心筋イオンチャネル病のリスク層別化と臨床管理におけるシミュレーションの応用

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 25136705
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Shiga University of Medical Science
• Principal Investigator: 伊藤 英樹 滋賀医科大学, 医学部, 助教 (30402738)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: QT延長症候群 / 筋緊張性ジストロフィー / イオンチャネル / シミュレーション / チャネル / ブルガダ症候群 / SCN5A

Outline of Annual Research Achievements

大阪大学神経内科の高橋正紀先生とフランスの研究施設と共同で筋緊張性ジストロフィー症の発症病態に関して研究に行い、特にコンピューター・シミュレーションを利用してイオンチャネルの動態変化にともなう心電図変化を検討した。筋緊張性ジストロフィー症患者においては、心筋ナトリウムチャネルの胎児型から成人型への切り替えが障害されていた。正常状態では、成人になるとともにナトリウムチャネルの選択的スプライシングの変化が起こることで成人型ナトリウムチャネルへの発現に変化するが、スプライシングの調節蛋白であるMBNLにCTGリピートが結合することで、MBNLがナトリウムチャネルのスプライシングを阻害していた。この現象はトランスジェニックマウスにおいても観察された。電気生理学的実験において胎児型と成人型のナトリウムチャネルの特性が異なることを明らかにし、胎児型ではloss of function(機能喪失型）であった。ヒト心筋モデル(O'Haraモデル）を利用し、ナトリウムチャネルの変化特性を組み込んだ心筋細胞を連結させ仮想心電図を構築すると、筋緊張性ジストロフィー症ではQRS幅の延長を確認でき、臨床像と一致する所見であった。筋緊張性ジストロフィー症例で認められるCTGリピートの延長が心筋ナトリウムチャネルの選択的スプライシングに関与するMBNLの作用を阻害し、loss of function型の機能を有する胎児型のナトリウムチャネルが発現し続ける事で心伝導障害が発症することが明らかとなった。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Mosaic KCNJ2 mutation in Andersen-Tawil syndrome: targeted deep sequencing is useful for the detection of mosaicism. (2015)
  • Author(s): Hasegawa K, Ohno S, Kimura H, Itoh H, Makiyama T, Yoshida Y, Horie M.
  • Journal Title: Clin Genet Volume: 87 Issue: 3 Pages: 279-83
  • DOI: 10.1111/cge.12357
  • Peer Reviewed / Open Access
• [Journal Article] Nonsense-mediated mRNA decay due to a CACNA1C splicing mutation in a patient with Brugada syndrome. (2014)
  • Author(s): Fukuyama M, Ohno S, Wang Q, Shirayama T, Itoh H, Horie M.
  • Journal Title: Heart Rhythm Volume: 11 Issue: 4 Pages: 629-34
  • DOI: 10.1016/j.hrthm.2013.12.011
  • Peer Reviewed
• [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] 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] 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] Long-term pharmacological therapy of Brugada syndrome: is J-wave attenuation a marker of drug efficacy? (2014)
  • Author(s): Hasegawa K, Ashihara T, Kimura H, Jo H, Itoh H, Yamamoto T, Aizawa Y, Horie M.
  • Journal Title: Intern Med Volume: 53 Pages: 1523-6
  • NAID: 130004466395
  • Peer Reviewed
• [Journal Article] Mosaic KCNJ2 Mutation in Andersen-Tawil syndrome: Targeted Deep Sequencing is Useful for the Detection of Mosaicism. (2014)
  • Author(s): Hasegawa K, Ohno S, Kimura H, Itoh H, Makiyama T, Yoshida Y, Horie M.
  • Journal Title: Clin Genet Volume: in press
  • Peer Reviewed
• [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 Pages: 1058-64
  • Peer Reviewed
• [Journal Article] Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench. (2014)
  • Author(s): Kato K, Makiyama T, Wu J, Ding WG, Kimura H, Naiki N, Ohno S, Itoh H, Nakanishi T, Matsuura H, Horie M.
  • Journal Title: J Cardiovasc Electrophysiol Volume: 25 Issue: 1 Pages: 66-73
  • DOI: 10.1111/jce.12270
  • 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-term Pharmacological Therapy of Brugada Syndrome: Is Attenuation of J waves a Marker of Drug Efficacy? (2014)
  • Author(s): Hasegawa K, Ashihara T, Kimura H, Jo Hikari, Itoh H, Yamamoto T, Aizawa Y, Horie M.
  • Journal Title: Internal Med Volume: in press
  • Peer Reviewed
• [Journal Article] Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long QT syndrome. (2013)
  • Author(s): Duchatelet S, Crotti L, Horie M. et al.
  • Journal Title: Circulation Cardiovasc Genet Volume: 6(4) Issue: 4 Pages: 354-61
  • DOI: 10.1161/circgenetics.113.000023
  • Peer Reviewed
• [Journal Article] Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan. (2013)
  • Author(s): Kawamura M, Ohno S, Naiki N, Nagaoka I, Dochi K, Wang Q, Hasegawa K, Kimura H, Miyamoto A, Mizusawa Y, Itoh H, Makiyama T, Sumitomo N, Ushinohama H, Oyama K, Murakoshi N, Aonuma K, Horigome H, Honda T, Yoshinaga M, Ito M, Horie M.
  • Journal Title: Circ J Volume: 77 Pages: 1705-13
  • NAID: 10031173750
  • Peer Reviewed
• [Journal Article] L-type calcium channel mutations in Japanese patients with inherited arrhythmias. (2013)
  • Author(s): Fukuyama M, Ohno S, Wang Q, Kimura H, Makiyama T, Itoh H, Ito M, Horie M.
  • Journal Title: Circ J Volume: 77 Pages: 1799-806
  • NAID: 10031173762
  • Peer Reviewed
• [Presentation] The genetics underlying the acquired long QT syndrome. Impact on management (2015)
  • Author(s): Itoh H, Spazzolini C, Crotti L, Aiba T, 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
  • Organizer: Heart Rhythm Society’s 36th Annual Scientific Sessions
  • Place of Presentation: Boston,アメリカ合衆国
  • Year and Date: 2015-05-13 – 2015-05-15
• [Presentation] Pregnancy in the Congenital Long-QT Syndrome: Efficacy and Safety of Beta-Blocker Therapy for Prevention of Lethal Ventricular Arrhythmias (2015)
  • Author(s): Ishibashi K, Aiba T, Sakaguchi H, Miyazaki A, Kamiya C, Yamauchi T, Ito H, Ohno S, Motomura H, Ogawa T, Goto H, Watanabe H, Yoshimatsu J, Kamakura S, Miyamoto Y, Shiraishi I, Yasuda S, Ogawa H, Horie M, Shimizu W, Kusano K
  • Organizer: The 79th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Electrophysiological Properties of L-type Calcium Channels in Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes (2015)
  • Author(s): Harita T, Makiyama T, Sasaki K, Hayano M, Nishiuchi S, Yamamoto Y, Kohjitani H, Chen J, Wuriyanghai Y, Ohno S, Ito H, Yoshida Y, Horie M, Kimura T
  • Organizer: The 79th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Usefulness of Benchtop Next Generation Sequencer in Research of Inherited Primary Arrhythmia Syndromes (2015)
  • Author(s): Ohno S, Fukuyama M, Itoh H, Makiyama T, Horie M
  • Organizer: The 79th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: Osaka
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] 完全房室ブロックに伴いTorsade de Pointesを発症した二次性QT延長症候群の１例 (2015)
  • Author(s): 諸戸礼知安, 加藤浩一, 藤居祐介, 小澤友哉, 芦原貴司, 伊藤英樹, 堀江 稔
  • Organizer: 第207回日本内科学会近畿地方会
  • Place of Presentation: 大阪
  • Year and Date: 2015-03-07
• [Presentation] 小児ＱＴ延長症候群:ＬＱＴ２は発症年齢が高いが重症例が多い (2015)
  • Author(s): 小澤淳一, 大野聖子, 伊藤英樹, 牧山 武, 堀江 稔
  • Organizer: 第26回滋賀不整脈研究会
  • Place of Presentation: 滋賀
  • Year and Date: 2015-02-28
• [Presentation] Short-coupled variant of torsade de pointesに対するverapamilの有効性 (2015)
  • Author(s): 藤居祐介、伊藤英樹、小澤友哉、服部哲久、芦原貴司、八木典章、松本祐一、木村紘美、酒井 宏、山本 孝、林 秀樹、大野聖子、堀江 稔、中川義久、山本 聖、松井由美恵
  • Organizer: 第13回特発性心室細動研究会
  • Place of Presentation: 東京
  • Year and Date: 2015-02-14
• [Presentation] Young long QT syndrome patients with KCNH2 mutations have late onset but severe symptoms (2014)
  • Author(s): Ozawa J, Ohno S, Itoh H, Makiyama T, Horie M
  • Organizer: AHA Scientific Sessions 2014
  • Place of Presentation: Chicago,アメリカ合衆国
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] The Prognosis of Andersen-Tawil syndrome is not so benign as ever thought (2014)
  • Author(s): Kimura H, Itoh H, Ohno S, Fukuyama M, Kato K, Ichikawa M, Fujii Y, Makiyama T, Horie M
  • Organizer: AHA Scientific Sessions 2014
  • Place of Presentation: Chicago,アメリカ合衆国
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Acquired long QT syndrome (2014)
  • Author(s): Itoh H
  • Organizer: 7th APHRS 2014
  • Place of Presentation: New Delhi,インド
  • 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 (2014)
  • Author(s): Ohno S, Fukuyama M, Itoh H, Makiyama T, Horie M
  • Organizer: ESC CONGRESS 2014
  • Place of Presentation: Barcelona,スペイン
  • 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): Ohno S, Fukuyama M, Itoh H, Makiyama T, Horie M
  • Organizer: ESC CONGRESS 2014
  • Place of Presentation: Barcelona,スペイン
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Identification of novel SCN10A variants in Brugada syndrome patients (2014)
  • Author(s): Fukuyama M, Ohno S, Makiyama T, Hasegawa K, Itoh H, Horie M
  • Organizer: ESC CONGRESS 2014
  • Place of Presentation: Barcelona,スペイン
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Genetics in acquired long QT syndrome (2014)
  • Author(s): Pedrazzini M, Itoh H, Crotti L, Aiba T, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Yamagishi M, Berthet M, Shimizu W, Guicheney P, Schwartz PJ, Horie M
  • Organizer: ESHG 2014
  • Place of Presentation: Milano,イタリア共和国
  • Year and Date: 2014-05-31 – 2014-06-03
• [Presentation] Mosaic KCNJ2 Mutation in Andersen-Tawil syndrome:Targeted Deep Sequencing is Useful for the Detection of Mosaicism (2014)
  • Author(s): Hasegawa K,Ohno S,Kimura H,Itoh H,Makiyama T,Yoshida Y,Horie M
  • Organizer: Heart Rhythm2014
  • Place of Presentation: San Francisco,アメリカ合衆国
  • Year and Date: 2014-05-06 – 2014-05-11
• [Presentation] Kir3.4変異はKir2.1に対する抑制作用を通してAndersen-Tawil 症候群を引き起こす (2014)
  • Author(s): 古田充、殻内洋介、中田智彦、坂田宗平、木村紘美、相庭武司、吉永正夫、大崎裕亮、中森雅之、伊藤秀樹、佐藤貴子、久保田智哉、門田一繁、進藤克郎、望月秀樹、清水渉、堀江稔、岡村康司、大野欽司、高橋正紀
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡
• [Presentation] 後天性QT延長症候群の発症病態 (2014)
  • Author(s): 伊藤英樹、Crotti Lia、Schwartz J Peter、林研至、中島忠、大野聖子、牧山武、山岸正和、井本敬二、Pascale Guicheney、堀江稔
  • Organizer: 第91回日本生理学会大会
  • Place of Presentation: 鹿児島
  • Invited
• [Presentation] Asymmetry of parental origin in Long QT syndrome. (2013)
  • Author(s): Itoh H, Berthet M, Fressart V, Denjoy I , Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Husemann A, Shimizu W, Wilde AA , Schulze-Bahr E, Horie M, du Montcel ST, Guicheney P.
  • Organizer: European Human Genetics Conference
  • Place of Presentation: Paris, France
• [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
  • Place of Presentation: Athens, Greek
• [Presentation] Underlying Mechanisms in Forme Fruste Long QT Syndrome Manifested by Acquired Factors. (2013)
  • Author(s): Itoh H.
  • Organizer: The 2nd HD Physiology International Symposium
  • Place of Presentation: Tokyo, Japan
• [Presentation] Novel CACNA1C mutations in Long QT syndrome patients- The subtype of Long QT syndrome type 8. (2013)
  • Author(s): Fukuyama M, Wang Q, Kato K, Ohno S, Kimura H, Makiyama T, Itoh H, Ito M, Matsuura H, Horie M.
  • Organizer: Denis Escande Symposium
  • Place of Presentation: Amsterdam, the Netherlands
• [Presentation] Copy number variation in KCNQ1 gene were frequently identified in the pediatric patients of long QT syndrome and caused exercise related QT prolongation. (2013)
  • Author(s): Ohno S, Fukuyama M, Itoh H, Makiyama T, Horie M.
  • Organizer: ESC CONGRESS
  • Place of Presentation: Amsterdam, the Netherlands
• [Presentation] Altered splicing of cardiac sodium channel might be responsible for cardiac conduction defects in myotonic dystrophy. (2013)
  • Author(s): Kokunai Y, Kino Y, Li M, Itoh H, Nakamori M, Kimura T, Matsumura T, Fujimura H, Nukina N, Sakoda S, Horie M, Imoto K, Ishiura S, Swanson MS, Charlet-Berguerand N, Takahashi MP.
  • Organizer: the 9th International Myotonic Dystrophy Consortium
  • Place of Presentation: Basque, Spain
• [Presentation] Phenotypic characterization of three patients with lethal arrhythmia related to KCNH2-R148W missense mutation. (2013)
  • Author(s): Ohno S, Wang Q, Hasegwas K, Itoh H, Makiyama T, Horie M.
  • Organizer: 6th APHRS & CardioRhythm
  • Place of Presentation: Hong Kong, China
• [Presentation] The High Prevalence of Early Repolarization in Genotyped Long QT Syndrome. (2013)
  • Author(s): Hasegawa K, Watanabe H, Ohno S, Itoh H, Makiyama T, Ashihara T, Hayashi H, Horie M.
  • Organizer: AHA Scientific Sessions
  • Place of Presentation: Dallas, USA
• [Presentation] 心室細動後の12誘導心電図で広範囲なST上昇を認めたJ wave syndromeの一例 (2013)
  • Author(s): 冨田行則、服部哲久、伊藤英樹、児玉 健二、福沢綾子、高橋宏明、八木典章、木村紘美、山科 聡、酒井 宏、小澤友哉、山本 孝、伊藤 誠、堀江 稔
  • Organizer: 第115回日本循環器学会近畿地方会
  • Place of Presentation: 京都
• [Presentation] KCNH2遺伝子変異による徐脈性QT延長症候群の一家系 (2013)
  • Author(s): 中泉伸彦、伊藤英樹、児玉 浩、富田行則、八木典章、服部哲久、木村紘美、酒井 宏、小澤友哉、山本 孝、伊藤 誠、堀江 稔、椙本 晃
  • Organizer: 第115回日本循環器学会近畿地方会
  • Place of Presentation: 京都
• [Presentation] 若年時に診断された催不整脈性右室心筋症・異形成（ARVC/D）患者の臨床的および遺伝的特徴 (2013)
  • Author(s): 大野聖子、福山 恵、長谷川奏恵、木村紘美、伊藤英樹、牧山 武、堀江 稔
  • Organizer: 第30回日本心電学会
  • Place of Presentation: 青森
• [Presentation] short-coupled variant of torsade de pointes の遺伝的背景 (2013)
  • Author(s): 堀本かんな、伊藤英樹、小澤友哉、内貴乃生、冨田行則、藤居祐介、八木典章、服部哲久、木村紘美、芦原貴司、松本祐一、酒井 宏、山本 孝、伊藤 誠、堀江 稔
  • Organizer: 第116回日本循環器学会近畿地方会
  • Place of Presentation: 大阪
• [Presentation] VerapamilがVF stormに有効であった突発性心室細動の１例 (2013)
  • Author(s): 藤居祐介、伊藤英樹、服部哲久、小澤友哉、芦原貴司、児玉健二、高橋宏明、福沢綾子、冨田行則、八木典章、松本祐一、内貴乃生、木村紘美、酒井 宏、山本 孝、伊藤 誠、堀江 稔
  • Organizer: 第75回滋賀県循環器疾患研究会
  • Place of Presentation: 滋賀
• [Book] 不整脈症候群 (2015)
  • Author(s): 伊藤英樹、他
  • Total Pages: 196
  • Publisher: 南江堂
• [Book] 見逃すな！薬物中毒と電解質異常. レジデントノート 心電図の読み方トレニーング (2013)
  • Author(s): 伊藤英樹
  • Publisher: 羊土社
• [Remarks] 滋賀医科大学 呼吸循環器内科
  • URL: http://www.shiga-med.ac.jp/~hqmed1/
• [Remarks] 滋賀医科大学 研究情報データベース
  • URL: http://www.shiga-med.ac.jp/db/pub_top.php