著者

Toshinao Takahashi Toshio Nagai Masato Kanda Mei-Lan Liu Naomichi Kondo Atsuhiko T Naito Takehiko Ogura Haruaki Nakaya Jong-Kook Lee Issei Komuro Yoshio Kobayashi

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.79, no.12, pp.2703-2712, 2015-11-25 (Released:2015-11-25)

参考文献数

42

被引用文献数

7 17

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Background:Adipose tissue is one of the sources of mesenchymal stem cells, which have the potential to differentiate into various types of cells, including myocytes. Whether brown adipose tissue (BAT)-derived cells might differentiate into the cardiac pacemaking-conducting cells, and have the potential to regenerate the cardiac conduction system (CCS), is investigated in this study.Methods and Results:BAT was isolated from the interscapular area of mice and enzymatically digested before culture. Round or fusiform cells showed spontaneous beating at 4–7 days after culturing of BAT-derived cells. Reverse transcriptase-polymerase chain reaction analysis and immunocytochemical analysis revealed that BAT-derived cells expressed several cardiomyocytes, the CCS and pacemaker (PM) cell marker genes and proteins. Patch-clamp techniques revealed that spontaneous electrical activity and the shape of the action potential showed properties of cardiac PM cells. Next, a complete atrioventricular (AV) block was created in mice and green fluorescent protein-positive (GFP (+)) BAT-derived cells were injected intramyocardially around the AV node. At 1 week after transplantation, 50% of BAT-derived cells injected mice showed a sinus rhythm or a 2:1 AV block. Immunohistochemical analysis revealed that injected GFP (+) cells were engrafted and some GFP (+) cells co-expressed several cardiac PM cell marker proteins.Conclusions:BAT-derived cells differentiate into the CCS and PM-like cells in vitro and in vivo, and may become a useful cell source for arrhythmia therapy. (Circ J 2015; 79: 2703–2712)

著者

Satoshi Kodera Hiroyuki Morita Arihiro Kiyosue Jiro Ando Tomoyuki Takura Issei Komuro

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2602-2608, 2018-09-25 (Released:2018-09-25)

参考文献数

39

被引用文献数

2 12

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Background: The addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy reduces the rate of cardiovascular events. This study examined the cost-effectiveness of PCSK9 inhibitor+statin compared with standard therapy (statin monotherapy) in the treatment of triple-vessel coronary artery disease (CAD) in Japan. Methods and Results: A Markov model was applied to assess the costs and benefits associated with PCSK9 inhibitor+statin over a projected 30-year period from the perspective of a public healthcare payer in Japan. The incremental cost-effectiveness ratio (ICER), expressed as the quality-adjusted life-years (QALYs), was estimated. The effects on survival and numbers of events were based on the FOURIER trial and the CREDO Kyoto registry. The ICER of PCSK9 inhibitor+statin over standard therapy was 13.5 million (95% confidence interval 7.6–23.5 million) Japanese Yen (JPY) per QALY gained for triple-vessel CAD. The probability of the cost-effectiveness of PCSK9 inhibitor+statin vs. standard therapy was 0.0008% at a cost-effectiveness threshold of 5 million JPY. In patients with poorly controlled familial hypercholesterolemia (FH) with triple-vessel CAD, the ICER was 3.4 million JPY per QALY gained. Conclusions: PCSK9 inhibitor plus statin did not show good cost-effectiveness for triple-vessel CAD; however, it showed good cost-effectiveness for patients with triple-vessel CAD and poorly controlled FH in Japan.

著者

Taku Sakai Atsuhiko T. Naito Yuki Kuramoto Masamichi Ito Katsuki Okada Tomoaki Higo Akito Nakagawa Masato Shibamoto Toshihiro Yamaguchi Tomokazu Sumida Seitaro Nomura Akihiro Umezawa Shigeru Miyagawa Yoshiki Sawa Hiroyuki Morita Jong-Kook Lee Ichiro Shiojima Yasushi Sakata Issei Komuro

出版者

International Heart Journal Association

雑誌

International Heart Journal (ISSN:13492365)

巻号頁・発行日

pp.17-730, (Released:2018-08-11)

参考文献数

28

被引用文献数

13

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Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by hypertrophy of the myocardium. Some of the patients are diagnosed for HCM during infancy, and the prognosis of infantile HCM is worse than general HCM. Nevertheless, pathophysiology of infantile HCM is less investigated and remains largely unknown. In the present study, we generated induced pluripotent stem cells (iPSCs) from two patients with infantile HCM: one with Noonan syndrome and the other with idiopathic HCM. We found that iPSC-derived cardiomyocytes (iPSC-CMs) from idiopathic HCM patient were significantly larger and showed higher diastolic intracellular calcium concentration compared with the iPSC-CMs from healthy subject. Unlike iPSC-CMs from the adult/adolescent HCM patient, arrhythmia was not observed as a disease-related phenotype in iPSC-CMs from idiopathic infantile HCM patient. Phenotypic screening revealed that Pyr3, a transient receptor potential channel 3 channel inhibitor, decreased both the cell size and diastolic intracellular calcium concentration in iPSC-CMs from both Noonan syndrome and idiopathic infantile HCM patients, suggesting that the target of Pyr3 may play a role in the pathogenesis of infantile HCM, regardless of the etiology. Further research may unveil the possibility of Pyr3 or its derivatives in the treatment of infantile HCM.

著者

Toshiya Kojima Katsuhito Fujiu Nobuaki Fukuma Hiroshi Matsunaga Tsukasa Oshima Jun Matsuda Takumi Matsubara Yu Shimizu Gaku Oguri Eriko Hasumi Hiroyuki Morita Issei Komuro

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-17-1114, (Released:2018-04-13)

参考文献数

20

被引用文献数

7

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Background:Periprocedural anticoagulation is important in catheter ablation (CA) of atrial fibrillation (AF) and there is increasing evidence that uninterrupted vitamin K antagonist (VKA) therapy is superior to interrupted anticoagulation strategies. Since the emergence of direct oral anticoagulants (DOACs), numerous studies have shown promising results for their use in uninterrupted strategies. However, further studies are needed to further define the efficacy and safety of performing AF ablation with uninterrupted factor XA inhibitors or direct thrombin inhibitors.Methods and Results:We have performed CA of AF without discontinuation of either VKA or DOAC therapy since April 2014. A total of 376 patients with AF underwent CA including pulmonary vein isolation. All of the patients were divided into 2 groups (uninterrupted VKA or uninterrupted DOACs). Anticoagulation with DOACs was associated with fewer complications than uninterrupted VKA therapy (P=0.04). There were significant differences between groups in the rates of congestive heart failure, left ventricular ejection fraction, body weight, and estimated glomerular filtration rate and of the CHADS2, CHA2DS2-VASc and HAS-BLED scores. Therefore, we also analyzed the results using the propensity score-matching method. We found no significant difference in periprocedural complications between uninterrupted VKA or DOACs therapy (P=0.65).Conclusions:CA of AF without discontinuation of DOACs is not inferior to CA without discontinuation of a VKA, with regard to ischemic or hemorrhagic complications.

著者

Tetsuo Minamino Shuichiro Higo Ryo Araki Shungo Hikoso Daisaku Nakatani Hiroshi Suzuki Takahisa Yamada Masaaki Okutsu Kouji Yamamoto Yasushi Fujio Yoshio Ishida Takuya Ozawa Kiminori Kato Ken Toba Yoshifusa Aizawa Issei Komuro EPO-AMI-II Investigators

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-17-0889, (Released:2018-02-02)

参考文献数

21

被引用文献数

15

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Background:Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4±9.3%, EPO 6,000 IU: 7.3±7.7%, Placebo: 8.1±8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by 99 mTc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events.Conclusions:Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721).

著者

Satoshi Kodera Hiroyuki Morita Arihiro Kiyosue Jiro Ando Issei Komuro

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-17-0995, (Released:2018-01-23)

参考文献数

33

被引用文献数

15

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Background:The addition of eicosapentaenoic acid (EPA) to statin therapy has been shown to reduce cardiovascular events. This study examined the cost-effectiveness of EPA plus statin (EPA+statin) combination therapy compared with statin monotherapy for primary and secondary prevention of cardiovascular disease (CVD) in Japan.Methods and Results:A Markov model was applied to assess the costs and benefits associated with EPA+statin combination therapy over a projected 30-year period from the perspective of a public healthcare funder in Japan. The incremental cost-effectiveness ratio (ICER), expressed as quality-adjusted life-years (QALY), was estimated for primary prevention and secondary prevention of CVD in patients with hypercholesterolemia. Impact on survival and number of events were based on the Japan EPA Lipid Intervention Study. Sensitivity analyses examined the influence of various input parameters on costs and outcomes of treatment. ICER was ¥29.6 million per QALY gained in primary prevention and ¥5.5 million per QALY gained in secondary prevention. The probabilities that EPA+statin combination therapy would be cost-effective compared with statin monotherapy were 39% in primary prevention and 49% in secondary prevention at a cost-effectiveness threshold of ¥5 million per QALY gained. Sensitivity analyses showed that EPA was cost-effective in secondary prevention.Conclusions:EPA+statin combination therapy showed acceptable cost-effectiveness for secondary prevention, but not primary prevention, of CVD in patients with hypercholesterolemia in Japan.

著者

Mashio Nakamura Masakatsu Nishikawa Issei Komuro Isao Kitajima Yoshio Uetsuka Takuji Yamagami Hiroki Minamiguchi Rika Yoshimatsu Kosuke Tanabe Nobushige Matsuoka Kazuhiro Kanmuri Hisao Ogawa

出版者

日本循環器学会

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-15-0195, (Released:2015-04-24)

参考文献数

14

被引用文献数

7 54

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Background:Anticoagulation is recommended as standard of care for venous thromboembolism (VTE) (pulmonary embolism [PE]/deep vein thrombosis [DVT]), for which unfractionated heparin (UFH) and warfarin are used in Japan. In the multi-regional AMPLIFY study, a fixed-dose regimen of apixaban alone was non-inferior to conventional therapy for treatment of PE/DVT and was associated with significantly fewer bleeding events.Methods and Results:Japan phase 3 study (AMPLIFY-J), randomized, active-controlled, open-label study in Japanese subjects with acute PE/DVT, was designed based on AMPLIFY. Key objectives were to investigate safety and efficacy of apixaban in symptomatic PE/DVT subjects during 24-week treatment. UFH/warfarin was used as control treatment. Apixaban was initiated at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 23 weeks. All endpoints and imaging for thrombotic burden were assessed by an event adjudication committee. Eighty subjects were randomized, 33 subjects (41.3%) were aged <65 years. Proportion of major/clinically relevant non-major bleeding was lower in apixaban (7.5%) compared with well-controlled UFH/warfarin (28.2%; median TTR, 70.1%). Recurrent VTE occurred in no subjects in apixaban and in 1 subject in UFH/warfarin. Thrombotic burden results were similar in both groups. Proportions of subjects with adverse events was generally similar in both groups.Conclusions:Apixaban was well-tolerated and had a favorable safety profile. No clinically important efficacy difference compared with UFH/warfarin was observed.

著者

Shun Minatsuki Ichiro Miura Atsushi Yao Hiroyuki Abe Hironori Muraoka Mariko Tanaka Teruhiko Imamura Toshiro Inaba Hisataka Maki Masaru Hatano Koichiro Kinugawa Takashi Yao Masashi Fukayama Ryozo Nagai Issei Komuro

出版者

一般社団法人 インターナショナル・ハート・ジャーナル刊行会

雑誌

International Heart Journal (ISSN:13492365)

巻号頁・発行日

pp.14-220, (Released:2015-02-23)

被引用文献数

2 40

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Pulmonary hypertension (PH) induced by pulmonary tumor thrombotic microangiopathy (PTTM) can be fatal because its rapid progression confounds diagnosis, and it is difficult to control with therapy. Here we describe a woman with symptomatic PTTM-PH accompanying gastric cancer that was suspected from perfusion scintigraphy. PTTM-PH was diagnosed by gastroesophageal endoscopy and lung biopsy after partial control of PH using the platelet-derived growth factor (PDGF) receptor (PDGFR) tyrosine kinase inhibitor, imatinib. Treatment with sildenafil and ambrisentan further decreased PH, and she underwent total gastrectomy followed by adjuvant TS-1 chemotherapy. PH did not recur before her death from metastasis. Postmortem histopathology showed recanalized pulmonary arteries where the embolized cancer masses disappeared. PDGF-A, -B, and PDGFR-α, β expression was detected in cancer cells and proliferating pulmonary vascular endothelial cells. Thus, PTTM-PH was successfully controlled using a combination of imatinib, drugs to treat pulmonary arterial hypertension, and cancer management.