Novel Non-invasive risk stratification of sudden cardiac death in patients with inherited arrhythmias

• Project/Area Number: 15K09150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: AIBA TAKESHI 国立研究開発法人国立循環器病研究センター, 病院, 医長 (40574348)
• Co-Investigator(Kenkyū-buntansha): 稲田 慎 姫路獨協大学, 医療保健学部, 准教授 (50349792) ; 松浦 博 滋賀医科大学, 医学部, 教授 (60238962)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 不整脈 / 電気生理学 / シミュレーション / 右室流出路 / 伝導 / 遺伝子 / ブルガダ / リスク評価 / 突然死 / Brugada症候群 / 心室細動 / 心電図 / イオンチャネル / マッピング / 脱分極 / ﾌﾞﾙｶﾞﾀﾞ症候群

Outline of Final Research Achievements

Local conduction abnormalities at the right ventricular outflow tract epicardium (RVOT-Epi) are one of the potent arrhythmogenic substrates in many heart diseases. However, how much delay at RVOT-Epi develops ventricular arrhythmias (VAs) is not quantitatively investigated. We constructed a 3-D human ventricular model to investigate the role of conduction delay in the RVOT-Epi on initiation and maintenance of the VAs.
No VAs occurred in the mild to moderate conduction delay of 2.3cm φ in the RVOT-Epi, but in the severe delay, propagation of the wave front was broken up into the multiple wavelets in the RVOT-Epi, thus, maintained the VAs. The VAs inducibility is much easier in the larger delayed size (3.0cmφ). In contrast, these findings could not be reproduced in the delayed conduction set at RV free wall (RVFW). These findings suggest that the structural vulnerability for VAs in RVOT-Epi as an arrhythmic risk of arrhythmogenic right ventricular cardiomyopathy or Brugada syndrome.

Research Products

• [Int'l Joint Research] St George's University of London(United Kingdom)
• [Int'l Joint Research] Academic Medical Center, Amsterdam(Netherlands)
• [Int'l Joint Research] St George's, University of London(United Kingdom)
• [Int'l Joint Research] Academic Medical Center, Amsterdam(Netherlands)
• [Journal Article] Profile of Brugada Syndrome Patients Presenting with Their First Documented Arrhythmic Event. Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS). (2018)
  • Author(s): Milman A, Andorin A, Gourraud JB, Postema PG, Sacher F, Mabo P, Kim SH, Juang J, Maeda S, Takahashi Y, Kamakura T, Aiba T, , Brugada J, Leenhardt A, Wilde AAM, Brugada P, Kusano K, Hirao K, NamMD GB, Probst V,Belhassen B.
  • Journal Title: Heart Rhythm Volume: in press Issue: 5 Pages: 716-724
  • DOI: 10.1016/j.hrthm.2018.01.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome. (2018)
  • Author(s): Michowitz Y, Milman A, Giustetto C, Tfelt-Hansen J, Wijeyeratne YD, Veltmann C, Corrado D, Kim SH, Delise P, Maeda S, Gourraud JB, Sacher F, Mabo P, Takahashi Y, Kamakura T, Aiba T, Kusano KF, Hirao K, Nam GB, Probst V, Belhassen B.
  • Journal Title: Heart Rhythm Volume: in press Issue: 9 Pages: 1394-1401
  • DOI: 10.1016/j.hrthm.2018.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The significance of coronary artery spasm diagnosis in patients with early repolarization syndrome. (2018)
  • Author(s): Kamakura T, Wada M, Ishibashi K, Inoue Y, Miyamoto K, Okamura H, Nagase S, Noda T, Aiba T, Yasuda S, Shimizu W, Kamakura S, Kusano K.
  • Journal Title: J Am Heart Assoc. Volume: in press Issue: 4
  • DOI: 10.1161/jaha.117.007942
  • Peer Reviewed / Open Access
• [Journal Article] Change in QRS morphology as a marker of spontaneous elimination in verapamil-sensitive idiopathic left ventricular tachycardia. (2018)
  • Author(s): Kawakami H, Aiba T, Ishibashi K, Nakajima I, Wada M, Kamakura T, Inoue Y, Miyamoto K, Okamura H, Nagase S, Noda T, Kokubo Y, Miyamoto Y, Yasuda S, Kamakura S, Kusano K.
  • Journal Title: J Cardiovasc Electrophysiol Volume: 29 Issue: 3 Pages: 446-455
  • DOI: 10.1111/jce.13403
  • Peer Reviewed / Open Access
• [Journal Article] Different responses to exercise between Andersen?Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia (2017)
  • Author(s): Inoue Yuko Y、Aiba Takeshi、Kawata Hiro、Sakaguchi Tomoko、Mitsuma Wataru、Morita Hiroshi、Noda Takashi、Takaki Hiroshi、Toyohara Keiko、Kanaya Yoshiaki、Itoi Toshiyuki、Mitsuhashi Takeshi、Sumitomo Naokata、Cho Yongkeun、Yasuda Satoshi、Kamakura Shiro、Kusano Kengo、Miyamoto Yoshihiro、Horie Minoru、Shimizu Wataru
  • Journal Title: Europace Volume: 印刷中 Issue: 10 Pages: 1675-1682
  • DOI: 10.1093/europace/eux351
  • Peer Reviewed / Open Access
• [Journal Article] Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients. (2017)
  • Author(s): Milman A, Andorin A, Gourraud JB, Sacher F, Mabo P, Kim SH, Maeda S, Takahashi Y, Kamakura T, Aiba T, Takagi M, Veltmann C, Delise P, Corrado D, Behr ER, Gaita F, Yan GX, Brugada J, Leenhardt A, Wilde AAM, Brugada P, Kusano KF, Hirao K, Nam GB, Probst V, Belhassen B.
  • Journal Title: Circulation Arrhythmia Electrophysiology Volume: in press Issue: 12
  • DOI: 10.1161/circep.117.005222
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers. (2017)
  • Author(s): Nishiuchi S, Makiyama T, Aiba T, Nakajima K, Hirose S, Kohjitani H, Yamamoto Y, Harita T, Hayano M, Wuriyanghai Y, Chen J, Sasaki K, Yagihara N, Ishikawa T, Onoue K, Murakoshi N, Watanabe I, Ohkubo K, Watanabe H, Ohno S, Doi T, Shizuta S, Minamino T, et.al
  • Journal Title: Circ Cardiovasc Genet. Volume: 6 Issue: 6
  • DOI: 10.1161/circgenetics.116.001603
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy (2017)
  • Author(s): Wada Yuko、Ohno Seiko、Aiba Takeshi、Horie Minoru
  • Journal Title: Mol Genet Genomic Med. Volume: 5 Issue: 6 Pages: 639-651
  • DOI: 10.1002/mgg3.311
  • Peer Reviewed / Open Access
• [Journal Article] Genotype-phenotype correlation of SCN5A mutation for clinical and electrocardiographic characteristics of probands with Brugada syndrome: Japanese Multicenter Registry. (2017)
  • Author(s): Yamagata K, Horie M, et al.
  • Journal Title: Circulation Volume: 印刷中 Issue: 23 Pages: 0-0
  • DOI: 10.1161/circulationaha.117.027983
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Arrhtyhmia risk and β-blocker therapy in pregnant women with long QT syndrome. (2017)
  • Author(s): Ishibashi K, Horie M, et al.
  • Journal Title: Heart Volume: 印刷中 Issue: 17 Pages: 0-0
  • DOI: 10.1136/heartjnl-2016-310617
  • Peer Reviewed / Open Access
• [Journal Article] Mid-Term Follow-up of School-Aged Children With Borderline Long QT Interval (2017)
  • Author(s): Miyazaki A, Sakaguchi H, Matsumura Y, Hayama Y, Noritake K, Negishi J, Tsuda E, Miyamoto Y, Aiba T, Shimizu W, Kusano K, Shiraishi I, Ohuchi H.
  • Journal Title: Circulation Journal Volume: 81 Issue: 5 Pages: 726-732
  • DOI: 10.1253/circj.CJ-16-0991
  • NAID: 130005612054
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction. (2017)
  • Author(s): Ishikawa T, Horie M, et al.
  • Journal Title: Heart Rhythm Volume: 印刷中 Issue: 5 Pages: 717-724
  • DOI: 10.1016/j.hrthm.2017.01.020
  • Peer Reviewed / Open Access
• [Journal Article] Differences in the onset mode of ventricular tachyarrhythmia between patients with J wave in anterior leads and those with J wave in inferolateral leads. (2017)
  • Author(s): Kamakura T, Wada M, Ishibashi K, Inoue YY, Miyamoto K, Okamura H, Nagase S, Noda T, Aiba T, Yasuda S, Shimizu W, Kamakura S, Kusano K
  • Journal Title: Heart Rhythm. Volume: 14 Issue: 4 Pages: 553-561
  • DOI: 10.1016/j.hrthm.2016.11.027
  • Peer Reviewed / Open Access
• [Journal Article] IRX3 variant as a modifier of Brugada syndrome with frequent ventricular fibrillation. (2016)
  • Author(s): Kimura Y, Aiba T, Sasano T, Furukawa T, Kusano K, Shimizu W.
  • Journal Title: HeartRhythm Case Reports Volume: 2 Issue: 6 Pages: 465-468
  • DOI: 10.1016/j.hrcr.2016.06.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phenotypic Variability of <i>ANK2</i> Mutations in Patients With Inherited Primary Arrhythmia Syndromes (2016)
  • Author(s): Ichikawa M, Horie M, et al.
  • Journal Title: Circulation Journal Volume: 80 Issue: 12 Pages: 2435-2442
  • DOI: 10.1253/circj.CJ-16-0486
  • NAID: 130005284992
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes. (2016)
  • Author(s): Yagihara N,Minamino T,33名中28番
  • Journal Title: J Am Heart Assoc. Volume: 19 Issue: 9 Pages: 644-650
  • DOI: 10.1161/jaha.116.003644
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study. (2016)
  • Author(s): Wilde AA, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J, Lopes C, Towbin JA, Spazzolini C, Crotti L, Zareba W, Goldenberg I, Kanters JK, Robinson JL, Qi M, Hofman N, Tester DJ, Bezzina CR, Alders M, Aiba T, Kamakura S, Miyamoto Y, Andrews ML, McNitt S, Polonsky B, Schwartz PJ, Ackerman MJ.
  • Journal Title: Circulation Volume: 134 Issue: 12 Pages: 872-882
  • DOI: 10.1161/circulationaha.116.021823
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Associated With Ryanodine Receptor (RyR2) Gene Mutations – Long-Term Prognosis After Initiation of Medical Treatment – (2016)
  • Author(s): Kawata H, Horie M, et al.
  • Journal Title: Circulation Journal Volume: 80 Issue: 9 Pages: 1907-1915
  • DOI: 10.1253/circj.CJ-16-0250
  • NAID: 130005406854
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [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] Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients With Type 3 Congenital Long QT Syndrome (2016)
  • Author(s): Funasako M, Aiba T, Ishibashi K, Nakajima I, Miyamoto K, Inoue Y, Okamura H, Noda T, Kamakura S, Anzai T, Noguchi T, Yasuda S, Miyamoto Y, Fukushima Kusano K, Ogawa H, Shimizu W.
  • Journal Title: Circulation Journal Volume: 80 Issue: 2 Pages: 340-345
  • DOI: 10.1253/circj.CJ-15-0984
  • NAID: 130005120922
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. (2016)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T.
  • Journal Title: European Heart Journal. Volume: 37 (18) Issue: 18 Pages: 1469-1475
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Significance of electrocardiogram recording in high intercostal spaces in patients with early repolarization syndrome. (2016)
  • Author(s): Kamakura T, Wada M, Nakajima I, Ishibashi K, Miyamoto K, Okamura H, Noda T, Aiba T, Takaki H, Yasuda S, Ogawa H, Shimizu W, Makiyama T, Kimura T, Kamakura S, Kusano K.
  • Journal Title: European Heart Journal. Volume: 37 (7) Issue: 7 Pages: 630-637
  • DOI: 10.1093/eurheartj/ehv369
  • Peer Reviewed / Open Access
• [Journal Article] Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes. (2015)
  • Author(s): Shigemizu D, Aiba T, Nakagawa H, Ozaki K, Miya F, Satake W, Toda T, Miyamoto Y, Fujimoto A, Suzuki Y, Kubo M, Tsunoda T, Shimizu W, Tanaka T.
  • Journal Title: PLoS One. Volume: 10 (7) Issue: 7 Pages: e0130329-e0130329
  • DOI: 10.1371/journal.pone.0130329
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Clinical Characteristics and Prognosis of Early Repolarization Syndrome. (2017)
  • Author(s): 2. Tsukasa Kamakura, Mitsuru Wada, Kohei Ishibashi, Yuko Inoue, Koji Miyamoto, Hideo Okamura, Satoshi Nagase, Takashi Noda, Takeshi Aiba, Teruo Noguchi, Toshihisa Anzai, Satoshi Yasuda, Kengo Kusano
  • Organizer: 第81回日本循環器学会総会・ 学術大会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Overall Clinical and Genetic Backgrounds of Ventricular Fibrillation or Cardiac Arrest in Patients with Inherited Primary Arrhythmia Syndromes. (2017)
  • Author(s): 4. Takeshi Aiba, Kengo Kusano, Yoshihito Miyamoto, Wataru Shimizu
  • Organizer: 第81回日本循環器学会総会・ 学術大会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] 22. Genetic-based risk stratification for cardiac disorders in LMNA mutation carriers. (2017)
  • Author(s): Nishiuchi S, Aiba T, Nakajima K, Hirose S, Kohjitani H, Yamamoto Y, Harita T, Hayano M, Sasaki K, Ishikawa T, Onoue K, Saito Y, Kusano K, Makita N, Shimizu W, Horie M, Kimura T.
  • Organizer: 第81回日本循環器学会学術集会,
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
• [Presentation] Arrhythmogenic Substrates in Heart Failure with Dyssynchronous Contraction and its Restoration by CRT. (2017)
  • Author(s): Aiba T
  • Organizer: APHRS 2017
  • Int'l Joint Research / Invited
• [Presentation] Genetics of IVF and SCD. (2017)
  • Author(s): Aiba T
  • Organizer: APHRS 2017
  • Int'l Joint Research / Invited
• [Presentation] Overall Clinical and Genetic Backgrounds of Ventricular Fibrillation or Cardiac Arrest in Patients with Inherited Primary Arrhythmia Syndromes. (2017)
  • Author(s): Aiba T, Kusano K, Miyamoto Y, Shimizu W:
  • Organizer: 第81回日本循環器学会総会・ 学術大会シンポジウム, 金沢,
• [Presentation] A Unique Genetic Background and Its Prognostic Impact on Non-Caucasian Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Probands (2016)
  • Author(s): Yuko Wada, Takeshi Aiba, Siko Ohno, Minoru Horie
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Genetics and Clinical Aspects of Arrhythmias associated with cardiomyopathy (2016)
  • Author(s): Aiba T
  • Organizer: Asia Pacific Heart Rhythm Society Scientific Sessions 2016
  • Place of Presentation: Seoul Korea
  • Year and Date: 2016-10-12
  • Int'l Joint Research / Invited
• [Presentation] Genetics and Clinical Aspects of Long-QTSyndrome (2016)
  • Author(s): Aiba T
  • Organizer: Asia Pacific Heart Rhythm Society Scientific Sessions 2016
  • Place of Presentation: Seoul
  • Year and Date: 2016-10-12
  • Int'l Joint Research / Invited
• [Presentation] Clinical Characteristics and long-term Prognosis of Patients with Genotype-unknown Long-QT Syndrome (2016)
  • Author(s): K. Shimamoto, T. Aiba, K. Ishibashi, T. Kamakura, M. Wada, K. Miyamoto, Y. Inoue-Yamada, H. Okamura, S. Nagase, T. Noda, S. Kamakura, Y. Miyamoto, M. Horie, W. Shimizu, K. Kusano
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-27
  • Int'l Joint Research
• [Presentation] Age and gender-dependent differences in the clinical manifestation in the lamin A/C mutation: Japanese single-center registry (2016)
  • Author(s): Kenzaburo Nakajima, Takeshi Aiba, Suguru Nishiuchi, Takeru Makiyama, Tsukasa Kamakura, Mitsuru Wada, Kohei Ishibashi, Yuko Inoue, Koji Miyamoto, Satoshi Nagase, Takashi Noda, Shiro Kamakura, Seiko Ohno, Minoru Horie, Wataru Shimizu, Kengo Kusano
  • Organizer: Heart Rhytym Society 2016
  • Place of Presentation: San Francisco, CA
  • Year and Date: 2016-05-04
  • Int'l Joint Research
• [Presentation] Calmodulin interacting genes as a novel candidate for pathogenesis of long-QT syndrome (2015)
  • Author(s): Aiba T, Shigemizu D, Ishibashi K, Wada M, Nakajima I, Miyamoto K, Okamura H, Noda T, Satake W, Toda T, Kusano K, Kamakura S, Sekine A, Miyamoto Y, Tanaka T, Ogawa H, Shimizu W
  • Organizer: AHA Scientific Session 2015
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-11-08
  • Int'l Joint Research
• [Presentation] A novel KCNJ3 mutation as a susceptibility for ventricular arrhythmias in long-QT Syndrome (2015)
  • Author(s): Aiba T, Toyoda F, Ono M, Ishibashi K, Wada M, Nakajima I, Miyamoto K, Okamura H, Noda T, Kamakura S, Kusano K, Sekine A, Tanaka T, Miyamoto Y, Matsuura H, Horie M, Shimizu W.
  • Organizer: 第30回日本不整脈学会・第32回日本心電学会合同学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-07-28
• [Remarks] 遺伝性不整脈疾患の遺伝子診断
  • URL: http://www.ncvc.go.jp/hospital/section/cvm/arrhythmia/d3.html