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Rotors as Drivers of Torsades de Pointes and Ventricular Fibrillation

Research Project

Project/Area Number 17K09511
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Cardiovascular medicine
Research InstitutionNagasaki University

Principal Investigator

TSUJI Yukiomi  長崎大学, 医歯薬学総合研究科(医学系), 講師 (60432217)

Co-Investigator(Kenkyū-buntansha) 山崎 正俊  東京大学, 大学院工学系研究科(工学部), 特任准教授 (30627328)
本荘 晴朗  名古屋大学, 環境医学研究所, 准教授 (70262912)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords電気的ストーム / 渦巻き型旋回興奮(ローター) / 遅延ナトリウム電流 / 神経型ナトリウムチャネル / 心室細動 / トルサードドポアント / 渦巻き型旋回興奮 / トルサード・ド・ポアンツ / 循環器
Outline of Final Research Achievements

Electrophysiological mechanisms of ventricular tachycardia and fibrillation (VT/VF) were explored, using a rabbit model of electrical storm featuring multiple defibrillator-firings for repetitive VT/VF by electrical remodeling (QT-prolongation) due to chronic atrioventricular block. A vortex-like reentrant activity termed a rotor underlies VT and VF, but they have the rotor frequency and dynamics particular to themselves. VT resulted from a rotor in the distinctive manner, possibly explaining the ECG pattern of Torsades de Pointes (TdP), and VF was maintained by high frequency rotors which became stationary at the septum. Late Na-current enhancement due to neural Na-channel NaV1.8 upregulation was a major contributor to the substrate favoring rotors to form TdP. Cardiac metabolism-related enzyme X was strikingly upregulated at the septum, suggesting that septal myocardium remodeling may play a crucial role in the conversion to VF-driving stationary rotors.

Academic Significance and Societal Importance of the Research Achievements

致死性不整脈による心臓突然死は年々増加しており、近未来には、さらに深刻な社会問題となることが予想されている。しかし、有用な治療・予防薬はなく、その発生機序や分子基盤についても未解決な点が数多く残されている。本研究では、重篤な心臓不整脈疾患「反復する心室頻拍・細動(電気的ストーム)」を再現したモデル動物を用いて、電気的ストームを光学マッピングで可視化するとともに、心筋組織の特性変化を解析した。致死性不整脈は渦巻き型旋回興奮波によって形成されること、その成立に神経型NaチャネルNaV1.8、心筋代謝酵素X(未発表)が関与することが判明した。新しい治療薬の開発につながる知見が得られた。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (19 results)

All 2019 2018 2017 Other

All Int'l Joint Research (6 results) Journal Article (2 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (10 results) (of which Int'l Joint Research: 6 results,  Invited: 7 results) Book (1 results)

  • [Int'l Joint Research] University of Montreal(カナダ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Duisburg-Essen University(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Duisburg-Essen University(ドイツ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] University of Montreal(カナダ)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] University of Duisburg-Essen(Germany)

    • Related Report
      2017 Research-status Report
  • [Int'l Joint Research] Montreal Heart Institute(Canada)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Electrical storm: mechanistic and therapeutic considerations to avoid death in the survivors.2018

    • Author(s)
      Tsuji Y, Dobrev D
    • Journal Title

      J Thorac Dis

      Volume: 10 (Suppl 33) Issue: S33 Pages: S4053-S4056

    • DOI

      10.21037/jtd.2018.09.111

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prognostic impact of electrical storm in patients with implantable cardioverter defibrillators: Mechanistic and therapeutic considerations to reduce the risk of death2018

    • Author(s)
      Tsuji Yukiomi、Dobrev Dobromir
    • Journal Title

      International Journal of Cardiology

      Volume: 255 Pages: 101-102

    • DOI

      10.1016/j.ijcard.2017.12.085

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Electrical storm and heart failure worsening: mechanistic and therapeutic considerations to avoid death in the survivors2019

    • Author(s)
      Tsuji Y
    • Organizer
      12th Asia Pacific Heart Rhythm Society Scientific Sessions
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Therapeutic targets to avoid ICD shocks-associated worsening heart failure.2019

    • Author(s)
      Tsuji Y.
    • Organizer
      第83回日本循環器学会学術集会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Torsadogenic action of late Na+ current in experimental electrical storm.2018

    • Author(s)
      Yamazaki M, Tsuji Y et al.
    • Organizer
      Heart Rhythm Scientific Sessions 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cellular and molecular mechanisms of electrical storm.2018

    • Author(s)
      Tsuji Y.
    • Organizer
      42nd Meeting of the European Society of Cardiology (ESC) Working Group on Cardiac Cellular Electrophysiology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] CaMKII as a target for novel therapy to treat lethal ventricular tachyarrhythmias.2018

    • Author(s)
      辻幸臣
    • Organizer
      第57回日本生体医工学学会大会(旧日本エム・イー学会)
    • Related Report
      2018 Research-status Report
  • [Presentation] Mechanisms of electrical storm associated with QT prolongation: successful mapping of Torsades de Pointes in rabbits.2018

    • Author(s)
      Tsuji Y, Yamazaki M et al.
    • Organizer
      American Heart Association Scientific Sessions 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] CaMKII-mediated phosphorylation of sodium channel and arrhythmogenesis in a rabbit model of electrical storm.2018

    • Author(s)
      Tsuji Yukiomi
    • Organizer
      2018 THRS Annual Conference in Conjunction with Tokyo-Taipei-Seoul Arrhythmia Joint Conference
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Electrical storm associated with bradycardia2017

    • Author(s)
      Tsuji Yukiomi
    • Organizer
      Asian Pacific Heart Rhythm Society Scientific Session 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 心室細動ストーム家兎モデルを用いた致死性不整脈のトランスレーション研究2017

    • Author(s)
      辻幸臣,山崎正俊,本荘晴朗,蒔田直昌
    • Organizer
      第24回法医病理セミナー・ワークショップ「心臓突然死への挑戦」
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] 致死性不整脈の発生に果たすNaチャネルリン酸化異常の意義:電気的ストーム実験モデルでの検討2017

    • Author(s)
      辻幸臣
    • Organizer
      名古屋大学平成29年度基盤医学特論
    • Related Report
      2017 Research-status Report
    • Invited
  • [Book] 不整脈 識る・診る・治す2018

    • Author(s)
      平尾見三、小室一成
    • Total Pages
      376
    • Publisher
      中山書店
    • ISBN
      9784521745855
    • Related Report
      2018 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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