title: High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia.
abstract: Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)<1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42+/-19 mg/dL and area under the RLP-C curve 415+/-82 mg. L(-1). h(-1), respectively) than did control subjects (7+/-3 mg/dL and 101+/-35 mg. L( -1). h(-1), respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13+/-3 mg/dL and 136+/-53 mg. L(-1). h(-1), respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24+/-10 versus 6.3+/-5.9 mg. L( -1). h(-1), P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.
authors.affiliation: Department of Cardiovascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: T B
authors.initials: TB
authors.lastname: Twickler
authors.forename: G M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: H W
authors.initials: HW
authors.lastname: de Valk
authors.forename: P C
authors.initials: PC
authors.lastname: Schreuder
authors.forename: H
authors.initials: H
authors.lastname: Jansen
authors.forename: M C
authors.initials: MC
authors.lastname: Cabezas
authors.forename: D W
authors.initials: DW
authors.lastname: Erkelens
mesh_terms: D001053:Apolipoproteins / Q000378:metabolism*; D001055:Apolipoproteins B / Q000097:blood; D002784:Cholesterol; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period / Q000187:drug effects*; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D000084562:Retinyl Esters; D019821:Simvastatin / Q000008:administration & dosage* / Q000097:blood; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001053:Apolipoproteins; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D012177:Retinol-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D000084562:Retinyl Esters; D014280:Triglycerides; C112017:remnant-like particle cholesterol; C022081:retinyl ester lipoprotein complex; D002784:Cholesterol; D019821:Simvastatin