Effective diagnosis and establishment of the therapy for catecholaminergic polymorphic ventricular tachycardia

• Project/Area Number: 15K09689
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Cardiovascular Center Research Institute (2017); Shiga University of Medical Science (2015-2016)
• Principal Investigator: Ohno Seiko 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025)
• Co-Investigator(Kenkyū-buntansha): 堀江 稔 滋賀医科大学, 医学部, 教授 (90183938)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 家族性突然死症候群 / カテコラミン誘発性多形性心室頻拍 / 不整脈 / カテコラミン誘発性多形成心室頻拍 / RYR2 / 遺伝子変異 / 心臓リアノジンチャネル / カテコラミン誘発性多型性心室頻拍 / リアノジンレセプターチャネル / QT延長症候群

Outline of Final Research Achievements

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease causing sudden cardiac death due to polymorphic ventricular tachycardia leading to VF in young patients. The major cause of CPVT is mutations in RYR2 with 105 exons, therefore the genetic analysis of CPVT has been difficult. However, we employed target gene sequencing and next generation sequencing system, and now, we can identify genetic mutations effectively.
Long QT syndrome (LQTS) is an inherited disease similar to CPVT, especially, CPVT is sometimes misdiagnosed as LQT type 1 (LQT1). We compared the results of exercise stress test in patient with LQT1 or CPVT and found that the QT shortenings were prominent in CPVT patients. We construct a system for differentiation between CPVT and LQT1.

Research Products

• [Journal Article] Bradycardia Is a Specific Phenotype of Catecholaminergic Polymorphic Ventricular Tachycardia Induced by <i>RYR2</i> Mutations (2018)
  • Author(s): Miyata Kazuaki、Ohno Seiko、Itoh Hideki、Horie Minoru
  • Journal Title: Internal Medicine Volume: 57 Issue: 13 Pages: 1813-1817
  • DOI: 10.2169/internalmedicine.9843-17
  • NAID: 130007387124
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2018-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Novel intracellular transport-refractory mutations in KCNH2 identified in patients with symptomatic long QT syndrome (2018)
  • Author(s): Fukumoto Daisuke、Ding Wei-Guang、Wada Yuko、Fujii Yusuke、Ichikawa Mari、Takayama Koichiro、Fukuyama Megumi、Kato Koichi、Itoh Hideki、Makiyama Takeru、Omatsu-Kanbe Mariko、Matsuura Hiroshi、Horie Minoru、Ohno Seiko
  • Journal Title: Journal of Cardiology Volume: 71 Issue: 4 Pages: 401-408
  • DOI: 10.1016/j.jjcc.2017.10.004
  • Peer Reviewed
• [Journal Article] Copy number variations of SCN5A in Brugada syndrome (2018)
  • Author(s): Sonoda Keiko、Ohno Seiko、Ozawa Junichi、Hayano Mamoru、Hattori Tetsuhisa、Kobori Atsushi、Yahata Mitsuhiko、Aburadani Isao、Watanabe Seiichi、Matsumoto Yuichi、Makiyama Takeru、Horie Minoru
  • Journal Title: Heart Rhythm Volume: - Issue: 8 Pages: 1179-1188
  • DOI: 10.1016/j.hrthm.2018.03.033
  • Peer Reviewed
• [Journal Article] A challenge for mutation specific risk stratification in long QT syndrome type 1 (2018)
  • Author(s): Yagi Noriaki、Itoh Hideki、Hisamatsu Takashi、Tomita Yukinori、Kimura Hiromi、Fujii Yusuke、Makiyama Takeru、Horie Minoru、Ohno Seiko
  • Journal Title: Journal of Cardiology Volume: 18 Issue: 1 Pages: 30012-1
  • DOI: 10.1016/j.jjcc.2017.12.011
  • Peer Reviewed
• [Journal Article] A hERG mutation E1039X produced a synergistic lesion on IKs together with KCNQ1-R174C mutation in a LQTS family with three compound mutations (2018)
  • Author(s): Wu Jie、Mizusawa Yuka、Ohno Seiko、Ding Wei-Guang、Higaki Takashi、Wang Qi、Kohjitani Hirohiko、Makiyama Takeru、Itoh Hideki、Toyoda Futoshi、James Andrew F.、Hancox Jules C.、Matsuura Hiroshi、Horie Minoru
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 3129-3129
  • DOI: 10.1038/s41598-018-21442-6
  • NAID: 120006529715
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential Diagnosis Between Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome Type 1: A Modified Schwartz Score (2018)
  • Author(s): Ozawa J, Ohno S, Fujii Y, Makiyama T, Suzuki H, Saitoh A, Horie M
  • Journal Title: Circulation Journal Volume: in press
  • NAID: 130007438837
  • 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] 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] Elimination of ventricular arrhythmia in catecholaminergic polymorphic ventricular tachycardia by targeting “catecholamine-sensitive area”: a dominant-subordinate relationship between origin sites of bidirectional ventricular premature contractions. (2017)
  • Author(s): Shirai Y, Horie M, et al.
  • Journal Title: PACE Volume: 印刷中 Issue: 5 Pages: 600-604
  • DOI: 10.1111/pace.13006
  • Peer Reviewed
• [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] Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin-45 Mutation. (2017)
  • Author(s): Seki A, Ishikawa T, Daumy X, Mishima H, Barc J, Sasaki R, Nishii K, Saito K, Urano M, Ohno S, Otsuki S, Kimoto H, Baruteau AE, Thollet A, Fouchard S, Bonnaud S, Parent P, Shibata Y, Perrin JP, Le Marec H, Hagiwara N, Mercier S, Horie M, Probst V, Yoshiura KI, Redon R, Schott JJ, Makita N.
  • Journal Title: J Am Coll Cardiol. Volume: 70 Issue: 3 Pages: 358-370
  • DOI: 10.1016/j.jacc.2017.05.039
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsade de pointe ventricular arrhythmia. (2016)
  • Author(s): Fujii Y, Horie M, et al.
  • Journal Title: Heart Rhythm Volume: 14 Issue: 1 Pages: 98-107
  • DOI: 10.1016/j.hrthm.2016.10.015
  • 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 genetic background of arrhythmogenic right ventricular cardiomyopathy (2016)
  • Author(s): Seiko Ohno
  • Journal Title: Journal of Arrhythmia Volume: 未定 Issue: 5 Pages: 398-403
  • DOI: 10.1016/j.joa.2016.01.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Pediatric Cohort With Long QT Syndrome – <i>KCNH2</i> Mutation Carriers Present Late Onset But Severe Symptoms – (2016)
  • Author(s): Ozawa, J. Ohno, S. Horie M, et al.
  • Journal Title: Circulation Journal Volume: 80 Issue: 3 Pages: 696-702
  • DOI: 10.1253/circj.CJ-15-0933
  • NAID: 130005128459
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia (2016)
  • Author(s): Sasaki K, Makiyama T, Yoshida Y, Wuriyanghai Y, Kamakura T, Nishiuchi S, Hayano M, Harita T, Yamamoto Y, Kohjitani H, Hirose S, Chen J, Kawamura M, Ohno S, Itoh H, Takeuchi A, Matsuoka S, Miura M, Sumitomo N, Horie M, Yamanaka S, Kimura T
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0164795-e0164795
  • DOI: 10.1371/journal.pone.0164795
  • NAID: 120005860036
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative Analysis of PKP2 and Neighboring Genes in a Patient with Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Heterozygous PKP2 Deletion. (2016)
  • Author(s): Sonoda K, Ohno S, Horie M, et al.
  • Journal Title: Europace Volume: 未定 Pages: 644-650
  • DOI: 10.1093/europace/euw038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients. (2015)
  • Author(s): Seiko Ohno, Kanae Hasegawa, Minoru Horie
  • Journal Title: PlosOne Volume: 10 Issue: 6 Pages: 6-6
  • DOI: 10.1371/journal.pone.0131517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] LQTS, Ventricular Arrhythmias and SCD Pathophysiology and Mechanisms Ion Channel Disorders (2018)
  • Author(s): Seiko Ohno
  • Organizer: EHRA2018
  • Int'l Joint Research / Invited
• [Presentation] 20.Detection of Copy Number Variations by Next Generation Sequencer, a Missing Genetic Defect. (2018)
  • Author(s): Seiko Ohno
  • Organizer: 第82回日本循環器学会 学術集会
• [Presentation] Can We Detect and Know All the Pathogenic Mutations by Next Generation Sequencer in Patients with Inherited Cardiovascular Diseases? (2017)
  • Author(s): Ohno S
  • Organizer: 日本循環器病学会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17
  • Int'l Joint Research / Invited
• [Presentation] RYR2 Mutations in LQTS (2017)
  • Author(s): Seiko Ohno
  • Organizer: APHRS 2017
  • Int'l Joint Research / Invited
• [Presentation] High frequency of CACNA1C mutation carriers in genotyped LQTS patients (2017)
  • Author(s): Ohno S, Ozawa J, Fukuyama M, Horie M.
  • Organizer: ESC Congress 2017
  • Int'l Joint Research
• [Presentation] Early Repolarization Syndrome Caused by a de novo KCND3 Gain-of-Function Mutation. (2017)
  • Author(s): Takayama K, Ohno S, Ding W-G, Kise H, Hoshiai M, Matsuura H, Horie M.
  • Organizer: AHA2017
  • Int'l Joint Research
• [Presentation] High prevalence of late onset T in patients with long QT syndrome type 8 (2016)
  • Author(s): Ohno S, Ozawa J, Fukuyama M, Makiyama T, Horie M
  • Organizer: American Heart Association meeting 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] The RYR2 Mutations Identified Not Only in CPVT But Also Short Coupled Variant of Torsade De Pointes and LQTS. (2016)
  • Author(s): Ohno S
  • Organizer: Asian Pacific Heart Rhythm Society Meeting
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-10-12
  • Int'l Joint Research / Invited
• [Presentation] Specific Phenotypes Caused by RYR2 Mutations Relate with Bradycardia but not with Mutation Locations in RYR2. (2016)
  • Author(s): Ohno S, Ozawa J, Fujii Y, Itoh H, Horie M
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-26
  • Int'l Joint Research
• [Presentation] Triple mutations in three major genes for long QT syndrome are very rare and cause complicated phenotypes with ventricular arrhythmia. (2016)
  • Author(s): Ohno S, Wu J, Mizusawa Y, Sonoda K, Itoh H, Makiyama T, Horie M
  • Organizer: ESC CONGRESS 2016
  • Place of Presentation: Rome, Italy
  • Year and Date: 2016-08-26
  • Int'l Joint Research
• [Presentation] CPVT:Challenging inherited arrhythmia syndromes: the latest. (2015)
  • Author(s): Seiko Ohno
  • Organizer: Asian Pacific Heart Rhythm Society 2015
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2015-11-19
  • Int'l Joint Research / Invited
• [Presentation] Brady and Atrial Arrhythmias in CPVT Patients with RYR2 Mutations (2015)
  • Author(s): Seiko Ohno
  • Organizer: Asian Pacific Heart Rhythm Society 2015
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2015-11-19
  • Int'l Joint Research / Invited
• [Presentation] Differential diagnosis of catecholaminergic polymorphic ventricular tachycardia vs. long QT syndrome type 1: a modified Schwartz scoring (2015)
  • Author(s): Junichi Ozawa, Seiko Ohno, Minoru Horie, et al,
  • Organizer: American Heart Association meeting 2015
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] SCN10A polymorphisms are associated with the clinical severity of probands with sodium channelopathies. (2015)
  • Author(s): Fukuyama M, Ohno S, Ichikawa M, Makiyama T, Horie M.
  • Organizer: Europace 2015
  • Place of Presentation: Milan, Italy
  • Year and Date: 2015-06-21
  • Int'l Joint Research
• [Presentation] Do desmosome gene mutations cause or modify the Brugada syndrome? (2015)
  • Author(s): Ohno S, Aizawa Y,Horie M. et,al.
  • Organizer: Heart Rhythm 2015
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-05-14
  • Int'l Joint Research
• [Book] 循環器ジャーナル 心電図診断スキルアップ (2017)
  • Author(s): 大野聖子
  • Total Pages: 9
  • Publisher: 医学書院
  • ISBN: 9784260029438