We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125T-labelled LDL by freshly isolated mononuclear leucocytes and the 24 h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20,40, and 80 mg day-') taken in a twicedaily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6%, 45.6% and 47.1% respectively on the three doses. High-affinity degradation of '"I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-' dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-I4C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15 h after the last dose of simvastatin) increased by 62%, 71 % and 29% in cells isolated from patients on 20, 40, and 80 mg day-' of simvastatin compared with values at baseline. In contrast, the 24 h excretion of mevalonic acid in the urine fell by 16.9%, 31.4% and 31.9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increases in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.

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Acid cholesteryl ester hydrolase (CEH) activity was assayed in mononuclear cells of patients with symptomatic atherosclerosis (transient ischemic attacks, TIA) and in age-matched controls showing no evidence of atherosclerosis. The acid CEH level of TIA patients was significantly lower than that of controls (1074 +/- 128 vs 2113 +/- 255 pmol/mg P/hr, mean +/- SE). Neither mononuclear cell nor plasma cholesterol and cholesteryl ester concentrations differed significantly between atherosclerotic and control groups. TIA women had lower mononuclear cell concentrations of free cholesterol than men.

L ovastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate-limiting enzyme in cholesterol biosynthesis.1 The hypocholesterolemic effects of lovastatin in patients with primary hypercholesterolemia have been well established, 2 -10 but the extent to which this drug affects cellular cholesterol homeostasis in humans is less well delineated. Previous in vivo studies in animals and in vitro studies in cells grown in tissue culture have shown that the administration of either lovastatin or a related drug, mevastatin (compactin), results in compensatory increases in the mass of HMG CoA reductase and in the high affinity receptor-mediated degradation of 125 l-low density lipoprotein (LDL) 11 -14 ; the question of whether or not clinically effective doses of lovastatin will induce similar changes in tissues or cells isolated from hypercholesterolemic patients on chronic therapy with lovastatin has, however, not been previously examined. Kinetic studies Received May 13,1988; revision accepted December 23,1988. with radiolabeted LDL have indicated that the hypocholesterolemic effects of lovastatin in patients with heterozygous familial hypercholesterolemia result from both an increased rate of LDL catabolism and a concurrent reduction in the rate of synthesis of LDL 3 The former is believed to be due to an increased number of high affinity LDL receptors expressed on cell membranes, particularly those in the liver.Previous studies have indteated that freshly isolated human mononuctear leukocytes show changes in cholesterol homeostasis that parallel those known to occur in the liver. 16 -18 For example, the rates of cholesterol synthesis and high affinity receptor-mediated degradation of I 12S -LDL in freshly isolated mononuctear leukocytes from patients with heterozygous familial hypercholesterolemia (FH) were both increased during therapy with the bile acid sequestrant colestipol.15 Similarty, dietary cholesterol has been shown to depress cholesterol synthesis or HMG CoA reductase activity in freshly isolated mononuclear leukocytes.1718 Both of these effects parallel those that are known to occur in the liver.In the present study, we utilized freshly isolated mononuclear leukocytes to examine whether therapy with lovastatin influences cholesterol homeostasis in patients with heterozygous FH treated with increasing doses of lovastatin. Methods SubjectsThe 23 adult patients who participated in this study were diagnosed as having heterozygous FH on the basis of persistent primary hypercholesterolemia greater than 355 by guest on May 12, 2018 http://atvb.ahajournals.org/ Downloaded from