Abstract 125: Small Dense LDL ApoB Is Catabolized More Slowly Than Large LDL ApoB in Subjects With Combined Hyperlipidemia, and Rosuvastatin Enhances Its Clearance

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LDL consists of particles varying in size, density, and composition. Small dense LDL (sdLDL) cholesterol (C) has been shown to be a better predictor of coronary heart disease risk than total LDL-C. Intensive statin therapy significantly lowers sdLDL-C as well as large buoyant LDL (lbLDL)-C. We tested the hypotheses that lbLDL and sdLDL apoB100 have different catabolic rates, and that statin therapy enhances the fractional catabolism of apoB100 in both particles. Six subjects (3 men and 3 women; age 63±5 years [mean±SEM]; BMI 25.5±1.5 kg/m 2 ) with combined hyperlipidemia (triglycerides [TG] 191±50 mg/dl; LDL-C 160±16 mg/dl; HDL-C 43±6 mg/dl) received placebo and rosuvastatin 40 mg/day for 8 weeks each in sequential order. At the end of each phase, the kinetics of apoB100 in triglyceride rich lipoproteins ([TRL] d <1.019 g/ml), lbLDL ( d =1.019-1.044 g/ml), and sdLDL ( d =1.044-1.063 g/ml) were determined using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Compared to placebo, rosuvastatin markedly decreased the plasma levels of LDL-C (52%; P =0.0002), TG (32%; P =0.06), and total apoB (42%; P <0.0001). ApoB100 pool size in TRL, lbLDL, and sdLDL decreased 32±6%, 39±5%, 41±4%, respectively. These changes were attributable to significant ( P <0.05) increases in apoB100 fractional catabolic rates in TRL (45±16%), lbLDL (131±66%), and sdLDL (97±32%). During both the placebo and rosuvastatin phases, sdLDL apoB100 was catabolized more slowly than lbLDL apoB100 ( P =0.01 and 0.004, respectively). Rosuvastatin did not alter apoB100 production rate or the percent of TRL apoB100 converted to each LDL subfraction. Proteomic analysis of the LDL particles indicated that rosuvastatin increased apoD abundance in lbLDL and decreased apoAIV abundance in sdLDL. No significant effects on other apolipoproteins were noted. These data indicate that sdLDL apoB100 is catabolized significantly more slowly than lbLDL apoB100 in dyslipidemic subjects on placebo or statin therapy. Maximal dose rosuvastatin decreases plasma apoB concentrations by enhancing apoB100 catabolism in TRL, lbLDL, and sdLDL and alters the distribution of minor apolipoproteins in LDL subfractions.