Mechanism of arrhythmo-genesis by exercise stress in long QT syndrome patients

• Project/Area Number: 24591575
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Shiga University of Medical Science
• Principal Investigator: OHNO Seiko 滋賀医科大学, アジア疫学研究センター, 講師 (20610025)
• Co-Investigator(Kenkyū-buntansha): HORIE Minoru 滋賀医科大学, 医学部, 教授 (90183938)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: QT延長症候群 / 不整脈 / 遺伝子変異 / カリウムチャネル / 運動誘発性 / 失神 / 先天性QT延長症候群 / 運動負荷 / 交感神経刺激 / パッチクランプ

Outline of Final Research Achievements

Among the long QT syndrome, type 1 and 5 are well known that the symptoms including syncope are related with exercise. The causes of the disease are mutations in KCNQ1 and KCNE1 which encoding slowly activated cardiac potassium ion current channel. Diverse clinical symptoms are depend on the location of the variants. Therefore we analyzed clinical symptoms depend on the mutation locations and performed functional analysis of the mutations using patch clamp methods.

Research Products

• [Journal Article] Novel SCN10A variants associated with Brugada syndrome (2015)
  • Author(s): Fukuyama M, Ohno S, Makiyama T, Horie M.
  • Journal Title: Europace Volume: 0 Issue: 6 Pages: 0-0
  • DOI: 10.1093/europace/euv078
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Molecular Mechanism for Adrenergic-Induced Long QT Syndrome. (2014)
  • Author(s): Wu J, Naiki N, Ding WG, Ohno S, Kato K, Zang WJ, Delisle BP, Matsuura H, Horie M.
  • Journal Title: J Am Coll Cardiol Volume: 63 Issue: 8 Pages: 819827-819827
  • DOI: 10.1016/j.jacc.2013.08.1648
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Gain-of-function KCNH2 mutations in patients with Brugada syndrome. (2014)
  • Author(s): Wang Q, Ohno S, Ding WG, Fukuyama M, Miyamoto A, Itoh H, Makiyama T, Wu J, Bai J, Hasegawa K, Shinohara T, Takahashi N, Shimizu A, Matsuura H, Horie M.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 25 Issue: 5 Pages: 522533-522533
  • DOI: 10.1111/jce.12361
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction (2014)
  • Author(s): Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T, Ushinohama H, Makita N, Horie M
  • Journal Title: Europace Volume: in press Issue: 11 Pages: 1646-1654
  • DOI: 10.1093/europace/eut382
  • Peer Reviewed
• [Journal Article] A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels. (2014)
  • Author(s): Hasegawa K, Ohno S, Ashihara T, Itoh H, Ding WG, Toyoda F, Makiyama T, Aoki H, Nakamura Y, Delisle BP, Matsuura H, Horie M.
  • Journal Title: Heart Rhythm Volume: 11 Issue: 1 Pages: 67-75
  • DOI: 10.1016/j.hrthm.2013.09.073
  • Peer Reviewed
• [Journal Article] Long QT Syndrome Type8: Novel CACNA1C Mutations Causing QT Prolongation and Variant Phenotypes. (2014)
  • Author(s): Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M.
  • Journal Title: Europace. Volume: in press Issue: 12 Pages: 1828-37
  • DOI: 10.1093/europace/euu063
  • Peer Reviewed / Open Access
• [Journal Article] A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation. (2014)
  • Author(s): Bartos DC, Giudicessi JR, Tester DJ, Ackerman MJ, Ohno S, Horie M, Gollob MH, Burgess DE, Delisle BP.
  • Journal Title: Heart Rhythm. Volume: 11 Issue: 3 Pages: 459-468
  • DOI: 10.1016/j.hrthm.2013.11.021
  • Peer Reviewed
• [Journal Article] Age-Dependent Clinical and Genetic Characteristics in Japanese Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (2013)
  • Author(s): Itoh H, Horie M
  • Journal Title: Circulation Journal Volume: 77 Issue: 6 Pages: 1534-1542
  • DOI: 10.1253/circj.CJ-12-1446
  • NAID: 10031158884
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [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] Genetic Background of Catecholaminergic Polymorphic Ventricular Tachycardia in Japan (2013)
  • Author(s): Kawamura M, Ohno S, Naiki N, Horie M. et al.
  • Journal Title: Circulation Journal Volume: 77 Issue: 7 Pages: 1705-1713
  • DOI: 10.1253/circj.CJ-12-1460
  • NAID: 10031173750
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] L-Type Calcium Channel Mutations in Japanese Patients With Inherited Arrhythmias (2013)
  • Author(s): Fukuyama M, Ohno S, Wang Q, Horie M. et al.
  • Journal Title: Circulation Journal Volume: 77 Issue: 7 Pages: 1799-1806
  • DOI: 10.1253/circj.CJ-12-1457
  • NAID: 10031173762
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Ultrastructural Maturation of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Long-Term Culture (2013)
  • Author(s): Kamakura T, Makiyama T, Horie M. et al.
  • Journal Title: Circulation Journal Volume: 77 Issue: 5 Pages: 1307-1314
  • DOI: 10.1253/circj.CJ-12-0987
  • NAID: 10031151395
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Novel <i>SCN3B</i> Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5 (2013)
  • Author(s): Ishikawa T
  • Journal Title: Circulation Journal Volume: 77 Issue: 4 Pages: 959-967
  • DOI: 10.1253/circj.CJ-12-0995
  • NAID: 10031138998
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Genetic Screening of KCNJ8 in Japanese Patients with J-wave Syndromes or Idiopathic Ventricular Fibrillation. (2013)
  • Author(s): Wang Q, Ohno S, Kato K, Horie M. et al.
  • Journal Title: Journal of Arrhythmia Volume: 29 Issue: 5 Pages: 261-264
  • DOI: 10.1016/j.joa.2013.01.013
  • Peer Reviewed
• [Journal Article] Flecainide reduces ventricular arrhythmias via a mechanism that differs from that of β-blockers in catecholaminergic polymorphic ventricular tachycardia (2013)
  • Author(s): DochiK, WatanabeH, KawamuraM, MiyamotoA, OzawaT, NakazawaY, AshiharaT, OhnoS, HayashiH, ItoM, SakazakiH, KawataH, UsinohamaH, KaszynskiRH, MinaminoT, SumitomoN, ShimizuW, HorieM
  • Journal Title: Journal of arrhythmia Volume: - Issue: 5 Pages: 255-260
  • DOI: 10.1016/j.joa.2013.01.011
  • Peer Reviewed
• [Journal Article] High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation. (2012)
  • Author(s): Burgess DE
  • Journal Title: Biochemistry. Volume: 51 Issue: 45 Pages: 9076-9085
  • DOI: 10.1021/bi3009449
  • Peer Reviewed
• [Journal Article] A novel gain-of-function KCNJ2 mutation associated with short QT syndrome impairs inward rectification of Kir2.1 currents. (2012)
  • Author(s): Hattori T
  • Journal Title: Cardiovasculer Research Volume: 93 Issue: 4 Pages: 666-673
  • DOI: 10.1093/cvr/cvr329
  • Peer Reviewed
• [Journal Article] Phenotype variability in patients carrying KCNJ2 mutations. (2012)
  • Author(s): Kimura H, Zhou J, Kawamura M, Itoh H, Mizusawa Y, Ding W-G, Wu J, Ohno S, Makiyama T, Miyamoto A, Naiki N, Wang Q, Xie Y, Suzuki T, Tateno S, Nakamura Y, Zang W-J, Ito M, Matsuura H, Horie M
  • Journal Title: Circ Cardiovasc Genet Volume: 5 Issue: 3 Pages: 344-353
  • DOI: 10.1161/circgenetics.111.962316
  • Peer Reviewed
• [Journal Article] KCNE3 T4A as the Genetic Basis of Brugada-Pattern Electrocardiogram (2012)
  • Author(s): Nakajima T, Ashihara T, et al.
  • Journal Title: Circulation Journal Volume: 76 Issue: 12 Pages: 2763-2772
  • DOI: 10.1253/circj.CJ-12-0551
  • NAID: 10031126046
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Presentation] Do desmosome gene mutations cause or modify the Brugada syndrome? (2015)
  • Author(s): S Ohno, Y Aizawa, M Fukuyama, T Makiyama, K Kosaki, K Fukuda, M Horie
  • Organizer: Heart Rhythm Society Meeting 2015
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-05-13 – 2015-05-16
• [Presentation] Usefulness of benchtop next generation sequencer in research of inherited primary arrhythmia syndromes (2015)
  • Author(s): S Ohno, M Fukuyama, H Itoh, T Makiyama, M Horie
  • Organizer: 第79回日本循環器病学会
  • Place of Presentation: 大阪、日本
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Young long QT syndrome patients with KCNH2 mutations have late onset but severe symptoms (2014)
  • Author(s): J Ozawa, S Ohno, H Itoh, T Makiyama, M Horie
  • Organizer: American Heart Association Meeting 2015
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-10 – 2014-11-19
• [Presentation] WHICH GENETIC TESTS:SINGLE GENES, PANELS OR GENOMES? (2014)
  • Author(s): S Ohno
  • Organizer: Asia Pacific Heart Rhythm Society Meeting 2014
  • Place of Presentation: Delhi, India
  • Year and Date: 2014-10-29 – 2014-11-01
  • Invited
• [Presentation] ARRHYTHMOGENICRIGHTVENTRICULARCARDIOMYOPATHY (2014)
  • Author(s): S Ohno
  • Organizer: Asia Pacific Heart Rhythm Society Meeting 2014
  • Place of Presentation: Delhi, India
  • Year and Date: 2014-10-29 – 2014-11-01
  • Invited
• [Presentation] Identification of latent mutations in primary inherited arrhythmia syndromes using benchtop next generation sequencer. Benchtop Next Generation Sequencer Has Facilitated the Genetic Analysis for Inherited Arrhythmias (2014)
  • Author(s): S Ohno, M Fukuyama, H Itoh, T Makiyama, M Horie
  • Organizer: European Society of Cardiology Meeting 2015
  • Place of Presentation: Barceｌona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Gender differences in the inheritance mode of RYR2 mutations in catecholaminergic polymorphic ventricular tachycardia patients (2014)
  • Author(s): S. Ohno, M. Kawamura, K. Hasegawa, M. Horie
  • Organizer: European Society of Cardiology Meeting 2015
  • Place of Presentation: Barceｌona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] High frequency of ANK2 mutations in patients with non-genotyped primary inherited arrhythmia syndromes. (2014)
  • Author(s): S Ohno, M Fukuyama, H Itoh, T Makiyama, M Horie
  • Organizer: European Society of Cardiology Meeting 2015
  • Place of Presentation: Barceｌona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Mosaic KCNJ2 Mutation in Andersen–Tawil syndrome: Targeted Deep Sequencing is Useful for the Detection of Mosaicism (2014)
  • Author(s): K Hasegawa, S Ohno, H Kimura, H Itoh, T Makiyama, Y Yoshida, M Horie
  • Organizer: Heart Rhythm Society Meeting 2014
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-05-07 – 2014-05-10
• [Presentation] Exon-3 deletion of RyR2 encoding cardiac ryanodine receptor related to left ventricular non-compaction (LVNC) with ventricular arrhythmia and bradycardia. (2013)
  • Author(s): S. Ohno, M. Omura, M. Kawamura, H. Kimua, H. Itoh, T. Makiyama, H. Ushinohama, N. Makita, M. Horie
  • Organizer: European Heart Rhythm Society Meeting
  • Place of Presentation: Athene、ギリシャ共和国
• [Presentation] Different regulation of IKs channels by two KCNE1 C-terminal variants predicts the QTc response to the exercise stress. (2013)
  • Author(s): Ohno S, Hasegawa K, Makiyama T, Doi S, Horie M
  • Organizer: Heart Rhythm 2013
  • Place of Presentation: Denver, CO, USA
• [Presentation] Exon-3 Deletion of RyR2 Encoding Cardiac Ryanodine Receptor Related to Left Ventricular Non-Compaction (LVNC) with Ventricular Arrhythmia and Bradycardia. (2013)
  • Author(s): Ohno S, Omura M, Kawamura M, Kimura H, Itoh H, Makiyama T, Ushinohama H, Makita N, Horie M
  • Organizer: EHRA Europace 2013
  • Place of Presentation: Athens, Greece
• [Presentation] Exon-3 Deletion of RYR2 Leads to Left Ventricular Non-compaction with Catecholaminergic Polymorphic Ventricular Tachycardia and Severe Bradycardia (2013)
  • Author(s): Ohno S, Kawamura M, Omura M, Kimura H, Itoh H, Makiyama T, Ushinohama H, Makita N, Horie M
  • Organizer: Japanese Circulation Cociety meeting 2013
  • Place of Presentation: 横浜、神奈川
• [Presentation] QT延長症候群合併Down症候群症例におけるSNaP shot法を用いたKCNE1-D85Nアレル頻度の同定 (2012)
  • Author(s): 大野聖子、高橋実穂、福山 恵、王 琦、木村紘美、伊藤英樹、牧山 武、堀米仁志、堀江 稔
  • Organizer: 第30回日本心電学会
  • Place of Presentation: 幕張、千葉
• [Presentation] Age dependent clinical and genetic characteristics in Japanese patients with Arrhythmogenic right ventricular cardiomyopathy/dysplasia (2012)
  • Author(s): Ohno S, Nishio Y, Nagaoka I, Fukuyama M, Kimura H, Itoh H, Makiyama T, Shimiu A, Horie M
  • Organizer: APHRS2012
  • Place of Presentation: Taipei, Taiwan
• [Presentation] 不整脈源性右室心筋症/異型性 (ARVC/D) における年齢依存性の臨床および遺伝的特徴 (2012)
  • Author(s): 大野聖子、西尾由貴子、長岡伊織、福山 恵、木村紘美、伊藤英樹、牧山武、清水昭彦、堀江稔
  • Organizer: 第60回心臓病学会
  • Place of Presentation: 金沢、石川
• [Presentation] Different regulation of IKS channels by two KCNE1 C-terminus variants predicts the QTc response to the exercise strress
  • Author(s): S Ono, K Hasegawa, T Makiyama, S Doi, M Horie
  • Organizer: Heart Rhythm Society Meeting
  • Place of Presentation: Denver、アメリカ合衆国
• [Presentation] Copy number variations in KCNQ1 gene were frequently identified in the pediatric patients of long QT syndrome and caused exercise related QT prolongation
  • Author(s): S. Ohno, M. Fukuyama, H. Itoh, T. Makiyama, M. Horie
  • Organizer: European Society of Cardiology Meeting
  • Place of Presentation: Amsterdam、オランダ王国
• [Presentation] Phenotypic characterization of two patients with lethal arrhythmia related to KCNH2-R148W variant
  • Author(s): S Ohno, W Qi, K Hasegwas, H Itoh, T Makiyama, M Horie
  • Organizer: Asian Pacific Heart Rhythm Society
  • Place of Presentation: 香港、中華人民共和国
• [Presentation] Benchtop Next Generation Sequencer Has Facilitated the Genetic Analysis for Inherited Arrhythmias
  • Author(s): S Ohno, K Hasegawa, M Fukuyama, T Makiyama, M Horie
  • Organizer: 日本循環器病学会
  • Place of Presentation: 東京国際フォーラム
• [Remarks] 滋賀医科大学呼吸循環器内科
  • URL: http://www.shiga-med.ac.jp/~hqmed1/