Impaired Cholesterol Efflux Capacity May Help Explain Development of Early Coronary Artery Disease in Subjects with Very High HDL-C
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Plasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with coronary artery disease (CAD), and high HDL-C is generally associated with apparent 'protection' from CAD. A minority of individuals with very high HDL-C levels also develops CAD, a paradoxical phenotype. We hypothesize that such individuals may have HDL with altered structure and/ or function, and compared these individuals (cases) to individuals with very high HDL-C without CAD (controls). We identified 55 subjects with HDL-C above the 90th percentile, early CAD, and no major risk factors for coronary disease. We selected 120 controls without CAD, each matched for race, gender, and HDL-C level. Controls were selected to be the same age or no more than 10 years older than the cases. Studies to assess HDL composition and size distribution, cholesterol efflux capacity, and lecithin-cholesterol acyltransferase (LCAT) activity in cases and controls were conducted. Comparison of HDL particle characteristics between cases and controls demonstrated a significant reduction in HDL phospholipid composition between cases and controls (92 ± 37 mg/dl vs. 109 ± 43 mg/dL, p value 0.0095). The mean plasma total cholesterol efflux capacity was significantly reduced in subjects with elevated HDL-C and CAD as compared to controls (1.96 ± 0.39 % efflux/ 2hr/ 1% plasma vs. 2.11 ± 0.43 % efflux/ 2hr/ 1% plasma, p value 0.040). The reduction became even more significant when looking at mean ABCA1- selective cholesterol efflux between cases and controls 0.60 ± 0.24 % efflux/ 2hr/ 1% plasma vs. 0.71 ± 0.32 % efflux/ 2hr/ 1% plasma, p value 0.033). Furthermore, there was a significant reduction in mean efflux per HDL particle in cases as compared to controls (0.023 ± 0.005 % efflux/ 2hr/ 1% plasma vs. 0.025 ± 0.006 % efflux/ 2hr/ 1% plasma, p value 0.029). No significant difference was observed between cases and controls in HDL particle size or plasma LCAT activity. Reduced cholesterol efflux capacity in cases with elevated HDL-C and CAD may explain the development of early coronary artery disease. This finding reinforces the belief that cholesterol efflux capacity may in fact be a better predictor of the risk of coronary disease then HDL-C levels alone. Furthermore, the reduction in HDL phospholipid in the cases may help account for impaired cholesterol efflux.