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

• Project/Area Number: 23790856
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi 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: ¥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.

Research Products

• [Journal Article] Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts (2012)
  • 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
  • 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): 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
  • 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): 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
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca^release leading to catecholaminergic polymorphic ventricular tachycardia (2011)
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Presentation] CaMKII-mediated aberrant Ca^release play a key role in the arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2013)
  • 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
• [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)
• [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)
• [Presentation] Correcting inter-domain interaction of cardiac ryanodine receptor inhibits aberrant Ca^ release in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy mouse model (2012)
  • 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
• [Presentation] CaMKII-mediated aberrant Ca^release may play a key role in the arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2012)
  • 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
• [Presentation] Enhanced Binding of Calmodulin to RyR2 Inhibits Aberrant Ca2+ Release and Arrhythmogenesis in CPVT-Associated Mutation (2012)
  • 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
• [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)
• [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)
• [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)
• [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
• [Presentation] Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation (2011)
  • 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
• [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): 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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [Book] シグナル伝達系からみた心不全の機序と治療戦略；Cardioligy Frontier (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 8
  • Publisher: ライフサイエンス
• [Book] 慢性心不全の治療 ；Medicament News (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 3
  • Publisher: ライフサイエンス