左肺動脈欠損症における肺血流の評価： RIアンギオグラフイの有用性

金沢大学大学院医学系研究

Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolemia

We studied the effects of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (KMG-CoA) reductase, on serum levels of lipoproteins and ubiquinone-10 in seven heterozygous patients with familial hypercholesterolemia. ML-236B was given at doses of 30 to 60 mg per day for 24 weeks. Serum cholesterol decreased from 390 ± 9 to 303 ± 8 mg per deciliter (10.1 ± 0.2 to 7.88 ± 0.2 mmol per liter, mean ± S.E.M.; P<0.001), and serum triglyceride decreased from 137 ± 18 to 87 ± 9 mg per deciliter (1.55 ± 0.20 to 0.98 ± 0.1 mmol per liter; P<0.05). Intermediate-density-lipoprotein (IDL) cholesterol, IDL triglyceride, low-density-lipoprotein (LDL) cholesterol, and LDL triglyceride decreased significantly (P<0.01, P<0.02, P<0.001, and P<0.001, respectively). However, there were no significant changes in very-low-density-lipoprotein (VLDL) cholesterol and triglyceride or high-density-lipoprotein (HDL) cholesterol. Serum ubiquinone-10 levels did not change, and LDL levels of ubiquinone-10 decreased by 50 per cent, from 0.39 ± 0.07 to 0.20 ± 0.01 μg per milliliter (P<0.05). No adverse effects were observed. We conclude that ML-236B is effective in lowering serum cholesterol without lowering serum ubiquinone-10 in heterozygous patients with familial hypercholesterolemia

Effects of ML-236B (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia

金沢大学大学院医学系研究科　We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of 125I-LDL were 0.5 ± 0.3 ng/mg protein (mean ± SEM), 14 ± 8 and 8 ± 6 ng/mg protein per 6 h (four normal cells; 44 ± 3, 386 ± 32, and 1,335 ± 214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of 12:5I-LDL were 6 ± 2, 29 ± 8, and 90 ± 32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed ~46% of the normal activities of receptor. ML-236B, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), completely inhibited the incorporation of [14C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 μg/ml. However, at 0.05 μg/ml of ML-236 B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 μg/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptor-negative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes

Differentiation between patients with takotsubo cardiomyopathy and those with anterior acute myocardial infarction

金沢大学大学院医学系研究科　Background: There has not been a comparison of the electrocardiographic (ECG) finding of ST-segment elevation in the precordial leads in patients with takotsubo cardiomyopathy (TC) and those with anterior acute myocardial infarction (AMI), with regard to the location of the culprit lesion. Methods and Results: The present study evaluated 18 patients with TC, and 85 with anterior AMI who were divided into 3 groups: group A had the culprit lesion proximal to both the first septal branch (S1) and the first diagonal branch (D1), group B had the culprit lesion proximal to either S1 or D1, and group C had the culprit lesion distal to both S1 and D1. In patients with TC, reciprocal ST-segment depression in the inferior leads was observed less frequently than in patients in groups A (p<0.0001) and B (p=0.0002), and abnormal Q waves and ST-segment elevation in the inferior leads were observed more frequently than in group A (p=0.0007, p=0.0057, respectively). The ECG findings in TC did not differ from those in group C. Conclusion: Electrocardiographic findings may differentiate TC from AMI with a proximal lesion of left anterior descending coronary artery, but not those with distal lesions

Effects of ML-236b (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia. J Clin Invest

A B S T R A C T We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH 29 December 1980. 1532 tion of 0.5 Ag/ml. However, at 0.05 ,ug/ml of sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 ,ug/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptornegative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and a heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes