Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24‐week follow‐up using J774 macrophages, boron dipyrromethene difluoride–labeled cholesterol, and apolipoprotein B–depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard β, 0.23; 95% CI, 0.05–0.41). This CEC‐raising effect was seen only in men ( P interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1‐1 haptoglobin genotype (standard β, 0.42; 95% CI, 0.16–0.69) but not the dysfunctional 2‐1/2‐2 genotypes ( P interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high‐density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.
Metabolic syndrome (MetS) is characterized by adiposity and atherogenic dyslipidemia consisting of elevated triglyceride and decreased high density lipoprotein cholesterol (HDL-C) levels however, cholesterol concentration alone does not reflect HDL functionality. Cholesterol efflux capacity (CEC) captures a key anti-atherosclerotic function of HDL; studies linking CEC to MetS have yielded inconsistent findings and lacked racial/ethnic diversity. The aim of this study was to evaluate the association between CEC and MetS in a large multi-ethnic population utilizing two different CEC assays interrogating overlapping but distinct reverse cholesterol transport pathways. A cross-sectional study was performed using the Dallas Heart Study cohort and cholesterol efflux was measured with radiolabeled and fluorescent cholesterol assays. The relationship between CEC and MetS was assessed using multivariable regression analyses. A total of 2241 participants were included (mean age was 50 years; 38% men and 53% Blacks). CEC was independently and inversely associated with MetS irrespective of efflux assay (CEC-radiolabeled, adjusted OR 0·71 [95% CI 0·65–0·80]. CEC-fluorescent, adjusted OR 0·85 [95% CI 0·77–0·94]). Both CEC measures were inversely associated with waist circumference and directly associated with HDL-C but not with other MetS components. There was an interaction by sex but not by race such that the inverse associations between CEC and MetS were somewhat attenuated in men (OR 0·86, 95%CI 0·74–1·01). In this large multi-ethnic cohort, impaired CEC is linked to MetS irrespective of efflux assay and race/ethnicity but less so among men. Future studies are needed to assess whether CEC mediates the atherosclerotic cardiovascular disease risk of MetS.
Objective: Cholesterol efflux capacity (CEC), the ability of extracellular acceptors to pick-up cholesterol from macrophages, is a clinically relevant cardiovascular biomarker. CEC is inversely associated with incident atherosclerotic cardiovascular disease events. However, CEC is only modestly associated with HDL-C (high-density lipoprotein cholesterol) levels, which may explain the failure of HDL-C raising therapies to improve atherosclerotic cardiovascular disease outcomes. Determinants of variation in CEC are not well understood. Thus, we sought to establish whether extreme high and low CEC is a robust persistent phenotype and to characterize associations with cholesterol, protein, and phospholipids across the particle size distribution. Approach and Results: CEC was previously measured in 2924 participants enrolled in the Dallas Heart Study, a multi-ethnic population-based study from 2000 to 2002. We prospectively recruited those who were below the 10th and above 90th percentile of CEC. Our study revealed that extreme low and high CEC are persistent, robust phenotypes after 15 years of follow-up. Using size exclusion chromatography, CEC to fractionated plasma depleted of apolipoprotein B (fraction-specific CEC) demonstrated significant differences in CEC patterns between persistent high and low efflux groups. Fraction-specific CEC was correlated with fraction-specific total phospholipid but not apolipoprotein A-I, cholesterol, or total protein. These correlations varied across the size distribution and differed among persistent high versus low efflux groups. Conclusions: Extreme high and low CEC are persistent and robust phenotypes. CEC patterns in fractionated plasma reveal marked variation across the size distribution. Future studies are warranted to determine specific molecular species linked to CEC in a size-specific manner.
High‐density lipoprotein cholesterol (HDL‐C) is well known to play an important anti‐atherogenic role via reverse cholesterol transport. Increasing number of studies in mice have also suggested a protective role of HDL in preserving muscle mitochondrial function via ApoA1‐induced enhancement of cellular respiration of glucose. However, data in humans are lacking. We therefore hypothesize that HDL levels and/or function are correlated with muscle mitochondrial function in humans. Accordingly, we conducted a cross‐sectional study to determine the relationship between levels and function of HDL and skeletal muscle mitochondrial function in 31 healthy adults without diabetes mellitus or cardiovascular disease. To estimate muscle mitochondrial function, we measured the oxygen recovery time constant (Tau) during supra‐systolic cuff‐occlusions following 2 minutes of rhythmic handgrip exercise at 30% maximal voluntary contraction in the forearm muscle, using near infrared spectroscopy (NIRS). To assess cholesterol efflux capacity (CEC), we used J774 macrophages, radiolabeled cholesterol, and ApoB‐depleted plasma to calculate cholesterol efflux normalized to a pooled sample. Of the 31 subjects, 13 (42%) were female, mean age was 40 +/‐ 16, mean BMI was 23.9 +/‐ 3.4 kg/m^2, and the mean total serum cholesterol was 198.4 +/‐ 43.1 mg/dL. We found a significant inverse correlation between HDL‐C levels and Tau, with a correlation coefficient (r) of ‐0.51 (p < 0.01, Figure. 1a). As expected, a positive correlation is observed between BMI and Tau (r= 0.50, p < 0.01, Figure 1c). In contrast, no significant correlation between fasting triglyceride, plasma glucose, insulin levels or HDL efflux function with Tau were found (all p‐values > 0.05). In conclusion, our study identifies a novel association between circulating HDL levels with muscle mitochondrial function. However, the CEC of our sample was not significantly correlated with Tau, therefore future investigations with larger studies or more measures of HDL function and composition may elucidate these findings. The association of HDL‐C and muscle mitochondrial function may explain increased prevalence of physical inactivity among populations with low HDL‐C, such as those with metabolic syndrome. Additionally, future studies are needed to determine if strategies to improve HDL‐C levels will result in improved muscle mitochondrial function and exercise capacity.
Introduction: While high-density lipoprotein (HDL) cholesterol is a component of metabolic syndrome, an ASCVD risk factor, other markers of HDL metabolism better associate with ASCVD. However, it is unclear whether these markers better discriminate between metabolic health and obese groups. Hypothesis: We hypothesized that higher cholesterol efflux capacity (CEC) and a favorable HDL profile would be associated with metabolically healthy profiles within each weight category. Methods: Data from the second phase of the Dallas Heart Study were used to classify participants (n=2156) into four groups based on a harmonized definition of metabolic health and obesity status: Metabolically Healthy, Normal Weight (MHNW); Metabolically Unhealthy, Normal Weight (MUNW); Metabolically Healthy, Obese (MHO); Metabolically Unhealthy, Obese (MUO). MU was classified as having one or more of the following: elevated blood pressure (SBP/DBP ≥130/85 mmHg), fasting glucose (≥100 mg/dL), or fasting triglycerides (≥150 mg/dL); a history of CVD or diabetes; or any medications for these conditions. Obesity was defined as BMI ≥ 30kg/m 2 . CEC was measured using J774 macrophages, BODIPY- and radio-labeled cholesterol, and apoB-precipitated plasma. HDL particle (HDL-P) subfractions were quantified by NMR spectroscopy. Generalized linear models were used to compare paired means of CEC and HDL traits between groups controlling for age, sex, race, and smoking. Results: Small HDL-P concentration was higher in MU groups regardless of weight status. Total and medium HDL-P concentrations and radio-labeled CEC were higher in NW groups, regardless of metabolic health status. Mean HDL-P size and large HDL-P concentrations were different across all groups, with the rank order being MHNW, MUNW, MHO, MUO (Table 1). Conclusions: In conclusion, associations between HDL subfractions, CEC and metabolic/weight status are heterogeneous, highlighting the complexity of HDL physiology as it pertains to body weight and metabolic disease.
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