An examination of mutation-specific precipitation factors for ventricular tachyarrhythmias in concealed inherited arrhythmia syndromes

• Project/Area Number: 26461056
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Gunma University
• Principal Investigator: Nakajima Tadashi 群馬大学, 医学部附属病院, 講師 (40510574)
• Co-Investigator(Kenkyū-buntansha): 倉林 正彦 群馬大学, 大学院医学系研究科, 教授 (00215047) ; 金古 善明 群馬大学, 大学院医学系研究科, 准教授 (60302478) ; 五條 理志 京都府立医科大学, 医学(系)研究科(研究院), 教授 (90316745) ; 林 研至 金沢大学, 附属病院, 助教 (00422642)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 遺伝性不整脈 / 潜在性 / 遺伝子変異 / 顕性化因子 / イオンチャネル / 致死性不整脈

Outline of Final Research Achievements

We tried to clarify the molecular mechanisms of phenotypic manifestations by mutation-specific precipitation factors for ventricular tachyarrhythmias in inherited arrhythmia syndromes. A SCN5A R1632C mutation was identified in a Brugada syndrome (BrS) family who presented with exercise-induced cardiac events (atypical BrS). The mutation had an enhanced fast inactivated-state stability of cardiac sodium channels, which could explain the phenotypic manifestation of atypical BrS. A KCNH2 G584S mutation was identified in a patient with fever-induced long QT syndrome (LQTS), and its molecular mechanisms was clarified. Two KCNQ1 mutations were identified in patients with fever-induced LQTS.
We found that transient myocardial ischemia due to coronary spasm could be the cause of post myocardial ischemia-associated torsades de pointes (TdP) in a SCN5A delF1617 carrier, and that left bundle branch block-related cardiac memory could be a novel precipitation factor for TdP in a SCN5A P621H carrier.

Research Products

• [Journal Article] Detection of sequential activation of left atrium and coronary sinus musculature in the general population. (2016)
  • Author(s): Ota M, Kaneko Y, Nakajima T, Irie T, Iijima T, Saito A, Kurabayashi M.
  • Journal Title: J Arrhythm Volume: 32 Issue: 6 Pages: 449-455
  • DOI: 10.1016/j.joa.2016.02.003
  • Peer Reviewed
• [Journal Article] The genetics underlying acquired long QT syndrome: impact for genetic screening. (2016)
  • Author(s): Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Pedrazzini M, Yamagishi M, Berthet M, Murakami Y, Shimizu W, Guicheney P, Schwartz PJ, Horie M.
  • Journal Title: European Heart Journal Volume: 37 (18) Issue: 18 Pages: 1456-1464
  • DOI: 10.1093/eurheartj/ehv695
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Implication of Left Bundle Branch Block-Related Cardiac Memory in the Initiation of Torsades de Pointes (2016)
  • Author(s): Yoshida K, Nakajima T, Kaneko Y, Kurabayashi M.
  • Journal Title: J Cardiovasc Electrophysiol Volume: 印刷中 Issue: 6 Pages: 757-758
  • DOI: 10.1111/jce.12884
  • Peer Reviewed
• [Journal Article] Atypical Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Incorporating a "Superior" Slow Pathway: A Distinct Supraventricular Tachyarrhythmia. (2016)
  • Author(s): Kaneko Y, Naito S, Okishige K, Morishima I, Tobiume T, Nakajima T, Irie T, Ota M, Iijima T, Iizuka T, Tamura M, Tamura S, Saito A, Igawa O, Kato R, Matsumoto K, Suzuki F, Kurabayashi M.
  • Journal Title: Circulation Volume: 133 Issue: 2 Pages: 114-123
  • DOI: 10.1161/circulationaha.115.018443
  • Peer Reviewed
• [Journal Article] An Abrupt Change in the Atrio-His Interval during Long RP Tachycardia: What Is the Underlying Mechanism? (2016)
  • Author(s): Kaneko Y, Nakajima T, Irie T, Ota M, Iijima T, Iizuka T, Kurabayashi M.
  • Journal Title: Pacing Clin Electrophysiol Volume: 39 Issue: 2 Pages: 190-193
  • DOI: 10.1111/pace.12763
  • Peer Reviewed
• [Journal Article] Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome (2015)
  • Author(s): Nakajima T, Kaneko Y, Saito A, Ota M, Iijima T, Kurabayashi M.
  • Journal Title: Heart Rhythm Volume: 12 Issue: 11 Pages: 2296-2304
  • DOI: 10.1016/j.hrthm.2015.05.032
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes (2015)
  • Author(s): Nakajima T, Kaneko Y, Kurabayashi M
  • Journal Title: Circulation Journal Volume: 79 Issue: 6 Pages: 1185-1192
  • DOI: 10.1253/circj.CJ-15-0322
  • NAID: 130005073124
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Electrical storm in patients with brugada syndrome is associated with early repolarization. (2014)
  • Author(s): Kaneko Y, Horie M, Niwano S, Kusano KF, Takatsuki S, Kurita T, Mitsuhashi T, Nakajima T, Irie T, Hasegawa K, Noda T, Kamakura S, Aizawa Y, Yasuoka R, Torigoe K Suzuki H, Ohe T, Shimizu A, Fukuda K, Kurabayashi M, Aizawa Y.
  • Journal Title: Circ Arrhythm Electrophysiol. Volume: 6 Issue: 6 Pages: 1122-8
  • DOI: 10.1161/circep.114.001806
  • Peer Reviewed / Open Access
• [Presentation] Hypertrabeculation at Left Ventricular Apex is highly Prevalent in Genotyped Long QT Syndrome. (2017)
  • Author(s): Tadashi Nakajima, Yoshiaki Kaneko, Koji Kurosawa, Takashi Iizuka, Tadanobu Irie, Masahiko Kurabayashi.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢都ホテル（金沢）
  • Year and Date: 2017-03-17
• [Presentation] Clinical, Electrocardiographic and Genetic Predispositions to Life-Threatening Ventricular Arrhythmias Associated with Vasospastic Angina. (2017)
  • Author(s): Tadashi Nakajima, Yoshiaki Kaneko, Yohei Ono, Takashi Iizuka, Tadanobu Irie, Michiko Imai, Ryuichi Funada, Noriaki Takama, Shu Kasama, Nogiku Niwamae, Shoichi Tange, Masahiko Kurabayashi.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: ANAクラウンプラザ（金沢）
  • Year and Date: 2017-03-17
• [Presentation] Identification of Rare Precipitation Factors for Torsades de Pointes in Patients with Genotyped Forme Fruste Long QT Syndrome. (2017)
  • Author(s): Tadashi Nakajima, Yoshiaki Kaneko, Takashi Iizuka, Michiko Imai, Nogiku Niwamae, Tadanobu Irie, Shoichi Tange, Masahiko Kurabayashi.
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢フォーラス（金沢）
  • Year and Date: 2017-03-17
• [Presentation] Mechanism of Fever-Induced QT Prolongation in Patients with KCNH2 Mutations in the S5-Pore Region: Evidence from Genotypic and Functional Analyses. (2016)
  • Author(s): Kenshi Hayashi, Tadashi Nakajima, Yasutaka Kurata, Shoichi Tange, Noboru Fujino, Kenji Sakata, Tetsuo Konno, Toyonobu Tsuda, Yoji Nagata, Ryota Teramoto, Yoshihiro Tanaka, Takekatsu Saito, Masa-aki Kawashiri, Yoshiaki Kaneko, Kunio Ohta, Masahiko Kurabayashi, Masakazu Yamagishi.
  • Organizer: American Heart Association, Scientific Sessions 2016
  • Place of Presentation: New Orleans (USA)
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Electrophysiological mechanisms of atypical Brugada syndrome. (2016)
  • Author(s): Tadashi Nakajima, Yoshiaki Kaneko, Akihiro Saito, Takashi Iizuka, Takafumi Iijima, Masaki Ota, Tadanobu Irie, Masahiko Kurabayashi.
  • Organizer: 第63回日本不整脈心電学会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2016-07-14
• [Presentation] Left bundle branch block myopathy and long QT syndrome associated with a SCN5A mutation. (2016)
  • Author(s): Tadashi Nakajima, Yoshiaki Kaneko, Kuniko Yoshida, Takashi Iizuka, Takafumi Iijima, Masaki Ota, Tadanobu Irie, Masahiko Kurabayashi.
  • Organizer: Heart Rhythm 2016
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] Atypical slow-fast atrioventricular nodal reentrant tachycardia incorporating “superior” slow pathway: a role of atrial differential entrainment pacing. (2016)
  • Author(s): Takashi Iizuka, Yoshiaki Kaneko, Tadashi Nakajima, Shiro Nakahara, Tadanobu Irie, Masaki Ota, Takafumi Iijima, Mio Tamura, Shuntaro Tamura, Akihiro Saito, Masahiko Kurabayashi.
  • Organizer: Heart Rhythm 2016 - 37th Annual Scientific Sessions
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] Left bundle branch block myopathy and long QT syndrome associated with a SCN5A mutation (2016)
  • Author(s): Nakajima T, Kaneko Y, Yoshida K, Iizuka T, Iijima T, Ota M, Irie T, Kurabayashi M
  • Organizer: Heart Rhythm 2016; 37th Annual Scientific Sessions
  • Place of Presentation: Moscone center (San Francisco)
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] Inherited arrhythmia syndrome presenting with exercise-induced cardiac events, prominent U-waves and sinus node dysfunction caused by KCNJ2-E118D (2016)
  • Author(s): Nakajima T, Kaneko Y, Iizuka T, Iijima T, Ohta M, Irie T, Kurabayashi M
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-03-18
• [Presentation] Phenotypic Variability of Patients with a SCN5A-A735E Mutation (2016)
  • Author(s): Iizuka T, Nakajima T, Sasaki T, Niwamae N, Iijima T, Ohta M, Irie T, Tange S, KanekoY, Kurabayashi M
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-03-18
• [Presentation] Severe loss-of-function of INa may be associated with exercise-induced cardiac events in young patients with Brugada syndrome (2016)
  • Author(s): Nakajima T, Kaneko Y, Iizuka T, Iijima T, Ohta M, Irie T, Kurabayashi M
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-03-18
• [Presentation] Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation R1632C as a cause of multiple electrophysiological phenotypes (2015)
  • Author(s): Nakajima T, Kaneko Y, Saito Y, Ota M, Iijima T, Kurabayashi M
  • Organizer: European Society of Cardiology (ESC) Congress 2015
  • Place of Presentation: ExCel London (London)
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Mechanisms of fever-induced QT prolongation in patients with KCNH2 mutations in the S5-pore region (2015)
  • Author(s): Hayashi K, Nakajima T, Tange S, Tsuda T, Tanaka Y, Kawashiri M, Ohta K, Kaneko Y, Kurabayashi M, Yamagishi M
  • Organizer: European Society of Cardiology (ESC) Congress 2015
  • Place of Presentation: ExCel London (London)
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation R1632C as a cause of multiple electrophysiological phenotypes (2015)
  • Author(s): Nakajima T, Kaneko Y, Saito A, Ota M, Iijima T, Kurabayashi M
  • Organizer: The joint meeting of the 30th Annual Meeting of the Japanese Heart Rhythm Society and the 32nd Annual Scientific Session of the Japanese Society of Electrocardiology
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2015-07-28
• [Presentation] Novel SCN5A-P621H Mutation Associated with Long QT Syndrome and Left-Bundle-Branch-Block Myopathy (2015)
  • Author(s): Tadashi Nakajima, Yoshiaki Kaneko, Kuniko Masuda, Takafumi Iijima, Masaki Ota, Masahiko Kurabayashi
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Clinical and Genetic Backgrounds of Fatal Arrhythmias Associated with Vasospastic Angina (2015)
  • Author(s): Yohei Ono, Tadashi Nakajima, Yoshiaki Kaneko, Akihiro Saito, Michiko Imai, Ryuichi Funada, Noriaki Takama, Koki Nakamura, Yukihiro Seta, katsumi Kaneko, Shitoshi Hiroi, Nogiku Niwamae, Masahiro Inoue, Shoichi Tange, Masahiko Kurabayashi
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] 稀有なtorsades de pointes発症様式を呈した一例 (2014)
  • Author(s): 増田くに子、中島忠、金古善明、太田昌樹、飯島貴史、倉林正彦
  • Organizer: 第62回日本心臓病学会学術集会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2014-09-26 – 2014-09-28
• [Presentation] 失神歴を有し多彩な心電図異常を認めたSCN5A R1632C変異キャリア (2014)
  • Author(s): 反町秀美、中島忠、金古善明、齋藤章宏、菊地聡一郎、太田昌樹、飯島貴史、倉林正彦
  • Organizer: 第62回日本心臓病学会学術集会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2014-09-26 – 2014-09-28
• [Presentation] Clinical and genetic characteristics of ventricular tachyarrhythmias associated with vasospastic angina (2014)
  • Author(s): Yohei Ono, Tadashi Nakajima, Yoshiaki Kaneko, Akihiro Saito, Michiko Imai, Tadanobu Irie, Masaki Ota, Takafumi Iijima, Ryuichi Funada, Noriaki Takama, Shitoshi Hiroi, Nogiku Niwamae, Masahiro Inoue, Shoichi Tange, Masahiko Kurabayashi
  • Organizer: 第29回日本不整脈学会
  • Place of Presentation: ザ・プリンスパークタワー東京（東京）
  • Year and Date: 2014-07-22 – 2014-07-25
• [Presentation] A unique initiation of torsades de pointes in a patient with a novel SCN5A mutation (2014)
  • Author(s): Kuniko Masuda, Tadashi Nakajima, Yoshiaki Kaneko, Masaki Ota, Takafumi Iijima, Masahiko Kurabayashi
  • Organizer: 第29回日本不整脈学会
  • Place of Presentation: ザ・プリンスパークタワー東京（東京）
  • Year and Date: 2014-07-22 – 2014-07-25