High Dose of Simvastatin Normalizes Postprandial Remnant-Like Particle Response in Patients With Heterozygous Familial Hypercholesterolemia

Abstract

Abstract-Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of ␤-hydroxy-␤-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)Ͻ1000 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 42Ϯ19 mg/dL and area under the RLP-C curve, respectively) than did control subjects (7Ϯ3 mg/dL and 101Ϯ35 mg ⅐ L Ϫ1 ⅐ h Ϫ1 , respectively; PϽ0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13Ϯ3 mg/dL and 136Ϯ53 mg ⅐ L Ϫ1 ⅐ h Ϫ1 , respectively; PϽ0.05 for both). Postprandial RE in the SfϽ1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24Ϯ10 versus 6.3Ϯ5.9 mg ⅐ L Ϫ1 ⅐ h

Elevated Remnant-Like Particles in Heterozygous Familial Hypercholesterolemia and Response to Statin Therapy

“…This observation was also made previously. 20 All these data indicate the presence of remnant particle accumulation in FH patients, irrespective of concomitant TG elevation. Likewise, stratification of the data according to baseline TG into quartiles resulted in an association between TG and RLP-C levels, but LDL-C levels were equally elevated in all quartiles.…”

“…This observation was reported previously in 7 FH patients. 20 Recently, 2 studies in patients with combined dyslipidemia showed similar results. 30,31 Stein et al 30 found that median elevated RLP-C levels of 0.34 mmol/L were reduced by simvastatin 20 mg (6.0%) and by atorvastatin 10 mg (25.9%) but not by pravastatin 40 mg in 22 patients in a crossover study.…”

“…To date, only 2 small studies (in 15 and 7 FH patients, respectively) reported RLP-C levels of FH patients and did indeed show increased RLP-C levels. 19,20 In the present study, we aimed to assess accumulation of RLP-C and also to evaluate whether RLP-C levels would be lowered by statin therapy in a large, well-defined cohort of FH patients.…”

Effects of Statin on Small Dense Low-Density Lipoprotein Cholesterol and Remnant-Like Particle Cholesterol in Heterozygous Familial Hypercholesterolemia

“…LDL-C, low-density lipoprotein cholesterol; Apo, apolipoprotein; sd-LDL-C, small dense low-density lipoprotein cholesterol; lb-LDL-C, large buoyant low-density lipoprotein cholesterol; RLP-C, remnant-like particle cholesterol. sd-LDL-C levels determined by this method were 37 20 mg/dL in hypercholesterolemic subjects with type 2 diabetes and 45 21 mg/dL in hypertriglyceridemic subjects with type 2 diabetes 31) . Compared with these data, mean levels of sd-LDL-C (44 20 mg/dL) in heterozygous FH were equal to or more than in subjects with MetS or type 2 diabetes.…”

Autosomal Recessive Hypercholesterolemia: A Mild Phenotype of Familial Hypercholesterolemia: Insight from the Kinetic Study using Stable Isotope and Animal Studies

“…In accordance with the process of internal lipoprotein metabolism, postprandial remnant lipoprotein metabolism, including that of chylomicron and its remnant, appears to be preserved, in contrast to that of FH caused by LDLR mutations, in which postprandial remnant lipoprotein metabolism has been shown to be severely impaired [43][44][45] . We performed an oral fat tolerance test in order to elucidate the clearance of both exogenous and endogenous lipoproteins 12)…”