Development of comprehensive treatment of heart failure, hypertrophy, and arrhythmia by regulating intracellular Ca

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390215
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YANO Masafumi 山口大学, 医学(系)研究科(研究院), 教授 (90294628)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Shigeki 山口大学, 医学部附属病院, 講師 (90397993)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 心不全 / 筋小胞体 / カルシウム / リアノジン受容体

Research Abstract

In this three years, we revealed that basic mechanism of arrhythmogenesity in CPVT and pressure overload HF is Ca leak from SR. The underlying mechanism of Ca leak is unzipping of channel reguratory domains and CaM binding domain. We also investigate the dantrolene, zipper of the channel reguratory domains and high affinity CaM as a therapeutic agents.

Research Products

• [Journal Article] Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes (2014)
  • Author(s): Fukuda M, Yamamoto T, Nishimura S, Kato T, Murakami W, Hino A, Ono M, Tateishi H, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M
  • Journal Title: Biochem Biophys Res Commun Volume: 448(1) Pages: 1-7
  • DOI: 10.1016/j.bbrc.2014.03.152
  • Peer Reviewed
• [Journal Article] A low-dose β 1-blocker effectively and safely slows the heart rate in patients with acute decompensated heart failure and rapid atrial fibrillation (2014)
  • Author(s): Kobayashi S, Murakami W, Myoren T, Tateishi H, Okuda S, Doi M, Nao T, Wada Y, Matsuzaki M, Yano M
  • Journal Title: Cardiology Volume: 127(2) Pages: 105-13
  • DOI: 10.1159/000355312
  • Peer Reviewed
• [Journal Article] Serial three-dimensional optical coherence tomography assessment of strut coverage and intraluminal structures after drug-eluting stent implantation (2014)
  • Author(s): Maeda T, Okamura T, Yamada J, Nao T, Tateishi H, Yoshimura M, Oda T, Shiraishi K, Nakashima T, Nakamura T, Miura T, Yano M
  • Journal Title: Cardiovasc Interv Ther Volume: 29(1) Pages: 31-9
  • DOI: 10.1007/s12928-013-0209-5
  • Peer Reviewed
• [Journal Article] Sarcomere gene mutations are associated with increased cardiovascular events in left ventricular hypertrophy : results from multicenter registration in Japan (2013)
  • Author(s): Fujita T, Fujino N, Anan R, Tei C, Kubo T, Doi Y, Kinugawa S, Tsutsui H, Kobayashi S, Yano M, Asakura M, Kitakaze M, Komuro I, Konno T, Hayashi K, Kawashiri MA, Ino H, Yamagishi M
  • Journal Title: JACC Heart Fail Volume: 1(6) Pages: 459-66
  • DOI: 10.1016/j.jchf.2013.08.007
  • Peer Reviewed
• [Journal Article] Does a ripple of Ca(2+) leak develop into a rogue wave that can trigger pathological hypertrophy? (2012)
  • Author(s): Yano M, Okuda S
  • Journal Title: J Am Coll Cardiol Volume: 63(15) Pages: 1580-2
  • DOI: 10.1016/j.jacc.2013.10.064
  • Peer Reviewed
• [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(3) Pages: 433-43
  • DOI: 10.1093/cvr/cvs271
  • 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): Susa 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 Ca²+ 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, Okuda S, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M
  • Journal Title: Circulation Volume: 124(6) Pages: 682-94
  • DOI: 10.1161/CIRCULATIONAHA
  • Peer Reviewed
• [Journal Article] Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters (2011)
  • Author(s): Yoshida M, Ohkusa T, Nakashima T, Takanari H, Yano M, Takemura G, Honjo H, Kodama I, Mizukami Y, Matsuzaki M
  • Journal Title: Cardiovasc Res Volume: 92(1) Pages: 95-105
  • DOI: 10.1093/cvr/cvr182
  • Peer Reviewed
• [Presentation] Dantrolene May Suppress Arrhythmogenesis by Inhibition of CaMKII-mediated Aberrant Ca2+ Release Within the Ryanodine Receptor in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2013)
  • Author(s): Shinichi Okuda, Masakazu Fukuda, Takayoshi Katoh, Shigehiko Nishimura, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas(U. S. A)
  • Year and Date: 2013-11-16
• [Presentation] A Novel Selective EP4 Receptor Agonist Improves Intracellular Ca2+ Handling and Cardiomyocyte Function in Intact Failing Cardiomyocytes (2013)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Takeki Myoren, Shigehiko Nishimura, Takayoshi Katoh, Masakazu Fukuda, Makoto Ono, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas(U. S. A)
  • Year and Date: 2013-11-16
• [Presentation] Dantrolene Inhibits Aberrant Ca2+ Release and Arrhythmogenesis via Enhancing Binding of Calmodulin to RyR2 in CPVT-Associated Mutation (2013)
  • Author(s): Masakazu Fukuda, Takeshi Yamamoto, Shigehiko Nishimura, Takeki Myouren, Takayoshi Katoh, Wakako Murakami, Makoto Ono, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas(U. S. A)
  • Year and Date: 2013-11-16
• [Presentation] Fixing Ca2+ Leakage From Cardiac Ryanodine Receptor by Low-dose of β Blocker Safely Enhances Inotropic Response to Milrinone in Acute Heart Failure (2012)
  • Author(s): Shigeki Kobayashi, Wakako Murakami, Takayoshi Kato, Masakazu Fukuda, Akihiro Hino, Hiroki Tateishi, Takeshi Yamamoto, Takeshi Yamamoto, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles(U. S. A)
  • Year and Date: 2012-11-03
• [Presentation] Urinary 8-hydroxy-2' -deoxyguanosine as a Novel Marker of Left Ventricular Remodelling in Patients With Dilated Cardiomyopathy (2012)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Takamasa Oda, Hiroki Tateishi, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles(U. S. A)
  • Year and Date: 2012-11-03
• [Presentation] Elevated Myocardial Oxidative Stress Induced by Catecholamines Related to Transient Left Ventricular Cysfunction in Patients With Takotsubo Cardiomyopathy (2012)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Tadamitsu Nakashima, Hiroki Tateishi, Shinichi Okuda, Masahiro Doi, Yasuaki Wada, Tomoko Nao, Jutaro Yamada, Takayuki Okamura, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles(U. S. A)
  • Year and Date: 2012-11-03
• [Presentation] Urinary 8-hydroxy-2' -deoxyguanosine, An Oxidative Stress Marker, Predicts The Inflammatory Activity within the Heart in Patients with Cardiac Sarcoidosi (2012)
  • Author(s): Shigeki Kobayashi, Wakako Murakami, Seiko Fukuta, Masakazu Fukuda, Shinichi Okuda, Tomoko Nao, Masahiro Doi, Yasuaki Wada, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles(U. S. A)
  • Year and Date: 2012-11-03