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Brousseau ME, O'Connor JJ, Ordovas JM, et al. Cholesteryl ester Transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease endpoints in men with HDL deficiency. Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol 2002; 22:1148-1154.
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Asztalos BF, Schaefer EJ, Horvath KV, et al. Role of LCAT in HDL remodeling: an investigation in LCAT deficiency states. J Lipid Res 2007; 48:592-599. Study investigating the role of lecithin:cholesterol acyl transferase on HDL remodeling. The data indicate that lack of lecithin:cholesterol acyl transferase results in the inability to form spherical HDL particles containing both apoA-I and A-II, and the accumulation of α-4 HDL that is discoidal, small and contains apoA-I without A-II. No major effect on apoE HDL was noted, except that here again the particles are likely to be discoidal rather than spherical due to the inability to esterify cholesterol and form cholesteryl ester in the core of HDL.
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Asztalos BF, Schaefer EJ, Horvath KV, et al. Role of LCAT in HDL remodeling: an investigation in LCAT deficiency states. J Lipid Res 2007; 48:592-599. Study investigating the role of lecithin:cholesterol acyl transferase on HDL remodeling. The data indicate that lack of lecithin:cholesterol acyl transferase results in the inability to form spherical HDL particles containing both apoA-I and A-II, and the accumulation of α-4 HDL that is discoidal, small and contains apoA-I without A-II. No major effect on apoE HDL was noted, except that here again the particles are likely to be discoidal rather than spherical due to the inability to esterify cholesterol and form cholesteryl ester in the core of HDL.
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High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants in the Framingham Offspring Study
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Asztalos BF, Cupples LA, Demissie S, et al. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants in the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 2004; 24:2181-2187.
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Asztalos BF, Collins D, Cupples LA, et al. Value of high density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol 2005; 25:2185-2191.
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Asztalos BF, Batista M, Horvath KV, et al. Change in alpha 1 HDL concentration predicts progression in coronary artery stenosis. Arterioscler Thromb Vasc Biol 2003; 23:847-852.
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Asztalos BF, LeMaulf F, Dallal GE, et al. Comparison of the effects of high doses of rosuvastatin versus atorvastatin on subpopulations of high density lipoproteins. Am J Cardiol 2007; 99:681-685. This study examined the effects of rosuvastatin 40 mg/day vs. atorvastatin 8 mg/day in the STELLAR study. The data indicates that both statins lower preβ-1 HDL by about 40, suggesting more efficient reverse cholesterol transport, but that rosuvastatin is about twice as effective at raising large α-1 HDL than atorvastatin, possibly because of its longer plasma residence time and greater efficacy. Greater increases in this HDL fraction have been linked to greater benefit in promoting regression of coronary atherosclerosis. These data may explain why rosuvastatin at 40 mg/day promoted median regression of coronary atheroma while atorvastatin 80 mg/day promoted lack of progression
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Asztalos BF, LeMaulf F, Dallal GE, et al. Comparison of the effects of high doses of rosuvastatin versus atorvastatin on subpopulations of high density lipoproteins. Am J Cardiol 2007; 99:681-685. This study examined the effects of rosuvastatin 40 mg/day vs. atorvastatin 8 mg/day in the STELLAR study. The data indicates that both statins lower preβ-1 HDL by about 40%, suggesting more efficient reverse cholesterol transport, but that rosuvastatin is about twice as effective at raising large α-1 HDL than atorvastatin, possibly because of its longer plasma residence time and greater efficacy. Greater increases in this HDL fraction have been linked to greater benefit in promoting regression of coronary atherosclerosis. These data may explain why rosuvastatin at 40 mg/day promoted median regression of coronary atheroma volume while atorvastatin 80 mg/day promoted lack of progression.
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Clark RW, Ruggieri RB, Cunningham D, Bamberger MJ. Description of the torcetrapib series of cholesteryl ester protein inhibitors, including mechanism of action. J Lipid Res 2006; 47:537-552. An important study which documented that torcetrapib and other Pfizer CETP inhibitors bind to CETP on the HDL particle. This binding process forms a nonproductive complex which may interfere with the functions of HDL, which include reverse cholesterol transport, prevention of inflammation and prevention of lipid oxidation.
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Clark RW, Ruggieri RB, Cunningham D, Bamberger MJ. Description of the torcetrapib series of cholesteryl ester protein inhibitors, including mechanism of action. J Lipid Res 2006; 47:537-552. An important study which documented that torcetrapib and other Pfizer CETP inhibitors bind to CETP on the HDL particle. This binding process forms a nonproductive complex which may interfere with the functions of HDL, which include reverse cholesterol transport, prevention of inflammation and prevention of lipid oxidation.
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Qui X, Mistry A, Ammirati MJ, et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four lipid bound molecules. Nat Struct Mol Biol 2007; 14:106-113. Documentation of the crystal structure of CETP revealing a long tunnel and four lipid-bound molecules. This tunnel allows for the transfer of cholesteryl ester and triglyceride between HDL and triglyceride-rich lipoproteins in a hydrophobic manner in the plasma space. Understanding the crystal structure of CETP should allow scientists to design optimal CETP inhibitors that do not bind to HDL or interfere with any of its functions.
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Qui X, Mistry A, Ammirati MJ, et al. Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four lipid bound molecules. Nat Struct Mol Biol 2007; 14:106-113. Documentation of the crystal structure of CETP revealing a long tunnel and four lipid-bound molecules. This tunnel allows for the transfer of cholesteryl ester and triglyceride between HDL and triglyceride-rich lipoproteins in a hydrophobic manner in the plasma space. Understanding the crystal structure of CETP should allow scientists to design optimal CETP inhibitors that do not bind to HDL or interfere with any of its functions.
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Molecular mechanism of the blockade of plasma cholesteryl ester protein by its physiologic inhibitor apolipoprotein CI
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Cheema SK, Agarwal-Mawal A, Murray CM, Tucker S. Lack of stimulation of cholesteryl ester transfer protein by cholesterol in the presence of a high fat diet. J Lipid Res 2005; 46:2356-2366.
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Kee P, Cantazza D, Rye KA, et al. Effect of inhibiting cholesteryl ester protein on the kinetics of high-density lipoprotein cholesteryl ester transport in plasma. In vivo studies in rabbits. Arterioscler Vasc Thromb Biol 2006; 26:884-890.
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Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion
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Brousseau ME, Diffenderfer MR, Millar JS, et al. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol 2005; 25:1057-1064.
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Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism
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Millar JS, Brousseau ME, Diffenderfer MR, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism. Arterioscler Thromb Vasc Biol 2006; 26:1350-1356.
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Lloyd DB, Lira ME, Woods LS, et al. Cholesteryl ester protein variants have differential stability but uniform inhibition by torcetrapib. J Biol Chem 2005; 280:14918-14922.
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Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia
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Kuivenhoven JA, De Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol 2005; 95:1085-1088.
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Pfizer. In the interests of patient safety, Pfizer stops all torcetrapib clinical trials; company has notified FDA and is in the process of notifying all clinical investigators and other regulatory authorities [news release]. New York: Pfizer 2006; http://mediaroom.pfizer.com/index.php?s= press_release&item=130.
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Pfizer. In the interests of patient safety, Pfizer stops all torcetrapib clinical trials; company has notified FDA and is in the process of notifying all clinical investigators and other regulatory authorities [news release]. New York: Pfizer 2006; http://mediaroom.pfizer.com/index.php?s= press_release&item=130.
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Nissen SE, Tardif JC, Nicholls SJ, et al. Effects of torcetrapib on progression of coronary atherosclerosis. N Engl J Med 2007; 356:1304-1316. In a study of 910 evaluable patients with coronary atherosclerosis who underwent IVUS at baseline and at 24 months, no significant benefit of the torcetrapib-atorvastatin combination was noted vs. atorvastatin alone on the primary endpoint which was percentage change in total atheroma despite marked increases in HDL-cholesterol.
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Nissen SE, Tardif JC, Nicholls SJ, et al. Effects of torcetrapib on progression of coronary atherosclerosis. N Engl J Med 2007; 356:1304-1316. In a study of 910 evaluable patients with coronary atherosclerosis who underwent IVUS at baseline and at 24 months, no significant benefit of the torcetrapib-atorvastatin combination was noted vs. atorvastatin alone on the primary endpoint which was percentage change in total atheroma volume, despite marked increases in HDL-cholesterol.
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Kastelein JJ, Van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007; 356:1620-1630. In a study of 850 patients with familial hypercholesterolemia treated with atorvastatin plus placebo or atorvastatin plus torcetrapib over 2 years carotid intimal medial thickness was assessed by ultrasound. No significant differences in treatment groups were observed for the primary endpoint (maximal carotid intima media thickness) between groups despite dramatic differences in HDL-cholesterol level.
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Kastelein JJ, Van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007; 356:1620-1630. In a study of 850 patients with familial hypercholesterolemia treated with atorvastatin plus placebo or atorvastatin plus torcetrapib over 2 years carotid intimal medial thickness was assessed by ultrasound. No significant differences in treatment groups were observed for the primary endpoint (maximal carotid intima media thickness) between groups despite dramatic differences in HDL-cholesterol level.
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