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| 1.
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Tada, Hayato ; Nomura, Akihiro ; Nohara, Atsushi ; Inazu, Akihiro ; Mabuchi, Hiroshi ; YAMAGISHI, Masakazu ; Kawashiri, Masa-aki ; 多田, 隼人 ; 野村, 章洋 ; 野原, 淳 ; 稲津, 明広 ; 馬淵, 宏 ; 山岸, 正和 ; 川尻, 剛照
概要:
金沢大学附属病院循環器内科<br />Aim: We aimed to clarify post-prandial accumulation of remnant-like particles (RLP) in patients with
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sitosterolemia.\nMethods: Oral fat tolerance test cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (m2); blood sampling was performed at 2 h intervals up to 6 h. Plasma lipoprotein fractions and RLP fractions were determined in four sitosterolemic subjects with double mutations in ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene (mean age=18 yr, median low-density lipoprotein cholesterol [LDL-C]=154 mg/dL), six heterozygous carriers (mean age=31 yr, median LDL-C=105 mg/dL), and five subjects with heterozygous familial hypercholesterolemia (FH, mean age=32 yr, median LDL-C=221 mg/dL). The incremental area under curve (iAUC) of lipids, including LDL-C, apolipoprotein B-48 (apoB48), RLP cholesterol (RLP-C), and RLP triglyceride (RLP-TG) were evaluated.\nResults: After oral fat load, there was no significant difference of the iAUC of LDL-C between sitosterolemia and heterozygous FH, whereas the iAUC of apoB48 was significantly larger in the sitosterolemic subjects compared with that of heterozygous FH (2.9 µg/mL×h vs. 1.3 µg/mL×h, p＜0.05). Under these conditions, the iAUCs of RLP-C and RLP-TG levels were significantly larger in the sitosterolemic subject compared with those of heterozygous FH (9.5 mg/dL×h vs. 5.7 mg/dL×h, p＜0.05; 149 mg/dL×h vs. 40 mg/dL×h, p＜0.05, respectively), whereas those of heterozygous carriers were comparable with those with heterozygous FH.\nConclusions: Post-prandial lipoprotein metabolism in sitosterolemia appeared to be impaired, leading to their elevation in serum sterol levels. (UMIN Clinical Trials Registry number, UMIN000020330)<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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Tada, Hayato ; Nohara, Atsushi ; Inazu, Akihiro ; Sakuma, Nagahiko ; Mabuchi, Hiroshi ; Kawashiri, Masa-aki ; 多田, 隼人 ; 野原, 淳 ; 稲津, 明広 ; 馬淵, 宏 ; 川尻, 剛照
概要:
金沢大学附属病院循環器内科<br />Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such a
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s sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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Nomura, Akihiro ; Tada, Hayato ; Nohara, Atsushi ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 野村, 章洋 ; 多田, 隼人 ; 野原, 淳 ; 川尻, 剛照 ; 山岸, 正和
概要:
金沢大学附属病院先端医療開発センター<br />Aim: Sitosterolemia is an extremely rare, autosomal recessive disease characterized by high plas
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ma cholesterols and plant sterols because of increased absorption of dietary cholesterols and sterols from the intestine, and decreased excretion from biliary tract. Previous study indicated that sitosterolemic patients might be vulnerable to post-prandial hyperlipidemia, including high remnant-like lipoprotein particles (RLP) level. Here we evaluate whether a loading dietary fat increases a post-prandial RLP cholesterol level in sitosterolemic patients compared to heterozygous familial hypercholesterolemic patients (FH).\nMethods: We recruit total of 20 patients: 5 patients with homozygous sitosterolemia, 5 patients with heterozygous sitosterolemia, and 10 patients with heterozygous FH as controls from May 2015 to March 2018 at Kanazawa University Hospital, Japan. All patients receive Oral Fat Tolerance Test (OFTT) cream (50 g/body surface area square meter, orally only once, and the cream includes 34% of fat, 74 mg of cholesterol, and rich in palmitic and oleic acids. The primary endpoint is the change of a RLP cholesterol level after OFTT cream loading between sitosterolemia and FH. We measure them at baseline, and 2, 4, and 6 hours after the oral fat loading.\nResults: This is the first study to evaluate whether sitosterolemia patients have a higher post-prandial RLP cholesterol level compared to heterozygous FH patients.\nConclusion: The result may become an additional evidence to restrict dietary cholesterols for sitosterolemia. This study is registered at University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000020330).<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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Tada, Hayato ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 多田, 隼人 ; 川尻, 剛照 ; 山岸, 正和
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金沢大学附属病院循環器内科<br />We have learned that low-density lipoprotein (LDL) cholesterol is the cause of atherosclerosis from v
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arious aspects, including a single case with familial hypercholesterolemia, other cases with different types of Mendelian dyslipidemias, large-scale randomized controlled trials using LDL cholesterol lowering therapies, and Mendelian randomization studies using common as well as rare variants associated with LDL cholesterol levels. There is no doubt that determinations of genotypes in lipid-associated genes have contributed not only to the genetic diagnosis for Mendelian dyslipidemias but also to the discoveries of novel therapeutic targets. Furthermore, recent studies have shown that such genetic information could provide useful clues for the risk prediction as well as risk stratification in general and in particular population. We provide the current understanding of genetic analyses relating to plasma lipids and coronary artery disease.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
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Tada, Hayato ; Kawashiri, Masa-aki ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; 多田, 隼人 ; 川尻, 剛照 ; 野原, 淳 ; 稲津, 明広 ; 小林, 淳二 ; 馬渕, 宏 ; 山岸, 正和
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金沢大学医薬保健研究域医学系<br />Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited disorder, the cause of
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which is mutations in the low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Only 36 families with 14 different mutations have been reported in the literature to date. The clinical phenotype of ARH is milder than that of homozygous familial hypercholesterolemia (FH) caused by LDL receptor gene mutations. Recently, the lipoprotein metabolism of ARH was investigated in both humans and mice by several investigators, including ourselves. Based on these findings the preserved clearance of LDL receptor-dependent very-LDL (VLDL) may be a possible mechanism underlying the responsiveness to statins and the milder phenotype of ARH. Although ARH has been described as being “recessive,” several studies, including ours, have indicated that a heterozygous carrier status of the LDLRAP1 gene is associated with mild hypercholesterolemia and exacerbates the phenotype of FH resulting from LDL receptor gene mutations. This review summarizes current understanding regarding ARH and its causative gene, LDLRAP1, and attempts to provide new insight into novel pharmacological targets for treating dyslipidemic patients. © Journal of Atherosclerosis and Thrombosis. All right received.<br />出版者照会後に全文公開
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Tada, Hayato ; Nohara, Atsushi ; Kawashiri, Masa-aki ; Inazu, Akihiro ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; 多田, 隼人 ; 野原, 淳 ; 川尻, 剛照 ; 稲津, 明広 ; 馬渕, 宏 ; 山岸, 正和
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金沢大学医薬保健研究域医学系<br />We herein report a case of marked transient hypercholesterolemia in a man receiving low-dose mitotan
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e as adjuvant chemotherapy for adrenocortical carcinoma.A 58-year-old man without any clinical symptoms or history of hypercholesterolemia was admitted to our hospital to treat an adrenocortical carcinoma detected on general screening using computed tomography. He reported no chest symptom and did not exhibit any established risk factors for coronary artery disease, such as diabetes, obesity, hypertension or relevant family history, with the exception of current smoking, on admission. A stress electrocardiogram showed negative findings. The left adrenal tumor as well as left kidney, spleen and distal portion of the pancreas were subsequently resected using radical surgery. The histopathological findings confirmed the preoperative diagnosis of adrenocortical carcinoma. After the operation, treatment with low-dose mitotane (1g/day) was introduced as adjuvant chemotherapy. Interestingly, the patient developed marked hyper-LDL cholesterolemia at a level equivalent to that of familial hypercholesterolemia (LDL cholesterol level ~ 300 mg/ dL) following the introduction of mitotane, without evidence of primary or secondary hypercholesterolemia due to other causes. A coronary angiogram performed to assess the new-onset angina revealed three-vessel disease, which was later revascularized via percutaneous coronary intervention eight months after the start of mitotane therapy. The cholesterol level normalized with the suspension of mitotane. This case suggests that mitotane can cause severe hypercholesterolemia, potentially resulting in coronary atherosclerosis. © 2014, Japan Atherosclerosis Society. All rights reserved.<br />出版者照会後に全文公開
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| 7.
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Kawashiri, Masaaki ; Higashikata, Toshinori ; Nohara, Atsushi ; Kobayashi, Junji ; Inazu, Akihiro ; Koizumi, Junji ; Mabuchi, Hiroshi
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金沢大学大学院医学系研究科 <br />Background: Colestimide, a 2-methylimidazole-epichlorohydrin polymer, is a new bile-acid-sequesterin
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g resin, that is 4-fold as powerful at lowering low-density lipoprotein cholesterol (LDL-C) as the conventional resin (cholestyramine). Moreover, colestimide has excellent patient compliance because it is available in tablet form. Methods and Results: The clinical efficacy of colestimide coadministered with atorvastatin on lipid and apolipoprotein concentrations was examined in 15 patients (M/F = 10/5, mean±SE age=54±9 years) with heterozygous familial hypercholesterolemia (FH). After a period of wash-out of any lipid-lowering drugs, atorvastatin (20-40mg) was administered to patients for at least 8 weeks, and then 3 g of colestimide was administered for a further 8 weeks. Total and LDL-C significantly (<0.0001) decreased by 35% from 361 to 233mg/dl and 41% from 274 to 161 mg/dl, respectively. Addition of colestimide caused a further significant 12% and 20% reduction, respectively, from the initial values to 205 and 129 mg/dl, respectively. Colestimide was also effective in reducing serum LDL-C concentrations in heterozygous FH patients with hypertriglyceridemia (triglycerides ≥150mg/dl). Conclusions: When monotherapy with atorvastatin is insufficient to treat severely hypercholesterolemic patients, such as those with heterozygous FH, colestimide acts to reinforce the action of statins.
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Yagi, Kunimasa ; Hifumi, Senshu ; Nohara, Atsushi ; Higashikata, Toshinori ; Inazu, Akihiro ; Mizuno, Kiyoo ; Namura, Masanobu ; Ueda, Kosei ; Kobayashi, Junji ; Shimizu, Masami ; Mabuchi, Hiroshi
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金沢大学大学院医学系研究科 <br />Background: The aim of the present study was to clarify the risk factors of several types of arterio
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sclerosis lesions in Japanese individuals with heterozygous familial hypercholesterolemia (FH): renal arteriosclerosis (RAS), abdominal aortic sclerosis (AOS), iliac arteriosclerosis (IAS) and coronary artery disease (CAD). Methods and Results: Coronary angiography (CAG) and abdominal aortic angiography (AAA) were performed in 117 consecutive heterozygous FH subjects (79 men, 38 women; age 22-76). RAS (stenotic lesion or aneurysm) was observed in 39 cases (33%), predominantly in the proximal portion (74%) and both sides equally (right/left=27/23). Most cases of RAS (64%) presented with <25% stenosis. The differences in the contributing risk factors for the progression and development of RAS, AOS, IAS and CAD in FH were then analyzed. Multiple logistic regression analyses showed independent risk factors for formation of atherosclerosis in each artery were: age alone for RAS; age and plasma low-density lipoprotein cholesterol (LDL-C) for AOS; age, LDL-C and high-density lipoprotein cholesterol (HDL-C) for IAS; and HDL-C and diabetes mellitus for CAD. Conclusion: In Japanese subjects with heterozygous FH, there are distinct risk factors for the development and progression of atherosclerosis in the renal, iliac, abdominal aorta, and coronary arteries.
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Yasuda, Toshihiko ; Shimizu, Masami ; Ino, Hidekazu ; Okeie, Kazuyasu ; Yamaguchi, Masato ; Fujino, Noboru ; Fujii, Hiroyuki ; Mabuchi, Tomohito ; Mabuchi, Hiroshi ; Mizuno, Sumio
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金沢大学大学院医学系研究科<br />The present study examined the angiographic characteristics and prognosis of young males under 40 yea
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rs of age with acute myocardial infarction (AMI) and familial hypercholesterolemia (FH). The study group was divided into an FH group (n = 16) and a non-FH group (n = 27). Lesion morphology was classified as complex or smooth. Overall 36 patients were followed up for an average of 9.4 years. The frequency of angiographic normal or non-obstructive culprit lesions was significantly higher in the non-FH group (p < 0.01). In contrast, the incidence of complex or totally occlusive lesions was higher in the FH group (p < 0.01). At 10-year follow-up, survival rates from cardiac death (FH 85% vs non-FH 100%, p = 0.06), from AMI (FH 43% vs non-FH 80%, p < 0.05), and from any ischemic event at a new lesion (FH 9% vs non-FH 67%, p < 0.01) were all reduced in the FH group. These results suggest that the mechanism of AMI in young male patients with FH differs from that in similar aged patients without FH, and that the overall prognosis of these patients is less favorable.
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Tsuchida, Masayuki ; Kawashiri, Masa-aki ; Tada, Hayato ; Takata, Mutsuko ; Nohara, Atsushi ; Ino, Hidekazu ; Inazu, Akihiro ; Kobayashi, Junji ; Koizumi, Junji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu ; 川尻, 剛照 ; 多田, 隼人 ; 野原, 淳 ; 井野, 秀一 ; 稲津, 明広 ; 小林, 淳二 ; 小泉 , 順二 ; 馬渕, 宏 ; 山岸, 正和
概要:
In 1982, a 49-year-old Japanese woman had been referred to our hospital for further investigation of her hypercholestero
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lemia. She was diagnosed as heterozygous familial hypercholesterolemia, because of Achilles tendon xanthoma and a family history of primary hypercholesterolemia. Three years later, she had chest pain on effort and angina pectoris was diagnosed by coronary angiography. At that time, she underwent coronary artery bypass grafting surgery with 2 saphenous vein grafts (SVG). Because more aggressive cholesterol-lowering therapy was needed for secondary prevention of coronary artery disease (CAD), weekly low-density lipoprotein (LDL) apheresis was started postoperatively, combined with drug therapy. Since 1986, her serum total cholesterol levels before and after LDL apheresis remained approximately 200 mg/dl and 90 mg/dl, respectively. Although her coronary sclerosis, including the SVG, did not progress appreciably for a period of 20 years, stenotic changes of the aortic valve developed rapidly at age 70, leading to aortic valve replacement surgery in 2005 at age 72. These findings suggest that careful attention to the progression of aortic valve stenosis is needed for extreme hypercholesterolemic patients even under optimal cholesterol-lowering therapy for the secondary prevention of CAD. (Circ J 2009; 73: 963 - 966)<br />出版者照会後に全文公開
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