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The therapeutic approach of inductive lethal arrhythmia by inhibiting Ca2+ leak through the cardiac ryanodine receptor in hypertrophic cardiomyopathy

Research Project

Project/Area Number 23790856
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Circulatory organs internal medicine
Research InstitutionYamaguchi University

Principal Investigator

OKUDA Shinichi  山口大学, 医学部附属病院, 助教 (90530212)

Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords肥大型心筋症 / カルシウムハンドリング / リアノジン受容体 / ドメイン連関 / 致死性不整脈
Research Abstract

Hypertrophic cardiomyopathy(HCM) is known to be a myocardial disorder characterized by severe hypertrophy of the left ventricule. In HCM patients, it is the cause of sudden death by lethal arrhythmia in younger age. Medical approach against inductive ventricular arrhythmia in HCM patients remains elusive. Here, we hypothesized that diastolic Ca2+ leak through Ryanodine receptor (RyR2) is one of the important factor of regulating arrhytmogenesis in HCM. To verify this hypothesis, we investigated the pathogenic role of Ca2+ leak through RyR2 in transgenic mouse (TG) model of Familial Hypertrophic cardiomyopathy-related cardiac troponin T mutation. Diastolic Ca2+ leak through defective RyR2 is induced by beta-adrenergic stimulation in TG cardiomyocytes. Dantrolene and Calmodulin-kinaseII inhibitor can inhibit Ca2+ leak by stabilizing RyR2. These results might suggest that the stabilization of RyR2 and inhibiting Ca2+ leak might play a role for the pathogenesis of lethal arrhythmia in HCM.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (31 results)

All 2013 2012 2011

All Journal Article (9 results) (of which Peer Reviewed: 9 results) Presentation (15 results) Book (7 results)

  • [Journal Article] Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts2012

    • Author(s)
      Hino A, Yano M, Kato T, Fukuda M, Suetomi T, Ono M, Murakami W, Susa T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M
    • Journal Title

      Cardiovasc Res

      Volume: 96 Pages: 433-43

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Low-dose β-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure2012

    • Author(s)
      Kobayashi S, Susa T, Tanaka T, Murakami W, Fukuta S, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Okamura T, Yano M, Matsuzaki M
    • Journal Title

      Circ J

      Volume: 76(7) Pages: 1646-53

    • NAID

      10030503344

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker for predicting cardiac events and evaluating the effectiveness of carvedilol treatment in patients with chronic systolic heart failure2012

    • Author(s)
      usa T, Kobayashi S, Tanaka T, Murakami W, Akashi S, Kunitsugu I, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Ueyama T, Okamura T, Yano M, Matsuzaki M
    • Journal Title

      Circ J

      Volume: 76(1) Pages: 117-26

    • NAID

      10030034360

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts.2012

    • Author(s)
      Akihiro Hino
    • Journal Title

      Cardiovascular Research

      Volume: 96 Pages: 433-443

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Low-dose β-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure.2012

    • Author(s)
      Shigeki Kobayashi
    • Journal Title

      Circulation Journal

      Volume: 76 Pages: 1646-1653

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker for predicting cardiac events and evaluating the effectiveness of carvedilol treatment in patients with chronic systolic heart failure.2012

    • Author(s)
      Takahisa Susa
    • Journal Title

      Circulation Journal

      Volume: 76 Pages: 117-126

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca^release leading to catecholaminergic polymorphic ventricular tachycardia2011

    • Author(s)
      Suetomi T, Yano M, Uchinoumi H, Fukuda M, Hino A, Ono M, Xu X, Tateishi H, OkudaS, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M
    • Journal Title

      Circulation

      Volume: 124 Pages: 682-94

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca2+release leading to catecholaminergic polymorphic ventricular tachycardia.2011

    • Author(s)
      Takeshi Suetomi, Masafumi Yano, Hitoshi Uchinoumi, Masakazu Fukuda, Akihiro Hino, Makoto Ono, Xiaojuan Xu, Hiroki Tateishi, Shinichi Okuda, Masunori Matsuzaki,et.al..
    • Journal Title

      Circulation

      Volume: 124 Pages: 682-694

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Urinary 8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure.2011

    • Author(s)
      Shigeki Kobayashi, Takehisa Susa, Takeo Tanaka, Wakako Murakami, Seiko Fukuta, Shinichi Okuda,Masafumi Yano, Masunori Matsuzaki.,et.al.
    • Journal Title

      European Journal of Heart Faililure

      Volume: 13 Pages: 29-36

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] CaMKII-mediated aberrant Ca^release play a key role in the arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy2013

    • Author(s)
      Okuda S, Fukuda M, Yano M, Suetomi T, Hino A, Kato T, Doi M, Kobayashi S, Yamamoto T, Matsuzaki M
    • Organizer
      apanese Circulation Society Scientific Meeting 2013
    • Place of Presentation
      Pacifico Yokohama, Japan
    • Year and Date
      2013-03-15
    • Related Report
      2012 Final Research Report
  • [Presentation] CaMKII-mediated aberrant Ca2+ release play a key role in the arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy.2013

    • Author(s)
      Shinichi Okuda
    • Organizer
      Japanese Circulation Spciety Scientific Meeting 2013
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Enhanced Binding of Calmodulin to RyR2 Inhibits Aberrant Ca2+ Release and Arrhythmogenesis in CPVT-Associated Mutation.2013

    • Author(s)
      Masakazu Fukuda
    • Organizer
      Japanese Circulation Spciety Scientific Meeting 2013
    • Place of Presentation
      パシフィコ横浜(横浜)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Correcting inter-domain interaction of cardiac ryanodine receptor inhibits aberrant Ca^ release in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy mouse model2012

    • Author(s)
      Okuda S, Yano M, Fukuda M, Suetomi T, Hino A, Kato T, Doi M, Kobayashi S, Yamamoto T, Matsuzaki M
    • Organizer
      The 16th Annual Scientific Meeting of the Japanese Heart Failure Society
    • Place of Presentation
      Sendai International center, Japan
    • Year and Date
      2012-11-30
    • Related Report
      2012 Final Research Report
  • [Presentation] CaMKII-mediated aberrant Ca^release may play a key role in the arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy2012

    • Author(s)
      Okuda S, Fukuda M, Yano M, Suetomi T, Hino A, Kato T, Doi M, Kobayashi S, Yamamoto T, Matsuzaki M
    • Organizer
      American Heart association Scientific meeting 2012
    • Place of Presentation
      Los Angels, USA
    • Related Report
      2012 Final Research Report
  • [Presentation] Enhanced Binding of Calmodulin to RyR2 Inhibits Aberrant Ca2+ Release and Arrhythmogenesis in CPVT-Associated Mutation2012

    • Author(s)
      Fukuda M, Yamamoto T, Kato T, Hino A, Suetomi T, Tateishi H, Doi M, Okuda S, Kobayashi S, Matsuzaki M, Yano M
    • Organizer
      American Heart association Scientific meeting
    • Place of Presentation
      Los Angels, USA
    • Related Report
      2012 Final Research Report
  • [Presentation] CaMKII-mediated aberrant Ca2+ release may play a key role in the arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy.2012

    • Author(s)
      Shinichi Okuda
    • Organizer
      American Heart Association Scientific Meeting 2012
    • Place of Presentation
      Los Angels (USA)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Correcting inter-domain interaction of cardiac ryanodine receptor inhibits aberrant Ca2+ release in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy mouse model.2012

    • Author(s)
      Shinichi Okuda
    • Organizer
      Japanese Heart Failure Society Scientific Meeting 2012
    • Place of Presentation
      仙台国際センター(仙台)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Enhanced Binding of Calmodulin to RyR2 Inhibits Aberrant Ca2+ Release and Arrhythmogenesis in CPVT-Associated Mutation.2012

    • Author(s)
      Masakazu Fukuda
    • Organizer
      American Heart Association Scientific Meeting 2012
    • Place of Presentation
      Los Angels (USA)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Coupled Conformational Changes in the Local and Global Inter-Domain Interactions Trigger Diastolic Ca2+ Release and Lethal Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)2011

    • Author(s)
      Suetomi T, Yano M, Kato T, Fukuda M, Hino A, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Matsuzaki M
    • Organizer
      American Heart association Scientific meeting 2011
    • Place of Presentation
      Orland, USA
    • Related Report
      2012 Final Research Report
  • [Presentation] Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation2011

    • Author(s)
      Fukuda M, Yano M, Kato T, Hino A, Suetomi T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Matsuzaki M
    • Organizer
      American Heart association Scientific meeting 2011
    • Place of Presentation
      Orland, USA
    • Related Report
      2012 Final Research Report
  • [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine as a Novel Biomarker of Inflammatory Activity in Patients with Cardiac Sarcoidosis: Insight From Immunohistochemical Technique and 18F-FDG PET/CT2011

    • Author(s)
      Fukuta S, Kobayashi S, Tanaka T, Susa T, Murakami W, Okuda S, Doi M, Wada Y, Nao T, Yamada J, Ueyama T, Okamura T, Kawamura S, Yano M, Matsuzaki M
    • Organizer
      American Heart association Scientific meeting 2011
    • Place of Presentation
      Orland, USA
    • Related Report
      2012 Final Research Report
  • [Presentation] Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation.2011

    • Author(s)
      Masakazu Fukuda, Masafumi Yano, Takayoshi Kato, Akihiro Hino, Takeshi Suetomi, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Yasuhiro Ikeda, Takeshi Yamamoto, Masunori Matsuzaki.
    • Organizer
      American Heart association Scientific meeting 2011
    • Place of Presentation
      Orland,USA
    • Related Report
      2011 Research-status Report
  • [Presentation] Conformational Changes in the Local and Global Inter-Domain Interactions Trigger Diastolic Ca2+ Release and Lethal Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).2011

    • Author(s)
      Takeshi Suetomi, Masafumi Yano, Takayoshi Kato, Masakazu Fukuda, Akihiro Hino, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Yasuhiro Ikeda, Takeshi Yamamoto, Masunori Matsuzaki.
    • Organizer
      American Heart association Scientific meeting 2011
    • Place of Presentation
      Orland,USA
    • Related Report
      2011 Research-status Report
  • [Presentation] Urinary 8-hydroxy-2'-deoxyguanosine as a Novel Biomarker of Inflammatory Activity in Patients with Cardiac Sarcoidosis: Insight From Immunohistochemical Technique and 18F-FDG PET/CT.2011

    • Author(s)
      Seiko Fukuta, Shigeki Kobayashi, Takeo Tanaka, Takamasa Susa, Wakako Murakami, Shinichi Okuda, Masafumi Yano, Masunori Matsuzaki,et al.
    • Organizer
      American Heart association Scientific meeting 2011
    • Place of Presentation
      Orland,USA
    • Related Report
      2011 Research-status Report
  • [Book] 心不全における心筋の興奮収縮連関とカルシウム ;クリニカルカルシウム2013

    • Author(s)
      奥田真一
    • Publisher
      医薬ジャーナル社
    • Related Report
      2012 Annual Research Report
  • [Book] 性心不全治療ガイドライン2011

    • Author(s)
      奥田真一、矢野雅文
    • Publisher
      日本臨床社
    • Related Report
      2012 Final Research Report
  • [Book] 慢性心不全の治療2011

    • Author(s)
      奥田真一、矢野雅文
    • Publisher
      ライフ・サイエンス
    • Related Report
      2012 Final Research Report
  • [Book] シグナル伝達系からみた心不全の機序と治療戦略2011

    • Author(s)
      奥田真一、矢野雅文
    • Publisher
      メディカルレビュー社
    • Related Report
      2012 Final Research Report
  • [Book] 慢性心不全治療ガイドライン;冠動脈疾患 下巻2011

    • Author(s)
      奥田真一、矢野雅文
    • Total Pages
      10
    • Publisher
      日本臨床社
    • Related Report
      2011 Research-status Report
  • [Book] シグナル伝達系からみた心不全の機序と治療戦略;Cardioligy Frontier2011

    • Author(s)
      奥田真一、矢野雅文
    • Total Pages
      8
    • Publisher
      ライフサイエンス
    • Related Report
      2011 Research-status Report
  • [Book] 慢性心不全の治療 ;Medicament News2011

    • Author(s)
      奥田真一、矢野雅文
    • Total Pages
      3
    • Publisher
      ライフサイエンス
    • Related Report
      2011 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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