 was impaired in monocytes from CKD patients with diabetic nephropathy (P<0.05), but we found no evidence for a circulating HDL-mediated defect in cholesterol efflux in CKD. Profiling of plasma metabolites showed that medium-chain acylcarnitines were both independently associated with lower levels of cholesterol transporter mRNA in CKD monocytes at baseline (P<0.05), and with cardiovascular events in CKD patients after median 2.6years of follow-up. CONCLUSIONS:Cholesterol efflux in humans varies in terms of cellular components. We report a cellular defect in ABCA1-mediated cholesterol efflux in monocytes from CKD patients with diabetic nephropathy. Unlike several traditional risk factors for atherosclerotic cardiovascular disease, plasma metabolites inversely associated with endogenous cholesterol transporters predicted cardiovascular events in CKD patients. (Funded by the National Institute of Diabetes and Digestive and Kidney DiseasesK23DK097288 and others.).

SUBMITTER: Ganda A

PROVIDER: S-EPMC5708851 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD.

Ganda Anjali A Yvan-Charvet Laurent L Zhang Yuan Y Lai Eric J EJ Regunathan-Shenk Renu R Hussain Farah N FN Avasare Rupali R Chakraborty Bibhas B Febus Annie J AJ Vernocchi Linda L Lantigua Rafael R Wang Ying Y Shi Xu X Hsieh Joanne J Murphy Andrew J AJ Wang Nan N Bijl Nora N Gordon Kristie M KM de Miguel Maria Hamm MH Singer Jessica R JR Hogan Jonathan J Cremers Serge S Magnusson Martin M Melander Olle O Gerszten Robert E RE Tall Alan R AR

Journal of molecular and cellular cardiology 20170504

<h4>Background</h4>Patients with chronic kidney disease (CKD) experience high rates of atherosclerotic cardiovascular disease and death that are not fully explained by traditional risk factors. In animal studies, defective cellular cholesterol efflux pathways which are mediated by the ATP binding cassette transporters ABCA1 and ABCG1 are associated with accelerated atherosclerosis. We hypothesized that cholesterol efflux in humans would vary in terms of cellular components, with potential implic ...[more]

PMID: 28478047

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Project description: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.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.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.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.).

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Dataset Information

Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD.

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Plasma metabolite profiles, cellular cholesterol efflux, and non-traditional cardiovascular risk in patients with CKD.

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