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

2012 Fiscal Year Final Research Report

• 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
• Keywords: 肥大型心筋症 / カルシウムハンドリング

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
  • 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
  • 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
• [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 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
  • Year and Date: 20121103-07
• [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
  • Year and Date: 20121103-07
• [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] 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
  • Year and Date: 20111112-16
• [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
  • Year and Date: 20111112-16
• [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
  • Year and Date: 20111112-16
• [Book] 性心不全治療ガイドライン (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 595-604
  • 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
  • Total Pages: 4-6
  • 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
  • Total Pages: 129-137
  • Publisher: メディカルレビュー社