Genetic-based risk of sudden arrhythmic death in the Brugada syndrome

• Project/Area Number: 24591086
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: AIBA Takeshi 独立行政法人国立循環器病研究センター, 病院, 医長 (40574348)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Wataru 日本医科大学, 循環器内科, 教授 (50399606) ; TAKAKI Hiroshi 国立循環器病研究センター, 研究所循環動態制御部, 室長 (80197053) ; MATSUURA Hiroshi 滋賀医科大学, 医学部・細胞機能生理学, 教授 (60238962)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: Brugada syndrome / genetics / sudden death / electrophysiology / Na channels / ventricular fibrillation / 心室細動 / 突然死 / ﾌﾞﾙｶﾞﾀﾞ症候群 / 遺伝子 / イオンチャネル / ブルガダ症候群 / ナトリウム / 不整脈 / J波

Outline of Final Research Achievements

We reported that common variants at SCN5A-SCN10A and HEY2 are associated with a high risk of sudden cardiac death (SCD) in Brugada syndrome, and a nonsynonymous polymorphism in semaphorin 3A as a risk factor for SCD due to VF. The genetic defects in a His-Purkinje system transcription factor, IRX3, are associated with lethal cardiac arrhythmias in conjunction with Na channel defect. These findings suggest that Brugada or related sudden arrhythmic death syndrome are not a monogenic disease but associated with multiple mechanisms.
We also non-invasively evaluated risk of sudden arrhythmic death in the Brugada or J-wave syndrome using standard 12-lead ECG and multi-channel magnetocardiography (MCG).

Research Products

• [Journal Article] Risk Stratification in Patients With Brugada Syndrome Without Previous Cardiac Arrest (2015)
  • Author(s): Okamura H, Kamakura T, Morita H, Tokioka K, Nakajima I, Wada M, Ishibashi K, Miyamoto K, Noda T, Aiba T, Nishii N, Nagase S, Shimizu W, Yasuda S, Ogawa H, Kamakura S, Ito H, Ohe T, Kusano KF
  • Journal Title: Circulation Journal Volume: 79 Issue: 2 Pages: 310-317
  • DOI: 10.1253/circj.CJ-14-1059
  • NAID: 130004704033
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations. (2015)
  • Author(s): Miyamoto K, Aiba T, Kimura H, Hayashi H, Ohno S, Yasuoka C, Tanioka Y, Tsuchiya T, Yoshida Y, Hayashi H, Tsuboi I, Nakajima I, Ishibashi K, Okamura H, Noda T, Ishihara M, Anzai T, Yasuda S, Miyamoto Y, Kamakura S, Kusano K, Ogawa H, Horie M, Shimizu W.
  • Journal Title: Heart Rhythm Volume: 12 Issue: 3 Pages: 596-603
  • DOI: 10.1016/j.hrthm.2014.12.009
  • Peer Reviewed / Open Access
• [Journal Article] Constitutive BDNF/TrkB signaling is required for normal cardiac contraction and relaxation. (2015)
  • Author(s): Feng N, Huke S, Zhu G, Tocchetti CG, Shi S, Aiba T, Kaludercic N, Hoover DB, Beck SE, Mankowski JL, Tomaselli GF, Bers DM, Kass DA, Paolocci N.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 112 Issue: 6 Pages: 1880-1885
  • DOI: 10.1073/pnas.1417949112
  • Peer Reviewed / Open Access
• [Journal Article] A Kir3.4 mutation causes Andersen–Tawil syndrome by an inhibitory effect on Kir2.1. (2014)
  • Author(s): Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP
  • Journal Title: Neurology Volume: 82 Issue: 12 Pages: 1058-64
  • DOI: 10.1212/wnl.0000000000000239
  • Peer Reviewed / Open Access
• [Journal Article] A mutation causing Brugada syndrome identifies a mechanism for altered autonomic and oxidant regulation of cardiac sodium currents. (2014)
  • Author(s): Aiba T, Farinelli F, Kostecki G, Hesketh GG, Edwards D, Biswas S, Tung L, Tomaselli GF.
  • Journal Title: Circ Cardiovasc Genet. Volume: 7 Issue: 3 Pages: 249-256
  • DOI: 10.1161/circgenetics.113.000480
  • Peer Reviewed / Open Access
• [Journal Article] Novel calmodulin mutations associated with congenital arrhythmia susceptibility. (2014)
  • Author(s): Makita N, Tsuji Y（39人中21番目）et al
  • Journal Title: Circ Cardiovasc Genet. Volume: 7 Issue: 4 Pages: 466-474
  • DOI: 10.1161/circgenetics.113.000459
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel cardiac ryanodine receptor gene (RyR2) mutation in an athlete with aborted sudden cardiac death: a case of adult-onset catecholaminergic polymorphic ventricular tachycardia (2014)
  • Author(s): Arakawa J, Hamabe A, Aiba T, Nagai T, Yoshida M, Touya T, Ishigami N, Hisadome H, Katsushika S, Tabata H, Miyamoto Y, Shimizu W.
  • Journal Title: Heart Vessels Volume: ePub Issue: 6 Pages: 835-840
  • DOI: 10.1007/s00380-014-0555-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Mutation Causing Brugada Syndrome Identifies a Mechanism for Altered Autonomic and Oxidant Regulation of Cardiac Sodium Currents (2014)
  • Author(s): Aiba T1, Farinelli F, Kostecki G, Hesketh GG, Edwards D, Biswas S, Tung L, Tomaselli GF.
  • Journal Title: Circulation Cardiovascular Genetics Volume: May
  • Peer Reviewed
• [Journal Article] Remodeling of the sarcomeric cytoskeleton in cardiac ventricular myocytes during heart failure and after cardiac resynchronization therapy (2014)
  • Author(s): Lichter JG1, Carruth E1, Mitchell C, Barth AS, Aiba T, Kass DA, Tomaselli GF, Bridge JH, Sachse FB.
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 72 Pages: 186-195
  • DOI: 10.1016/j.yjmcc.2014.03.012
  • Peer Reviewed
• [Journal Article] Congenital long QT syndrome with compound mutations in the KCNH2 gene (2013)
  • Author(s): Bando S, Soeki T, Matsuura T, Niki T, Ise T, Yamaguchi K, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Akaike M, Aiba T, Shimizu W, Sata M.
  • Journal Title: Heart Vessels Volume: - Issue: 4 Pages: 554-559
  • DOI: 10.1007/s00380-013-0406-2
  • NAID: 130002130326
  • Peer Reviewed / Open Access
• [Journal Article] Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. (2013)
  • Author(s): Bezzina CR, Makita N(63人中31番目)et al
  • Journal Title: Nat Genet. Volume: 45 Issue: 9 Pages: 1044-1049
  • DOI: 10.1038/ng.2712
  • Peer Reviewed / Open Access
• [Journal Article] Congenital long QT syndrome with compound mutations in the KCNH2 gene. (2013)
  • Author(s): Bando S, Soeki T, Matsuura T, Niki T, Ise T, Yamaguchi K, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Akaike M, Aiba T, Shimizu W, Sata M.
  • Journal Title: Heart and Vessels Volume: 22
  • NAID: 130002130326
  • Peer Reviewed
• [Journal Article] Significance of non-type 1 anterior early repolarization in patients with inferolateral early repolarization syndrome. (2013)
  • Author(s): Kamakura T, Kawata H, Nakajima I, Yamada Y, Miyamoto K, Okamura H, Noda T, Satomi K, Aiba T, Takaki H, Aihara N, Kamakura S, Kimura T, Shimizu W.
  • Journal Title: Journal of American Collage of Cardiology Volume: 62 Issue: 17 Pages: 1610-1618
  • DOI: 10.1016/j.jacc.2013.05.081
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure. (2013)
  • Author(s): Aiba T, Barth AS, Hesketh GG, Hashambhoy YL, Chakir K, Tunin RS, Greenstein JL, Winslow RL, Kass DA, Tomaselli GF.
  • Journal Title: Circulation Arrhythmia and Electrophysiology Volume: 6 Issue: 3 Pages: 546-54
  • DOI: 10.1161/circep.113.000400
  • Peer Reviewed / Open Access
• [Journal Article] A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation (2013)
  • Author(s): Nakano Y, Makita N, (32人中31番目) et al
  • Journal Title: PLOS Genet Volume: 9 Issue: 4 Pages: e1003364-e1003364
  • DOI: 10.1371/journal.pgen.1003364
  • NAID: 120006985866
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac Resynchronization Therapy Improves Altered Na Channel Gating in Canine Model of Dyssynchronous Heart Failure (2013)
  • Author(s): Aiba Takeshi
  • Journal Title: Circulation Arrhythmia and Electrophysiology Volume: in press
  • Peer Reviewed
• [Journal Article] Disease characterization using LQTS-specific induced pluripotent stem cells. (2012)
  • Author(s): Egashira T, Yuasa S, Suzuki T, Tohyama S, et al.
  • Journal Title: Cardiovasc. Res. Volume: 95 Issue: 4 Pages: 419-29
  • DOI: 10.1093/cvr/cvs206
  • Peer Reviewed
• [Presentation] .Exome Sequencing-based Risk Stratification of Sudden Cardiac Death in the Long-QT Syndrome (2014)
  • Author(s): Aiba Takeshi
  • Organizer: APHRS 2014
  • Place of Presentation: New Deli, India
  • Year and Date: 2014-10-29 – 2014-11-01
  • Invited
• [Presentation] Genetic-based Risk Stratification of Sudden Cardiac Death in the Long-QT Syndrome. (2014)
  • Author(s): Aiba Takeshi
  • Organizer: The 29th Annual Meeting of the Japanese Heart Rhythm Society The 31th Annual Meeting of the Japanese Society of Electrocardiography
  • Place of Presentation: Tokyo
  • Year and Date: 2014-07-23 – 2014-07-25
  • Invited
• [Presentation] High Resolution Magnetocardiography as a Novel Noninvasive Tool to Distinguish between Benign and Malignant Early Repolarization Pattern (2014)
  • Author(s): Takeshi Aiba, Naotsugu Iwakami, Hiroshi Takaki, Kohei Ishibashi, Ikutaro Nakajima, Koji Miyamoto, Hideo Okamura, Takashi Noda, Kengo Kusano, Satoshi Yasuda, Masaru Sugimachi, Wataru Shimizu, Shiro Kamakura, Hisao Ogawa.
  • Organizer: 日本循環器学会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Clinical and Genetic Features of Japanese Patients with Congenital Long QT syndrome (2013)
  • Author(s): 相庭武司
  • Organizer: 日本循環器学会
  • Place of Presentation: 横浜
• [Presentation] Noninvasive Evaluation of Arrhythmic Substrate in the Brugada Syndrome using High Resolution Magnetocardiography (2012)
  • Author(s): Aiba Takeshi
  • Organizer: 米国心臓病協会年次総会
  • Place of Presentation: ロサンゼルス
• [Presentation] Ｊ波の機序：From Cell to Bedside. (2012)
  • Author(s): 相庭武司
  • Organizer: 日本心電学会学術集会
  • Place of Presentation: 幕張（千葉）
  • Invited
• [Presentation] Diverse Gender risk on Long QT Syndrome and Brugada Syndrome
  • Author(s): Aiba T
  • Organizer: Taiwan-Heart Rhythm Society
  • Place of Presentation: WESTIN Taipei
  • Invited
• [Book] 遺伝性不整脈の薬物療法 (2014)
  • Author(s): 相庭武司
  • Total Pages: 6
  • Publisher: メジカルレビュー