Jan A. Gevers Leuven

Supplementation With Low Doses of Vitamin E Protects LDL From Lipid Peroxidation in Men and Women

There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant D,L-alpha-tocopherol (vitamin E), far above the recommended daily intake (ie, 12 to 15 IU/d for adults), increases the oxidation resistance of LDL. In this study, we ascertained the minimal supplementary dose of vitamin E necessary to protect LDL against oxidation in vitro. Twenty healthy volunteers (10 men and 10 women, aged 21 to 31 years) ingested consecutively 25, 50, 100, 200, 400, and 800 IU/d, D,L-alpha-tocopherol acetate during six 2-week periods. No changes were observed in LDL triglyceride content, fatty acid composition of LDL, or LDL size during the intervention. Concentrations of alpha-tocopherol in plasma and LDL were both 1.2 times the baseline values after the first period (25 IU/d) and 2.6 and 2.2 times, respectively, after the last period (800 IU/d). There was a linear increase in LDL alpha-tocopherol levels up to an intake of 800 IU/d (r = .79, P < .0001) and a good correlation between alpha-tocopherol in plasma and LDL (r = .66, P < .0001). Simultaneously, the resistance of LDL to oxidation was elevated dose-dependently (+28% after the last period) and differed significantly from the baseline resistance time even after ingestion of only 25 IU/d.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia

In a group of 120 patients with heterozygous familial hypercholesterolemia (FH) the influence of the apolipoprotein E (apoE) polymorphism on pre-treatment plasma lipid levels and on the response to treatment with simvastatin was studied. The apoE phenotype distribution did not differ significantly between the FH group and a sample group of the Dutch population. Differences in pre-treatment lipid levels were not related to the apoE polymorphism in this FH population. After 12 weeks use of a daily dose of 40 mg simvastatin, the plasma total cholesterol, low density lipoprotein (LDL)-cholesterol and plasma triglyceride levels were reduced on average by 33%, 38% and 19%, respectively. At the same time high density lipoprotein (HDL)-cholesterol concentration increased on average by 7%. In the combined FH patient group (males and females) a considerable interindividual variation in response to simvastatin was observed, but was not related to the apoE polymorphism. However, considering males and females separately, we found that female FH patients with the apoE3E3 phenotype responded better on simvastatin treatment with respect to LDL-cholesterol than male FH patients with the apoE3E3 phenotype.

Simvastatin (MK-733): a potent cholesterol synthesis inhibitor in heterozygous familial hypercholesterolaemia

Simvastatin (MK-733), a new inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was administered to 38 patients with heterozygous familial hypercholesterolaemia for 24 weeks. A dose of 40 mg per day produced a mean reduction in low density lipoprotein cholesterol of 43-45% and in triglycerides of 21-31%. Mean high density lipoprotein cholesterol increased significantly by 10-13%. There were no major differences in response whether the drug was taken in one or two doses. MK-733 was tolerated well. Adverse effects were infrequent and limited to slight increases of alanine aminotransferase, creatine phosphokinase and bilirubin. This drug appears to be a potent inhibitor of cholesterol synthesis and has produced the largest therapeutic response as monotherapy in patients with familial hypercholesterolaemia.

Effect of 17β-Estradiol on Plasma Lipids and LDL Oxidation in Postmenopausal Women With Type II Diabetes Mellitus

In type II diabetes mellitus the altered hormonal state after menopause may represent an additional cardiovascular risk factor. Estrogen replacement therapy (ERT) is associated with a decreased cardiovascular risk, at least in nondiabetic post-menopausal women. We studied the effect of ERT on plasma lipids and lipoproteins and on LDL oxidation in 40 postmenopausal women with type II diabetes but with minimal vascular complications in a randomized placebo-controlled trial. Twenty patients were treated orally with 2 mg/d micronized 17β-estradiol and 20 patients with placebo for 6 weeks. Plasma total cholesterol (-6%, P=.04), LDL cholesterol (-16%, P=.0001), and apoB (- 11%, P=.001) levels decreased and HDL cholesterol (20%, P=.0001) and apoA-I (14%, P=.0001) levels increased after ERT compared with placebo. Glycated hemoglobin (HbA1c) decreased significantly after ERT (-3%, P=.03), the cholesterol content of the LDL particles decreased (-5%, P=.006), triglyceride content increased (16%, P=.01), and LDL particle size did not change significantly. ERT had no effect on parameters of LDL oxidation. We conclude that plasma levels of HDL cholesterol, apoA-I, LDL cholesterol, apoB, and glycated hemoglobin are improved in postmenopausal women with type II diabetes mellitus after treatment with 17β-estradiol, indicative of a better metabolic control, and that ERT has no effect on LDL oxidizability.

Activated platelets in patients with severe hypertriglyceridemia: effects of triglyceride-lowering therapy

Hypertriglyceridemia, a risk factor for cardiovascular disease, has been associated with hypercoagulability, but whether platelet activation is implicated is unknown. This study was designed to compare the in vivo platelet activation status between patients with severe hypertriglyceridemia and age- and sex-matched control subjects, and to evaluate the effects of triglyceride-lowering therapy. Sixteen patients with primary hypertriglyceridemia were included in a double-blind, placebo-controlled cross-over trial with 400 mg bezafibrate once daily. Platelet activation was analysed by double label flow cytometry, using monoclonal antibodies against GP53, P-selectin, and platelet-bound fibrinogen. Surface expression of the lysosomal membrane protein GP53 was significantly higher in the hypertriglyceridemic patients at baseline as compared to the group of age- and sex-matched controls (16.3+/-4.8% vs. 8.9+/-3.4%, respectively, P<0.001). No differences in the expression of P-selectin and fibrinogen binding were observed. In response to bezafibrate therapy, the expression of GP53 in the patient group decreased from 16.3+/-4.8% to 13.1+/-4.1% (P=0.018). The expression of P-selectin and fibrinogen binding was not affected by bezafibrate therapy. In conclusion, patients with hypertriglyceridemia have an increased in vivo platelet activation status, which can be improved by bezafibrate therapy.

Bezafibrate reduces heart rate and blood pressure in patients with hypertriglyceridemia.

ObjectiveIn hypertriglyceridemic patients, hypertension occurs frequently and may be associated with hyperinsulinemia and elevated plasma levels of free fatty acids (FFA). Besides the lipid-lowering effects, fibrates have been shown to reduce blood pressure in hypertensive patients. The present stud

Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations

In patients heterozygous for familial hypercholesterolemia, the low-density lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.

The T705I mutation of the low density lipoprotein receptor gene (FH Paris-9) does not cause familial hypercholesterolemia

Abstract Familial hypercholesterolemia (FH) is a genetic disease caused by mutations in the low-density lipoprotein receptor gene. Among the more than 200 mutations so far identified, the T705I substitution in exon 15, designated FH-Paris 9, has been previously described as an FH-causing mutation. During the course of denaturing gradient gel electrophoretic screening of exon 15 we have identified the T705I single-base substitution not only in an FH family but also in a control, normocholesterolemic population. Therefore, we conclude that FH-Paris 9 is a missense mutation not associated with FH.

Estrogenic effect of gestodene- or desogestrel-containing oral contraceptives on lipoprotein metabolism.

In a randomized comparative study, changes in lipoprotein metabolism during the use of two low-dose oral contraceptives with similar doses of ethinyl estradiol but with different progestogenically active compounds were evaluated for their effective estrogen/androgen balance. Sixty-eight healthy women who did not take hormonally active drugs or were pregnant the previous 3 months took either 75 micrograms of gestodene + 30 micrograms of ethinyl estradiol or 150 micrograms of desogestrel + 30 micrograms ethinyl estradiol during 12 cycles. During the first three cycles serum levels of the following parameters increased: triglycerides, cholesterol in high-density lipoprotein, and apolipoproteins A1, A2, and B. Additional increase was observed in apolipoprotein B only after three and six cycles. The induced changes were not significantly different in the two groups, and the levels generally remained within normal limits. The changes seen with both pills reflect a mild estrogenic dominance. On the basis of current knowledge, moderately altered lipoprotein metabolism is not expected to impose an extra risk of atherosclerosis.

Effect of simvastatin on the apparent size of LDL particles in patients with type IIB hyperlipoproteinemia

After 15 weeks of simvastatin therapy (20 mg/day), low density lipoprotein particle size in sera of 16 patients with type IIb hyperlipoproteinemia increased significantly from 233 +/- 5.0 A to 237 +/- 7.0 A (P less than 0.05), analyzed by 2-16% polyacrylamide gradient gel electrophoresis. Under simvastatin therapy the concentrations of total cholesterol, total triglyceride, very low density lipoprotein cholesterol and triglyceride, low density lipoprotein cholesterol and apolipoprotein B in serum fell significantly by 30%, 30%, 43%, 28%, 36% and 26%, respectively, and the concentration of high density lipoprotein cholesterol rose significantly by 14%. The changes of low density lipoprotein particle size induced by simvastatin therapy were correlated best with the changes of very low density lipoprotein triglyceride concentration (r2 = 0.438, P less than 0.01). Our results suggest that simvastatin therapy, additionally to a reduction of the serum cholesterol concentration, increases low density lipoprotein particle size which may contribute to reduction of the risk of coronary heart disease in patients with type IIb hyperlipoproteinemia.