Arrhythmogenic gap junction remodeling in diseased hearts

• Project/Area Number: 15K09078
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: Honjo Haruo 名古屋大学, 環境医学研究所, 准教授 (70262912)
• Co-Investigator(Kenkyū-buntansha): 辻 幸臣 長崎大学, 医歯薬学総合研究科(医学系), 講師 (60432217) ; 山崎 正俊 東京大学, 大学院工学系研究科(工学部), 特任研究員 (30627328)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 不整脈 / ギャップ結合 / 心臓電気生理学 / 活動電位 / イオンチャネル / 心臓電気生理 / 電気生理学

Outline of Final Research Achievements

Arrhythmogenic remodeling of myocardial gap junctions was investigated using a transgenic mouse model with cardiac dysfunction/lethal ventricular arrhythmias, and a rabbit electrical storm model induced by sustained severe bradycardia. In diseased hearts, connexin43 expression was decreased in the intercalated disc region of ventricular myocytes, which was associated with a reduction of conduction velocity and an increase in the spatial heterogeneity of action potential repolarization, leading to increased susceptibility of reentrant ventricular tachyarrhythmias. In addition, the results suggested that the renin-angiotensin system and calmodulin/CAMKII are involved in arrhythmogenic gap junction remodeling in diseased hearts.

Research Products

• [Journal Article] Interaction of Phase Singularities on Spiral Wave Tail: Reconsideration of Caputuring Excitable Gap. (2018)
  • Author(s): Tomii N, Yamazaki M, Arafune T, Kamiya K, Nakazawa K, Honjo H, Shibata N, Sakuma I.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: in press Issue: 2 Pages: 318-326
  • DOI: 10.1152/ajpheart.00558.2017
  • Peer Reviewed
• [Journal Article] Ranolazine Facilitates Termination of Ventricular Tachyarrhythmia Associated With Acute Myocardial Ischemia Through Suppression of Late <b><i>I</i></b>_Na-Mediated Focal Activity (2017)
  • Author(s): Ogawa T, Honjo H, Yamazaki M, Kushiyama Y, Sakuma I, Kodama I, Kamiya K.
  • Journal Title: Circulation Journal Volume: 81 Issue: 10 Pages: 1411-1428
  • DOI: 10.1253/circj.CJ-17-0128
  • NAID: 130006099889
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Partial IK1 blockade destabilizes spiral wave rotation center without inducing wave breakup and facilitates termination of reentrant arrhythmias in ventricles (2016)
  • Author(s): Kushiyama Y, Honjo H, Niwa R, Takanari H, Yamazaki M, Takemoto Y, Sakuma I, Kodama I, Kamiya K
  • Journal Title: American Journal of Physiology Heart and Circulatory Physiology Volume: 311 Issue: 1 Pages: 750-758
  • DOI: 10.1038/srep34198
  • NAID: 120005946586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Calmodulin/CaMK II inhibition improves intercellular communication and impulse propagation in the heart, and is anti-arrhythmic under conditions when fibrosis is absent (2016)
  • Author(s): Takanari H, Bourqonje VJ, Fontes MS, Raaijmakers AJ, Driessen H, Jansen JA, van der Nagel R, Kok B, van Stuijvenberg L, Boulaksil M, Takemoto Y, Yamazaki M, Tsuji Y, Honjo H, Kamiya K. Kodama I, Anderson ME, van der Heyden MA, van Rijen HV, van Veen TA, Vos MA
  • Journal Title: Cardiovascular Research Volume: 111 Issue: 4 Pages: 410-421
  • DOI: 10.1093/cvr/cvw173
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The renin-angiotensin system promotes arrhythmogenic substrates andalethal arrhythmias in mice with non-ischemic cardiomyopathy (2016)
  • Author(s): Yamada C, Kuwahara K, Yamazaki M, Nakagawa Y, Nishikimi T, Kinoshita H, Kuwabara Y, Minami T, Yamada Y, Shibata J, Nakao K, , Arai Y, Honjo H, Kamiya K, Nakao K, Kimura T
  • Journal Title: Cardiovascular Research Volume: 109 Issue: 1 Pages: 162-173
  • DOI: 10.1093/cvr/cvv248
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Detection Algorithm of Phase Singularity Using Phase Variance Analysis for Epicardial Optical Mapping Data (2015)
  • Author(s): Naoki Tomii, Masatoshi Yamazaki, Tatsuhiko Arafune, Haruo Honjo, Nitaro Shibata, and Ichiro Sakuma
  • Journal Title: IEEE transactions on bio-medical engineering Volume: Vol.PP Issue: 9 Pages: 1795-1803
  • DOI: 10.1109/tbme.2015.2502726
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mechanisms of Cardiac Impulse Propagation and Arrhythmogenesis (2015)
  • Author(s): 本荘晴朗
  • Journal Title: Transactions of Japanese Society for Medical and Biological Engineering Volume: 53 Issue: 3 Pages: 123-129
  • DOI: 10.11239/jsmbe.53.123
  • NAID: 130005106896
  • ISSN: 1347-443X, 1881-4379
  • Open Access
• [Presentation] Novel panoramic endocardial optical mapping reveals a role of the superior vena cava in the maintenance of atrial fibrillation (2017)
  • Author(s): Takemoto Y, Yamazaki M, Honjo H, Murohara T
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂他, 金沢市
  • Year and Date: 2017-03-17
• [Presentation] Effects of stretch-activated channel and Ca2+/calmodulin-dependent protein kinase II on atrial fibrillation (2017)
  • Author(s): 植田典浩, 小川貴史, 竹本芳雄, 櫛山泰規, 丹羽良子, 山崎正俊, 本荘晴朗, 神谷香一郎
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 石川県立音楽堂他, 金沢市
  • Year and Date: 2017-03-17
• [Presentation] Computer simulation study of low energy defibrillation by multiple point stimuli (2017)
  • Author(s): Tomii N, Yamazaki M, Honjo H, Kamiya K, Shibata N, Sakuma I
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research
• [Presentation] Accumulated phase variance analysis of cardiac spiral wave dynamics (2017)
  • Author(s): Seno H, Tomii N, Yamazaki M, Honjo H, Kamiya K, Shibata N, Sakuma I
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research
• [Presentation] Analysis of the current stimulus phenomenon in the ventricle film by optical measurement. (2017)
  • Author(s): Monma M, Yatabe J, Tomii N, Shibata N, Yamazaki M, Honjo H, Arafune T
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research
• [Presentation] The derivation method of cardiac fiber direction using virtual electrode polarization. (2017)
  • Author(s): Yatabe J, Tomii N, Shibata, Yamazaki M, Honjo H, Yaguchi T, Arafune T, Honma A.
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research
• [Presentation] Spiral wave reentry in endocardium of ventricle using optical mapping system. (2017)
  • Author(s): Kawashima K, Yatabe J, Tomii N, Shibata N, Yamazaki M, Honjo H, Arafune T, Sakuma I.
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research
• [Presentation] シミュレーションモデルを用いた点通電刺激によるspiral wave停止プロトコルに関する研究 (2017)
  • Author(s): 富井直樹, 山崎正俊, 神谷香一郎, 柴田仁太郎, 本荘晴朗, 佐久間一郎
  • Organizer: 第32回心電情報処理ワークショップ
• [Presentation] 累積位相分散解析を用いた心臓旋回性興奮の挙動解析 (2017)
  • Author(s): 瀬野宏, 富井直樹, 山崎正俊, 本荘晴朗, 神谷香一郎, 柴田仁太郎, 佐久間一郎
  • Organizer: 第32回心電情報処理ワークショップ
• [Presentation] Electrical storm associated with bradycardia (2017)
  • Author(s): Tsuji Y
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research / Invited
• [Presentation] Therapeutic target of atrial fibrillation (2017)
  • Author(s): Yamazaki M
  • Organizer: APHRS/JHRS2017
  • Int'l Joint Research / Invited
• [Presentation] Effective point electric stimulation for cardiac spiral wave termination (2016)
  • Author(s): Tomii N, Yamazaki M, Arafune T, Kamiya K, Honjo H, Shibata N, Sakuma I
  • Organizer: AHA Scientific Sessions 2016
  • Place of Presentation: Ernest N. Memorial Convention Center, New Orleans, USA
  • Year and Date: 2016-11-12
• [Presentation] Roles of late INa-mediated focal electrical activities in ventricular tachyarrhythmia associated with acute myocardial ischemia (2016)
  • Author(s): Ogawa T, Honjo H, Yamazaki M, Niwa R, Ueda N, Kamiya K
  • Organizer: ESC Congress 2016
  • Place of Presentation: Fiera di Rome, Rome, Italy
  • Year and Date: 2016-08-27
• [Presentation] Simultaneous optical mapping of membrane voltage and intracellular calcium without excitation-contraction uncoupler (2016)
  • Author(s): Tachiyanagi N, Arafune T, Shibata N, Ogawa T, Yamazaki M, Honjo H, Kamiya K, Homma A
  • Organizer: 第63回日本不整脈心電学会学術集会
  • Place of Presentation: 札幌コンベンションセンター, 札幌市
  • Year and Date: 2016-07-14
• [Presentation] Phase shift mechanisms of spiral reentry induced by low energy stimulation (2016)
  • Author(s): Yatabe J, Tachiyanagi N, Tomii N, Noguchi H, Shibata N, Ogawa T, Yamazaki M, Honjo H, Arafune T, Homma A
  • Organizer: 第63回日本不整脈心電学会学術集会
  • Place of Presentation: 札幌コンベンションセンター, 札幌市
  • Year and Date: 2016-07-14
• [Presentation] Basic concept and clinical implications of phase mapping (2016)
  • Author(s): Arafune T, Sakuma I, Shibata N, Ashihara T, Yamazaki M, Honjo H: Basic concept and clinical implications of phase mapping
  • Organizer: 第63回日本不整脈心電学会学術集会
  • Place of Presentation: 札幌コンベンションセンター, 札幌市
  • Year and Date: 2016-07-14
• [Presentation] 3-D atrial scroll wave as a mechanism of persistent atrial fibrillation (2016)
  • Author(s): Yamazaki M, Honjo H, Takemoto Y, Kamiya K, Kalifa J
  • Organizer: 第55回日本生体医工学会大会
  • Place of Presentation: 富山国際会議場, 富山市
  • Year and Date: 2016-04-26
  • Invited
• [Presentation] 位相分散マップによる心臓旋回興奮解析 (2016)
  • Author(s): 富井直輝, 山﨑正俊, 荒船龍彦, 本荘晴朗, 神谷香一郎, 柴田仁太郎, 佐久間一郎
  • Organizer: 第55回日本生体医工学会大会
  • Place of Presentation: 富山国際会議場, 富山市
  • Year and Date: 2016-04-26
• [Presentation] 膜電位/Ca2+同時工学マッピングを用いたCa2+バーストの解析 (2016)
  • Author(s): 立柳紀林, 野口展士, 柴田仁太郎, 山﨑正俊, 本荘晴朗, 荒船龍彦, 本間章彦
  • Organizer: 第55回日本生体医工学会大会
  • Place of Presentation: 富山国際会議場, 富山市
  • Year and Date: 2016-04-26
• [Presentation] Cardiac excitation wave propagation and arrhythmogenesis (2016)
  • Author(s): Honjo H
  • Organizer: 第９３回日本生理学会大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] Multi-scale simulation studies of excitation conduction including cardiac conduction systems and whole ventricles (2016)
  • Author(s): Inada S, Harrell DT, Haraguchi R, Ashihara T, Aiba T, Ikeda T, Mitsui K, Honjo H, Nakazawa K
  • Organizer: 第９３回日本生理学会大会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] Spontaneous activity of pulmonary vein myocardial sleeves (2015)
  • Author(s): Honjo H
  • Organizer: 第３０回日本巣性脈学会/第３２回日本心電学会
  • Place of Presentation: 京都
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] Rotors and the dynamics of atrial fibrillation in isolated sheep hearts (2015)
  • Author(s): Yamazaki M, Honjo H, Kodama I, Kamiya K
  • Organizer: 第３０回日本巣性脈学会/第３２回日本心電学会
  • Place of Presentation: 京都
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] Can computer simulation technique contribute regenerative medicine? (2015)
  • Author(s): Inada S, Harrell DT, Haraguchi R, Ashihara T, Aiba T, Ikeda T, Mitsui K, Honjo H, Shibata N, Makita N, Kamiya K, Kodama I, Nakazawa K
  • Organizer: 第３０回日本巣性脈学会/第３２回日本心電学会
  • Place of Presentation: 京都
  • Year and Date: 2015-07-28
  • Invited