横田 卓 (ヨコタ タカシ)

北海道大学病院 医療・ヘルスサイエンス研究開発機構特任講師

研究者基本情報

■ 学位
  • 医学博士, 北海道大学
■ URL
researchmap URLホームページURL■ ID 各種
研究者番号
  • 90374321
J-Global ID■ 研究キーワード・分野
研究キーワード
  • 気象学
  • 骨格筋・マイオカイン
  • 栄養学
  • 動脈硬化
  • 遠隔医療
  • 異所性脂肪
  • 冬眠
  • 睡眠
  • リハビリテーション
  • 遺伝学的検査
  • データサイエンス
  • 予防医療
  • 高血圧
  • ICT
  • デジタルヘルス
  • スポーツ医学
  • 運動生理学
  • 心不全
  • ミトコンドリア
  • 腸内フローラ
  • 糖尿病
  • 酸化ストレス
研究分野
  • 情報通信, 生命、健康、医療情報学, デジタルヘルス
  • ライフサイエンス, 循環器内科学
  • ライフサイエンス, スポーツ科学

経歴

■ 経歴
経歴
  • 2025年11月 - 現在
    北海道大学, 大学院医学研究院医学研究AI支援部門, 特任講師, 日本国
  • 2024年04月 - 現在
    北海道大学病院パーソナルヘルスセンター (PHC), 次世代健診部門長, 日本国
  • 2019年04月 - 現在
    北海道大学病院データマネージメント部門, 副部門長, 日本国
  • 2019年04月 - 現在
    北海道大学病院, 医療・ヘルスサイエンス研究開発機構, 特任講師, 日本国
  • 2013年 - 2019年03月
    北海道大学, 大学院医学研究院循環病態内科学, 助教
  • 2013年09月 - 2018年08月
    北海道大学, 保健センター, 助教, 日本国
  • 2011年 - 2013年
    デンマーク・コペンハーゲン大学, 医学部, 博士研究員, デンマーク王国
  • 2009年11月 - 2011年
    北海道大学, 大学院医学研究院循環病態内科学, 助教
学歴
  • 2005年04月 - 2008年03月, 北海道大学, 大学院医学研究院 (博士課程)
  • 1992年04月 - 1998年03月, 北海道大学, 医学部
委員歴
  • 2022年09月 - 現在
    NPO法人北海道心不全医療連携アカデミー, 副理事長, その他
  • 2019年04月 - 現在
    NPO法人北海道医療連携ネットワーク, 理事, その他
  • 2018年11月 - 現在
    日本心臓リハビリテーション学会 AsiaPRevent部会, 部員, 学協会
  • 2013年09月 - 現在
    日本心臓リハビリテーション学会, 評議員, 学協会
  • 2022年09月 - 2024年03月
    日本心臓リハビリテーション学会 卒前・卒後教育対策部会, 部員, 学協会
  • 2016年04月 - 2021年03月
    日本心臓リハビリテーション北海道支部, 庶務幹事, 学協会
  • 2018年04月 - 2020年03月
    札幌市指定難病審査委員会委員, 自治体
  • 2015年03月 - 2019年03月
    北海道指定難病審査専門委員会特別委員, 自治体
  • 2014年06月 - 2016年05月
    北海道特定疾患対策協議会審査専門委員, 自治体

研究活動情報

■ 受賞
  • 2022年, 大和証券ヘルス財団調査研究助成
    横田 卓
  • 2017年, 中冨健康科学振興財団研究助成
    横田 卓
  • 2016年, 北海道大学総長奨励賞
    横田 卓
  • 2015年, 持田記念医学薬学振興財団研究助成
    横田 卓
  • 2012年, 楡刀会外科医学研究助成
    横田 卓
  • 2010年, 鈴木万平糖尿病財団留学助成
    横田 卓
■ 論文
  • Comment on "Associations between animal and plant protein intakes and the mortality and hospitalization of patients with chronic heart failure"
    Tasuku Inao; Yoichi M Ito; Takashi Yokota; Arata Fukushima; Taisuke Ono; Takeshi Sota; Yoshiharu Kinugasa; Masashige Takahashi; Ryuichi Matsukawa; Ichiro Yoshida; Shigeo Kakinoki; Kazuya Yonezawa; Yoshihiro Himura; Isao Yokota; Kazuhiro Yamamoto; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa
    Clinical Nutrition ESPEN, 2026年06月, [査読有り], [招待有り], [責任著者]
    英語, 研究論文(学術雑誌)
  • Associations between animal and plant protein intakes and the mortality and hospitalization of patients with chronic heart failure.
    Tasuku Inao; Yoichi M Ito; Takashi Yokota; Arata Fukushima; Taisuke Ono; Takeshi Sota; Yoshiharu Kinugasa; Masashige Takahashi; Ryuichi Matsukawa; Ichiro Yoshida; Shigeo Kakinoki; Kazuya Yonezawa; Yoshihiro Himura; Isao Yokota; Kazuhiro Yamamoto; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa
    Clinical Nutrition ESPEN, 103307, 2026年04月29日, [査読有り], [責任著者], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND & AIMS: Associations between dietary animal and plant protein intakes and the mortality and morbidity in non-HF (heart failure) populations have been reported, but no study has evaluated these intakes' association with adverse events in patients with HF. We determined the associations of chronic HF patients' intakes of animal and plant proteins with mortality and hospitalization. METHODS: This prospective study enrolled 146 patients with chronic HF who were treated between Dec. 2012 and Sept. 2014 at 10 hospitals across Japan. Their dietary intake information was collected at baseline by a validated brief self-administered diet-history questionnaire. The primary outcomes were (i) all-cause death and hospitalization and (ii) cardiac death and HF hospitalization. We divided the total HF cohort into high and low animal and plant protein intakes, using the cut-off values of 10.3% and 6.0% of total energy consumption for animal and plant protein respectively, based on the spline's trends. RESULTS: During the 1-year follow-up, six patients died and 28 patients were hospitalized. A multivariable analysis demonstrated that compared to a high plant protein intake, a low plant protein intake was associated with all-cause death and hospitalization with a 1.93 risk ratio (95% CI: 1.03-3.60); no significant association of animal protein intake with the primary outcomes was observed. The combination of high animal protein and low plant protein intake was associated with both primary outcomes. CONCLUSIONS: Dietary plant protein intake was inversely associated with all-cause mortality and hospitalization in patients with chronic HF.
  • Reduced hemoglobin-corrected diffusing capacity in pulmonary arterial hypertension with preserved pulmonary function and morphology
    Ayako Igarashi-Sugimoto; Ichizo Tsujino; Hideki Shima; Junichi Nakamura; Toshitaka Nakaya; Takahiro Sato; Taku Watanabe; Hiroshi Ohira; Kaoruko Shimizu; Takashi Yokota; Sari Iwasaki; Satonori Tsuneta; Isao Yokota; Satoshi Konno
    Respiratory Investigation, 63, 4, 600, 607, Elsevier BV, 2025年07月, [国内誌]
    英語, 研究論文(学術雑誌)
  • Reduction in Acetylation of Superoxide Dismutase 2 in Skeletal Muscle Improves Exercise Capacity in Mice With Heart Failure
    Tomoka Masunaga; Tomoyasu Suenaga; Shouji Matsushima; Toru Hashimoto; Shingo Takada; Eri Noda; Yoshizuki Fumoto; Soichiro Hata; Takashi Yokota; Shintaro Kinugawa
    Journal of Cachexia, Sarcopenia and Muscle, 16, 3, e13850, Wiley, 2025年06月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), ABSTRACT

    Background

    Skeletal muscle abnormalities, including mitochondrial dysfunction, play a crucial role in decreasing exercise capacity in patients with heart failure (HF). Although enhanced reactive oxygen species (ROS) production in skeletal muscle mitochondria has been implicated in skeletal muscle abnormalities, the underlying mechanisms have not been fully elucidated to date. Superoxide dismutase 2 (SOD2), an antioxidant enzyme present in mitochondria, is modified by acetylation, which reduces its activity. The aim of this study was to clarify whether reducing SOD2 acetylation by sirtuins 3 (SIRT3) activation improves skeletal muscle mitochondrial function and exercise capacity in HF model mice.

    Methods

    Myocardial infarction (MI) by ligation of the coronary artery or sham surgery was performed in male C57BL/6 J mice. Two weeks after surgery, these mice were treated with either the SIRT3 activator Honokiol (5 mg/kg body weight/day, i.p.) or vehicle. After 2 weeks of treatment, exercise capacity was evaluated by the treadmill test. Gastrocnemius muscle samples collected from the mice were used to measure mitochondrial function, as well as the levels of SIRT3, acetylated SOD2, and ROS production. Finally, the effect of adeno‐associated virus serotype 9 (AAV9)‐mediated overexpression of SIRT3 in the skeletal muscle on the exercise capacity of MI mice was investigated.

    Results

    MI mice showed decreased cardiac function and skeletal muscle weight, but Honokiol did not affect these. Exercise capacity was significantly decreased in MI mice compared with sham mice by 24.9%, and Honokiol treatment improved the exercise capacity of MI mice by 40.4% (p < 0.05). The mitochondrial oxygen consumption rate was impaired in MI mice, but was improved by Honokiol treatment. SIRT3 expression was decreased by 26.8%, and SOD2 acetylation was increased by 36.9% in the skeletal muscle of MI mice compared with sham (p < 0.05), and Honokiol treatment resulted in complete recovery of these levels (p < 0.05). Consistent with SOD2 acetylation, ROS production in the skeletal muscle was increased in MI mice and was ameliorated by Honokiol (p < 0.05). SIRT3 expression was increased in MI + AAV9‐SIRT3 mice compared with MI + AAV9‐Control mice. The overexpression of SIRT3 improved exercise capacity without altering cardiac function.

    Conclusions

    The SIRT3 activator Honokiol improved exercise capacity in MI model mice with HF, by improving mitochondrial function in skeletal muscle through the reduction of SOD2 acetylation. SIRT3 activation may thus be a novel therapeutic target for improving exercise capacity in patients with HF.
  • Development and validation of an algorithm for identifying patients undergoing dialysis from patients with advanced chronic kidney disease
    Takahiro Imaizumi; Takashi Yokota; Kouta Funakoshi; Kazushi Yasuda; Akiko Hattori; Akemi Morohashi; Tatsumi Kusakabe; Masumi Shojima; Sayoko Nagamine; Toshiaki Nakano; Yong Huang; Hiroshi Morinaga; Miki Ohta; Satomi Nagashima; Ryusuke Inoue; Naoki Nakamura; Hideki Ota; Tatsuya Maruyama; Hideo Gobara; Akira Endoh; Masahiko Ando; Yoshimune Shiratori; Shoichi Maruyama
    Clinical and Experimental Nephrology, 29, 5, 650, 661, Springer Science and Business Media LLC, 2025年05月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌), Abstract

    Background

    Identifying patients on dialysis among those with an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 remains challenging. To facilitate clinical research in advanced chronic kidney disease (CKD) using electronic health records, we aimed to develop algorithms to identify dialysis patients using laboratory data obtained in routine practice.

    Methods

    We collected clinical data of patients with an eGFR < 15 mL/min/1.73 m2 from six clinical research core hospitals across Japan: four hospitals for the derivation cohort and two for the validation cohort. The candidate factors for the classification models were identified using logistic regression with stepwise backward selection. To ensure transplant patients were not included in the non-dialysis population, we excluded individuals with the disease code Z94.0.

    Results

    We collected data from 1142 patients, with 640 (56%) currently undergoing hemodialysis or peritoneal dialysis (PD), including 426 of 763 patients in the derivation cohort and 214 of 379 patients in the validation cohort. The prescription of PD solutions perfectly identified patients undergoing dialysis. After excluding patients prescribed PD solutions, seven laboratory parameters were included in the algorithm. The areas under the receiver operation characteristic curve were 0.95 and 0.98 and the positive and negative predictive values were 90.9% and 91.4% in the derivation cohort and 96.2% and 94.6% in the validation cohort, respectively. The calibrations were almost linear.

    Conclusions

    We identified patients on dialysis among those with an eGFR < 15 ml/min/1.73 m2. This study paves the way for database research in nephrology, especially for patients with non-dialysis-dependent advanced CKD.
  • Contemporary clinical characteristics and management patterns in hypertrophic cardiomyopathy: insights from baseline enrolment data in a nationwide prospective Japanese registry
    Toru Kubo; Kenta Sugiura; Yukichi Tokita; Hitoshi Takano; Itaru Takamisawa; Morimasa Takayama; Yoshinori L Doi; Yuichiro Minami; Shota Shirotani; Mio Ebato; Miki Tsujiuchi; Takeru Nabeta; Takayuki Inomata; Takao Kato; Ryuji Okamoto; Kaoru Dohi; Yasuyoshi Takei; Taishiro Chikamori; Eiichi Watanabe; Azusa Furugen; Hirosato Doi; Keitaro Akita; Yuichiro Maekawa; Akiyoshi Ogimoto; Norio Tada; Takashi Yokota; Shuntaro Ikeda; Osamu Yamaguchi; Yasuhiro Izumiya; Atsushi Shibata; Seiji Takashio; Kenichi Tsujita; Yasuhiro Maejima; Noboru Fujino; Akihiro Nomura; Yuichi Akasaki; Koji Higuchi; Shuichi Fujita; Masaaki Hoshiga; Yasuyuki Shiraishi; Masaki Ieda; Yuya Miyamoto; Hiroaki Kitaoka
    Heart, BMJ, 2025年03月04日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Background

    The Japanese Hypertrophic Cardiomyopathy Registry Study was designed to provide comprehensive, real-world insights into the clinical characteristics and management of hypertrophic cardiomyopathy (HCM) in Japan.

    Methods

    This multicentre, prospective study enrolled consecutive patients with HCM from 24 referral hospitals across Japan starting in 2016. The baseline characteristics of 1485 patients enrolled by December 2019 are presented in this analysis.

    Results

    The median ages at registration and diagnosis were 69 and 60 years, respectively, with men accounting for 54% of the cohort. Familial HCM was confirmed in 18% of cases. Of the cohort, 36% had hypertrophic obstructive cardiomyopathy (HOCM), while 8% had mid-ventricular obstruction, 14% had apical HCM and 4% were in the end-stage phase. Atrial fibrillation was observed in 27% of patients, though the majority were asymptomatic or had mild symptoms at registration. Adverse outcomes included prior sustained ventricular tachycardia or fibrillation (6%), heart failure requiring hospitalisation (11%) and embolic events (5%). Defibrillator implantation was performed in 11% of patients. Differences in the defibrillator indications for primary prevention in the current three guidelines and status of defibrillator deployment at registration were clarified: the percentages of class IIa recommendation in the whole cohort and of patients with defibrillator implantation in class IIa were 22% and 19% in the Japanese guidelines, 4% and 39% in the European guidelines and 28% and 22% in the American guidelines, respectively. Beta blockers were prescribed to 90% of patients with HOCM, while 51% received cibenzoline. Septal reduction therapies were performed in 22% of patients with HOCM, with 6% undergoing surgical myectomy.

    Conclusions

    As the first large-scale, prospective HCM registry in Japan, this study provides valuable baseline data on the clinical characteristics and management of HCM. These findings will help address gaps between current practice and guideline recommendations, improving the care of patients with HCM.
  • Efficacy and safety of the urate-lowering agent febuxostat in chronic heart failure patients with hyperuricemia: results from the LEAF-CHF study
    Takashi Yokota; Shintaro Kinugawa; Arata Fukushima; Takahiro Okumura; Toyoaki Murohara; Hiroyuki Tsutsui
    Heart and Vessels, 40, 2, 111, 122, Springer Science and Business Media LLC, 2025年02月, [査読有り], [筆頭著者, 責任著者], [国内誌]
    英語, 研究論文(学術雑誌)
  • Associations of sarcopenia and malnutrition with 30-day in-hospital morbidity and mortality after cardiac surgery
    Takahiro Abe; Tasuku Inao; Yasushige Shingu; Akira Yamada; Shingo Takada; Arata Fukushima; Noriko Oyama-Manabe; Isao Yokota; Satoru Wakasa; Shintaro Kinugawa; Takashi Yokota
    European Journal of Cardio-Thoracic Surgery, 67, 1, ezae456, Oxford University Press (OUP), 2025年01月, [査読有り], [最終著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    OBJECTIVES

    Sarcopenia and malnutrition often occur simultaneously in adults with cardiovascular diseases. Our objective was to determine the associations of preoperative sarcopenia and malnutrition with major adverse cardiac and cerebral events (MACCE) after cardiac surgery

    METHODS

    We retrospectively analyzed 154 consecutive patients who underwent elective cardiac surgery between January 2015 and June 2018 at two institutions in Japan. Sarcopenia and nutritional status were preoperatively assessed by bilateral psoas muscle volume index (PMVI) using CT scans and the prognostic nutritional index (PNI), respectively.

    RESULTS

    The median age in the total cohort was 69 years, and 43% were women. Within 30 days after surgery, 20 patients developed in-hospital MACCE and 7 patients died of any cause. Low PMVI (&lt;72.25 cm3/m2) and low PNI (&lt;48.15) were each independent predictors of postoperative MACCE occurrence with odds ratios (95% confidence interval) of 3.58 (1.22–10.53) and 3.73 (1.25–11.09) when adjusted for age and sex, and 3.25 (1.07–9.87) and 3.27 (1.08–9.89) when adjusted for preoperative left ventricular ejection fraction, angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, and anticoagulant. In addition, the combination of low PMVI and low PNI conferred the highest risk of in-hospital MACCE among the 4 groups (ie, the low PMVI, low PNI, low PMVI+low PNI, and neither low PMVI nor low PNI groups).

    CONCLUSIONS

    Preoperative low PMVI and low PNI were respectively associated with 30-day in-hospital MACCE occurrence after cardiac surgery. Notably, coexistence of these reductions further enhanced the risk of postoperative MACCE.
  • Associations of serum branched-chain amino acid and marine omega-3 fatty acid levels with exercise intolerance in heart failure patients
    Takeshi Sota; Yoshiharu Kinugasa; Natsuko Nakayama; Kensuke Nakamura; Masayuki Hirai; Masahiko Kato; Taisuke Ono; Masashige Takahashi; Hisashi Matsuo; Ryuichi Matsukawa; Ichiro Yoshida; Shigeo Kakinoki; Kazuya Yonezawa; Yoshihiro Himura; Takashi Yokota; Kazuhiro Yamamoto; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa
    Clinical Nutrition Open Science, 57, 241, 252, Elsevier BV, 2024年10月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Skeletal muscle mitochondria: A potential target for postmenopausal hormone replacement therapy
    Takashi Yokota
    Acta Physiologica, 240, 6, e14149, Wiley, 2024年04月17日, [査読有り], [招待有り], [筆頭著者, 最終著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Influence of epicardial adipose tissue inflammation and adipocyte size on postoperative atrial fibrillation in patients after cardiovascular surgery
    Hiroyuki Natsui; Masaya Watanabe; Takashi Yokota; Satonori Tsuneta; Yoshizuki Fumoto; Haruka Handa; Matsushima Shouji; Jiro Koya; Kotaro Nishino; Daishiro Tatsuta; Takuya Koizumi; Takahide Kadosaka; Motoki Nakao; Taro Koya; Taro Temma; Yoichi M. Ito; Hatanaka C. Kanako; Yutaka Hatanaka; Shingu Yasushige; Satoru Wakasa; Shuhei Miura; Takahiko Masuda; Naritomo Nishioka; Shuichi Naraoka; Kayoko Ochi; Tomoko Kudo; Tsugumine Ishikawa; Toshihisa Anzai
    Physiological Reports, 12, 6, e15957, Wiley, 2024年03月28日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Epicardial adipose tissue (EAT) is an active endocrine organ that is closely associated with occurrence of atrial fibrillation (AF). However, the role of EAT in the development of postoperative AF (POAF) remains unclear. We aimed to investigate the association between EAT profile and POAF occurrence in patients who underwent cardiovascular surgery. We obtained EAT samples from 53 patients to evaluate gene expression, histological changes, mitochondrial oxidative phosphorylation (OXPHOS) capacity in the EAT, and protein secretion in EAT‐conditioned medium. EAT volume was measured using computed tomography scan. Eighteen patients (34%) experienced POAF within 7 days after surgery. Although no significant difference was observed in EAT profile between patients with and without POAF, logistic regression analysis identified that the mRNA expression levels of tumor necrosis factor‐alpha (TNF‐α) were positively correlated and adipocyte size in the EAT was inversely correlated with onset of POAF, respectively. Mitochondrial OXPHOS capacity in the EAT was not associated with POAF occurrence; however, it showed an inverse correlation with adipocyte size and a positive correlation with adiponectin secretion. In conclusion, changes in the secretory profile and adipocyte morphology of the EAT, which represent qualitative aspects of the adipose tissue, were present before the onset of AF.
  • Author Correction: Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults
    Ryosuke Shirakawa; Takayuki Nakajima; Aya Yoshimura; Yukako Kawahara; Chieko Orito; Miwako Yamane; Haruka Handa; Shingo Takada; Takaaki Furihata; Arata
    Scientific Reports, 14, 1, 6786, Springer Science and Business Media LLC, 2024年03月21日, [査読有り], [最終著者, 責任著者]
    英語, 研究論文(学術雑誌)
  • Muscular stress is equal when resistance exercise with blood flow restriction is matched in total work volume: A cross‐sectional, cross‐over study
    Koichi Okita; Masashi Omokawa; Shingo Takada; Tomoyasu Kadoguchi; Noriteru Morita; Takashi Yokota
    Acta Physiologica, 240, 3, e14097, Wiley, 2024年01月17日, [査読有り], [最終著者], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Aim

    We compared muscular metabolic stress during exercise performed at multiple intensities, from very low to moderate, with blood flow restriction (BFR) adjusted by the same work volume.

    Methods

    Twenty‐five healthy young adults performed unilateral plantar flexion at 1 repetition/2 s in a magnetic resonance system. The BFR exercise protocols were as follows: (A) exercise with 10% of one repetition maximum (1‐RM) for 360 s, (B) 15% 1‐RM for 240 s, (C) 20% 1‐RM for 180 s, (D) 30% 1‐RM for 120 s, and (E) 40% 1‐RM for 90 s. All protocols had the same total work volume (load × repetitions = 1800). A high‐intensity protocol at 65% 1‐RM without BFR (60 s) was also performed for comparison. We used 31P‐magnetic resonance spectroscopy to evaluate the muscular metabolic stress in the subjects' calf muscle, defined as decreases in phosphocreatine and intramuscular pH.

    Results

    The phosphocreatine depletion (A: 15.6 ± 0.7, B: 14.8 ± 0.8, C: 15.2 ± 0.6, D: 14.3 ± 0.6, E: 10.9 ± 0.5 mM; no significant difference [ns]) and the intramuscular pH decrease (A: 6.82 ± 0.02, B: 6.84 ± 0.01, C: 6.83 ± 0.02, D: 6.83 ± 0.02, E: 6.77 ± 0.02; ns) at the end of each exercise were similar and greater than those produced by the 65% 1‐RM without BFR.

    Conclusion

    If the total work volumes are equal, the metabolic stress in exercising muscle may reach similar levels at the end of exercise with BFR and could provide similar successful training effects.
  • The AppCare-HF randomized clinical trial: a feasibility study of a novel self-care support mobile app for individuals with chronic heart failure
    Takashi Yokota; Arata Fukushima; Miyuki Tsuchihashi-Makaya; Takahiro Abe; Shingo Takada; Takaaki Furihata; Naoki Ishimori; Takeo Fujino; Shintaro Kinugawa; Masayuki Ohta; Shigeo Kakinoki; Isao Yokota; Akira Endoh; Masanori Yoshino; Hiroyuki Tsutsui
    European Heart Journal - Digital Health, 4, 4, 325, 336, Oxford University Press (OUP), 2023年05月10日, [査読有り], [筆頭著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Aims

    We evaluated a self-care intervention with a novel mobile application (app) in chronic heart failure (HF) patients. To facilitate patient-centred care in HF management, we developed a self-care support mobile app to boost HF patients’ optimal self-care.

    Methods and results

    We conducted a multicentre, randomized, controlled study evaluating the feasibility of the self-care support mobile app designed for use by HF patients. The app consists of a self-monitoring assistant, education, and automated alerts of possible worsening HF. The intervention group received a tablet personal computer (PC) with the self-care support app installed, and the control group received a HF diary. All patients performed self-monitoring at home for 2 months. Their self-care behaviours were evaluated by the European Heart Failure Self-Care Behaviour Scale. We enrolled 24 outpatients with chronic HF (ages 31–78 years; 6 women, 18 men) who had a history of HF hospitalization. During the 2 month study period, the intervention group (n = 13) showed excellent adherence to the self-monitoring of each vital sign, with a median [interquartile range (IQR)] ratio of self-monitoring adherence for blood pressure, body weight, and body temperature at 100% (92–100%) and for oxygen saturation at 100% (91–100%). At 2 months, the intervention group’s self-care behaviour score was significantly improved compared with the control group (n = 11) [median (IQR): 16 (16–22) vs. 28 (20–36), P = 0.02], but the HF Knowledge Scale, the General Self-Efficacy Scale, and the Short Form-8 Health Survey scores did not differ between the groups.

    Conclusion

    The novel mobile app for HF is feasible.
  • Enhanced mitochondrial oxidative metabolism in peripheral blood mononuclear cells is associated with fatty liver in obese young adults
    Ryosuke Shirakawa; Takayuki Nakajima; Aya Yoshimura; Yukako Kawahara; Chieko Orito; Miwako Yamane; Haruka Handa; Shingo Takada; Takaaki Furihata; Arata Fukushima; Naoki Ishimori; Masao Nakagawa; Isao Yokota; Hisataka Sabe; Satoshi Hashino; Shintaro Kinugawa; Takashi Yokota
    Scientific Reports, 13, 1, 5203, 5203, Springer Science and Business Media LLC, 2023年03月30日, [査読有り], [最終著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Systemic inflammation underlies the association between obesity and nonalcoholic fatty liver disease (NAFLD). Here, we investigated functional changes in leukocytes’ mitochondria in obese individuals and their associations with NAFLD. We analyzed 14 obese male Japanese university students whose body mass index was > 30 kg/m2 and 15 healthy age- and sex-matched lean university students as controls. We observed that the mitochondrial oxidative phosphorylation (OXPHOS) capacity with complex I + II-linked substrates in peripheral blood mononuclear cells (PBMCs), which was measured using a high-resolution respirometry, was significantly higher in the obese group versus the controls. The PBMCs’ mitochondrial complex IV capacity was also higher in the obese subjects. All of the obese subjects had hepatic steatosis defined by a fatty liver index (FLI) score ≥ 60, and there was a positive correlation between their FLI scores and their PBMCs’ mitochondrial OXPHOS capacity. The increased PBMCs’ mitochondrial OXPHOS capacity was associated with insulin resistance, systemic inflammation, and higher serum levels of interleukin-6 in the entire series of subjects. Our results suggest that the mitochondrial respiratory capacity is increased in the PBMCs at the early stage of obesity, and the enhanced PBMCs’ mitochondrial oxidative metabolism is associated with hepatic steatosis in obese young adults.
  • Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats
    Takuya Koizumi; Masaya Watanabe; Takashi Yokota; Masumi Tsuda; Haruka Handa; Jiro Koya; Kotaro Nishino; Daishiro Tatsuta; Hiroyuki Natsui; Takahide Kadosaka; Taro Koya; Motoki Nakao; Hikaru Hagiwara; Rui Kamada; Taro Temma; Shinya Tanaka; Toshihisa Anzai
    Frontiers in Cardiovascular Medicine, 10, 1005408, 1005408, Frontiers Media SA, 2023年02月06日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Introduction

    Recent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis.

    Methods

    A high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured.

    Results

    Inducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium.

    Discussion

    These data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM.
  • Luseogliflozin preserves the pancreatic beta-cell mass and function in db/db mice by improving mitochondrial function
    Yuki Yamauchi; Akinobu Nakamura; Takashi Yokota; Kiyohiko Takahashi; Shinichiro Kawata; Kazuhisa Tsuchida; Kazuno Omori; Hiroshi Nomoto; Hiraku Kameda; Kyu Yong Cho; Toshihisa Anzai; Shinya Tanaka; Yasuo Terauchi; Hideaki Miyoshi; Tatsuya Atsumi
    Scientific Reports, 12, 1, 9740, 9740, Springer Science and Business Media LLC, 2022年12月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    We aimed to determine the mechanism by which the sodium glucose co-transporter 2 inhibitor, luseogliflozin, preserves pancreatic beta-cell mass and function in db/db mice. Six-week-old db/db mice were fed to standard chow or standard chow containing 0.01% luseogliflozin. After 4 weeks, DNA microarray analysis, real-time PCR analysis, and measurement of mitochondrial respiratory capacity and reactive oxygen species (ROS) generation were performed using isolated islets. Immunohistochemistry and electron microscopic analysis were performed using pancreatic tissues. Metabolites extracted from the islets were measured by capillary electrophoresis mass spectrometry. The expression of genes involved in the tricarboxylic acid (TCA) cycle and electron transport chain was upregulated by luseogliflozin. Luseogliflozin improved the mitochondrial complex II-linked oxidative phosphorylation capacity and reduced ROS generation. Mitochondrial morphology was normally maintained by luseogliflozin. Luseogliflozin increased NK6 homeobox 1 (NKX6.1) expression and TCA cycle metabolites. Relief of glucotoxicity by luseogliflozin may involve lower mitochondrial ROS generation and an improvement in complex II-linked mitochondrial respiration. Reducing ROS generation through preventing complex II damage likely increases NKX6.1 expression and ameliorate glucose metabolism in the TCA cycle, contributing to the protection of pancreatic beta-cells. Protection of complex II in pancreatic beta-cells represents a novel therapeutic target for type 2 diabetes.
  • Cross-disease communication between cancer and heart failure provides a rational approach to prevention and treatment of both diseases
    Shingo Takada; Shintaro Kinugawa; Haruka Handa; Takashi Yokota; Hisataka Sabe
    Frontiers in Oncology, 12, 1006322, 1006322, Frontiers Media SA, 2022年10月31日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Accumulating clinical data have demonstrated a clear positive association between cancer and cardiac disorders, particularly chronic heart failure (CHF). These two diseases can be mutual drivers of each other, and hence frequently co-occur in patients. The immune system is the core mechanism that eliminates transformed cells from our bodies. However, immune cells often play distinct or even conflicting roles in cancer and CHF. Moreover, CHF alters the properties of immune cells, particularly those of regulatory T cells. Our previous study showed that the oxidative phosphorylation capacity of peripheral blood mononuclear cells is impaired in CHF, leading to the increased production of reactive oxygen species. Therefore, the co-occurrence of cancer and CHF becomes a serious problem, affecting the treatment of both diseases, and consequently negatively affecting patient survival rates. To date, few methods have been identified that effectively treat both diseases at the same time. Mitochondria activity may change in immune cells during their activation and exhaustion, and in CHF. Mitochondria activity is also largely affected in myocardia in CHF. We here focus on the mitochondrial abnormalities of immune cells in cancer and CHF, and discuss possible ways to treat cancer and CHF at the same time by targeting mitochondrial abnormalities. Many cancer cells are inevitably produced daily in our bodies, mostly owing to enzymatic nucleotide errors of DNA replication and repair. Therefore, the possibility of ways to prevent cancer by preventing the onset of heart failure will also be discussed.
  • Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure
    Shingo Takada; Satoshi Maekawa; Takaaki Furihata; Naoya Kakutani; Daiki Setoyama; Koji Ueda; Hideo Nambu; Hikaru Hagiwara; Haruka Handa; Yoshizuki Fumoto; Soichiro Hata; Tomoka Masunaga; Arata Fukushima; Takashi Yokota; Dongchon Kang; Shintaro Kinugawa; Hisataka Sabe
    Proc Natl Acad Sci U S A, 119, 41, e2203628119, Proceedings of the National Academy of Sciences, 2022年10月11日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Heart failure (HF) is a leading cause of death and repeated hospitalizations and often involves cardiac mitochondrial dysfunction. However, the underlying mechanisms largely remain elusive. Here, using a mouse model in which myocardial infarction (MI) was induced by coronary artery ligation, we show the metabolic basis of mitochondrial dysfunction in chronic HF. Four weeks after ligation, MI mice showed a significant decrease in myocardial succinyl-CoA levels, and this decrease impaired the mitochondrial oxidative phosphorylation (OXPHOS) capacity. Heme synthesis and ketolysis, and protein levels of several enzymes consuming succinyl-CoA in these events, were increased in MI mice, while enzymes synthesizing succinyl-CoA from α-ketoglutarate and glutamate were also increased. Furthermore, the ADP-specific subunit of succinyl-CoA synthase was reduced, while its GDP-specific subunit was almost unchanged. Administration of 5-aminolevulinic acid, an intermediate in the pathway from succinyl-CoA to heme synthesis, appreciably restored succinyl-CoA levels and OXPHOS capacity and prevented HF progression in MI mice. Previous reports also suggested the presence of succinyl-CoA metabolism abnormalities in cardiac muscles of HF patients. Our results identified that changes in succinyl-CoA usage in different metabolisms of the mitochondrial energy production system is characteristic to chronic HF, and although similar alterations are known to occur in healthy conditions, such as during strenuous exercise, they may often occur irreversibly in chronic HF leading to a decrease in succinyl-CoA. Consequently, nutritional interventions compensating the succinyl-CoA consumption are expected to be promising strategies to treat HF.
  • Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure
    Aya Shiraki; Jun-ichi Oyama; Takahiko Shimizu; Takayuki Nakajima; Takashi Yokota; Koichi Node
    European Journal of Pharmacology, 931, 175194, 175194, Elsevier BV, 2022年08月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Diagnostic performance of nutritional indicators in patients with heart failure
    Yoshiharu Kinugasa; Takeshi Sota; Hiroko Kamitani; Natsuko Nakayama; Kensuke Nakamura; Masayuki Hirai; Kiyotaka Yanagihara; Masahiko Kato; Taisuke Ono; Masashige Takahashi; Hisashi Matsuo; Ryuichi Matsukawa; Ichiro Yoshida; Shigeo Kakinoki; Kazuya Yonezawa; Yoshihiro Himura; Takashi Yokota; Kazuhiro Yamamoto; Miyuki Tsuchihashi‐Makaya; Shintaro Kinugawa
    ESC Heart Failure, 9, 4, 2096, 2106, Wiley, 2022年08月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Impact of citrus fruit intake on the mental health of patients with chronic heart failure
    Naoya Kakutani; Takashi Yokota; Arata Fukushima; Yoshikuni Obata; Taisuke Ono; Takeshi Sota; Yoshiharu Kinugasa; Masashige Takahashi; Hisashi Matsuo; Ryuichi Matsukawa; Ichiro Yoshida; Shigeo Kakinoki; Kazuya Yonezawa; Yoshihiro Himura; Isao Yokota; Kazuhiro Yamamoto; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa
    Journal of Cardiology, 79, 6, 719, 726, Elsevier BV, 2022年06月, [査読有り], [責任著者], [国内誌]
    英語, 研究論文(学術雑誌), BACKGROUND: The full impact of the intake of citrus fruits on the risk of depression in individuals with chronic heart failure (HF) is unknown. Here, we examined the associations between the estimated habitual intakes of citrus fruits and depressive symptoms in patients with chronic HF. METHODS: We enrolled 150 stable outpatients with chronic HF who had a history of worsening HF. To assess the patients' daily dietary patterns, we used a brief self-administered diet-history questionnaire to calculate the daily consumption of foods and nutrients. To assess the patients' mental state, we used a nine-item Patient Health Questionnaire (PHQ-9). RESULTS: Twelve patients (8%) were identified as having moderate-to-severe depression (PHQ-9 score ≥10). The patients with PHQ-9 ≥10 had lower daily intakes of citrus fruits compared to those with no or mild depressive symptoms (PHQ-9 <10). The daily intakes of various antioxidants, including vitamin C, β-carotene, and β-cryptoxanthin, all of which are abundant in citrus fruits, were reduced in the patients with PHQ-9 ≥10, accompanied by higher serum levels of 8-isoprostane (an oxidative stress marker). A multivariate logistic regression analysis using forward selection showed that a lowered daily intake of citrus fruits was an independent predictor of the comorbidity of moderate-to-severe depression in patients with chronic HF, after adjustment for age, gender, and the hemoglobin value. CONCLUSIONS: A lower daily consumption of citrus fruits was associated with higher prevalence of depression in patients with chronic HF. Our findings support the hypothesis that a daily consumption of citrus fruits has a beneficial effect on the prevention and treatment of depression in chronic HF patients.
  • Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma
    Takashi Ishio; Sarvesh Kumar; Joji Shimono; Anusara Daenthanasanmak; Sigrid Dubois; Yuquan Lin; Bonita Bryant; Michael N. Petrus; Emmanuel Bachy; Da Wei Huang; Yandan Yang; Patrick L. Green; Hiroo Hasegawa; Michiyuki Maeda; Hideki Goto; Tomoyuki Endo; Takashi Yokota; Kanako C. Hatanaka; Yutaka Hatanaka; Shinya Tanaka; Yoshihiro Matsuno; Yibin Yang; Satoshi Hashino; Takanori Teshima; Thomas A. Waldmann; Louis M. Staudt; Masao Nakagawa
    Blood, 139, 10, 1541, 1556, American Society of Hematology, 2022年03月10日, [査読有り], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌), Abstract
    Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.
  • Loeys-Dietz Cardiomyopathy? Long-term Follow-up After Onset of Acute Decompensated Heart Failure
    Takashi Yokota; Hiroaki Koiwa; Shouji Matsushima; Shingo Tsujinaga; Masanao Naya; Hiroko Morisaki; Takayuki Morisaki
    Canadian Journal of Cardiology, 38, 3, 389, 391, Elsevier BV, 2022年03月, [査読有り], [筆頭著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice
    Takaaki Furihata; Satoshi Maekawa; Shingo Takada; Naoya Kakutani; Hideo Nambu; Ryosuke Shirakawa; Takashi Yokota; Shintaro Kinugawa
    BMC Pharmacology and Toxicology, 22, 1, 27, Springer Science and Business Media LLC, 2021年12月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Background

    Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice.

    Methods

    First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.).

    Results

    In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice.

    Conclusions

    Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive.
  • Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients
    Takashi Yokota; Shintaro Kinugawa; Kagami Hirabayashi; Mayumi Yamato; Shingo Takada; Tadashi Suga; Ippei Nakano; Arata Fukushima; Shouji Matsushima; Koichi Okita; Hiroyuki Tsutsui
    Scientific Reports, 11, 1, Springer Science and Business Media LLC, 2021年12月, [査読有り], [筆頭著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌), AbstractOxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.
  • Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure
    Takaaki Furihata; Shingo Takada; Naoya Kakutani; Satoshi Maekawa; Masaya Tsuda; Junichi Matsumoto; Wataru Mizushima; Arata Fukushima; Takashi Yokota; Nobuyuki Enzan; Shouji Matsushima; Haruka Handa; Yoshizuki Fumoto; Junko Nio-Kobayashi; Toshihiko Iwanaga; Shinya Tanaka; Hiroyuki Tsutsui; Hisataka Sabe; Shintaro Kinugawa
    Communications Biology, 4, 1, Springer Science and Business Media LLC, 2021年12月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), AbstractHeart failure (HF) occurs frequently among older individuals, and dysfunction of cardiac mitochondria is often observed. We here show the cardiac-specific downregulation of a certain mitochondrial component during the chronological aging of mice, which is detrimental to the heart. MitoNEET is a mitochondrial outer membrane protein, encoded by CDGSH iron sulfur domain 1 (CISD1). Expression of mitoNEET was specifically downregulated in the heart and kidney of chronologically aged mice. Mice with a constitutive cardiac-specific deletion of CISD1 on the C57BL/6J background showed cardiac dysfunction only after 12 months of age and developed HF after 16 months; whereas irregular morphology and higher levels of reactive oxygen species in their cardiac mitochondria were observed at earlier time points. Our results suggest a possible mechanism by which cardiac mitochondria may gradually lose their integrity during natural aging, and shed light on an uncharted molecular basis closely related to age-associated HF.
  • A Brief, Individualized Exercise Program at Intensities Below the Ventilatory Threshold Exerts Therapeutic Effects for Depression: A Pilot Study
    Yuri Sakai; Chong Chen; Atsuhito Toyomaki; Naoki Hashimoto; Kan Kitagawa; Takao Inoue; Asumi Sato; Keisuke Makihara; Rie Kameyama; Yumi Wakatsuki; Niki Udo; Ryosuke Shirakawa; Takashi Yokota; Shin Nakagawa; Ichiro Kusumi
    Frontiers in Behavioral Neuroscience, 15, 787688, 787688, Frontiers Media SA, 2021年11月22日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Due to the fact that existing pharmacological treatments for depression are not ideal, effort has been devoted to the development of complementary, alternative therapies such as physical exercise. The antidepressant effect of exercise is well documented. However, current recommendations and prescriptions of exercise may be too demanding for depressed patients, as some complain about the design of exercise programs and depression is associated with reduced motivation and capacity to exercise. Therefore, appropriately designed, patient-friendly exercise programs may prove critical for the long-term maintenance and therapeutic effects of exercise. In this pilot study, we developed an exercise program based on patients’ individual level of ventilatory threshold (VT), a submaximal index of aerobic capacity measured by Cardiopulmonary Exercise Testing (CPX). Compared to traditional measures, CPX provides more trustable indices of aerobic capacity and more homogenous exercise prescriptions. The main episode of the program consisted of 15–25 min of cycling twice a week at an intensity that approached but never went higher than subjects’ VT (considered low to moderate in intensity). We found that in patients diagnosed with major depressive disorder or persistent depressive disorder (n = 8), the program resulted in a significant reduction in depressive symptoms at week 8, which was maintained at week 16. Meanwhile, patients’ social functioning, quality of life, and cognitive functions improved. Although we used a single arm, non-randomized design, our results suggest that even a brief, low to moderate intensity exercise program may exert therapeutic effects for depression and CPX may be a useful tool for exercise prescriptions.
  • Natural Killer T Cells Are Involved in Atherosclerotic Plaque Instability in Apolipoprotein-E Knockout Mice
    Yoshinori Ohmura; Naoki Ishimori; Akimichi Saito; Takashi Yokota; Shunpei Horii; Satoshi Tokuhara; Kazuya Iwabuchi; Hiroyuki Tsutsui
    International Journal of Molecular Sciences, 22, 22, 12451, 12451, MDPI AG, 2021年11月18日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), The infiltration and activation of macrophages as well as lymphocytes within atherosclerotic lesion contribute to the pathogenesis of plaque rupture. We have demonstrated that invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens, play a crucial role in atherogenesis. However, it remained unclear whether iNKT cells are also involved in plaque instability. Apolipoprotein E (apoE) knockout mice were fed a standard diet (SD) or a high-fat diet (HFD) for 8 weeks. Moreover, the SD- and the HFD-fed mice were divided into two groups according to the intraperitoneal injection of α-galactosylceramide (αGC) that specifically activates iNKT cells or phosphate-buffered saline alone (PBS). ApoE/Jα18 double knockout mice, which lack iNKT cells, were also fed an SD or HFD. Plaque instability was assessed at the brachiocephalic artery by the histological analysis. In the HFD group, αGC significantly enhanced iNKT cell infiltration and exacerbated atherosclerotic plaque instability, whereas the depletion of iNKT cells attenuated plaque instability compared to PBS-treated mice. Real-time PCR analyses in the aortic tissues showed that αGC administration significantly increased expressional levels of inflammatory genes such as IFN-γ and MMP-2, while the depletion of iNKT cells attenuated these expression levels compared to those in the PBS-treated mice. Our findings suggested that iNKT cells are involved in the exacerbation of plaque instability via the activation of inflammatory cells and upregulation of MMP-2 in the vascular tissues.
  • Angiotensin‐converting enzyme inhibitor prevents skeletal muscle fibrosis in diabetic mice
    Naoya Kakutani; Shingo Takada; Hideo Nambu; Satoshi Maekawa; Hikaru Hagiwara; Katsuma Yamanashi; Yoshikuni Obata; Ippei Nakano; Yoshizuki Fumoto; Soichiro Hata; Takaaki Furihata; Arata Fukushima; Takashi Yokota; Shintaro Kinugawa
    Experimental Physiology, 106, 8, 1785, 1793, Wiley, 2021年08月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), NEW FINDINGS: What is the central question of this study? We questioned whether an angiotensin-converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice. What is the main finding and its importance? Administration of ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after induction of diabetes by streptozotocin. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. ABSTRACT: Fibrosis is characterized by the excessive production and accumulation of extracellular matrix components, including collagen. Although the extracellular matrix is an essential component of skeletal muscle, fibrosis can have negative effects on muscle function. Skeletal muscle fibrosis was shown to be increased in spontaneously hypertensive rats and to be prevented by an angiotensin-converting enzyme (ACE) inhibitor, an antihypertensive drug, in dystrophic mice or a mouse model of myocardial infarction. In this study, we therefore analysed whether (1) there is increased skeletal muscle fibrosis in streptozotocin (STZ)-induced diabetic mice, and (2) a preventive effect on skeletal muscle fibrosis by administration of an ACE inhibitor. Skeletal muscle fibrosis was significantly increased in STZ-induced diabetic mice compared with control mice from 2 to 14 days post-STZ. The ACE inhibitor prevented both skeletal muscle fibrosis and the reduction in muscle function in STZ-treated mice. Our study demonstrated that administration of an ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after onset of diabetes. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Future studies are required to clarify whether skeletal muscle fibrosis is also linked directly to physical activity.
  • Impact of Inadequate Calorie Intake on Mortality and Hospitalization in Stable Patients with Chronic Heart Failure
    Yoshikuni Obata; Naoya Kakutani; Shintaro Kinugawa; Arata Fukushima; Takashi Yokota; Shingo Takada; Taisuke Ono; Takeshi Sota; Yoshiharu Kinugasa; Masashige Takahashi; Hisashi Matsuo; Ryuichi Matsukawa; Ichiro Yoshida; Isao Yokota; Kazuhiro Yamamoto; Miyuki Tsuchihashi-Makaya
    Nutrients, 13, 3, 874, 874, MDPI AG, 2021年03月08日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Malnutrition is highly prevalent in patients with heart failure (HF), but the precise impact of dietary energy deficiency on HF patients’ clinical outcomes is not known. We investigated the associations between inadequate calorie intake and adverse clinical events in 145 stable outpatients with chronic HF who had a history of hospitalization due to worsening HF. To assess the patients’ dietary pattern, we used a brief self-administered diet-history questionnaire (BDHQ). Inadequate calorie intake was defined as <60% of the estimated energy requirement. In the total chronic HF cohort, the median calorie intake was 1628 kcal/day. Forty-four patients (30%) were identified as having an inadequate calorie intake. A Kaplan–Meier analysis revealed that the patients with inadequate calorie intake had significantly worse clinical outcomes including all-cause death and HF-related hospitalization during the 1-year follow-up period versus those with adequate calorie intake (20% vs. 5%, p < 0.01). A multivariate logistic regression analysis showed that inadequate calorie intake was an independent predictor of adverse clinical events after adjustment for various factors that may influence patients’ calorie intake. Among patients with chronic HF, inadequate calorie intake was associated with an increased risk of all-cause mortality and rehospitalization due to worsening HF. However, our results are preliminary and larger studies with direct measurements of dietary calorie intake and total energy expenditure are needed to clarify the intrinsic nature of this relationship.
  • Inhibition of xanthine oxidase in the acute phase of myocardial infarction prevents skeletal muscle abnormalities and exercise intolerance
    Hideo Nambu; Shingo Takada; Satoshi Maekawa; Junichi Matsumoto; Naoya Kakutani; Takaaki Furihata; Ryosuke Shirakawa; Takashi Katayama; Takayuki Nakajima; Katsuma Yamanashi; Yoshikuni Obata; Ippei Nakano; Masaya Tsuda; Akimichi Saito; Arata Fukushima; Takashi Yokota; Junko Nio-Kobayashi; Hironobu Yasui; Kei Higashikawa; Yuji Kuge; Toshihisa Anzai; Hisataka Sabe; Shintaro Kinugawa
    Cardiovascular Research, 117, 3, 805, 819, Oxford University Press (OUP), 2021年02月22日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Aims
    Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischaemic tissue. Here, we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production.




    Methods and results
    Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analysed. XO-derived ROS production was significantly increased in MI mice from Days 1 to 3 post-surgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham + vehicle (Sham + Veh), MI + vehicle (MI + Veh), and MI + febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI + Feb). Febuxostat or vehicle was administered at 1 and 24 h before surgery, and once-daily on Days 1–7 post-surgery. On Day 28 post-surgery, exercise capacity and mitochondrial respiration in skeletal muscle fibres were significantly decreased in MI + Veh compared with Sham + Veh mice. An increase in damaged mitochondria in MI + Veh compared with Sham + Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibres (higher XO-derived ROS) was reduced via the down-regulation of protein synthesis-associated mTOR-p70S6K signalling in MI + Veh compared with Sham + Veh mice. These impairments were ameliorated in MI + Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function.




    Conclusion
    XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF.


  • Brain-Derived Neurotrophic Factor Improves Impaired Fatty Acid Oxidation Via the Activation of Adenosine Monophosphate-Activated Protein Kinase-ɑ – Proliferator-Activated Receptor-r Coactivator-1ɑ Signaling in Skeletal Muscle of Mice With Heart Failure
    Junichi Matsumoto; Shingo Takada; Takaaki Furihata; Hideo Nambu; Naoya Kakutani; Satoshi Maekawa; Wataru Mizushima; Ippei Nakano; Arata Fukushima; Takashi Yokota; Shinya Tanaka; Haruka Handa; Hisataka Sabe; Shintaro Kinugawa
    Circulation: Heart Failure, 14, 1, e005890, Ovid Technologies (Wolters Kluwer Health), 2021年01月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌),
    Background:
    We recently reported that treatment with rhBDNF (recombinant human brain-derived neurotrophic factor) improved the reduced exercise capacity of mice with heart failure (HF) after myocardial infarction (MI). Since BDNF is reported to enhance fatty acid oxidation, we herein conducted an in vivo investigation to determine whether the improvement in exercise capacity is due to the enhancement of the fatty acid oxidation of skeletal muscle via the AMPKα-PGC1α (adenosine monophosphate-activated protein kinase-ɑ–proliferator-activated receptor-r coactivator-1ɑ) axis.




    Methods:
    MI and sham operations were conducted in C57BL/6J mice. Two weeks postsurgery, we randomly divided the MI mice into groups treated with rhBDNF or vehicle for 2 weeks. AMPKα-PGC1α signaling and mitochondrial content in the skeletal muscle of the mice were evaluated by Western blotting and transmission electron microscopy. Fatty acid β-oxidation was examined by high-resolution respirometry using permeabilized muscle fiber. BDNF-knockout mice were treated with 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside, an activator of AMPK.




    Results:
    The rhBDNF treatment significantly increased the expressions of phosphorylated AMPKα and PGC1α protein and the intermyofibrillar mitochondrial density in the MI mice. The lowered skeletal muscle mitochondrial fatty acid oxidation was significantly improved in the rhBDNF-treated MI mice. The reduced exercise capacity and mitochondrial dysfunction of the BDNF-knockout mice were improved by 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside.




    Conclusions:
    Beneficial effects of BDNF on the exercise capacity of mice with HF are mediated through an enhancement of fatty acid oxidation via the activation of AMPKα-PGC1α in skeletal muscle. BDNF may become a therapeutic option to improve exercise capacity as an alternative or adjunct to exercise training.


  • Type 2 diabetes is an independent predictor of lowered peak aerobic capacity in heart failure patients with non-reduced or reduced left ventricular ejection fraction
    Takahiro Abe; Takashi Yokota; Arata Fukushima; Naoya Kakutani; Takashi Katayama; Ryosuke Shirakawa; Satoshi Maekawa; Hideo Nambu; Yoshikuni Obata; Katsuma Yamanashi; Ippei Nakano; Shingo Takada; Isao Yokota; Koichi Okita; Shintaro Kinugawa; Toshihisa Anzai
    Cardiovascular Diabetology, 19, 1, 142, 142, Springer Science and Business Media LLC, 2020年12月, [査読有り], [責任著者], [国際誌]
    英語, 研究論文(学術雑誌), Abstract

    Background
    Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients’ peak aerobic capacity.




    Methods
    We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort.




    Results
    The mean peak oxygen uptake (VO2) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO2 was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of − 0.93 (− 1.82 to − 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of − 1.05 (− 1.96 to − 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO2 at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O2 pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO2 in CHF patients with non-reduced LVEF and those with reduced LVEF.




    Conclusions
    T2DM was associated with lowered peak VO2 in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients’ exercise capacity, and the degree of impact is partly dependent on their LV systolic function.


  • Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice
    Yoshikuni Obata; Naoki Ishimori; Akimichi Saito; Shintaro Kinugawa; Takashi Yokota; Shingo Takada; Ippei Nakano; Naoya Kakutani; Katsuma Yamanashi; Toshihisa Anzai
    European Journal of Preventive Cardiology, 27, 19, 2358, 2361, Oxford University Press (OUP), 2020年12月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • BDNF as a novel therapeutic candidate for Kennedy's disease
    Takashi Yokota
    The Journal of Physiology, 598, 13, 2543, 2544, Wiley, 2020年07月, [査読有り], [招待有り], [筆頭著者, 最終著者, 責任著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Loop diuretic use is associated with skeletal muscle wasting in patients with heart failure
    Nakano I, Tsuda M, Kinugawa S, Fukushima A, Kakutani N, Takada S, Yokota T
    J Cardiol, 76, 1, 109, 114, 2020年07月, [査読有り], [最終著者], [国内誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Loop diuretics are widely used for the management of fluid retention in patients with heart failure (HF). Sarcopenia, defined as decreased skeletal muscle mass, is frequently present in patients with HF and is associated with poor prognosis. The effects of loop diuretics on skeletal muscle in HF patients have not been fully elucidated. Here, we investigated the impact of loop diuretics on the skeletal muscle mass in patients with HF. METHODS: We conducted a subanalysis of a cross-sectional study from 10 hospitals evaluating 155 patients with HF (age 67 ± 13 yrs, 69% men). RESULTS: We compared the HF patients who were treated with loop diuretics (n = 120) with the patients who were not (n = 35). The thigh and arm circumferences were significantly small in the group treated with loop diuretics compared to those not so treated (39.9 ± 4.8 vs. 43.5 ± 6.9 cm, p < 0.001 and 26.7 ± 3.5 vs. 28.9 ± 6.2 cm, p < 0.001, respectively). In a univariate analysis, higher age, lower body mass index, lower hemoglobin, and loop diuretic use were significantly associated with smaller thigh circumference. In a multivariable analysis, the use of loop diuretics was independently associated with smaller thigh circumference (β = -0.51, 95% confidence interval -0.98 to -0.046, p = 0.032). CONCLUSION: Loop diuretics are associated with decreased thigh and arm circumferences in patients with HF, independent of the severity of HF. Our findings revealed for the first time the adverse effects of loop diuretics on skeletal muscle wasting. These findings will have a significant impact in clinical practice regarding the frequent use of loop diuretics in HF patients.
  • Validation of Gene Therapy for Mutant Mitochondria by Delivering Mitochondrial RNA Using a MITO-Porter.
    Eriko Kawamura; Minako Maruyama; Jiro Abe; Akira Sudo; Atsuhito Takeda; Shingo Takada; Takashi Yokota; Shintaro Kinugawa; Hideyoshi Harashima; Yuma Yamada
    Molecular therapy. Nucleic acids, 20, 687, 698, 2020年06月05日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Here, we report on validating a mitochondrial gene therapy by delivering nucleic acids to mitochondria of diseased cells by a MITO-Porter, a liposome-based carrier for mitochondrial delivery. We used cells derived from a patient with a mitochondrial disease with a G625A heteroplasmic mutation in the tRNAPhe of the mitochondrial DNA (mtDNA). It has been reported that some mitochondrial gene diseases are caused by heteroplasmic mutations, in which both mutated and wild-type (WT) genes are present, and the accumulation of pathological mutations leads to serious, intractable, multi-organ diseases. Therefore, the decrease of the mutated gene rate is considered to be a useful gene therapy strategy. To accomplish this, wild-type mitochondrial pre-tRNAPhe (pre-WT-tRNAPhe), prepared by in vitro transcription, was encapsulated in the MITO-Porter. The pre-WT-tRNAPhe encapsulated in the MITO-Porter was transfected into diseased mitochondrial cells, and the resulting mutant levels were examined by an amplification refractory mutation system (ARMS)-quantitative PCR. The mutation rate of tRNAPhe was decreased, and this therapeutic effect was sustained even on the 8th day after transfection. Furthermore, mitochondrial respiratory activity of the disease cells was increased after the transfection of therapeutic pre-WT-tRNAPhe. These results support the conclusion that the mitochondrial delivery of therapeutic nucleic acids represents a viable strategy for mitochondrial gene therapy.
  • Branched-chain amino acid supplementation ameliorates angiotensin II-induced skeletal muscle atrophy.
    Katsuma Yamanashi; Shintaro Kinugawa; Arata Fukushima; Naoya Kakutani; Shingo Takada; Yoshikuni Obata; Ippei Nakano; Takashi Yokota; Yasuyuki Kitaura; Yoshiharu Shimomura; Toshihisa Anzai
    Life sciences, 250, 117593, 117593, 2020年06月01日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), AIMS: Sarcopenia is characterized by muscle mass and strength loss and reduced physical activity. Branched-chain amino acids (BCAAs) were recently described as an activator of protein synthesis via mammalian target of rapamycin (mTOR) signaling for muscle atrophy. In cardiovascular diseases, excessive activation of the renin-angiotensin system may induce an imbalance of protein synthesis and degradation, and this plays a crucial role in muscle atrophy. We investigated the effects of BCAAs on angiotensin II (Ang II)-induced muscle atrophy in mice. MATERIALS AND METHODS: We administered Ang II (1000 ng/kg/min) or vehicle to 10-12-week-old male C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks with or without BCAA supplementation (3% BCAA in tap water). KEY FINDINGS: The skeletal muscle weight/tibial length and cross-sectional area were smaller in the Ang II mice than the vehicle mice; these changes were induced by an imbalance of protein synthesis and degradation signaling such as Akt/mTOR and MuRF-1/Atrogin-1. Compared to the Ang II mice, the mTOR signaling was significantly activated and Ang II-induced muscle atrophy was ameliorated in the Ang II + BCAA mice, and this attenuated the reduction of exercise capacity. Notably, the decrease of muscle weight/tibial length in the fast-twitch dominant muscles (e.g., the extensor digitorum longus) was significantly ameliorated compared to that in the slow-twitch dominant muscles (e.g., soleus). Histologically, the effect of BCAA was larger in fast-twitch than slow-twitch fibers, which may be related to the difference in BCAA catabolism. SIGNIFICANCE: BCAA supplementation could contribute to the prevention of skeletal muscle atrophy induced by Ang II.
  • Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice.
    Naoya Kakutani; Shingo Takada; Hideo Nambu; Junichi Matsumoto; Takaaki Furihata; Takashi Yokota; Arata Fukushima; Shintaro Kinugawa
    Skeletal muscle, 10, 1, 11, 11, 2020年04月25日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Transforming growth factor beta (TGF-β)-Smad2/3 is the major signaling pathway of fibrosis, which is characterized by the excessive production and accumulation of extracellular matrix (ECM) components, including collagen. Although the ECM is an essential component of skeletal muscle, fibrosis may be harmful to muscle function. On the other hand, our previous studies have shown that levels of angiotensin II, which acts upstream of TGF-β-Smad2/3 signaling, is increased in mice with myocardial infarction (MI). In this study, we found higher skeletal muscle fibrosis in MI mice compared with control mice, and we investigated the mechanisms involved therein. Moreover, we administered an inhibitor based on the above mechanism and investigated its preventive effects on skeletal muscle fibrosis. METHODS: Male C57BL/6 J mice with MI were created, and sham-operated mice were used as controls. The time course of skeletal muscle fibrosis post-MI was analyzed by picrosirius-red staining (days 1, 3, 7, and 14). Mice were then divided into 3 groups: sham + vehicle (Sham + Veh), MI + Veh, and MI + lisinopril (an angiotensin-converting enzyme [ACE] inhibitor, 20 mg/kg body weight/day in drinking water; MI + Lis). Lis or Veh was administered from immediately after the surgery to 14 days postsurgery. RESULTS: Skeletal muscle fibrosis was significantly increased in MI mice compared with sham mice from 3 to 14 days postsurgery. Although mortality was lower in the MI + Lis mice than the MI + Veh mice, there was no difference in cardiac function between the 2 groups at 14 days. Skeletal muscle fibrosis and hydroxyproline (a key marker of collagen content) were significantly increased in MI + Veh mice compared with the Sham + Veh mice. Consistent with these results, protein expression of TGF-β and phosphorylated Smad2/3 in the skeletal muscle during the early time points after surgery (days 1-7 postsurgery) and blood angiotensin II at 14 days postsurgery was increased in MI mice compared with sham mice. These impairments were improved in MI + Lis mice, without any effects on spontaneous physical activity, muscle strength, muscle weight, and blood pressure. CONCLUSIONS: ACE inhibitor administration prevents increased skeletal muscle fibrosis during the early phase after MI. Our findings indicate a new therapeutic target for ameliorating skeletal muscle abnormalities in heart diseases.
  • Correlation between increased atrial expression of genes related to fatty acid metabolism and autophagy in patients with chronic atrial fibrillation
    Yasushige Shingu; Shingo Takada; Takashi Yokota; Ryosuke Shirakawa; Akira Yamada; Tomonori Ooka; Hiroki Katoh; Suguru Kubota; Yoshiro Matsui
    PLoS One, 15, 4, e0224713, 2020年04月21日, [査読有り], [責任著者], [国際誌]
    英語, 研究論文(学術雑誌), Atrial metabolic disturbance contributes to the onset and development of atrial fibrillation (AF). Autophagy plays a role in maintaining the cellular energy balance. We examined whether atrial gene expressions related to fatty acid metabolism and autophagy are altered in chronic AF and whether they are related to each other. Right atrial tissue was obtained during heart surgery from 51 patients with sinus rhythm (SR, n = 38) or chronic AF (n = 13). Preoperative fasting serum free-fatty-acid levels were significantly higher in the AF patients. The atrial gene expression of fatty acid binding protein 3 (FABP3), which is involved in the cells' fatty acid uptake and intracellular fatty acid transport, was significantly increased in AF patients compared to SR patients; in the SR patients it was positively correlated with the right atrial diameter and intra-atrial electromechanical delay (EMD), parameters of structural and electrical atrial remodeling that were evaluated by an echocardiography. In contrast, the two groups' atrial contents of diacylglycerol (DAG), a toxic fatty acid metabolite, were comparable. Importantly, the atrial gene expression of microtubule-associated protein light chain 3 (LC3) was significantly increased in AF patients, and autophagy-related genes including LC3 were positively correlated with the atrial expression of FABP3. In conclusion, in chronic AF patients, the atrial expression of FABP3 was upregulated in association with autophagy-related genes without altered atrial DAG content. Our findings may support the hypothesis that dysregulated cardiac fatty acid metabolism contributes to the progression of AF and induction of autophagy has a cardioprotective effect against cardiac lipotoxicity in chronic AF.
  • Mitochondrial respiration of complex II is not lower than that of complex I in mouse skeletal muscle
    Satoshi Maekawa; Shingo Takada; Takaaki Furihata; Arata Fukushima; Takashi Yokota; Shintaro Kinugawa
    Biochemistry and Biophysics Reports, 21, 100717, 100717, Elsevier BV, 2020年03月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.
    Ippei Nakano; Shintaro Kinugawa; Hiroaki Hori; Arata Fukushima; Takashi Yokota; Shingo Takada; Naoya Kakutani; Yoshikuni Obata; Katsuma Yamanashi; Toshihisa Anzai
    International heart journal, 61, 1, 96, 102, 2020年01月31日, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌), Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (β-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.
  • Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure.
    Hideo Nambu; Shingo Takada; Arata Fukushima; Junichi Matsumoto; Naoya Kakutani; Satoshi Maekawa; Ryosuke Shirakawa; Ippei Nakano; Takaaki Furihata; Takashi Katayama; Katsuma Yamanashi; Yoshikuni Obata; Akimichi Saito; Takashi Yokota; Shintaro Kinugawa
    European journal of pharmacology, 866, 172810, 172810, 2020年01月05日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Decreased exercise capacity, which is an independent predictor of the poor prognosis of patients with heart failure (HF), is attributed to markedly impaired skeletal muscle mitochondrial function and fatty acid oxidation. Previous studies reported that the administration of an inhibitor of sodium-glucose cotransporter 2 (SGLT2) increases ketone body production and fat utilization in type 2 diabetic mice. In this study, we investigated the effects of SGLT2 inhibitor administration on exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a murine model of HF after the induction of myocardial infarction (MI). Two weeks post-MI, HF mice were divided into 2 groups, i.e., with or without treatment with the SGLT2 inhibitor empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared with the sham and HF mice 4 weeks after the start of Empa administration. Exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice, without any effects on cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weight. Mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle of HF mice, and this decrease was ameliorated in the HF+Empa mice. Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle.
  • A mitochondrial delivery system using liposome-based nanocarriers that target myoblast cells.
    Takashi Katayama; Shintaro Kinugawa; Shingo Takada; Takaaki Furihata; Arata Fukushima; Takashi Yokota; Toshihisa Anzai; Mitsue Hibino; Hideyoshi Harashima; Yuma Yamada
    Mitochondrion, 49, 66, 72, 2019年11月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Mitochondrial function is reduced in skeletal muscles of many patients with systemic diseases and it is difficult to deliver medicinal substances to mitochondria in such tissue. In this study, we report on attempts to develop liposome-based carriers for mitochondrial delivery using mouse myoblasts (C2C12) by varying the lipid composition of the carriers. We found that a liposome that contains an optimal lipid modified with the KALA peptide (a cellular uptake and mitochondrial targeting device) was the most effective nanocarrier for achieving mitochondrial delivery in C2C12 cells. We also report on successful mitochondrial transgene expression using the carriers encapsulating a mitochondrial DNA vector as we previously reported.
  • Mitochondrial reactive oxygen species generation in blood cells is associated with disease severity and exercise intolerance in heart failure patients.
    Ryosuke Shirakawa; Takashi Yokota; Takayuki Nakajima; Shingo Takada; Miwako Yamane; Takaaki Furihata; Satoshi Maekawa; Hideo Nambu; Takashi Katayama; Arata Fukushima; Akimichi Saito; Naoki Ishimori; Flemming Dela; Shintaro Kinugawa; Toshihisa Anzai
    Scientific reports, 9, 1, 14709, 14709, 2019年10月11日, [査読有り], [責任著者], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌), Systemic oxidative stress plays a key role in the development of chronic heart failure (CHF). We tested the hypothesis that mitochondrial reactive oxygen species (ROS) generation in circulating peripheral blood mononuclear cells (PBMCs) contributes to CHF progression. A total of 31 patients who had a history of hospital admission due to worsening HF were enrolled and grouped as having either mild CHF defined as New York Heart Association (NYHA) functional class I-II or moderate-to-severe CHF defined as NYHA functional class III. ROS levels in PBMC mitochondria were significantly increased in CHF patients with NYHA functional class III compared to those with NYHA functional class I-II, accompanied by impaired mitochondrial respiratory capacity in PBMCs. ROS generation in PBMC mitochondria was positively correlated with urinary 8-hydroxydeoxyguanosine, a systemic oxidative stress marker, in CHF patients. Importantly, mitochondrial ROS generation in PBMCs was directly correlated with plasma levels of B-type natriuretic peptide, a biomarker for severity of HF, and inversely correlated with peak oxygen uptake, a parameter of exercise capacity, in CHF patients. The study showed that ROS generation in PBMC mitochondria was higher in patients with advanced CHF, and it was associated with disease severity and exercise intolerance in CHF patients.
  • Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure.
    Ippei Nakano; Hiroaki Hori; Arata Fukushima; Takashi Yokota; Shintaro Kinugawa; Shingo Takada; Katsuma Yamanashi; Yoshikuni Obata; Yasuyuki Kitaura; Naoya Kakutani; Takahiro Abe; Toshihisa Anzai
    Journal of cardiac failure, 26, 8, 685, 693, 2019年09月15日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Skeletal muscle is quantitatively and qualitatively impaired in patients with heart failure (HF), which is closely linked to lowered exercise capacity. Ultrasonography (US) for skeletal muscle has emerged as a useful, noninvasive tool to evaluate muscle quality and quantity. Here we investigated whether muscle quality based on US-derived echo intensity (EI) is associated with exercise capacity in patients with HF. METHODS AND RESULTS: Fifty-eight patients with HF (61 ± 12 years) and 28 control subjects (58 ± 14 years) were studied. The quadriceps femoris echo intensity (QEI) was significantly higher and the quadriceps femoris muscle thickness (QMT) was significantly lower in the patients with HF than the controls (88.3 ± 13.4 vs 81.1 ± 7.5, P= .010; 5.21 ± 1.10 vs 6.54 ±1.34 cm, P< .001, respectively). By univariate analysis, QEI was significantly correlated with age, peak oxygen uptake (VO2), and New York Heart Association class in the HF group. A multivariable analysis revealed that the QEI was independently associated with peak VO2 after adjustment for age, gender, body mass index, and QMT: β-coefficient = -11.80, 95%CI (-20.73, -2.86), P= .011. CONCLUSION: Enhanced EI in skeletal muscle was independently associated with lowered exercise capacity in HF. The measurement of EI is low-cost, easily accessible, and suitable for assessment of HF-related alterations in skeletal muscle quality.
  • Resistance training with interval blood flow restriction effectively enhances intramuscular metabolic stress with less ischemic duration and discomfort
    Koichi Okita; Shingo Takada; Noriteru Morita; Masashige Takahashi; Kagami Hirabayashi; Takashi Yokota; Shintaro Kinugawa
    Applied Physiology, Nutrition, and Metabolism, 44, 7, 759, 764, Canadian Science Publishing, 2019年07月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Increases in muscle size and strength similar to those obtained with high resistance load can be achieved by combining lower loads with continuous blood flow restriction (BFR). However, high ratings for distress have been reported for continuous BFR. Therefore, we investigated the efficacy (metabolic stress) of BFR applied only during intervals in resistance exercise. Seven healthy men performed three 1-min sets of plantar flexion (30 reps/min) with 1-min rest intervals under 4 conditions: low-load resistance exercise (L, 20% 1-repetition maximum (1RM)) without BFR (L-noBFR), L with BFR during exercise sets (L-exBFR), L with BFR during rest intervals (L-intBFR), and L with continuous BFR during both exercise and rest intervals (L-conBFR). Based on the results of the first experiment, we performed additional protocols using a moderate load (M, 40% 1RM) with intermittent (exercise or rest intervals) BFR (M-exBFR and M-intBFR). Intramuscular metabolic stress, defined as decreases in phosphocreatine and intramuscular pH, was evaluated by 31P magnetic resonance spectroscopy. Rated perceived exertion (RPE) was also assessed. At the end of exercise, total decreases in phosphocreatine and intramuscular pH were similar among L-noBFR, L-intBFR, and L-exBFR and significantly less than those in L-conBFR (p < 0.05). In contrast, changes in these variables in M-intBFR but not in M-exBFR were similar to those in L-conBFR. Nevertheless, RPE was lower in M-intBFR than in both M-exBFR and L-conBFR (p < 0.05). The effect of intermittent BFR during exercise might be insufficient to induce metabolic stress when using a low load. However, effective metabolic stress for muscle adaptation could be obtained by moderate-load resistance exercise with BFR during intervals with less ischemic duration and discomfort.
  • Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure
    Kazunori Omote; Toshiyuki Nagai; Naoya Asakawa; Kiwamu Kamiya; Yusuke Tokuda; Tadao Aikawa; Arata Fukushima; Keiji Noguchi; Yoshiya Kato; Hirokazu Komoriyama; Mutsumi Nishida; Yusuke Kudo; Hiroyuki Iwano; Takashi Yokota; Toshihisa Anzai
    Heart and Vessels, 34, 6, 984, 991, Springer Science and Business Media LLC, 2019年06月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Clinical Impact and Associated Factors of Delayed Ambulation in Patients With Acute Heart Failure
    Koji Ishikawa; Arata Fukushima; Takashi Yokota; Shingo Takada; Takaaki Furihata; Naoya Kakutani; Katsuma Yamanashi; Yoshikuni Obata; Ippei Nakano; Takahiro Abe; Shintaro Kinugawa; Toshihisa Anzai
    Circulation Reports, 1, 4, 179, 186, Japanese Circulation Society, 2019年04月10日, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌), Background: In heart failure (HF) management, early ambulation is recommended to prevent physical deconditioning. The effects of delayed ambulation on later clinical outcomes and the factors linked to delayed ambulation in hospitalized HF patients, however, remain unestablished. Methods and Results: We retrospectively investigated 101 patients (mean age, 66±17 years) who were hospitalized for acute decompensated HF. During the mean follow-up of 244±15 days after hospital discharge, 34 patients had cardiovascular events leading to death or unplanned readmission. Patients with cardiovascular events had longer median days to acquire ambulation than those without cardiovascular events (11 days, IQR, 8-20 days vs. 7 days, IQR, 5-15 days, P<0.001). The optimal cut-off period until initiation of ambulation to discriminate cardiovascular events was 8 days, indicating that longer days (≥8 days) to acquire ambulation was associated with higher rates of cardiovascular events, even after adjustment of multiple confounders. On multivariate analysis, age >65 years (odds ratio [OR], 2.49; 95% confidence interval [CI]: 1.04-6.09) and increase in blood urea nitrogen (BUN; OR, 1.04; 95% CI: 1.01-1.08) were independent predictors of delayed ambulation. Conclusions: Delayed ambulation is associated with older age and increased BUN in patients with acute HF. Time to ambulation in the recovery phase of acute HF is important, and delayed ambulation may increase the rate of cardiovascular events after hospital discharge.
  • Diastolic Intra-Left Ventricular Pressure Difference During Exercise: Strong Determinant and Predictor of Exercise Capacity in Patients With Heart Failure.
    Shingo Tsujinaga; Hiroyuki Iwano; Miwa Sarashina; Taichi Hayashi; Michito Murayama; Ayako Ichikawa; Masahiro Nakabachi; Hisao Nishino; Shinobu Yokoyama; Arata Fukushima; Takashi Yokota; Kazunori Okada; Sanae Kaga; Pavlos P Vlachos; Toshihisa Anzai
    Journal of cardiac failure, 25, 4, 268, 277, 2019年04月, [査読有り], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Although the enhancement of early-diastolic intra-left ventricular pressure difference (IVPD) during exercise is considered to maintain exercise capacity, little is known about their relationship in heart failure (HF). METHODS AND RESULTS: Cardiopulmonary exercise testing and exercise-stress echocardiography were performed in 50 HF patients (left ventricular [LV] ejection fraction 39 ± 15%). Echocardiographic images were obtained at rest and submaximal and peak exercise. Color M-mode Doppler images of LV inflow were used to determine IVPD. Thirty-five patients had preserved exercise capacity (peak oxygen consumption [VO2] ≥14 mL·kg-1·min-1; group 1) and 15 patients had reduced exercise capacity (group 2). During exercise, IVPD increased only in group 1 (group 1: 1.9 ± 0.9 mm Hg at rest, 4.1 ± 2.0 mm Hg at submaximum, 4.7 ± 2.1 mm Hg at peak; group 2: 1.9 ± 0.8 mm Hg at rest, 2.1 ± 0.9 mm Hg at submaximum, 2.1 ± 0.9 mm Hg at peak). Submaximal IVPD (r = 0.54) and peak IVPD (r = 0.69) were significantly correlated with peak VO2. Peak IVPD determined peak VO2 independently of LV ejection fraction. Moreover, submaximal IVPD could well predict the reduced exercise capacity. CONCLUSION: Early-diastolic IVPD during exercise was closely associated with exercise capacity in HF. In addition, submaximal IVPD could be a useful predictor of exercise capacity without peak exercise in HF patients.
  • Progressive Mobilization Program for Patients With Acute Heart Failure Reduces Hospital Stay and Improves Clinical Outcome
    Naoya Kakutani; Arata Fukushima; Shintaro Kinugawa; Takashi Yokota; Tatsuya Oikawa; Mikito Nishikawa; Risako Nakamura; Takanori Tsukada; Shigeki Mori; Ichiro Yoshida; Toshihisa Anzai
    Circulation Reports, 1, 3, 123, 130, Japanese Circulation Society, 2019年03月08日, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌), Background: Early ambulation has been shown to be associated with shorter hospital stay and better clinical outcomes in patients with acute heart failure (HF). Early mobilization program in combination with structured exercise training is recommended, but has yet to be developed and implemented in HF. Methods and Results: We developed a progressive mobilization program for HF patients that classifies the mobilization process into 7 stages based on disease condition and physical function. We retrospectively analyzed 136 patients with acute HF (80±11 years), who were assigned either to the mobilization program (intervention group, n=75) or to usual care (control group, n=61). The program was safely implemented without any adverse events. Hospital stay was significantly reduced in the intervention group compared with the control group (33±25 vs. 51±36 days, P<0.01). The intervention group had higher activities of daily living (ADL) score at discharge evaluated using the Barthel index (64±38 vs. 49±36, P<0.05). The intervention group also had a higher percentage of discharge to home (71% vs. 52%, P<0.05) and a lower rate of HF-related readmission (16% vs. 36%, P<0.05) compared with the control group. Conclusions: The progressive mobilization program for acute HF was feasible and was associated with better ADL and reduced hospital stay, leading to improvement of clinical outcome.
  • Impaired mitochondrial oxidative phosphorylation capacity in epicardial adipose tissue is associated with decreased concentration of adiponectin and severity of coronary atherosclerosis.
    Takayuki Nakajima; Takashi Yokota; Yasushige Shingu; Akira Yamada; Yutaka Iba; Kosuke Ujihira; Satoru Wakasa; Tomonori Ooka; Shingo Takada; Ryosuke Shirakawa; Takashi Katayama; Takaaki Furihata; Arata Fukushima; Ryosuke Matsuoka; Hiroshi Nishihara; Flemming Dela; Katsuhiko Nakanishi; Yoshiro Matsui; Shintaro Kinugawa
    Scientific reports, 9, 1, 3535, 3535, 2019年03月05日, [査読有り], [責任著者], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌), Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.
  • Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure.
    Junichi Matsumoto; Shingo Takada; Shintaro Kinugawa; Takaaki Furihata; Hideo Nambu; Naoya Kakutani; Masaya Tsuda; Arata Fukushima; Takashi Yokota; Shinya Tanaka; Hidehisa Takahashi; Masashi Watanabe; Shigetsugu Hatakeyama; Masaki Matsumoto; Keiichi I Nakayama; Yutaro Otsuka; Hisataka Sabe; Hiroyuki Tsutsui; Toshihisa Anzai
    Circulation, 138, 18, 2064, 2066, 2018年10月30日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Impact of High Respiratory Exchange Ratio During Submaximal Exercise on Adverse Clinical Outcome in Heart Failure.
    Naoya Kakutani; Arata Fukushima; Takashi Yokota; Takashi Katayama; Hideo Nambu; Ryosuke Shirakawa; Satoshi Maekawa; Takahiro Abe; Shingo Takada; Takaaki Furihata; Kota Ono; Koichi Okita; Shintaro Kinugawa; Toshihisa Anzai
    Circulation journal : official journal of the Japanese Circulation Society, 82, 11, 2753, 2760, 2018年10月25日, [査読有り], [責任著者], [国内誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Oxygen uptake (V̇O2) at peak workload and anaerobic threshold (AT) workload are often used for grading heart failure (HF) severity and predicting all-cause mortality. The clinical relevance of respiratory exchange ratio (RER) during exercise, however, is unknown. Methods and Results: We retrospectively studied 295 HF patients (57±15 years, NYHA class I-III) who underwent cardiopulmonary exercise testing. RER was measured at rest; at AT workload; and at peak workload. Peak V̇O2 had an inverse correlation with RER at AT workload (r=-0.256), but not at rest (r=-0.084) or at peak workload (r=0.090). Using median RER at AT workload, we divided the patients into high RER (≥0.97) and low RER (<0.97) groups. Patients with high RER at AT workload were characterized by older age, lower body mass index, anemia, and advanced NYHA class. After propensity score matching, peak V̇O2 tended to be lower in the high-RER than in the low-RER group (14.9±4.5 vs. 16.1±5.0 mL/kg/min, P=0.06). On Kaplan-Meier analysis, HF patients with a high RER at AT workload had significantly worse clinical outcomes, including all-cause mortality and rate of readmission due to HF worsening over 3 years (29% vs. 15%, P=0.01). CONCLUSIONS: High RER during submaximal exercise, particularly at AT workload, is associated with poor clinical outcome in HF patients.
  • Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure.
    Masaya Tsuda; Arata Fukushima; Junichi Matsumoto; Shingo Takada; Naoya Kakutani; Hideo Nambu; Katsuma Yamanashi; Takaaki Furihata; Takashi Yokota; Koichi Okita; Shintaro Kinugawa; Toshihisa Anzai
    Journal of cachexia, sarcopenia and muscle, 9, 5, 844, 859, 2018年10月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post-translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF. METHODS: We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2 ) in HF patients. We then created a murine model of HF (n = 11) or sham-operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. RESULTS: The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham-operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid β-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (β-hydroxyacyl CoA dehydrogenase) activity and fatty acid-driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced β-hydroxyacyl CoA dehydrogenase activity. CONCLUSIONS: Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.
  • Randomized Trial of Effect of Urate-Lowering Agent Febuxostat in Chronic Heart Failure Patients with Hyperuricemia (LEAF-CHF)
    Takashi Yokota; Arata Fukushima; Shintaro Kinugawa; Takahiro Okumura; Toyoaki Murohara; Hiroyuki Tsutsui
    International Heart Journal, 59, 5, 976, 982, International Heart Journal (Japanese Heart Journal), 2018年09月01日, [査読有り], [筆頭著者], [国内誌]
    英語, 研究論文(学術雑誌), Hyperuricemia is an independent predictor of mortality in patients with chronic heart failure. The aim of the study is to determine whether a urate-lowering agent febuxostat, an inhibitor of xanthine oxidase, may improve the clinical outcomes in chronic heart failure patients with hyperuricemia when compared to conventional treatment. This multicenter, prospective, randomized, open-label, blinded endpoint study with a follow-up period of 24 weeks will enroll 200 Japanese chronic heart failure patients with hyperuricemia. The eligibility criteria include a diagnosis of chronic heart failure (New York Heart Association functional class II-III with a history of hospitalization due to worsening of heart failure within the last 2 years), reduced left ventricular systolic function (left ventricular ejection fraction < 40%) and increased plasma natriuretic peptide [plasma B-type natriuretic peptide (BNP) ≥ 100 pg/mL or N-terminal pro BNP (NT-proBNP) ≥ 400 pg/mL], and hyperuricemia (serum uric acid >7.0 mg/dL and ≤ 10 mg/dL) at the screening visit. The primary outcome is the difference in the plasma BNP levels between the baseline and 24 weeks of treatment. The plasma BNP levels are measured in the central laboratory in a blinded manner. This study investigates the efficacy and safety of febuxostat in chronic heart failure patients with hyperuricemia.
  • Initial brain aging: heterogeneity of mitochondrial size is associated with decline in complex I-linked respiration in cortex and hippocampus
    Thomsen K, Yokota T, Hasan-Olive MM, Sherazi N, Fakouri NB, Desler C, Regnell CE, Larsen S, Rasmussen LJ, Dela F, Bergersen LH, Lauritzen M
    Neurobiol Aging, 61, 215, 224, 2018年01月, [査読有り], [筆頭著者], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy
    Tomoyasu Kadoguchi; Shingo Takada; Takashi Yokota; Takaaki Furihata; Junichi Matsumoto; Masaya Tsuda; Wataru Mizushima; Arata Fukushima; Koichi Okita; Shintaro Kinugawa
    BioMed Research International, 2018, 1, 10, Wiley, 2018年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg−1 min−1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.
  • Decreased gene expression of fatty acid binding protein 3 in the atrium of patients with new onset of atrial fibrillation in cardiac perioperative phase
    Yasushige Shingu; Takashi Yokota; Shingo Takada; Haruki Niwano; Tomonori Ooka; Hiroki Katoh; Tsuyoshi Tachibana; Suguru Kubota; Yoshiro Matsui
    Journal of Cardiology, 71, 1, 65, 70, Japanese College of Cardiology (Nippon-Sinzobyo-Gakkai), 2018年01月01日, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome
    Yokota T, Kinugawa S, Hirabayashi K, Suga T, Takada S, Omokawa M, Kadoguchi T, Takahashi M, Fukushima A, Matsushima S, Yamato M, Okita K, Tsutsui H
    J Diabetes Investig, 8, 535, 541, 2017年07月, [査読有り], [筆頭著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Pre-ischaemic mitochondrial substrate constraint by inhibition of malate-aspartate shuttle preserves mitochondrial function after ischaemia-reperfusion
    Jespersen NR, Yokota T, Støttrup NB, Bergdahl A, Paelestik KB, Povlsen JA, Dela F, Bøtker HE
    J Physiol, 595, 12, 3765, 3780, 2017年06月, [査読有り], [責任著者], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes
    Mizushima W, Takahashi H, Watanabe M, Kinugawa S, Matsushima S, Takada S, Yokota T, Furihata T, Matsumoto J, Tsuda M, Chiba I, Nagashima S, Yanagi S, Matsumoto M, Nakayama KI, Tsutsui H, Hatakeyama S
    J Mol Cell Cardiol, 100, 43, 53, 2016年11月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Serum myostatin levels are independently associated with skeletal muscle wasting in patients with heart failure
    Takaaki Furihata; Shintaro Kinugawa; Arata Fukushima; Shingo Takada; Tsuneaki Homma; Yoshihiro Masaki; Takahiro Abe; Takashi Yokota; Koji Oba; Koichi Okita; Hiroyuki Tsutsui
    INTERNATIONAL JOURNAL OF CARDIOLOGY, 220, 483, 487, 2016年10月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling
    Shouji Matsushima; Junya Kuroda; Peiyong Zhai; Tong Liu; Shohei Ikeda; Narayani Nagarajan; Shin-ichi Oka; Takashi Yokota; Shintaro Kinugawa; Chiao-Po Hsu; Hong Li; Hiroyuki Tsutsui; Junichi Sadoshima
    JOURNAL OF CLINICAL INVESTIGATION, 126, 9, 3403, 3416, 2016年09月, [査読有り], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling
    Shingo Takada; Yoshihiro Masaki; Shintaro Kinugawa; Junichi Matsumoto; Takaaki Furihata; Wataru Mizushima; Tomoyasu Kadoguchi; Arata Fukushima; Tsuneaki Homma; Masashige Takahashi; Shinichi Harashima; Shouji Matsushima; Takashi Yokota; Shinya Tanaka; Koichi Okita; Hiroyuki Tsutsui
    CARDIOVASCULAR RESEARCH, 111, 4, 338, 347, 2016年09月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • The experimental model of transition from compensated cardiac hypertrophy to failure created by transverse aortic constriction in mice.
    Takaaki Furihata; Shintaro Kinugawa; Shingo Takada; Arata Fukushima; Masashige Takahashi; Tsuneaki Homma; Yoshihiro Masaki; Masaya Tsuda; Junichi Matsumoto; Wataru Mizushima; Shouji Matsushima; Takashi Yokota; Hiroyuki Tsutsui
    International journal of cardiology. Heart & vasculature, 11, 24, 28, 2016年06月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore, we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. METHODS AND RESULTS: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LV wall thickness, end-diastolic dimension, fractional shortening were measured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure. With the 0.385 mm pin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. CONCLUSION: TAC with the diameter of 0.385 mm can effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival.
  • Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice
    Arata Fukushima; Shintaro Kinugawa; Shingo Takada; Junichi Matsumoto; Takaaki Furihata; Wataru Mizushima; Masaya Tsuda; Takashi Yokota; Shouji Matsushima; Koichi Okita; Hiroyuki Tsutsui
    EUROPEAN JOURNAL OF PHARMACOLOGY, 779, 147, 156, 2016年05月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Low-intensity exercise under ischemic conditions enhances metabolic stress in patients with heart failure
    Masashige Takahashi; Shintaro Kinugawa; Shingo Takada; Kagami Hirabayashi; Takashi Yokota; Shouji Matsushima; Akimichi Saito; Koichi Okita; Hiroyuki Tsutsui
    International Journal of Cardiology, 201, 142, 144, 2015年12月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Sesamin prevents decline in exercise capacity and impairment of skeletal muscle mitochondrial function in mice with high-fat diet-induced diabetes
    Shingo Takada; Shintaro Kinugawa; Shouji Matsushima; Daisuke Takemoto; Takaaki Furihata; Wataru Mizushima; Arata Fukushima; Takashi Yokota; Yoshiko Ono; Hiroshi Shibata; Koichi Okita; Hiroyuki Tsutsui
    EXPERIMENTAL PHYSIOLOGY, 100, 11, 1319, 1330, 2015年11月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Skeletal muscle mitochondrial H2O2 emission increases with immobilization and decreases after aerobic training in young and older men
    Martin Gram; Andreas Vigelso; Takashi Yokota; Jorn Wulff Helge; Flemming Dela; Martin Hey-Mogensen
    JOURNAL OF PHYSIOLOGY-LONDON, 593, 17, 4011, 4027, 2015年09月, [査読有り], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • Tissue-specific and substrate-specific mitochondrial bioenergetics in feline cardiac and skeletal muscles
    Liselotte Bruun Christiansen; Flemming Dela; Jorgen Koch; Takashi Yokota
    JOURNAL OF VETERINARY MEDICAL SCIENCE, 77, 6, 669, 675, 2015年06月, [査読有り], [最終著者, 責任著者], [国際共著], [国内誌]
    英語, 研究論文(学術雑誌)
  • AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress
    Mikito Nishikawa; Naoki Ishimori; Shingo Takada; Akimichi Saito; Tomoyasu Kadoguchi; Takaaki Furihata; Arata Fukushima; Shouji Matsushima; Takashi Yokota; Shintaro Kinugawa; Hiroyuki Tsutsui
    NEPHROLOGY DIALYSIS TRANSPLANTATION, 30, 6, 934, 942, 2015年06月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy
    Liselotte B. Christiansen; Flemming Dela; Jorgen Koch; Christina N. Hansen; Pall S. Leifsson; Takashi Yokota
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 308, 10, H1237, H1247, 2015年05月, [査読有り], [最終著者, 責任著者], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle
    Tomoyasu Kadoguchi; Shintaro Kinugawa; Shingo Takada; Arata Fukushima; Takaaki Furihata; Tsuneaki Homma; Yoshihiro Masaki; Wataru Mizushima; Mikito Nishikawa; Masashige Takahashi; Takashi Yokota; Shouji Matsushima; Koichi Okita; Hiroyuki Tsutsui
    EXPERIMENTAL PHYSIOLOGY, 100, 3, 312, 322, 2015年03月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Serum brain-derived neurotropic factor level predicts adverse clinical outcomes in patients with heart failure
    Fukushima A, Kinugawa S, Homma T, Masaki Y, Furihata T, Yokota T, Matsushima S, Takada S, Kadoguchi T, Oba K, Okita K, Tsutsui H
    J Card Fail, 21, 4, 300, 6, 2015年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Brain-derived neurotropic factor (BDNF) is involved in cardiovascular diseases as well as skeletal muscle energy metabolism and depression. We investigated whether serum BDNF level was associated with prognosis in patients with heart failure (HF). METHODS AND RESULTS: We measured the serum BDNF level in 58 patients with HF (59.2 ± 13.7 years old, New York Heart Association functional class I-III) at baseline, and adverse events, including all cardiac deaths and HF rehospitalizations, were recorded during the median follow-up of 20.3 months. In a univariate analysis, serum BDNF levels were significantly associated with peak oxygen capacity (β = 0.547; P = .003), anaerobic threshold (β = 0.929; P = .004), and log minute ventilation/carbon dioxide production slope (β = -10.15; P = .005), but not Patient Health Questionnaire scores (β = -0.099; P = .586). A multivariate analysis demonstrated that serum BDNF level was an independent prognostic factor of adverse events (hazard ratio 0.41, 95% confidence interval 0.20-0.84; P = .003). The receiver operating characteristic curve demonstrated that low levels of BDNF (<17.4 ng/mL) were associated with higher rates of adverse events compared with high levels of BDNF (≥17.4 ng/mL; log rank test: P < .001). CONCLUSIONS: Decreased serum BDNF levels were significantly associated with adverse outcomes in HF patients, suggesting that these levels can be a useful prognostic biomarker.
  • Serum choline plasmalogens-those with oleic acid in sn-2-are biomarkers for coronary artery disease
    Nishimukai M, Maeba R, Ikuta A, Asakawa N, Kamiya K, Yamada S, Yokota T, Sakakibara M, Tsutsui H, Sakurai T, Takahashi Y, Hui SP, Chiba H, Okazaki T, Hara H
    Clin Chim Acta, 437, 147, 154, 2014年11月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Two weeks of one-leg immobilization decreases skeletal muscle respiratory capacity equally in young and elderly men
    Gram M, Vigelsø A, Yokota T, Hansen CN, Helge JW, Hey-Mogensen M, Dela F
    Exp Gerontol, 58, 269, 278, 2014年, [査読有り], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • Intramyocellular lipid is increased in the skeletal muscle of patients with dilated cardiomyopathy with lowered exercise capacity
    Hirabayashi K, Kinugawa S, Yokota T, Takada S, Fukushima A, Suga T, Takahashi M, Ono T, Morita N, Omokawa M, Harada K, Oyama-Manabe N, Shirato H, Matsushima S, Okita K, Tsutsui H
    Int J Cardiol, 176, 1110, 1112, 2014年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • (Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice
    Fukushima A, Kinugawa S, Takada S, Matsushima S, Sobirin MA, Ono T, Takahashi M, Suga T, Homma T, Masaki Y, Furihata T, Kadoguchi T, Yokota T, Okita K, Tsutsui H
    Am J Physiol Endocrinol Metab, 307, E503, E514, 2014年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Clinical characteristics and CHADS(2) score in patients with heart failure and atrial fibrillation: Insights from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)
    Hamaguchi S, Kinugawa S, Matsushima S, Fukushima A, Yokota T, Sakakibara M, Yokoshiki H, Tsuchihashi-Makaya M, Tsutsui H
    Int J Cardiol, 176, 239, 242, 2014年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice
    Takada S, Hirabayashi K, Kinugawa S, Yokota T, Matsushima S, Suga T, Kadoguchi T, Fukushima A, Homma T, Mizushima W, Masaki Y, Furihata T, Katsuyama R, Okita K, Tsutsui H
    Eur J Pharmacol, 740, 690, 696, 2014年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Combination of exercise training and diet restriction normalizes limited exercise capacity and impaired skeletal muscle function in diet-Induced diabetic mice
    Suga T, Kinugawa S, Takada S, Kadoguchi T, Fukushima A, Homma T, Masaki Y, Furihata T, Takahashi M, Sobirin MA, Ono T, Hirabayashi K, Yokota T, Tanaka S, Okita K, Tsutsui H
    Endocrinology, 155, 68, 80, 2014年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Systemic Oxidative Stress Is Associated With Lower Aerobic Capacity and Impaired Skeletal Muscle Energy Metabolism in Patients With Metabolic Syndrome
    Takashi Yokota; Shintaro Kinugawa; Mayumi Yamato; Kagami Hirabayashi; Tadashi Suga; Shingo Takada; Kuniaki Harada; Noriteru Morita; Noriko Oyama-Manabe; Yasuka Kikuchi; Koichi Okita; Hiroyuki Tsutsui
    DIABETES CARE, 36, 5, 1341, 1346, 2013年05月, [査読有り], [筆頭著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Angiotensin II receptor blocker improves the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice
    Shingo Takada; Shintaro Kinugawa; Kagami Hirabayashi; Tadashi Suga; Takashi Yokota; Masashige Takahashi; Arata Fukushima; Tsuneaki Homma; Taisuke Ono; Mochamad A. Sobirin; Yoshihiro Masaki; Wataru Mizushima; Tomoyasu Kadoguchi; Koichi Okita; Hiroyuki Tsutsui
    JOURNAL OF APPLIED PHYSIOLOGY, 114, 7, 844, 857, 2013年04月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Acute hemodynamic effects of adaptive servo-ventilation in patients with heart failure
    Yamada S, Sakakibara M, Yokota T, Kamiya K, Asakawa N, Iwano H, Yamada S, Oba K, Tsutsui H
    Circ J, 77, 5, 1214, 20, 2013年, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Adaptive servo-ventilation (ASV) improves cardiac function in patients with heart failure (HF). We compared the hemodynamics of control and HF patients, and identified the predictors for acute effects of ASV in HF. METHODS AND RESULTS: We performed baseline echocardiographic measurements and hemodynamic measurements at baseline and after 15 min of ASV during cardiac catheterization in 11 control and 34 HF patients. Heart rate and blood pressure did not change after ASV in either the control or HF group. Stroke volume index (SVI) decreased from 49.3±7.6 to 41.3±7.6 ml/m2 in controls (P<0.0001) but did not change in the HF patients (from 34.8±11.5 to 32.8±8.9 ml/m2, P=0.148). In the univariate analysis, pulmonary capillary wedge pressure (PCWP), mitral regurgitation (MR)/left atrial (LA) area, E/A, E/e', and the sphericity index defined by the ratio between the short-axis and long-axis dimensions of the left ventricle significantly correlated with % change of SVI from baseline during ASV. PCWP and MR/LA area were independent predictors by multivariate analysis. Moreover, responders (15 of 34 HF patients; 44%) categorized by an increase in SVI showed significantly higher PCWP, MR, and sphericity index. CONCLUSIONS: Left ventricular structure and MR, as well as PCWP, could predict acute favorable effects on hemodynamics by ASV therapy in HF patients.
  • Decreased serum brain-derived neurotrophic factor levels are correlated with exercise intolerance in patients with heart failure
    Fukushima A, Kinugawa S, Homma T, Masaki Y, Furihata T, Yokota T, Matsushima S, Abe T, Suga T, Takada S, Kadoguchi T, Katsuyama R, Oba K, Okita K, Tsutsui H
    Int J Cardiol, 168, e142, e144, 2013年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Clinical characteristics and outcomes of dilated phase of hypertrophic cardiomyopathy: Report from the registry data in Japan
    Daisuke Goto; Shintaro Kinugawa; Sanae Hamaguchi; Mamoru Sakakibara; Miyuki Tsuchihashi-Makaya; Takashi Yokota; Satoshi Yamada; Hisashi Yokoshiki; Hiroyuki Tsutsui
    JOURNAL OF CARDIOLOGY, 61, 1-2, 65, 70, 2013年01月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Effect of multiple set on intramuscular metabolic stress during low-intensity resistance exercise with blood flow restriction
    Tadashi Suga; Koichi Okita; Shingo Takada; Masashi Omokawa; Tomoyasu Kadoguchi; Takashi Yokota; Kagami Hirabayashi; Masashige Takahashi; Noriteru Morita; Masahiro Horiuchi; Shintaro Kinugawa; Hiroyuki Tsutsui
    EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY, 112, 11, 3915, 3920, 2012年11月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Low-intensity exercise can increase muscle mass and strength proportionally to enhanced metabolic stress under ischemic conditions
    Shingo Takada; Koichi Okita; Tadashi Suga; Masashi Omokawa; Tomoyasu Kadoguchi; Takashi Sato; Masashige Takahashi; Takashi Yokota; Kagami Hirabayashi; Noriteru Morita; Masahiro Horiuchi; Shintaro Kinugawa; Hiroyuki Tsutsui
    JOURNAL OF APPLIED PHYSIOLOGY, 113, 2, 199, 205, 2012年07月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Blood Flow Restriction Exercise in Sprinters and Endurance Runners
    Shingo Takada; Koichi Okita; Tadashi Suga; Masashi Omokawa; Noriteru Morita; Masahiro Horiuchi; Tomoyasu Kadoguchi; Masashige Takahashi; Kagami Hirabayashi; Takashi Yokota; Shintaro Kinugawa; Hiroyuki Tsutsui
    MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, 44, 3, 413, 419, 2012年03月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle
    Naoki Inoue; Shintaro Kinugawa; Tadashi Suga; Takashi Yokota; Kagami Hirabayashi; Satoshi Kuroda; Koichi Okita; Hiroyuki Tsutsui
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 302, 5, H1202, H1210, 2012年03月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Sleep-disordered breathing is an independent risk factor of aborted sudden cardiac arrest in patients with coronary artery spasm
    Sakakibara M, Yamada S, Kamiya K, Yokota T, Oba K, Tsutsui H
    Circ J, 76, 9, 2204, 10, 2012年, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌), BACKGROUND: Sleep-disordered breathing (SDB) is often associated with sudden cardiac arrest (SCA) during sleep. Coronary artery spasm (CS) also occurs during sleep and is rarely associated with SCA, but the role of SDB in the risk of SCA is unknown in CS patients. This study evaluated the breathing patterns during sleep in CS patients with a prior history of aborted SCA. METHODS AND RESULTS: This study enrolled 24 patients (age 61.6 ± 11.0 years, male/female 19/5) with CS proven by an acetylcholine provocation test. They were divided into 2 groups: prior history of aborted SCA due to fatal arrhythmia (SCA group; n=9) and no such history (no-SCA group; n=15). Patients underwent overnight polysomnography with ambulatory electrocardiography. The overall prevalence of SDB (apnea hypopnea index ≥15) was 45.8% in this cohort. SDB was more frequent in the SCA group than in the no-SCA group (88.9% vs. 20.0% P=0.001) and identified as a pivotal risk factor of aborted SCA (odds ratio: 38.9, 95% CI: 2.80-1,498.2, P=0.01). Very-low-frequency was significantly correlated with the apnea hypopnea index in patients with SCA (P=0.01, r=0.78) during sleep. CONCLUSIONS: SDB is a significant risk factor for SCA in CS patients and autonomic instability during sleep might be involved in this association.
  • Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure
    Ohta Y, Kinugawa S, Matsushima S, Ono T, Sobirin MA, Inoue N, Yokota T, Hirabayashi K, Tsutsui H
    Am J Physiol Heart Circ Physiol, 300, H1637, H1644, 2011年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Lower aerobic capacity was associated with abnormal intramuscular energetics in patients with metabolic syndrome
    Yokota T, Kinugawa S, Okita K, Hirabayashi K, Suga T, Hattori M, Nakagawa Y, Oyama-Manabe N, Shirato H, Tsutsui H
    Hypertens Res, 34, 1029, 1034, 2011年, [査読有り], [筆頭著者], [国内誌]
    英語, 研究論文(学術雑誌)
  • Predictors of long-term adverse outcomes in elderly patients over 80 years hospitalized with heart failure. - A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)
    Hamaguchi S, Kinugawa S, Goto D, Tsuchihashi-Makaya M, Yokota T, Yamada S, Yokoshiki H, Takeshita A, Tsutsui H
    Circ J, 75, 2403, 2410, 2011年, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Hyperuricemia predicts adverse outcomes in patients with heart failure
    Hamaguchi S, Furumoto T, Tsuchihashi-Makaya M, Goto K, Goto D, Yokota T, Kinugawa S, Yokoshiki H, Takeshita A, Tsutsui H
    Int J Cardiol, 151, 143, 147, 2011年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Estimation of skeletal muscle energy metabolism in Machado-Joseph disease using (31)P-MR spectroscopy.
    Ichiro Yabe; Khin K Tha; Takashi Yokota; Kazunori Sato; Hiroyuki Soma; Asako Takei; Satoshi Terae; Koichi Okita; Hidenao Sasaki
    Movement disorders : official journal of the Movement Disorder Society, 26, 1, 165, 8, 2011年01月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), The aim of this study was to determine if muscle energy metabolism, as measured by (31)P-magnetic resonance spectroscopy (MRS), is a metabolic marker for the efficacy of treatment of Machado-Joseph disease (MJD). We obtained (31)P-MRS in the calf muscle of 8 male patients with MJD and 11 healthy men before, during, and after a 4 minute plantar flexion exercise in a supine position. The data showed that there was a significant difference between the groups in terms of the PCr/(Pi + PCr) ratio at rest (P = 0.03) and the maximum rate of mitochondrial ATP production (V(max)) (P < 0.01). In addition, V(max) was inversely correlated with the scale for the assessment and rating of ataxia score (r = -0.34, P = 0.04). The MJD group also showed a reduction in V(max) over the course of 2 years (P < 0.05). These data suggest that this noninvasive measurement of muscle energy metabolism may represent a surrogate marker for MJD.
  • Oxidative stress in cardiac and skeletal muscle dysfunction associated with diabetes mellitus
    Tsutsui H, Kinugawa S, Matsushima S, Yokota T
    J Clin Biochem Nutr, 48, 68, 71, 2011年, [査読有り], [招待有り], [最終著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Body Mass Index Is an Independent Predictor of Long-Term Outcomes in Patients Hospitalized With Heart Failure in Japan - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)
    Sanae Hamaguchi; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa; Daisuke Goto; Takashi Yokota; Kazutomo Goto; Satoshi Yamada; Hisashi Yokoshiki; Akira Takeshita; Hiroyuki Tsutsui
    CIRCULATION JOURNAL, 74, 12, 2605, 2611, 2010年12月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure
    Sanae Hamaguchi; Shintaro Kinugawa; Miyuki Tsuchihashi-Makaya; Kazutomo Goto; Daisuke Goto; Takashi Yokota; Satoshi Yamada; Hisashi Yokoshiki; Akira Takeshita; Hiroyuki Tsutsui
    AMERICAN HEART JOURNAL, 160, 6, 1156, 1162, 2010年12月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Beta-Blocker Use at Discharge in Patients Hospitalized for Heart Failure Is Associated With Improved Survival
    Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa; Hisashi Yokoshiki; Sanae Hamaguchi; Takashi Yokota; Daisuke Goto; Kazutomo Goto; Akira Takeshita; Hiroyuki Tsutsui
    CIRCULATION JOURNAL, 74, 7, 1364, 1371, 2010年07月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Dose effect on intramuscular metabolic stress during low-intensity resistance exercise with blood flow restriction
    Tadashi Suga; Koichi Okita; Noriteru Morita; Takashi Yokota; Kagami Hirabayashi; Masahiro Horiuchi; Shingo Takada; Masashi Omokawa; Shintaro Kinugawa; Hiroyuki Tsutsui
    Journal of Applied Physiology, 108, 6, 1563, 1567, American Physiological Society, 2010年06月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌), Our previous study reported that metabolic stress in skeletal muscle achieved by combining moderate blood flow restriction (BFR) with low-intensity resistance exercise at 20% of one repetition maximum (1 RM) could not reach the level achieved by high-intensity resistance exercise. Since the previous protocol is typical of current regimens of this type, we sought in this study to optimize the exercise protocol for low-intensity resistance exercise with BFR by examining the dose effects of exercise intensity and pressure. Twelve healthy subjects participated in this study. They were asked to perform unilateral plantar flexion for 2 min (30 repetitions/min) under six different conditions: two resistance exercises (20% 1 RM and 65% 1 RM) without BFR, and four BFR protocols. The four BFR protocols included three different exercise intensities (20, 30, and 40% 1 RM) with moderate pressure (MP) using 130% of systolic blood pressure (147 ± 17 mmHg, mean ± SD) and 20% 1 RM with high pressure at 200 mmHg. Intramuscular metabolites and pH were obtained by 31P-magnetic resonance spectroscopy. Significant dose effects on intramuscular metabolites and pH were observed for exercise intensity ( P < 0.001) but not for BFR pressure. The BFR protocol combining 30% 1 RM with MP had similar results as the high-intensity load at 65% 1 RM. Intramuscular metabolic stress during BFR exercise might be susceptible to increasing exercise intensity. To replace high-intensity resistance exercise, the BFR protocol might require an intensity of ≥30% 1 RM.
  • Effects of Oral Single-Dose Administration of Sarpogrelate Hydrochloride on Saturation O(2) of Calf Muscle During Plantar Flexion Exercise
    Masahiro Horiuchi; Koichi Okita; Shingo Takada; Masashi Omokawa; Tadashi Suga; Noriteru Morita; Kagami Hirabayashi; Takashi Yokota; Shintaro Kinugawa; Hiroyuki Tsutsui
    OXYGEN TRANSPORT TO TISSUE XXXI, 662, 531, 536, 2010年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Effects of Atrial Fibrillation on Long-Term Outcomes in Patients Hospitalized for Heart Failure in Japan - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)
    Sanae Hamaguchi; Hisashi Yokoshiki; Shintaro Kinugawa; Miyuki Tsuchihashi-Makaya; Takashi Yokota; Akira Takeshita; Hiroyuki Tsutsui
    CIRCULATION JOURNAL, 73, 11, 2084, 2090, 2009年11月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Characteristics and Outcomes of Hospitalized Patients With Heart Failure and Reduced vs Preserved Ejection Fraction - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)
    Miyuki Tsuchihashi-Makaya; Sanae Hamaguchi; Shintaro Kinugawa; Takashi Yokota; Daisuke Goto; Hisashi Yokoshiki; Norihiro Kato; Akira Takeshita; Hiroyuki Tsutsui
    CIRCULATION JOURNAL, 73, 10, 1893, 1900, 2009年10月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Anemia is an Independent Predictor of Long-Term Adverse Outcomes in Patients Hospitalized With Heart Failure in Japan - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)
    Sanae Hamaguchi; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa; Takashi Yokota; Akira Takeshita; Hisashi Yokoshiki; Hiroyuki Tsutsui
    CIRCULATION JOURNAL, 73, 10, 1901, 1908, 2009年10月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice
    Takashi Yokota; Shintaro Kinugawa; Kagami Hirabayashi; Shouji Matsushima; Naoki Inoue; Yukihiro Ohta; Sanae Hamaguchi; Mochamad A. Sobirin; Taisuke Ono; Tadashi Suga; Satoshi Kuroda; Shinya Tanaka; Fumio Terasaki; Koichi Okita; Hiroyuki Tsutsui
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 297, 3, H1069, H1077, 2009年09月, [査読有り], [筆頭著者], [国際誌]
    英語, 研究論文(学術雑誌)
  • Chronic Kidney Disease as an Independent Risk for Long-Term Adverse Outcomes in Patients Hospitalized With Heart Failure in Japan - Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) -
    Sanae Hamaguchi; Miyuki Tsuchihashi-Makaya; Shintaro Kinugawa; Takashi Yokota; Tomomi Ide; Akira Takeshita; Hiroyuki Tsutsui
    CIRCULATION JOURNAL, 73, 8, 1442, 1447, 2009年08月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes
    Shouji Matsushima; Shintaro Kinugawa; Takashi Yokota; Naoki Inoue; Yukihiro Ohta; Sanae Hamaguchi; Hiroyuki Tsutsui
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 297, 1, H409, H416, 2009年07月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Intramuscular metabolism during low-intensity resistance exercise with blood flow restriction
    Tadashi Suga; Koichi Okita; Noriteru Morita; Takashi Yokota; Kagami Hirabayashi; Masahiro Horiuchi; Shingo Takada; Tomohiro Takahashi; Masashi Omokawa; Shintaro Kinugawa; Hiroyuki Tsutsui
    JOURNAL OF APPLIED PHYSIOLOGY, 106, 4, 1119, 1124, 2009年04月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart
    Hiroyuki Tsutsui; Shouji Matsushima; Shintaro Kinugawa; Tomomi Ide; Naoki Inoue; Yukihiro Ohta; Takashi Yokota; Sanae Hamaguchi; Kenji Sunagawa
    HYPERTENSION RESEARCH, 30, 5, 439, 449, 2007年05月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
  • Lower prevalence of circulating natural killer T cells in patients with angina: a potential novel marker for coronary artery disease
    Yasuhiro Andoh; Satoshi Fujii; Kazuya Iwabuchi; Takashi Yokota; Naoki Inoue; Yukihito Nakai; Tetsuya Mishima; Takehiro Yamashita; Toshiaki Nakagawa; Akira Kitabatake; Kazunori Onoe; Hiroyuki Tsutsui
    CORONARY ARTERY DISEASE, 17, 6, 523, 528, 2006年09月, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart
    Shouji Matsushima; Shintaro Kinugawa; Tomomi Ide; Hidenori Matsusaka; Naoki Inoue; Yukihiro Ohta; Takashi Yokota; Kenji Sunagawa; Hiroyuki Tsutsui
    American Journal of Physiology - Heart and Circulatory Physiology, 291, 5, H2237, H2245, 2006年, [査読有り], [国際誌]
    英語, 研究論文(学術雑誌)
  • Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms
    N Makita; K Sasaki; WA Groenewegen; T Yokota; H Yokoshiki; T Murakami; H Tsutsui
    HEART RHYTHM, 2, 10, 1128, 1134, 2005年10月, [査読有り], [国際共著], [国際誌]
    英語, 研究論文(学術雑誌)
  • Mural thrombus in an ectatic right coronary artery caused acute myocardial infarction at downstream coronary artery
    K Urasawa; N Inoue; T Yokota; N Oyama; H Sakai; S Fujii; A Kitabatake
    INTERNATIONAL HEART JOURNAL, 46, 2, 313, 316, 2005年03月, [査読有り], [国内誌]
    英語, 研究論文(学術雑誌)
■ その他活動・業績
■ 講演・口頭発表等
  • 非監視型リハビリにおける セルフケアアプリ・IoT機器の活用
    横田 卓
    第3回遠隔心臓リハビリテーション研究会, 2026年04月16日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2026年04月16日, [招待講演]
  • “診る”から”支える”へ ~デジタルヘルス・AIが拓く次世代医療~
    横田 卓
    社会保険支払基金北海道支部講演会, 2026年03月29日, 日本語, 口頭発表(招待・特別)
    2026年03月29日, [招待講演]
  • ゲノム情報を活用した次世代型健診 ~ポリジェニックリスクスコア(PRS)による疾病発症リスク予測~
    横田 卓
    令和7年度 日臨技北日本支部「染色体・遺伝子検査部門」研修会, 2026年02月16日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2026年02月16日 - 2026年02月28日, [招待講演]
  • 新しいデバイス (IoT、遠隔など) を用いた心臓リハの取り組み
    横田 卓
    第44回日本臨床運動療法学会学術集会, 2025年09月13日, 日本語, シンポジウム・ワークショップパネル(指名)
    2025年09月13日 - 2025年09月14日, [招待講演]
  • Use of digital technology in heart failure management and cardiac rehabilitation in Japan
    横田 卓
    AsiaPRevent Expert Lecture, 2025年07月20日, 日本心臓リハビリテーション学会, 英語, シンポジウム・ワークショップパネル(指名)
    2025年07月19日 - 2025年07月20日, 名古屋, 日本国, Digital therapeutics is becoming a promising approach to facilitate patient-centered care in prevention and treatment of cardiovascular diseases. There are various digital health tools including mobile apps and wearable sensor devices that can be used for clinical practice. Here I highlight recent advances and current trends of digital and sports cardiology focusing on heart failure management and cardiac rehabilitation in Japan., [招待講演], [国際会議]
  • これからの心臓リハビリテーションについて
    横田 卓
    Collaborate Web Seminar~多職種で診るこれからの地域医療~, 2025年06月20日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2025年06月20日, [招待講演]
  • 高血圧予防とアンチエイジング
    横田 卓
    第15回産業保健フォーラムTomorrow, 2025年02月05日, 日本語, 口頭発表(招待・特別)
    [招待講演]
  • 高血圧・ダイアベティス (糖尿病) とゲノム健診
    横田 卓
    第7回MeCCSフォーラム, 2024年12月23日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2024年12月23日 - 2024年12月23日, [招待講演]
  • Role of epicardial fat in cardiovascular diseases
    Takashi Yokota
    10th Asian Preventive Cardiology & Cardiac Rehabilitation Conference, 2024年11月24日, 英語, 口頭発表(招待・特別)
    2024年11月22日 - 2024年11月24日, [招待講演]
  • Self-care intervention using mobile application to reduce cardiovascular risks
    Takashi Yokota
    10th Asian Preventive Cardiology & Cardiac Rehabilitation Conference, 2024年11月23日, 英語, 口頭発表(招待・特別)
    2024年11月22日 - 2024年11月24日, [招待講演]
  • 肥満における筋内脂肪蓄積と 運動機能障害
    横田 卓
    第43回日本臨床運動療法学会学術集会, 2024年09月14日, 日本語, シンポジウム・ワークショップパネル(指名)
    2024年09月14日 - 2024年09月15日, [招待講演]
  • ゲノム情報を活用した次世代型健診: 生活習慣病・認知症
    横田 卓
    第65回日本人間ドック・予防医療学会学術大会, 2024年09月06日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2024年09月06日 - 2024年09月07日, [招待講演]
  • Self-care intervention using mobile application and IoT devices to reduce cardiovascular risk
    Takashi Yokota
    第30回日本心臓リハビリテーション学会学術集会 JACR-EAPC Joint Session, 2024年07月13日, 英語, シンポジウム・ワークショップパネル(指名)
    2024年07月13日 - 2024年07月14日, [招待講演]
  • 高血圧症についてもっと知ろう!~予防に取り組む意義とその発症要因~
    横田 卓
    オンラインセミナー, 2024年06月04日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2024年06月04日, [招待講演]
  • 試合開始時刻がプロ野球選手の夜間睡眠に及ぼす影響 ―ウェアラブルセンサーを用いた評価―
    宮城和; 松浦倫子; 水島仁; 横田卓; 山仲勇二郎
    日本睡眠学会第45回定期学術集会, 2023年09月16日, 日本語, ポスター発表
    2023年09月15日 - 2023年09月17日
  • Brain-derived neurotrophic factor: A key molecule to regulate skeletal muscle function and exercise capacity in heart failure
    横田 卓
    第87回日本循環器学会学術集会, 2023年03月11日, 英語, シンポジウム・ワークショップパネル(指名)
    2023年03月10日 - 2023年03月12日, [招待講演]
  • 循環器疾患・糖尿病診療における デジタルヘルスの活用
    横田 卓
    Hokkaido GLP-1 Conference, 2022年07月07日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2022年07月07日, [招待講演]
  • 臨中ネット基盤を用いたユースケース
    横田 卓
    第9回臨中ネット教育セミナー, 2022年02月03日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2022年02月03日 - 2022年02月03日, [招待講演]
  • 心臓リハビリテーションとCPX (心肺運動負荷検査)
    横田 卓
    なの花アカデミーサテライト研修会, 2021年11月16日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • 新しい医療連携のあり方: 医療連携とデジタルヘルスの活用
    横田 卓
    医療連携を見据えた糖尿病治療~循環器内科から見た糖尿病治療~, 2021年11月10日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • 基礎から臨床へ ~トランスレーショナルリサーチとしての ミトコンドリア研究の可能性~
    横田 卓
    第94回日本生化学学会大会, 2021年11月04日, 英語, シンポジウム・ワークショップパネル(指名)
    2021年11月03日 - 2021年11月05日, [招待講演]
  • 医療施設におけるリアルワールドデータ (RWD) の利用
    横田 卓
    第2回臨中ネット教育セミナー, 2021年07月14日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    2021年07月14日 - 2021年07月14日, [招待講演]
  • 心臓リハビリテーション・ 心肺運動負荷検査 (CPX) の基本と応用
    横田 卓
    第2回恵庭地区心臓リハビリテーションスキルアップセミナー, 2021年03月05日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • ICT・IoTを活用した セルフケア強化の取り組み
    横田 卓
    札幌BI LAB ブレインストーミング, 2020年12月04日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • 生活習慣の是正を目指したセルフケアアプリの活用
    横田 卓
    第39回日本臨床運動療法学会学術集会, 2020年09月05日, 日本語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • IoT・ICTを活用した 心血管病予防
    横田 卓
    第26回日本心臓リハビリテーション学会学術集会, 2020年07月18日, 日本語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • 心血管病・生活習慣病における血球ミトコンドリアの バイオマーカーとしての活用の可能性について
    横田 卓
    第5回Cardiac Biomarker研究会, 2019年11月09日, 日本語, 口頭発表(招待・特別)
    [招待講演]
  • Association of mitochondrial reactive oxygen species generation in circulating blood cells with disease severity and exercise intolerance in patients with chronic heart failure
    Takashi Yokota; Ryosuke Shirakawa; Takayuki Nakajima; Miwako Yamane; Shingo Takada; Shintaro Kinugawa
    ASMRM16 and J-mit19, 2019年10月04日, 英語, 口頭発表(一般)
  • Application of high-resolution respirometry to mitochondrial research
    Takashi Yokota
    ASMRM16 and J-mit19, 2019年10月03日, 英語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • Exercise testing and cases
    Takashi Yokota
    IAEA Workshop, 2019年10月01日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Role of mitochondria in cardiovascular disease
    Takashi Yokota
    Mitochondrial Physiology 2019 (Copenhagen, Denmark), 2019年08月23日, 英語, 口頭発表(招待・特別)
    [招待講演]
  • Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in patients with heart failure
    Takashi Yokota; Shintaro Kinugawa; Hiroyuki Tsutsui
    ACC.19; 68th Annual Scientific Sessions (New Orleans), 2019年03月18日, 英語, 口頭発表(一般)
  • ICTを活用した 生活習慣病・心血管病の予防
    横田 卓
    日立北大ラボ 産学・地域協働シンポジウム, 2019年02月12日, 日本語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • 心肺運動負荷試験CPXを活用した労作時息切れの鑑別
    横田 卓
    北海道PAHレベルアップ塾, 2019年01月25日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • ICT and IoT in heart failure management and prevention
    Takashi Yokota
    The 6th SNUH-HUH-SHH Joint Symposium, 2018年11月09日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Heart failure and ICT
    Takashi Yokota
    The 9th Asian Pacific Congress of Heart Failure, 2018年10月13日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • 心不全診療における包括的心臓リハビリテーション
    横田 卓
    苫小牧心不全チーム医療カンファレンス, 2018年09月18日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • セルフケアを含めた包括的心臓リハビリテーション
    横田 卓
    高齢者心不全 包括的ケア講演会, 2018年07月06日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • 心不全のお話:北海道大学における心不全治療の現状
    横田 卓
    時計台循環器ミーティング, 2018年01月16日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • 心不全治療における遠隔モニタリング
    横田 卓
    第21回日本適応医学会学術集会, 2017年12月02日, 日本語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • 高齢心不全に対する ICTを活用した次世代型疾病管理
    横田 卓
    高齢化社会における循環器疾患の現状と展望, 2017年11月29日, 日本語, 口頭発表(基調)
    [招待講演]
  • 心不全を合併した Loeys-Dietz症候群の一例
    横田 卓; 津田 正哉; 松島 将士
    第118回日本循環器学会北海道地方会, 2017年11月25日, 日本語, 口頭発表(一般)
  • 内科・外科の垣根を越えた包括的心不全治療
    横田 卓
    心不全治療のTotal Management, 2017年10月18日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • ICTを活用した心不全の 次世代型疾病管理
    横田 卓; 筒井 裕之
    第4回日本心血管脳卒中学会学術集会, 2017年06月03日, 日本語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • A novel self-care management tool using information and communication technology for elderly patients with heart failure
    Takashi Yokota; Miyuki Tsuchihashi-Makaya; Masanori Yoshino; Hiroyuki Tsutsui
    第81回日本循環器学会学術集会, 2017年03月17日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Pioglitazone improves aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome
    Takashi Yokota; Shintaro Kinugawa; Kagami Hirabayashi; Tadashi Suga; Shingo Takada; Koichi Okita; Hiroyuki Tsutsui
    第20回日本心不全学会, 2016年10月07日, 英語, 口頭発表(一般)
  • 高度の心機能異常を呈したダノン病の一例
    横田 卓
    北海道先天性代謝異常研究会, 2016年08月27日, 日本語, 口頭発表(一般)
  • 生活習慣病・心血管病における 骨格筋ミトコンドリアの役割
    横田 卓
    クリニカルサイエンス談話会, 2016年04月28日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • Advanced self-care support system using information and communication technology (ICT) for patients with chronic heart failure
    Takashi Yokota; Miyuki Tsuchihashi-Makaya; Arata Fukushima; Yoko Ikeda; Takahiro Abe; Shingo Takada; Akimichi Saito; Wataru Takeuchi; Tomohiko Mizuguchi; Keiji Kobashi; Masanori Yoshino; Hiroyuki Tsutsui
    第80回日本循環器学会学術集会, 2016年03月20日, 日本語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • 患者中心の医療システムを実現するために
    横田 卓
    COI 2021 Conference, 2016年01月29日, 日本語, シンポジウム・ワークショップパネル(指名)
    2016年01月29日 - 2016年01月29日, [招待講演]
  • 生活習慣病・心血管病における 骨格筋ミトコンドリアの役割~健康長寿を目指して~
    横田 卓
    函館循環器病懇談会, 2016年01月20日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • 心肺運動負荷検査 (CPX) を活用して“労作時息切れ”の原因を探索する
    横田 卓
    6th Young Diabetologist & Cardiologist Forum, 2015年07月02日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • Role of brain mitochondria in premature aging
    Takashi Yokota
    CCH Symposium (Taichung), 2014年11月15日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Gradual wake-up of mitochondria during early reperfusion: The effect of inhibition of the malate-aspartate shuttle on mitochondrial function and ROS production against myocardial ischemia-reperfusion injury
    Takashi Yokota
    11th ASMRM (Taipei), 2014年11月14日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Impaired mitochondrial oxidative phosphorylation and fatty acid oxidation with enhanced mitochondrial oxidative stress in spontaneously-occurring feline hypertrophic cardiomyopathy
    Takashi Yokota; Liselotte B. Christiansen; Flemming Dela
    第18回日本心不全学会学術集会, 2014年10月10日, 英語, 口頭発表(一般)
  • 心臓リハビリテーションのガイドライン
    横田 卓
    第4回 北大病院循環器内科生涯教育講座, 2014年09月25日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • Myocardial mitochondrial respiration in human heart failure
    Flemming Dela; Nis Stride; Liselotte B. Christiansen; Takashi Yokota
    The Federation of European Physiological Societies (FEPS) (Budapest, Hungary), 2014年08月28日, 英語, 口頭発表(招待・特別)
    [招待講演]
  • Role of brain mitochondria in premature aging
    Takashi Yokota
    BIT's 4th Annual World Congress of Molecular & Cell Biology (CMCB-2014) (Dalian, China), 2014年04月27日, 英語, 口頭発表(一般)
    [招待講演]
  • Role of mitochondria in ischaemia-reperfusion injury in cardiac muscle
    Takashi Yokota
    Mitochondrial Physiology 2013 (Copenhagen, Denmark), 2013年08月30日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Brain mitochondrial dysfunction in a mouse-model of premature aging
    Takashi Yokota
    Mitochondrial Physiology 2013 (Copenhagen, Denmark), 2013年08月28日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Inhibition of the malate-aspartate shuttle during early reperfusion preserves mitochondrial function and attenuates reactive oxygen species production in ischemia/reperfusion injured heart
    Takashi Yokota
    3rd Targeting Mitochondria (Berlin, Germany), 2012年11月09日, 英語, 口頭発表(一般)
  • Brain Mitochondrial Dysfunction in Premature Aging Disorder
    Takashi Yokota
    CEHA-SAB Meeting (Copenhagen, Denmark), 2012年09月28日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • The Effects of Malate-Aspartate Shuttle Inhibition on Mitochondrial Respiration and Oxidative Stress in Ischemia/Reperfusion Injured Heart
    Takashi Yokota
    CEHA-SAB Meeting (Copenhagen, Denmark), 2012年09月28日, 英語, シンポジウム・ワークショップパネル(指名)
    [招待講演]
  • Enhanced systemic oxydative stress is associated with impaired fatty acid metabolism in skeletal muscle in patients with metabolic syndrome
    Takashi Yokota; Shintaro Kinugawa; Kagami Hirabayashi; Tadashi Suga; Shingo Takada; Koichi Okita; Flemming Dela; Hiroyuki Tsutsui
    MiP Conference 2011 (Bordeaux, France), 2011年09月06日, 英語, 口頭発表(一般)
  • インスリン抵抗性と酸化ストレス~骨格筋ミトコンドリア~
    横田 卓
    Young Diabetologist and Cardiologist Forum 2011, 2011年02月03日, 日本語, 公開講演,セミナー,チュートリアル,講習,講義等
    [招待講演]
  • Pioglitazone increases the aerobic capacity with improved skeletal muscle energetics in patients with insulin resistance
    Takashi Yokota; Shintaro Kinugawa; Kagami Hirabayashi; Tadashi Suga; Shingo Takada; Masashige Takahashi; Taisuke Ono; Sobilin A. Mochamad; Koichi Okita; Hiroyuki Tsutsui
    European Association for the Study of Diabetes (EASD) Annual Meeting 2010 (Stockholm, Sweden), 2010年09月21日, 英語, 口頭発表(一般)
  • Pioglitazone improves aerobic capacity and skeletal muscle high-energy phosphate metabolism in patients with metabolic syndrome
    Yokota T; Kinugawa S; Hirabayashi K; Suga T; Matsushima S; Sobirin AM; Ono T; Morita N; Takada S; Omokawa M; Okita K; Tsutsui H
    American Heart Association (AHA) Scientific Sessions 2009 (Orlando), 2009年11月18日, 英語, 口頭発表(一般)
  • 致死性不整脈を合併した冠攣縮性狭心症
    横田 卓; 榊原 守; 山田 史郎; 正木 芳宏; 筒井 裕之
    日本心血管インターベンション学会 (CVIT) 第29回北海道地方会, 2009年09月12日, 日本語, 口頭発表(一般)
  • Lowered aerobic exercise capacity was associated with impaired skeletal muscle metabolism in patients with metabolic syndrome
    第73回日本循環器学会学術集会, 2009年03月22日, 日本語, 口頭発表(一般)
  • Impaired skeletal muscle energy metabolism limits systemic aerobic exercise capacity in patients with metabolic syndrome
    Yokota T; Kinugawa S; Hirabayashi K; Suga T; Morita N; Inoue N; Ohta Y; Matsushima S; Sobirin AM; Hamaguchi S; Ono T; Horiuchi M; Okita K; Tsutsui H
    American Heart Association (AHA) Scientific Sessions 2008 (New Orleans), 2008年11月10日, 英語, 口頭発表(一般)
  • メタボリック症候群では、骨格筋エネルギー代謝異常が有酸素運動能を低下させる
    横田 卓; 絹川 真太郎; 平林 鑑; 菅 唯志; 濱口 早苗; 小野 太祐; ソビリン アリ; 高田 真吾; 面川 雅司; 沖田 孝一; 筒井 裕之
    第58回循環器負荷研究会, 2008年08月02日, 日本語, 口頭発表(一般)
  • Lowered aerobic exercise capacity was associated with impaired skeletal muscle metabolism in patients with metabolic syndrome
    Yokota T; Kinugawa S; Hirabayashi K; Suga T; Morita N; Inoue N; Ohta Y; Matsushima S; Sobirin AM; Hamaguchi S; Ono T; Horiuchi M; Okita K; Tsutsui H
    European College of Sport Science (ECSS) 2008 (Estoril, Portugal), 2008年07月10日, 英語, 口頭発表(一般)
  • Oxidative stress impairs mitochondrial respiration in skeletal muscle and limits exercise capacity in diabetic mice
    Yokota T; Kinugawa S; Matsushima S; Inoue N; Ohta Y; Hirabayashi K; Hamaguchi S; Ono T; Okita K; Tsutsui H
    第72回日本循環器学会学術集会, 2008年03月30日, 日本語, 口頭発表(一般)
  • 糖尿病モデルマウスにおいてNAD(P)H oxidase 由来の骨格筋酸化ストレス (O2-)が 運動能力を制限する
    横田 卓; 絹川 真太郎; 松島 将士; 井上 直樹; 大田 幸博; 濱口 早苗; ソビリン モハマド アリ; 小野 太祐; 平林 鑑; 沖田 孝一; 筒井 裕之
    第57回循環器負荷研究会, 2007年08月, 日本語, 口頭発表(一般)
  • Superoxide anion (O2-) derived from NADPH oxidase impairs mitochondrial oxidative respiration in skeletal muscle and limits exercise capacity in diabetic mice
    Takashi Yokota; Shintaro Kinugawa; Syouji Matsushima; Naoki Inoue; Yukihiro Ohta; Sanae Hamaguchi; Kouichi Okita; Hiroyuki Tsutsui
    The American College of Sports Medicine (ACSM) Annual Meeting 2007 (New Orleans), 2007年06月01日, 英語, 口頭発表(一般)
    2007年05月30日 - 2007年06月02日
  • Reactive oxygen species derived from NAD(P)H oxidase cause the limitation of exercise capacity in diabetic mice
    Takashi Yokota; Shintaro Kinugawa; Syouji Matsushima; Naoki Inoue; Yukihiro Ohta; Sanae Hamaguchi; Kouichi Okita; Hiroyuki Tsutsui
    第71回日本循環器学会学術集会, 2007年03月16日, 日本語, 口頭発表(一般)
  • インスリン抵抗性が運動能力・骨格筋機能に及ぼす影響
    横田 卓; 絹川 真太郎; 松島 将士; 井上 直樹; 大田 幸博; 濱口 早苗; 沖田 孝一; 筒井 裕之
    第56回循環器負荷研究会, 2006年08月05日, 日本語, 口頭発表(一般)
  • 左室拡張機能評価が無症候性心筋虚血診断 の端緒となった発作性心房細動の1例
    横田 卓; 山田 聡; 小松 博史; 小室 薫; 加賀 早苗; 横式 尚司; 浦沢 一史; 佐久間 一郎; 北畠 顕
    第231回日本内科学会北海道地方会, 2004年06月05日, 日本語, 口頭発表(一般)
■ 主な担当授業
  • ゲノム情報科学特論, 2024年, 修士課程, 情報科学院
  • ゲノム情報科学特論, 2024年, 博士後期課程, 情報科学研究科
  • ゲノム情報科学特論, 2024年, 博士後期課程, 情報科学院
■ 共同研究・競争的資金等の研究課題
  • ひと・AI/DX・しくみの三位一体的整備による次世代AI活用・データ駆動・情報循環型医学研究の戦略的推進 (PRISM-HU)
    医学系研究支援プログラム
    2025年10月 - 2028年03月
    日本医療研究開発機構 (AMED), 北海道大学
  • 冬眠原理の追求とその社会展開に向けた分野横断型基礎研究
    J-PEAKs アクセラレーションステージ
    2025年04月 - 2028年03月
    山口 良文; 岡松 優子; 曽根 正光; 山内 彩加林; 下鶴 倫人; 加藤 美羅; 山仲 勇二郎; 新宮 康栄; 横田 卓; 高氏 修平
    国立大学法人北海道大学, 北海道大学, 研究分担者
  • 生活習慣病・認知症の遺伝学的リスク評価が被検者のライフスタイルに及ぼす影響
    科学研究費助成事業
    2025年04月 - 2028年03月
    横田 卓; 畑中 豊
    日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 25K14955
  • Real World Evidence創出のための取り組み (臨中ネット)
    医療技術実用化総合促進事業
    2019年04月 - 2028年03月
    日本医療研究開発機構 (AMED), 北海道大学病院
  • 治験・臨床試験におけるAI利活用の推進に係る取組み
    医療技術実用化総合促進事業
    2026年02月 - 2027年03月
    日本医療研究開発機構 (AMED), 北海道大学病院
  • 北の社会イノベーション
    2025年01月 - 2027年03月
    横田 卓
    日立北大ラボ, 北海道大学, 研究分担者
  • 分散型臨床試験 (DCT) の取り組み
    医療技術実用化総合促進事業
    2022年04月 - 2027年03月
    日本医療研究開発機構 (AMED), 北海道大学病院
  • 日本ハムファイターズ選手を対象としたOura Ringを用いた睡眠などのデータ収集・評価および睡眠改善を目指した研究
    2022年06月 - 2026年03月
    山仲 勇二郎; 横田 卓
    株式会社Ambi・北海道日本ハムファイターズ, 研究分担者
  • 心房細動の病態進行における心臓周囲脂肪ミトコンドリア機能の役割
    科学研究費助成事業
    2022年04月 - 2025年03月
    渡邉 昌也; 畑中 豊; 新宮 康栄; 横田 卓
    日本学術振興会, 基盤研究(C), 北海道大学, 研究分担者, 22K08197
  • 末梢血単核球ミトコンドリア機能を筋ジストロフィーの重症度評価・治療に応用する。
    科学研究費助成事業
    2021年04月 - 2025年03月
    山澤 弘州; 武田 充人; 横田 卓; 矢部 一郎
    筋ジストロフィーはいまだ根本的な治療法が見つかっていない難治性の遺伝性疾患である。初発の症状は骨格筋障害による運動機能低下であるが、病状の進行に伴い多臓器障害および全身の代謝異常を来たし、終末期には生活の質 (QOL) の著しい低下により寝たきり状態となり、多くは心不全または致死性不整脈により死亡する。この筋ジストロフィーの臨床像は骨格筋・心筋障害を主症状とするミトコンドリア病と多くの点で類似している。これまでにも筋ジストロフィーの発症・進展にミトコンドリア機能障害が関与している可能性が示唆されていたが、ヒトの骨格筋や心筋から組織を採取しミトコンドリア機能を直接
    測定することは侵襲性の面で困難であり、十分に検証されてこなかった。
    そこで本研究の最終目的は侵襲の少ない末梢血単核球(PBMC)を用い、『筋ジストロフィーの進展にはPBMCミトコンドリア機能異常が関わっており、骨格筋障害のみならず心筋障害などの多臓器不全に関与する』という仮説を検証することにある。
    仮説が正しいなら筋ジストロフィーにおいて実際PBMCミトコンドリア機能異常がある事を証明することがまず第一歩になる。下記の進捗に示す通り対象者のリクルートは概ね順調に進んでおり、結果の詳細はここでは控えさせて頂きたいが、測定も順調に進んでいる。
    更に骨格筋機能や画像による心機能、心筋障害評価結果との関連性の検討を現在進行形で進めている。統計学的な解析結果はここでは控えさせて頂きたい。
    日本学術振興会, 基盤研究(C), 北海道大学, 研究分担者, 21K08071
  • PHRを活用した機械学習モデルによる心血管病の重症化予防を目指した研究
    科学研究費助成事業
    2021年04月 - 2025年03月
    横田 卓; 中岡 慎治; 中村 公則
    わが国は超高齢社会を迎え、心血管病の患者数は増加の一途を辿っており、早急に患者本人が主体的にセルフモニタリングを行い疾病予防に取り組む「患者中心の医療 (patient-centered care)」 を実現する必要に迫られている。心血管病の予防・治療の基本は食事・運動をはじめとする生活習慣の是正であるが、在宅で取得可能なパーソナル・ヘルス・レコード (PHR) の活用が必要不可欠である。さらにCOVID-19感染拡大をきっかけにオンライン診療が広く推奨されるようになり、とりわけ情報通信技術 (ICT) を活用したPHRのニーズが高まっている。そこで我々は、在宅で取得するPHRを活用し適切なセルフケアの実践を促すスマートフォン対応セルフケアサポートアプリを開発した。本研究の目的は、このアプリで収集する血圧・体重・体脂肪率・体温・酸素飽和度・塩分摂取量・身体活動量・睡眠時間などのバイタルサインや食事・運動内容、さらには便を用いた腸内フローラ解析データなどの多様なPHRを活用し、機械学習モデルを用いて、心血管病の重症化予測を行うとともに重症化予防のための個々に最適な食事・運動療法を提案することである。
    臨床試験『スマートフォンアプリを活用した統合型高血圧セルフケアサポートシステムの有効性の検証 (AppCare-HT Study)』については、全症例数 (360名) のフォローアップが完了し、論文化へ向けて解析を進めている。また、心不全患者を対象にした臨床試験についても研究実施中で、順次データ解析を進めている。
    日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 21K08120
  • アドリアマイシン心筋症における免疫老化の果たす役割の解明と早期検出法の開発
    科学研究費助成事業
    2021年04月 - 2024年03月
    石森 直樹; 横田 卓; 加畑 馨
    近年わが国では急速な高齢化が進行してがん患者数は増加し、国民の2人に1人は生涯がんに罹患すると言われている。がんの早期発見や治療法の進歩により、がん患者の生命予後は著しく改善してきたが、再発がん患者では「がん死」に次いで死因第2位に「心血管病」が挙がっており、がん診療での心血管病の制御はきわめて重要な課題となっている。
    アドリアマイシンをはじめとするアントラサイクリン系抗がん剤は、分子標的薬が登場した現代においてもリンパ腫、乳がんおよび肉腫などに対する標準的化学療法薬として重要な位置づけにある。しかし、累積使用量(アドリアマイシン換算)400mg/m2で約5%、700mg/m2では約25%と用量依存的に心筋障害を合併し、時に難治性心不全をきたして死に至る。疫学研究によって累積使用量のほか、年齢や放射線治療歴など心筋障害合併リスク因子が明らかにされているが、化学療法から年余を経て突然心不全を発症し、薬剤性心筋症と診断される例も少なくなく、細心の注意が必要である。
    近年、加齢関連疾患の病態形成においていわゆる老化関連T細胞が出現する「免疫老化」の寄与が注目されている。我々はアドリアマイシン心筋症の発症・進展において「免疫老化」を基盤として慢性炎症が遷延し、心筋症発症に寄与するとの仮説を立てた。本研究の遂行によって、アドリアマイシン心筋症発症リスクのより正確な予測が可能となるばかりでなく、慢性炎症の制御という新たなコンセプトに基づくアドリアマイシン心筋症の予防・治療法の開発に貢献することが期待して本研究を立案した。
    現在、標準的化学療法薬としてアドリアマイシンを用いたレジメで治療された悪性リンパ腫患者の治療フローを確認しながら、アドリアマイシン心筋症に関するレジストリ構築中である。
    日本学術振興会, 基盤研究(C), 北海道大学, 研究分担者, 21K08046
  • マイオカインによる老化進展制御機構の解明
    科学研究費助成事業
    2021年04月 - 2024年03月
    絹川 真太郎; 佐邊 壽孝; 高田 真吾; 松島 将士; 横田 卓
    日本学術振興会, 基盤研究(B), 九州大学, 研究分担者, 21H03360
  • 小腸由来αディフェンシンによる腸内細菌叢制御機構に着目した心不全の進展機序解明
    科学研究費助成事業
    2018年04月 - 2024年03月
    横田 卓; 安斉 俊久; 綾部 時芳; 絹川 真太郎; 福島 新
    心不全の発症・進展において全身の慢性炎症が重要な役割を果たしていることは広く知られており、全身の免疫に関わる腸内フローラの役割に関心が集まっている。本研究では、この腸内フローラを制御する抗菌ペプチドである小腸Paneth細胞由来αディフェンシン (HD5; human defensin-5) の役割に着目し、『心不全患者では小腸Paneth細胞由来αディフェンシンの産生量が低下しており、腸内環境の破綻”dysbiosis”が全身炎症を惹起し、心不全の進展に寄与する』という仮説を検証することを目的とし、基礎・臨床研究の両面から、心腸連関として心不全が腸内環境に及ぼす影響を評価することとした。
    基礎研究については、左冠動脈結紮による心筋梗塞モデルマウス (MIマウス) を用いて評価を行ったところ、shamマウス (対照群) と比較して、心筋梗塞発症
    早期よりPaneth細胞由来のαディフェンシン産生量が減少し、小腸陰窩の萎縮ならびにPaneth細胞数の減少を認めた。一方、心筋梗塞発症後28日目には心不全を発症しており、αディフェンシン産生量の減少のみならず、腸内フローラのα多様性およびβ多様性の低下を認め、dysbiosisが生じていた。
    臨床研究「心不全における腸管上皮細胞由来αディフェンシンの役割 (UMIN: 000032796)」については、これまでに計49例 (心不全患者39例・健常者10例) が参加した。今後さらに症例数を増やしていくとともに、今後小腸Paneth細胞由来のαディフェンシン産生量および腸内フローラの多様性と心不全重症度との関連を評価する予定である。
    日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 18K08022
  • 左室駆出率の保たれた心不全患者における心筋線維化、左室拡張機能、運動耐容能の関連
    科学研究費助成事業
    2018年04月01日 - 2022年03月31日
    岩野 弘幸; 横田 卓; 納谷 昌直; 安斉 俊久
    運動耐容能の低下は心不全の主症状であり、左室駆出率の保たれた心不全(HFpEF)には、左室に明らかな器質的異常のないフェノタイプが認められるが、この病態における運動耐容能の規定因子は明らかではない。そこで、この病態における運動耐容能低下の機序を、運動負荷心エコー法ならびに心臓MRIを用いて検討した。
    49例の左室肥大をかくHFpEF症例で心肺運動負荷試験、運動負荷心エコー検査、造影心臓MRI検査を行い、運動耐容能の規定因子を検討したところ、運動時の左室拡張能指標ではなく、運動誘発性肺高血圧ならびに右室-肺動脈カップリングの崩れが運動耐容能と関連していることが明らかとなった。
    日本学術振興会, 基盤研究(C), 北海道大学, 18K07622
  • COI STREAM『食と健康の達人』拠点
    センター・オブ・イノベーション (COI) プログラム
    2015年04月 - 2022年03月
    文部科学省・科学技術振興機構 (JST), 北海道大学, 研究分担者
  • 脳由来神経栄養因子によるミトコンドリア機能制御機構の解明
    科学研究費助成事業
    2018年04月01日 - 2021年03月31日
    絹川 真太郎; 福島 新; 横田 卓; 高田 真吾
    脳由来神経栄養因子(BDNF)が骨格筋細胞から分泌されるマイオカインであることを明らかにするとともに、骨格筋細胞内ミトコンドリアに存在することを見出した。BDNF骨格筋ミトコンドリア量・機能制御、特に脂肪酸酸化に重要な役割を果たしていることを見出した。さらに、このBDNFの効果はAMPKα、PGC-1αシグナルを介していた。心筋梗塞後心不全モデルマウスに対して、ヒトリコンビナントBDNFを投与することによって、骨格筋のBDNFの増加、AMPKα-PGC-1αシグナルの改善とともに、持久運動能力が改善した。このBDNFによる治療効果は運動療法と同等の効果を示し、同じシグナルを介していた。
    日本学術振興会, 基盤研究(B), 18H03187
  • 先天性心疾患におけるアセチル化修飾の役割の検討
    科学研究費助成事業
    2017年04月01日 - 2020年03月31日
    福島 新; 絹川 真太郎; 高田 真吾; 横田 卓
    心不全を合併した先天性心疾患における心筋代謝変化を検討した。幼若家兎の先天性心疾患モデル (CHD群)では、偽手術群と比較し脂肪酸代謝およびエネルギー産生量が有意に低下した。心筋組織では脂肪酸β酸化酵素(β-HAD, LCAD)の翻訳後修飾(アセチル化)がCHD群で減弱し、酵素活性や脂肪酸代謝率の低下と関連した。ミトコンドリアアセチル基転移酵素(GCN5L1)の蛋白発現がCHD群で低下しており、培養心筋細胞を用いてGCN5L1の遺伝子欠損操作を行うとLCAD, β-HADのアセチル化は減弱し細胞は病的心肥大を呈した。外科的修復術を受けた先天性心疾患患者の心筋サンプルでも同様の現象が確認された。
    日本学術振興会, 基盤研究(C), 北海道大学, 17K10137
  • IoTセルフケアアプリを活用した高血圧性疾患の重症化予防を目指した研究
    平成30年度 IoT等活用行動変容研究事業研究事業
    2018年08月 - 2020年03月
    日本医療研究開発機構 (AMED), 北海道大学, 研究分担者
  • 虚血再還流を併用した筋力トレーニングによる疲労耐性および他臓器保護効果の検証
    科学研究費助成事業
    2015年04月01日 - 2018年03月31日
    沖田 孝一; 絹川 真太郎; 横田 卓
    本研究では、直接および間接的preconditioningが下肢最大筋力と筋疲労に与える効果と必要回数を検証したが、回数によらず明らかなパフォーマンス向上効果は得られなかった。成果のpreliminaryデータを、国内学会(日本体力医学会2016, 2017年)にて発表した。問題点を考察し、実践的な運動(連続跳躍)での検証、機序に関わる一酸化窒素発生を助長する食餌性硝酸塩の併用も試みたが、統計学的に有意なパフォーマンス向上、筋保護効果は認められなかった(臨床運動療法学会, 日本心臓リハビリテーション学会2017年)。最終データは本年の国内学会で発表予定であり、国際論文として投稿準備中である。
    日本学術振興会, 基盤研究(C), 北翔大学, 15K01625
  • 心血管病における心臓周囲脂肪ミトコンドリアの役割
    科学研究費助成事業
    2015年04月 - 2018年03月
    横田 卓; 絹川 真太郎; 筒井 裕之; 松島 将士
    心臓周囲脂肪 (EAT) は異所性脂肪の一種であるが、近年EAT量の増加が冠動脈硬化の重症度と関連があることが報告された。一方、EATの質的変化が冠動脈硬化に及ぼす影響については明らかにされておらず、本研究では心臓手術で採取されるEATを用いて脂肪組織の代謝能などを評価した。非動脈硬化性心疾患患者と比べて冠動脈疾患患者ではEATミトコンドリア呼吸能が低下しており、EAT由来のアディポネクチン産生量と正の相関を、冠動脈疾患の重症度と負の相関を示した。したがって、EATにおけるミトコンドリア機能障害が少なくとも一部はアディポネクチン産生能低下を介して、冠動脈硬化の進行に寄与する可能性が示唆された。
    日本学術振興会, 基盤研究(C), 北海道大学, 研究代表者, 15K09115
  • 骨格筋不全におけるmitoNEETによるミトコンドリア機能制御の分子機構の解明
    科学研究費助成事業
    2014年04月01日 - 2017年03月31日
    絹川 真太郎; 降旗 高明; 高田 真吾; 筒井 裕之; 松島 将士; 横田 卓
    複数の慢性疾患モデルにおいて、運動能力が低下し、骨格筋不全(骨格筋ミトコンドリア機能障害、骨格筋線維型変移)を呈し、mitoNEET発現の減少とともに、ミトコンドリア鉄容量が増加し、酸化ストレス産生が増加した。mitoNEET欠損マウスにおいて、ミトコンドリア鉄容量の増加、酸化ストレス亢進およびミトコンドリア形態・機能異常と同時に、運動能力が低下した。既知のミトコンドリアの鉄流出入に関わるタンパクに変化がなかった。タンパク相互作用の検討において、鉄代謝に関わる細胞質タンパク(X)とミトコンドリア内への物質を輸送する可能性があるミトコンドリア内膜タンパク(Y)とmitoNEETが結合した。
    日本学術振興会, 基盤研究(C), 北海道大学, 26350879
  • 脳卒中・循環器病の遠隔医療の開発と検証のための研究
    循環器疾患・糖尿病等生活習慣病対策実用化研究事業
    2015年09月 - 2017年03月
    日本医療研究開発機構 (AMED), 北海道大学, 研究分担者
  • 血流制限を併用した筋力トレーニングの基礎生理学的検討から発展的臨床応用まで
    科学研究費助成事業
    2011年 - 2013年
    沖田 孝一; 絹川 真太郎; 横田 卓; 堀内 雅弘; 森田 憲輝
    本研究において基礎的及び臨床的検討から、筋力トレーニング効果の大きさが、血流制限により増強する骨格筋内の代謝的ストレスに依存することを明らかにし(J Appl Physiol 2012)、その知見のもとで個体差や疾患を考慮した血流制限併用トレーニングの至適プロトコールを考案することができた(Med Sci Sports Exerc 2012, Eur J Appl Physiol 2012, Circ J 2013)。また本法の多面的効果を検証し、疾患および競技者への臨床応用を提言することができた(Int J Vasc Med 2012, J Nov Physiother 2013)。
    日本学術振興会, 基盤研究(C), 北翔大学, 23500784
■ 産業財産権
  • 心不全の病態の評価のための方法、バイオマーカー、候補化合物の評価方法、医薬用組成物及び心不全の治療剤
    特許権, 高田 真吾; 前川 聡; 横田 卓; 白川 亮介; 佐邊 壽孝, 北海道大学
    特願2020-548000, 2019年06月28日
    WO2020059242, 2020年03月26日
    特許7430916, 2024年02月05日
■ 学術・社会貢献活動/その他
社会貢献活動
  • 遺伝子×フィットネス? 検査結果から読み解く体質別の運動事例とその場でできる簡単エクササイズ
    2025年12月20日
    講師
    北海道大学
    サイエンスフェスタ2025
  • 高血圧を防ぐ新常識~おいしく食べて元気に暮らす~
    2025年11月25日
    講師
    シニアのための健康セミナー (札幌)
  • えっ、高血圧も?~認知症と生活習慣病のつながり~
    2025年10月18日
    講師
    倶知安町社会福祉協議会
    第4回倶知安町社会福祉大会
  • あなたの遺伝子からわかること~糖尿病・高血圧・認知症は予防できるのか?~
    2024年12月15日
    講師
    北海道大学
    サイエンスフェスタ2024
  • 人生100年時代のゲノムドック (遺伝学的検査) を活用した予防医療
    2024年10月10日
    講師
    ほくでん
    WEB健康セミナー~いつもの健診と"その先へ"~
  • 体質リスクを把握して高血圧を予防する時代へ
    2024年08月31日
    講師
    第17回 北海道大学病院 検査・輸血部市民フォーラム
  • 今さら聞けない高血圧予防~アンチエイジングの観点から~
    2024年08月20日
    講師
    北海道岩見沢市
    保健推進会研修会
  • 予防・医療分野におけるPHRの活用について
    2024年03月26日
    講師
    喜茂別町在宅医療介護連携推進事業 多職種連携研修会
    その他
  • 心臓メンテで元気をキープ! 心不全を知る
    2023年11月18日
    講師
    北海道心不全医療連携アカデミー
    楽しく知ろう!ハートケア最前線 心不全撲滅宣言 2023 in SAPPORO
    社会人・一般
  • 高血圧予防のためのデジタルヘルスの活用
    2023年02月17日 - 2023年02月23日
    パネリスト, 司会, 講師
    北海道大学病院
    オンライン市民公開講座「デジタルヘルスが切り拓く未来~高血圧・脳卒中の予防と治療、遠隔医療への応用~」
  • 高血圧を正しく予防するために
    2022年06月23日
    講師
    北海道石狩市
    市民公開講座
  • ストップ!! 高血圧
    2021年10月18日
    講師
    北海道石狩市
    市民公開講座
  • 楽しく生活習慣を改善して元気なからだを作ろう!
    2020年12月08日
    講師
    北海道石狩市
    市民公開講座 (血液さらさら教室)
  • 新型コロナウイルスから身をまもるために~できることからやってみよう!セルフケア~
    2020年11月25日
    講師
    北海道岩見沢市
    いわみざわ市民大学特別公開講座
  • 教えて先生!生活習慣病に負けない元気なカラダ作り
    2018年12月07日
    講師
    札幌市北区保健福祉部
    市民公開講座
  • 自分の健康状態が見えるセルフケアアプリの開発
    2018年06月04日
    講師
    北海道岩見沢市
    岩見沢市 ICT利活用セミナー2018 「健康で快適な生活を送るためのICT利活用」
  • 脂肪の分布と 生活習慣病・心血管病との関わり
    2018年05月09日
    講師
    北海道大学保健センター
    健康支援セミナー
  • 日常生活で体調を管理しよう!!
    2016年10月09日
    講師
    日本心不全学会
    第20回日本心不全学会学術集会 市民公開講座
  • 心不全の新たなセルフケアツール
    2016年06月25日
    講師
    さっぽろ循環器懇話会
    市民公開フォーラム~がんと心臓病から身を守るために~