Tomio Kametani

Intermediate-density lipoprotein and cholesterol-rich very low density lipoprotein in angiographically determined coronary artery disease.

The relationship between the concentrations of intermediate-density lipoprotein (IDL) and other lipoproteins and the extent of coronary artery disease (CAD) was studied in 182 consecutive patients evaluated by selective coronary cineangiography. On univariate analysis, the extent of CAD correlated significantly and positively with very low density lipoprotein (VLDL) cholesterol, IDL cholesterol and lowdensity lipoprotein (LDL) cholesterol, and negatively with high-density lipoprotein (HDL) cholesterol. Analysis of four subgroups divided by IDL cholesterol and LDL cholesterol levels indicated that moderately increased levels of IDL cholesterol were closely associated with a high frequency of CAD. Moreover, multivariate regression analysis demonstrated that IDL cholesterol for men, LDL cholesterol for men and women and HDL cholesterol for men were significant variables of use in the final weighting procedure. IDL cholesterol was closely associated with cholesterol-rich VLDL. This study shows that IDL and cholesterol-rich VLDL combine to contribute to the development of CAD.

Homozygous familial hypercholesterolemia in Japan

Abstract Fifty-one homozygous patients with familial hypercholesterolemia, including our six patients, are described in this paper. Twenty were men and 31 were women. Their ages ranged between two and 52 years, with a mean of 16.8 years. Six patients exceeded the third decade. The mean age at death in seven patients was 17 years. The serum cholesterol levels were between 508 and 1,108 mg/dl. The mean and standard deviation (SD) of serum cholesterol were 713 ± 142 mg/dl. The serum cholesterol levels in the 35 parents (obligate heterozygotes) were between 246 and 571 mg/dl, except in one patient in whom the serum cholesterol level (936 mg/dl) was suggestive of homozygous familial hypercholesterolemia, considering the serum cholesterol level (354 mg/dl) of her heterozygous husband. The mean and SD of serum cholesterol levels of the 34 heterozygote parents were 342 ± 79 mg/dl. The mean and SD of serum cholesterol in 119 normal subjects were 187 ± 30 mg/dl. Thus, trimodai distribution was evident in the serum cholesterol levels of normal subjects, the heterozygotes and the homozygotes in Japan. The frequency of parental consanguinity was at least 33 per cent. The frequencies of ischemic heart disease in the age groups 0–9, 10–19 and above 20 years were 25 per cent (four of 16 patients), 33 per cent (six of 18 patients) and 53 per cent (nine of 17 patients), respectively. The frequency of homozygotes in Japan was in close accordance with those of Western countries. Therefore, the treatment of hypercholesterolemia and prevention of premature coronary heart disease in familial hypercholesterolemic patients are very important problems in Japan as well as in the West.

Serum lipids and coronary heart disease in heterozygous familial hypercholesterolemia in the Hokuriku district of Japan

The serum cholesterol and triglyceride levels and the incidence of ischemic heart disease were studied in 122 (55 men and 67 women) consecutive heterozygous familial hypercholesterolemic patients in the Hokuriku district of Japan. (1) The mean +/-SD of serum cholesterol level was 354.0 +/- 71.0 mg/100 ml, which was lower than those of the Western countries by about 60--70 mg/100 ml. (2) The mean +/-SD of serum triglyceride level was 116.5 +/- 54.0 mg/100 ml. (3) The average serum cholesterol values in the 20--50-year-old group showed no differences from those of the Western countries. However, in the above 50 years of age group the serum cholesterol levels were much lower than those in the United States. (4) The occurrence of ischemic heart disease in 83 heterozygous familial hypercholesterolemic patients was 43.3%. The incidence of myocardial infarction was 20.5%. Thus, familial hypercholesterolemia is as highly atherogenic as that of the Western countries even in Japan where the low incidence of coronary heart disease in the general population has been attributed to the low level of serum cholesterol.

Serum lipids, lipoprotein lipids and coronary heart disease in patients with xanthelasma palpebrarum.

Serum lipids and lipoprotein lipids were studied in 53 patients (21 males and 32 females) with xanthelasma palpebrarum and 40 age-matched normal controls (20 males and 20 females). Patients were subdivided into patients with normolipidemia, hyperlipidemia or familial hypercholesterolemia (FH). In both male and female patients with hyperlipidemia or FH, the serum cholesterol (Chol) levels were significantly higher than in normal controls. In both male and female patients with normolipidemia or hyperlipidemia, the VLDL-Chol levels were significantly higher than in normal controls. Male patients with FH showed significantly higher levels of VLDL-Chol than normal controls. Both male and female patients with normolipidemia, hyperlipidemia or FH showed significantly higher levels of LDL-Chol, lower HDL-Chol levels and lower HDL-Chol/LDL-Chol ratios than normal controls. In both male and female patients with hyperlipidemia and in male patients with FH, the serum triglyceride (TG) levels were significantly higher than in normal controls. Both male and female hyperlipidemic patients showed significantly higher levels of VLDL-TG than normal controls. In male patients with FH, the VLDL-TG levels were significantly above the control levels. In male patients with normolipidermia, the LDL-TG levels were significantly higher than in normal controls. In both male and female patients with hyperlipidemia or FH, the LDL-TG levels were significantly higher than in normal controls. The HDL-TG levels in patients with normolipidemia (males) or FH (females) were significantly lower than in normal controls. The prevalence of coronary heart disease in patients with normolipidemia, hyperlipidemia or FH was 29.4%, 24.0% and 45.4%, respectively.

Serum lipid and lipoprotein levels in Japanese patients with familial hypercholesterolemia

Abstract Serum lipid and lipoprotein levels were studied in 17 normal subjects, and in 40 heterozygous and 4 homozygous patients with familial hypercholesterolemia (FH) in Japan. The serum cholesterol (Chol) levels (mean ± SD) in normal subjects, heterozygotes and homozygotes were 173 ± 22, 358 ± 70 and 532 ± 44 mg/dl, respectively. LDL-Chol levels in heterozygotes (254 ± 59 mg/dl) were significantly higher than in normal subjects (94 ± 21 mg/dl) and lower than in homozygotes (432 ± 66 mg/dl). IDL-Chol levels in heterozygotes and homozygotes were significantly higher than normal; serum triglyceride (TG) levels in heterozygotes were significantly higher than normal; LDL-TG levels in patients with FH were significantly higher than normal, as were serum phospholipid (PL) levels. LDL-PL levels in heterozygotes were significantly higher than in normal subjects ( P P Serum Chol levels correlated highly with the LDL-Chol levels. The regression equation was Y(LDL-Chol in mg/dl)= 0.873X(serum Chol in mg/dl)−58.132 ( r : 0.977, P r : 0.913, v P

Effects of ML-236B (Compactin) on Sterol Synthesis and Low Density Lipoprotein Receptor Activities in Fibroblasts of Patients with Homozygous Familial Hypercholesterolemia

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 (125)I-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 (125)I-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 approximately 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 [(14)C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 mug/ml. However, at 0.05 mug/ml of ML-236B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 mug/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 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.

Occurrence of Renovascular Hypertension in Two Sisters

Renovascular hypertension in two sisters, aged 22 and 20, respectively, has been described. Renal artery stenoses were observed unilaterally in the elder patient and bilaterally in the younger one. In both patients, the functional significance of unilateral stenosis of the renal artery was documented by the renal vein renin ratio between the affected side and the contralateral or less affected side. High blood pressure and elevated plasma renin activity have been normalized with a unilateral revascularization in the elder patient, and with the treatment of propranolol in the younger one. The histological examination of the stenotic renal artery in the elder patient showed a finding comparable to the perimedial fibroplasia in Harrison and McCormacks classification of idiopathic fibromuscular stenosis.

Regulation of fatty acid synthesis in isolated hepatocytes by intestinal chylomicrons and their remnants.

Dietary fatty acids are incorporated into chylomicrons and the chylomicron triglycerides are degraded by the action of lipoprotein lipase. The resultant particles, remnants, are selectively metabolized by the liver [ 11. Sherrill and Dietschy demonstrated that unmetabolized chylomicrons were taken up at very low rates, whereas chylomicron remnants were taken up by the perfused liver at much higher velocities [2]. Recently, Carrella and Cooper demonstrated that there was a high affinity receptor for the chylomicron remnant on the surface of the hepatocytes [3]. This study was undertaken to examine the effects of chylomicrons and their remnants on the fatty acid synthesis in isolated rat hepatocytes. Chylomicrons in the medium containing postheparin rat plasma significantly inhibited fatty acid synthesis in hepatocytes. On the other hand, chylomicrons in the medium containing pre-heparin rat plasma caused inhibition to a much smaller extent. Remnants prepared from the chylomicrons injected into functionally hepatectomized rats inhibited fatty acid synthesis to a greater extent than unmetabolized chylomicrons. Thus the chylomicron remnants produced by the action of lipoprotein lipase may play an important role in the regulation of hepatic fatty acid synthesis.

Studies on the Diagnosis of Type III Hyperlipoproteinemia A suggestion of chemical criteria based on VLDL-cholesterol and VLDL-cholesterol/VLDL-triglyceride

血中リポ蛋白の中間代謝産物 (ILDL, remnant) が異常に増加するIII型高脂血症は, 血清 Chol, TG値からは診断できず, 超遠心分離および電気泳動により, β-VLDLを証明する必要がある. しかしβ-VLDLの証明はやや客観性に乏しく, 本症診断における特異性にも問題がある. 最近III型高脂血症に特異的で感度の高い診断方法が数多く報告されているが, 未だ十分なものはない. 今回我々は, 臨床像およびリポ蛋白泳動によりβ-VLDLを証明した典型的なIII型高脂血症と思われる症例の血清脂質およびリポ蛋白を頻回に測定し, 他のタイプの高脂血症と比較検討し, 以下の結論を得た.1) III型高脂血症の血清 Chol は182～540mg/dlでTGは142～898mg/dlであった. 血清 Chol, TG値のみではIIb, IV型と鑑別できなかった. また Chol/TG比は0.53～1.75で, 正常, IIb, IV型との鑑別はできなかった.2) III型のVLDL-Chol は常に50mg/dl以上であったがIIb型9例中1例, IV型5例中1例が50mg/dl以上であった.3) III型のVLDL-Chol/VLDL-TG比は0.27～1.93であり正常, IIa, IIb, IV型との鑑別は不可能であった.4) VLDL-Chol/Chol 比は, III型では常に0.15以上で, 正常, IIa, IIbとの鑑別は可能であるが, IV型との鑑別はできなかった.5) III型のVLDL-Chol/TG比は常に0.20以上であるが, 正常, IIa, IIb型でも0.20以上を示す例があった. Fredrickson らの診断基準0.30を越えるものはすべてIII型であったが, III型の28測定中13測定が0.30以下であった.6) 今回, 我々は新しい診断方法として, VLDL-Chol 55mg/dl以上の例でVLDL-Chol/VLDL-TG比が0.33以上をIII型の診断基準と考えた.

Diagnostic Criteria for Familial Hypercholesterolemia in Japan

家族性高コレステロール (chol) 血症の診断基準は, 欧米では既に確立されているが, 食生活が異なるわが国でも適応されるか否か未だ検討されていない. 今回われわれは腱黄色腫を認める家族性高 chol 血症55例について検討し以下の結論を得た.i) 家族性高 chol 血症の血清 chol は255～908mg/dl (平均±SEM, 385±14mg/dl) であった.ii) 家族性高 chol 血症の血清トリグリセライド (TG) 値は54～307mg/dl (平均±SEM, 128±9mg/dl) であった.iii) リポ蛋白分画について検討した7例のLDL (低比重リポ蛋白) -chol は226～360mg/dlであつた.iv) 以上の成績より, 家族性高 chol 血症の診断基準は, (1)血清 chol が250mg/dl以上で腱黄色腫又は, アキレス腱の肥厚を認めるか, (2)一等親に家族性高 chol 血症があり, 血清 chol が250mg/dl以上のいづれかである.