Pathophysiological significance of myokine in cardiomyopathy and its therapeutic application

• Project/Area Number: 19K17592
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Nagoya University
• Principal Investigator: Okumura Takahiro 名古屋大学, 医学部附属病院, 病院講師 (60635598)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: マイオカイン / 心筋疾患 / オートタキシン

Outline of Research at the Start

心筋疾患では、心筋細胞肥大や間質の線維化といった心臓の組織学的および構造的変化（リモデリング）を伴う。近年、骨格筋がFSTL-1やマイオネクチン、FGF-21などの生理活性物質（マイオカイン）を産生することが報告された。動物モデルを用いた最近の研究により、マイオカインが細胞死抑制作用や抗炎症作用を介して心臓保護的に働くことが明らかとなった。申請者は、血中マイオカイン濃度が心筋疾患における心負荷・心不全重症度を反映し、リモデリングに関与するとの仮説を立てた。このため本研究では、ヒト検体でのマイオカイン血中濃度を測定し、血行動態や心不全重症度、心リモデリング、予後との関連を検討する。

Outline of Final Research Achievements

We investigated the association between serum follistatin-like 1 (FSTL1) levels, particularly the transcardiac gradient, and hemodynamics and prognosis in 32 patients with dilated cardiomyopathy (DCM). The transcardiac gradient (FSTL1 CS-Ao), defined as the difference between serum FSTL1 levels in the coronary sinus and aortic root, was significantly correlated with pulmonary artery wedge pressure. In survival analysis, the incidence of cardiac events was significantly higher in the low FSTL1 CS-Ao group. In Cox regression analysis, FSTL1 CS-Ao was an independent predictor of cardiac events, suggesting that a lower transcardiac gradient of FSTL1 might be a novel prognostic factor for DCM.

Academic Significance and Societal Importance of the Research Achievements

研究代表者らは,拡張型心筋症患者におけるFSTL1血中濃度の経心臓勾配が肺動脈楔入圧と有意に相関することを示した。また,FSTL1の経心臓勾配の低下は,不良な予後と関連し,心臓イベントの独立した予測因子であることを明らかにした。この結果は,FSTL1経心臓勾配が拡張型心筋症の不良な血行動態を反映し,予後改善のための新たな治療ターゲットとなりうる可能性が示唆された。この結果は,DCMの発症や進展予防のメカニズム解明のヒントとなり,新たな診断法や治療の開発といった臨床応用に展開するための基盤となりうる可能性がある。

Research Products

• [Journal Article] Serum autotaxin as a novel prognostic marker in patients with non‐ischaemic dilated cardiomyopathy (2022)
  • Author(s): Araki Takashi、Okumura Takahiro、Hiraiwa Hiroaki、Mizutani Takashi、Kimura Yuki、Kazama Shingo、Shibata Naoki、Oishi Hideo、Kuwayama Tasuku、Kondo Toru、Morimoto Ryota、Takefuji Mikito、Murohara Toyoaki
  • Journal Title: ESC Heart Failure Volume: 9 Issue: 2 Pages: 1304-1313
  • DOI: 10.1002/ehf2.13817
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic value of resting cardiac power index depends on mean arterial pressure in dilated cardiomyopathy (2021)
  • Author(s): Morimoto Ryota、Mizutani Takashi、Araki Takashi、Oishi Hideo、Kimura Yuki、Kazama Shingo、Shibata Naoki、Kuwayama Tasuku、Hiraiwa Hiroaki、Kondo Toru、Furusawa Kenji、Okumura Takahiro、Murohara Toyoaki
  • Journal Title: ESC Heart Failure Volume: 8 Issue: 4 Pages: 3206-3213
  • DOI: 10.1002/ehf2.13446
  • Peer Reviewed / Open Access
• [Journal Article] 拡張型心筋症を臨床的予測スコアで層別化する (2021)
  • Author(s): 奥村貴裕、木村祐樹、室原豊明
  • Journal Title: 心臓 Volume: 53 Pages: 772-776
• [Journal Article] Two cases of dilated cardiomyopathy with blood pressure-limited tolerability of cardioprotective agents improved by ivabradine (2021)
  • Author(s): Okumura Takahiro、Hiraiwa Hiroaki、Araki Takashi、Mizutani Takashi、Kimura Yuki、Kazama Shingo、Shibata Naoki、Oishi Hideo、Kuwayama Tasuku、Kondo Toru、Morimoto Ryota、Murohara Toyoaki
  • Journal Title: Journal of Cardiology Cases Volume: 23 Issue: 4 Pages: 149-153
  • DOI: 10.1016/j.jccase.2020.11.007
  • Peer Reviewed / Open Access
• [Journal Article] A clinical score for predicting left ventricular reverse remodelling in patients with dilated cardiomyopathy (2021)
  • Author(s): Kimura Yuki、Okumura Takahiro、Morimoto Ryota、Kazama Shingo、Shibata Naoki、Oishi Hideo、Araki Takashi、Mizutani Takashi、Kuwayama Tasuku、Hiraiwa Hiroaki、Kondo Toru、Murohara Toyoaki
  • Journal Title: ESC Heart Failure Volume: 8 Issue: 2 Pages: 1359-1368
  • DOI: 10.1002/ehf2.13216
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of Plasma Branched-Chain Amino Acid Analysis in Predicting Outcomes of Patients with Nonischemic Dilated Cardiomyopathy (2020)
  • Author(s): Kimura Yuki、Okumura Takahiro、Kazama Shingo、Shibata Naoki、Oishi Hideo、Arao Yoshihito、Kuwayama Tasuku、Kato Hiroo、Yamaguchi Shogo、Hiraiwa Hiroaki、Kondo Toru、Morimoto Ryota、Murohara Toyoaki
  • Journal Title: International Heart Journal Volume: 61 Issue: 4 Pages: 739-747
  • DOI: 10.1536/ihj.20-010
  • NAID: 130007882143
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2020-07-30
  • Peer Reviewed
• [Journal Article] Usefulness of the plasma branched-chain amino acid/Aromatic amino acid ratio for predicting future cardiac events in patients with heart failure (2020)
  • Author(s): Hiraiwa Hiroaki, Okumura Takahiro, Kondo Toru, Kato Toshiaki, Kazama Shingo, Ishihara Toshikazu, Iwata Etsuo, Shimojo Masafumi, Kondo Sayano, Aoki Soichiro, Kanzaki Yasunori, Tanimura Daisuke, Sano Hiroaki, Awaji Yoshifumi, Yamada Sumio, Murohara Toyoaki
  • Journal Title: Journal of Cardiology Volume: 75 Issue: 6 Pages: 689-696
  • DOI: 10.1016/j.jjcc.2019.12.016
  • Peer Reviewed
• [Journal Article] Pathological changes of the myocardium in reworsening of anthracycline-induced cardiomyopathy after explant of a left ventricular assist device (2020)
  • Author(s): Hiroaki Hiraiwa, Takahiro Okumura, Shinya Shimizu, Yoshihito Arao, Hideo Oishi, Hiroo Kato, Tasuku Kuwayama, Shogo Yamaguchi, Tomoaki Haga, Toru Kondo, Naoaki Kano, Naoki Watanabe, Kenji Furusawa, Akinori Sawamura, Ryota Morimoto, Kazuro Fujimoto, Masato Mutsuga, Akihiko Usui, Toyoaki Murohara
  • Journal Title: Nagoya Journal of Medical Science Volume: 82 Issue: 1 Pages: 129-134
  • DOI: 10.18999/nagjms.82.1.129
  • NAID: 120006797881
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/29361
  • Peer Reviewed
• [Presentation] Prognostic Value of 123I-Metaiodobenzylguanide Scintigraphy in Patients with Non Ischemic Dilated Cardiomyopathy (2022)
  • Author(s): Takashi Mizutani, Ryota Morimoto, Takahiro Okumura, Shingo Kazama, Yuki Kimura, Takashi Araki, Hideo Oishi, Tasuku Kuwayama, Hiroaki Hiraiwa, Toyoaki Murohara.
  • Organizer: 第86回日本循環器学会学術集会
• [Presentation] 拡張型心筋症患者におけるリバースリモデリング予測スコア (2021)
  • Author(s): 木村祐樹, 奥村貴裕, 森本竜太, 風間信吾, 柴田直紀, 大石英生, 荒木孝, 水谷崇, 桒山輔, 平岩宏章, 近藤徹, 室原豊明.
  • Organizer: 第7回日本心筋症研究会
• [Presentation] Serum autotaxin level predicts future cardiac events in patients with dilated cardiomyopathy (2021)
  • Author(s): Takashi Araki, Takahiro Okumura, Takashi Mizutani, Yuki Kimura, Shingo Kazama, Naoki Shibata, Hideo Oishi, Tasuku Kuwayama, Hiroaki Hiraiwa, Toru Kondo, Ryota Morimoto, Mikito Takefuji, Toyoaki Murohara.
  • Organizer: ESC Congress 2021 The digital experience
  • Int'l Joint Research
• [Presentation] The Prognostic Impact of Transcardiac Gradient of Follistatin-like 1 In Patients With Non-ischemic Dilated Cardiomyopathy (2020)
  • Author(s): Oishi H, Okumura T, Ohashi K, Kimura Y, Kazama S, Shibata N, Arao Y, Kato H, Kuwayama T, Yamaguchi S, Kondo T, Hiraiwa H, Morimoto R, Ouchi N, Murohara T.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] 拡張型心筋症におけるリバースリモデリングを実臨床でどう予測するか？ (2020)
  • Author(s): 木村祐樹，奥村貴裕，森本竜太，風間信吾，柴田直紀，大石英生，荒木孝，水谷崇，桒山輔，平岩宏章，近藤徹，室原豊明
  • Organizer: 第24回日本心不全学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] The Prognostic Impact of Human Epididymis Protein 4 Levels in Patients With Dilated Cardiomyopathy (2020)
  • Author(s): Okumura T, Oishi H, Araki T, Mizutani T, Kazama S, Shibata N, Kuwayama T, Hiraiwa H, Kondo T, Morimoto R, Takefuji M, Murohara T.
  • Organizer: American Heart Association (AHA) Scientific Sessions 2020
  • Int'l Joint Research
• [Presentation] Transcardiac Gradient of Follistatin-like 1 Perdicts Future Cardiac Events in Patients with Non-ischemic Dilated Cardiomyopathy (2019)
  • Author(s): Hideo Oishi, Takahiro Okumura, Koji Ohashi, Yuki Kimura, Shingo Kazama, Naoki Shibata, Yoshihito Arao, Hiroo Kato, Tasuku Kuwayama, Shogo Yamaguchi, Toru Kondo, Hiroaki Hiraiwa, Ryota Morimoto, Noriaki Ouchi, Toyoaki Murohara
  • Organizer: 第23回 日本心不全学会学術集会
• [Book] 循環器コンプリートシリーズ 心筋症 (2021)
  • Author(s): 奥村貴裕
  • Total Pages: 272
  • Publisher: 学研メディカル秀潤社