Effect of Atorvastatin on Apolipoprotein B 48 Metabolism and Low-Density Lipoprotein Receptor Activity in Normolipidemic Patients With Coronary Artery Disease Cheryl A. Dane-Stewart, Gerald F. Watts, Sebely Pal, Dick Chan, Peter Thompson, Joseph Hung, and John C.L. Mamo We aimed to examine postprandial dyslipidemia in normolipidemic patients with coronary artery disease (CAD) and the effects of treatment with an hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor (atorvastatin). Subjects with angiographicaly established CAD were randomized to treatment for 12 weeks with 80 mg/d atorvastatin or placebo and the effects on markers of postprandial lipoproteins and low-density lipoprotein (LDL)-receptor binding determined. LDL-receptor binding was determined in mononuclear cells, as a surrogate for hepatic activity. Fasting levels of cholesterol (P < .001), LDL-cholesterol (P < .001), apolipoprotein (apo)B 48 (P  .019), remnant-like particle-cholesterol (RLP-C) (P  .032), and total postprandial apoB 48 area under the curve (AUC) (P  .013) significantly decreased with atorvastatin compared with placebo. Atorvastatin also significantly increased LDL-receptor binding activity (P < .001), and this was correlated with changes in fasting apoB 48 (r  .80, P  .01). We report that aberrations in chylomicron metabolism in normolipidemic CAD subjects are correctable with atorvastatin by a mechanism involving increased LDL-receptor activity. This effect may, in part, explain the cardiovascular benefit of statins used in clinical trials of CAD patients with normal lipid levels. © 2003 Elsevier Inc. All rights reserved. T HERE HAS BEEN intensive focus on the effects of hy- droxymethyl glutaryl coenzyme A (HMG-CoA) reduc- tase inhibitors on lowering plasma low-density lipoprotein (LDL)-cholesterol levels. Clinical trials have shown that im- provements in plasma LDL levels are associated with retarda- tion of atherosclerosis and reduction in coronary artery mor- bidity and mortality. 1,2 More recently, however, chylomicron remnants have been increasingly implicated in progression of atherosclerosis, 3-5 with elevated fasting remnant lipoprotein levels shown to independently predict clinical events in coro- nary artery disease (CAD) patients. 6 Postprandial dyslipidemia has been found to be associated with endothelial dysfunction 7,8 an early indicator of atherogen- esis. 9 Previous studies have shown that normolipidemic pa- tients with coronary disease have elevated postprandial levels of intestinal triglyceride-rich lipoproteins (TRLs) and their remnants compared with healthy control subjects. 10-15 Elevated remnant lipoprotein levels have also been associated with cor- onary endothelial dysfunction, 16 with remnants shown to stim- ulate expression of proatherothrombotic molecules in endothe- lial cells. 17 Hence, the prevention and treatment of atherosclerosis merits pharmacotherapy targeted at regulating postprandial dyslipidemia. 18 Possible mechanisms suggested for abnormal accumulation of intestinal lipoproteins postprandially in plasma are defective clearance via receptor-mediated pathways (eg, the LDL-recep- tor) and/or increased competition for high-affinity processes because of increased numbers of intestinally and hepatically derived particles postprandially. 18,19 HMG-CoA reductase in- hibitors decrease cellular cholesterol synthesis and conse- quently reduce the hepatic production of very–low-density li- poproteins (VLDL) and increase expression of LDL- receptors. 20 These properties of statins suggest that they may be potential agents for regulating the plasma levels of atherogenic chylomicron remnants. Atorvastatin is an HMG-CoA reductase inhibitor found to be effective in lowering fasting LDL-cholesterol and triglyceride levels. 21,22 Favorable effects of atorvastatin on postprandial lipoprotein metabolism have been reported in miniature pigs 23 and healthy normolipidemic human subjects. 24 Whether ator- vastatin improves postprandial lipemia in normolipidemic pa- tients with documented CAD has not yet been demonstrated. In the present study, we used plasma triglyceride and apoli- poprotein (apo) B 48 , a specific marker for chylomicrons and their remnants, to investigate postprandial lipoprotein metabo- lism. We investigated whether the postprandial responses of CAD patients could be improved with atorvastatin and whether this effect involved alterations in LDL-receptor activity. SUBJECTS AND METHODS Subjects We recruited 18 patients (15 men, 3 women) with angiographically documented CAD (1 or more vessels occluded) from the Cardiology Units at Royal Perth Hospital and Sir Charles Gairdner Hospitals, Perth, Western Australia. Subjects were excluded on the following criteria: total cholesterol  6.0 mmol/L, triglycerides  1.8 mmol/L, LDL-cholesterol  3.0 mmol/L, high-density lipoprotein (HDL)-cho- lesterol  1.0 mmol/L, body mass index (BMI)  29 kg/m 2 , smokers, hypertension, E2 homozygosity, diabetes mellitus, gastrointestinal and renal disorders, endocrine and liver diseases, alcohol abuse, use of drugs known to influence lipid metabolism, and myocardial infarction or stroke within the last 6 months. From the Department of Medicine, University of Western Australia, Bentley; Department of Nutrition, Dietetics and Food Science, Curtin University, Bentley; and the Department of Cardiovascular Medicine, Sir Charles Gairdinar Hospital, Western Australian Heart Research Institute, Bentley, Western Australia. Submitted November 12, 2002; accepted May 23, 2003. Supported by the National Heart Foundation of Australia, Royal Perth Hospital Centre for Excellence, and Pfizer. Address reprint requests to John C.L. Mamo, PhD, Department of Nutrition, Dietetics and Food Science, School of Public Health, Curtin University of Technology, Hayman Rd, Bentley, Western Australia 6102. © 2003 Elsevier Inc. All rights reserved. 0026-0495/03/5210-0017$30.00/0 doi:10.1016/S0026-0495(03)00281-6 1279 Metabolism, Vol 52, No 10 (October), 2003: pp 1279-1286