Organization
Graduate School of Medicine Designated associate professor
Title
Designated associate professor
TSUJI, Yukiomi
Degree 1
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博士（医学） （ 2001.3 名古屋大学 ）
Research Interests 1
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心臓電気生理学
Research Areas 1
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Life Science / Cardiology
Research History 3
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Nagoya University Endowed chair associate professor
2022.4
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Nagasaki University Lecturer
2013.4 - 2022.3
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Nagoya University Assistant Professor
2006.3 - 2012.3
Education 2
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Nagoya University
- 2001.3
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Kanazawa University
- 1992.3
Country： Japan
Awards 3
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日本学術振興会科学研究費助成事業平成28年度審査表彰
2016.9
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名古屋大学環境医学研究所若手優秀論文賞
2012.11
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第12回医科学応用研究財団助成による日本心電学会論文賞
2012.10
Papers 43
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Mechanisms of torsades de pointes: an update. Invited Reviewed International journal
Tsuji Y, Yamazaki M, Shimojo M, Yanagisawa S, Inden Y, Murohara T
Frontiers in cardiovascular medicine Vol. 11 page： 1363848 2024
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Chronic total occlusion of infarct-related artery: A bystander or a risk factor of electrical storm?
Tsuji Y, Dobrev D
International journal of cardiology Vol. 359 page： 36 - 37 2022.7
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Recent insights into mechanisms and cinical approaches to electrical storm
Elsokkari Ihab, Tsuji Yukiomi, Sapp John L., Nattel Stanley
CANADIAN JOURNAL OF CARDIOLOGY Vol. 38 ( 4 ) page： 439 - 453 2022.4
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Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm.
Yamazaki M, Tomii N, Tsuneyama K, Takanari H, Niwa R, Honjo H, Kodama I, Arafune T, Makita N, Sakuma I, Dobrev D, Nattel S, Tsuji Y
Heart rhythm Vol. 19 ( 2 ) page： 318 - 329 2022.2
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Implantable cardioverter-defibrillator therapy in primary versus secondary prevention: Reliable prediction of appropriate therapies and mortality is still an unmet need
Tsuji Yukiomi, Dobrev Dobromir
IJC HEART & VASCULATURE Vol. 32 page： 100740 2021.2
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Molecular mechanisms of binge drinking-induced atrial fibrillation
Tsuji Yukiomi
CIRCULATION JOURNAL Vol. 84 ( 11 ) page： 1909 - 1911 2020.11
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Electrical storm: mechanistic and therapeutic considerations to avoid death in the survivors
Tsuji Yukiomi, Dobrev Dobromir
JOURNAL OF THORACIC DISEASE Vol. 10 ( Suppl 33 ) page： S4053 - S4056 2018.11
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Prognostic impact of electrical storm in patients with implantable cardioverter defibrillators: Mechanistic and therapeutic considerations to reduce the risk of death
Tsuji Yukiomi, Dobrev Dobromir
INTERNATIONAL JOURNAL OF CARDIOLOGY Vol. 255 page： 101 - 102 2018.3
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Inherited bradyarrhythmia: A diverse genetic background.
Ishikawa T, Tsuji Y, Makita N
Journal of arrhythmia Vol. 32 ( 5 ) page： 352 - 358 2016.10
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Calmodulin/CaMKII inhibition improves intercellular communication and impulse propagation in the heart and is antiarrhythmic under conditions when fibrosis is absent
Takanari Hiroki, Bourgonje Vincent J. A., Fontes Magda S. C., Raaijmakers Antonia J. A., Driessen Helen, Jansen John A., van der Nagel Roel, Kok Bart, van Stuijvenberg Leonie, Boulaksil Mohamed, Takemoto Yoshio, Yamazaki Masatoshi, Tsuji Yukiomi, Honjo Haruo, Kamiya Kaichiro, Kodama Itsuo, Anderson Mark E., van der Heyden Marcel A. G., van Rijen Harold V. M., van Veen Toon A. B., Vos Marc A.
CARDIOVASCULAR RESEARCH Vol. 111 ( 4 ) page： 410 - 421 2016.9
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Alogliptin, a dipeptidyl peptidase-4 inhibitor, regulates the atrial arrhythmogenic substrate in rabbits
Yamamoto Toshihiko, Shimano Masayuki, Inden Yasuya, Takefuji Mikito, Yanagisawa Satoshi, Yoshida Naoki, Tsuji Yukiomi, Hirai Makoto, Murohara Toyoaki
HEART RHYTHM Vol. 12 ( 6 ) page： 1362 - 1369 2015.6
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Novel Mutation in the alpha-Myosin Heavy Chain Gene Is Associated With Sick Sinus Syndrome
Ishikawa Taisuke, Jou Chuanchau J., Nogami Akihiko, Kowase Shinya, Arrington Cammon B., Barnett Spencer M., Harrell Daniel T., Arimura Takuro, Tsuji Yukiomi, Kimura Akinori, Makita Naomasa
Circulation-Arrhythmia and Electrophysiology Vol. 8 ( 2 ) page： 400 - U200 2015.4
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Novel Calmodulin Mutations Associated With Congenital Arrhythmia Susceptibility
Makita Naomasa, Yagihara Nobue, Crotti Lia, Johnson Christopher N., Beckmann Britt-Maria, Roh Michelle S., Shigemizu Daichi, Lichtner Peter, Ishikawa Taisuke, Aiba Takeshi, Homfray Tessa, Behr Elijah R., Klug Didier, Denjoy Isabelle, Mastantuono Elisa, Theisen Daniel, Tsunoda Tatsuhiko, Satake Wataru, Toda Tatsushi, Nakagawa Hidewaki, Tsuji Yukiomi, Tsuchiya Takeshi, Yamamoto Hirokazu, Miyamoto Yoshihiro, Endo Naoto, Kimura Akinori, Ozaki Kouichi, Motomura Hideki, Suda Kenji, Tanaka Toshihiro, Schwartz Peter J., Meitinger Thomas, Kaeaeb Stefan, Guicheney Pascale, Shimizu Wataru, Bhuiyan Zahurul A., Watanabe Hiroshi, Chazin Walter J., George Alfred L. Jr.
CIRCULATION-CARDIOVASCULAR GENETICS Vol. 7 ( 4 ) page： 466 - U209 2014.8
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Sodium Channelopathy Underlying Familial Sick Sinus Syndrome With Early Onset and Predominantly Male Characteristics
Abe Keisuke, Machida Taku, Sumitomo Naokata, Yamamoto Hirokazu, Ohkubo Kimie, Watanabe Ichiro, Makiyama Takeru, Fukae Satoki, Kohno Masaki, Harrell Daniel T., Ishikawa Taisuke, Tsuji Yukiomi, Nogami Akihiko, Watabe Taichi, Oginosawa Yasushi, Abe Haruhiko, Maemura Koji, Motomura Hideki, Makita Naomasa
CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Vol. 7 ( 3 ) page： 511 - 517 2014.6
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Cystatin C as a Predictor of Mortality and Cardiovascular Morbidity After Cardiac Resynchronization Therapy
Yamamoto Toshihiko, Shimano Masayuki, Inden Yasuya, Miyata Shinjiro, Inoue Yoko, Yoshida Naoki, Tsuji Yukiomi, Hirai Makoto, Murohara Toyoaki
CIRCULATION JOURNAL Vol. 77 ( 11 ) page： 2751 - 2756 2013.11
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Electrical storm: recent pathophysiological insights and therapeutic consequences
Tsuji Yukiomi, Heijman Jordi, Nattel Stanley, Dobrev Dobromir
BASIC RESEARCH IN CARDIOLOGY Vol. 108 ( 2 ) page： 336 2013.3
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Safety and efficacy of vernakalant for acute cardioversion of atrial fibrillation: an update.
Tsuji Y, Dobrev D
Vascular health and risk management Vol. 9 page： 165 - 75 2013
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Ca2+-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm
Tsuji Yukiomi, Hojo Mayumi, Voigt Niels, El-Armouche Ali, Inden Yasuya, Murohara Toyoaki, Dobrev Dobromir, Nattel Stanley, Kodama Itsuo, Kamiya Kaichiro
CIRCULATION Vol. 123 ( 20 ) page： 2192 - U67 2011.5
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Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model
Kitamura Kazuhisa, Shibata Rei, Tsuji Yukiomi, Shimano Masayuki, Inden Yasuya, Murohara Toyoaki
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Vol. 300 ( 5 ) page： H1814 - H1821 2011.5
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Novel transitional zone index allows more accurate differentiation between idiopathic right ventricular outflow tract and aortic sinus cusp ventricular arrhythmias
Yoshida Naoki, Inden Yasuya, Uchikawa Tomohiro, Kamiya Hiromi, Kitamura Kazuhisa, Shimano Masayuki, Tsuji Yukiomi, Hirai Makoto, Murohara Toyoaki
HEART RHYTHM Vol. 8 ( 3 ) page： 349 - 356 2011.3
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Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart
Harada Masahide, Tsuji Yukiomi, Ishiguro Yuko S., Takanari Hiroki, Okuno Yusuke, Inden Yasuya, Honjo Haruo, Lee Jong-Kook, Murohara Toyoaki, Sakuma Ichiro, Kamiya Kaichiro, Kodama Itsuo
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Vol. 300 ( 2 ) page： H565 - H573 2011.2
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Electrical storm and calcium signaling: a review
Tsuji Yukiomi
JOURNAL OF ELECTROCARDIOLOGY Vol. 44 ( 6 ) page： 725 - 729 2011
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Maximum Derivative of Left Ventricular Pressure Predicts Cardiac Mortality After Cardiac Resynchronization Therapy
Suzuki Hirohiko, Shimano Masayuki, Yoshida Yukihiko, Inden Yasuya, Muramatsu Takashi, Tsuji Yukiomi, Tsuboi Naoya, Hirayama Haruo, Shibata Rei, Murohara Toyoaki
CLINICAL CARDIOLOGY Vol. 33 ( 12 ) page： E18 - E23 2010.12
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Combined assessment of left ventricular dyssynchrony and contractility by speckled tracking strain imaging: A novel index for predicting responders to cardiac resynchronization therapy
Inden Yasuya, Ito Rieko, Yoshida Naoki, Kamiya Hiromi, Kitamura Kazuhisa, Kitamura Tomoya, Shimano Masayuki, Uchikawa Tomohiro, Tsuji Yukiomi, Shibata Rei, Hirai Makoto, Murohara Toyoaki
HEART RHYTHM Vol. 7 ( 5 ) page： 655 - 661 2010.5
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Small animal models for arrhythmia studies
Lee Jong-Kook, Tsuji Yukiomi
CARDIAC ELECTROPHYSIOLOGY METHODS AND MODELS page： 261 - 279 2010
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Reactive oxidative metabolites are associated with atrial conduction disturbance in patients with atrial fibrillation
Shimano Masayuki, Shibata Rei, Inden Yasuya, Yoshida Naoki, Uchikawa Tomohiro, Tsuji Yukiomi, Murohara Toyoaki
HEART RHYTHM Vol. 6 ( 7 ) page： 935 - 940 2009.7
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The Calcium/Calmodulin/Kinase System and Arrhythmogenic Afterdepolarizations in Bradycardia-Related Acquired Long-QT Syndrome
Qi XiaoYan, Yeh Yung-Hsin, Chartier Denis, Xiao Ling, Tsuji Yukiomi, Brundel Bianca J. J. M., Kodama Itsuo, Nattel Stanley
CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Vol. 2 ( 3 ) page： 295 - 304 2009.6
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Circulating homocysteine levels in patients with radiofrequency catheter ablation for atrial fibrillation
Shimano Masayuki, Inden Yasuya, Tsuji Yukiomi, Kamiya Hiromi, Uchikawa Tomohiro, Shibata Rei, Murohara Toyoaki
EUROPACE Vol. 10 ( 8 ) page： 961 - 966 2008.8
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Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome
Diness Thomas G., Yeh Yung-Hsin, Qi Xiao Yan, Chartier Denis, Tsuji Yukiomi, Hansen Rie S., Olesen Soren-Peter, Grunnet Morten, Nattel Stanley
CARDIOVASCULAR RESEARCH Vol. 79 ( 1 ) page： 61 - 69 2008.7
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Circulating adiponectin levels in patients with atrial fibrillation
Shimano Masayuki, Shibata Rei, Tsuji Yukiomi, Kamiya Hiromi, Uchikawa Tomohiro, Harata Shuji, Muto Masahiro, Ouchi Noriyuki, Inden Yasuya, Murohara Toyoaki
CIRCULATION JOURNAL Vol. 72 ( 7 ) page： 1120 - 1124 2008.7
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Circulating adiponectin levels in patients with atrial fibrillation.
Shimano M, Shibata R, Tsuji Y, Kamiya H, Uchikawa T, Harata S, Muto M, Ouchi N, Inden Y, Murohara T
Circulation journal : official journal of the Japanese Circulation Society Vol. 72 ( 7 ) page： 1120 - 4 2008.7
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Untitled - Response
Shimano Masayuki, Tsuji Yukiomi, Inden Yasuya, Kitamura Kazuhisa, Uchikawa Tomohiro, Harata Shuji, Nattel Stanley, Murohara Toyoaki
HEART RHYTHM Vol. 5 ( 4 ) page： 636 - 637 2008.4
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Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure
Shimano Masayuki, Tsuji Yukiomi, Inden Yasuya, Kitamura Kazuhisa, Uchikawa Tomohiro, Harata Shuji, Nattel Stanley, Murohara Toyoaki
HEART RHYTHM Vol. 5 ( 3 ) page： 451 - 459 2008.3
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Aldosterone modulates I-f current through gene expression in cultured neonatal rat ventricular myocytes
Muto Takao, Ueda Norihiro, Opthof Tobias, Ohkusa Tomoko, Nagata Kohzo, Suzuki Shinsuke, Tsuji Yukiomi, Horiba Mitsuru, Lee Jong-Kook, Honjo Haruo, Kamiya Kaichiro, Kodama Itsuo, Yasui Kenji
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Vol. 293 ( 5 ) page： H2710 - H2718 2007.11
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Acute and chronic effects of cardiac resynchronization in patients developing heart failure with long-term pacemaker therapy for acquired complete atrioventricular block
Shimano Masayuki, Tsuji Yukiomi, Yoshida Yukihiko, Inden Yasuya, Tsuboi Naoya, Itoh Teruo, Suzuki Hirohiko, Muramatsu Takashi, Okada Taro, Harata Shuji, Yamada Takumi, Hirayama Haruo, Nattel Stanley, Murohara Toyoaki
EUROPACE Vol. 9 ( 10 ) page： 869 - 874 2007.10
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Does RV lead positioning provide additional benefit to cardiac resynchronization therapy in patients with advanced heart failure?
Shimano Masayuki, Inden Yasuya, Yoshida Yukihiko, Tsuji Yukiomi, Tsuboi Naoya, Okada Taro, Yamada Takum, Murakami Yoshimasa, Takada Yasunobu, Hirayama Haruo, Murohara Toyoak
PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Vol. 29 ( 10 ) page： 1069 - 1074 2006.10
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Does RV lead positioning provide additional benefit to cardiac resynchronization therapy in patients with advanced heart failure?
Shimano M, Inden Y, Yoshida Y, Tsuji Y, Tsuboi N, Okada T, Yamada T, Murakami Y, Takada Y, Hirayama H, Murohara T
Pacing and clinical electrophysiology : PACE Vol. 29 ( 10 ) page： 1069 - 74 2006.10
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Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia - Discrete arrhythmogenic consequences related to differential delayed-rectifier changes
Tsuji Y, Zicha S, Qi XY, Kodama I, Nattel S
CIRCULATION Vol. 113 ( 3 ) page： 345 - 355 2006.1
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P19 embryonal carcinoma cells: a suitable model system for cardiac electrophysiological differentiation at the molecular and functional level
van der Heyden MAG, van Kempen MJA, Tsuji Y, Rook MB, Jongsma HJ, Opthof T
CARDIOVASCULAR RESEARCH Vol. 58 ( 2 ) page： 410 - 422 2003.5
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Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block
Tsuji Y, Opthof T, Yasui K, Inden Y, Takemura H, Niwa N, Lu ZB, Lee JK, Honjo H, Kamiya K, Kodama I
CIRCULATION Vol. 106 ( 15 ) page： 2012 - 2018 2002.10
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Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle
Tsuji Y, Opthof T, Kamiya K, Yasui K, Liu WR, Lu ZB, Kodama I
CARDIOVASCULAR RESEARCH Vol. 48 ( 2 ) page： 300 - 309 2000.11
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Antiarrhythmic efficacy of dipyridamole in treatment of reperfusion arrhythmias - Evidence for cAMP-mediated triggered activity as a mechanism responsible for reperfusion arrhythmias
Yoshida Y, Hirai M, Yamada T, Tsuji Y, Kondo T, Inden Y, Akahoshi M, Murakami Y, Tsuda M, Tsuboi N, Hirayama H, Okamoto M, Ito T, Saito H, Toyama J
CIRCULATION Vol. 101 ( 6 ) page： 624 - 630 2000.2
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Heterogeneous distribution of the two components of delayed rectifier K+ current: a potential mechanism of the proarrhythmic effects of methanesulfonanilide class III agents
Cheng JH, Kamiya K, Liu WR, Tsuji Y, Toyama J, Kodama I
CARDIOVASCULAR RESEARCH Vol. 43 ( 1 ) page： 135 - 147 1999.7
KAKENHI (Grants-in-Aid for Scientific Research) 14
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非可逆的電気穿孔法の出力設定最適化と心室性不整脈治療への応用に関する検討
Grant number：22K08177 2022.4 - 2025.3
科学研究費助成事業 基盤研究(C)
因田 恭也, 辻 幸臣
Authorship：Coinvestigator(s)
カテーテルアブレーションにおける高周波に代わるエネルギー源として電界パルスを用いた非可逆的電気穿孔法が考案された。本法はその通電設定により心筋に特異的な障害を加えることが可能で、本法による心房細動治療の実験的検討が行われ、さらに臨床応用が始まろうとしている。しかし、これまでの報告では、電界パルスの幅、回数、頻度、電界などの条件は十分に検討されておらず、また心室性不整脈に対する治療効果は不明である。本研究の目的は、電界パルスを用いた非可逆的電気穿孔法の設定条件を心筋及び周囲組織の組織学的な検討を踏まえ検討し、さらに心室頻拍心室細動などの難治性不整脈に対する治療効果を実験的に検討することである。
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Development of painless ICD system by cardiac conductive fiber net
Grant number：21K08859 2021.4 - 2024.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Authorship：Coinvestigator(s)
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神経型ナトリウムチャネルを標的とする新しい抗不整脈薬開発のための基盤研究
Grant number：20K08450 2020.4 - 2023.3
科学研究費助成事業 基盤研究(C)
辻 幸臣, 山崎 正俊, 常山 幸一
Authorship：Principal investigator
Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）
致死性不整脈による心臓突然死は年々増加しており、近未来には、さらに深刻な社会問題となることが予想されている。しかし、有用な治療・予防薬はなく、その発生機序や分子基盤についても未解決な点が数多く残されている。本研究では、治療標的として神経型Naチャネル蛋白Nav1.8を取り上げ、薬理学的・遺伝学的Nav1.8阻害による効果を、重篤な不整脈疾患「反復する心室細動（電気的ストーム）」を再現した実験モデル動物で検討するとともに、Nav1.8発現が心筋で増加するメカニズムを追究し、その病態生理学的役割を明らかにする。心臓突然死の原因究明や新薬開発につながる基礎的知見の獲得を目指す。
Naチャネル電流の持続成分である遅延Na電流は、様々な心臓疾患に伴って増大する催不整脈電流で、その抑制によって有益な治療効果がもたらされると期待されている。本研究では、神経型NaチャネルNav1.8の心筋細胞での出現に着目し、Nav1.8阻害による遅延Na電流遮断効果、抗不整脈効果、その発現増加のメカニズムを、電気的ストーム家兎モデルを用いて検討する。このモデル動物は、完全房室ブロックの作成と除細動器の埋め込みを組み合わせることで作成され、QT時間延長、Torsades de Pointes（TdP）の反復発生、頻回の心室細動エピソードを特徴とする。本年度、その左室心室筋組織のNav1.8チャネル蛋白の発現が亢進していること、生体レベルでの検討にて、特異的Nav1.8チャネル遮断薬A-803467を静注すると、エピネフリン負荷誘発TdPは、QTcが短縮することで抑制されること、この抗不整脈効果は、A-803467の前投薬によっても得られることを観察した。さらに、DNAマイクロアレイ解析を行い、心室筋組織の全遺伝子発現のプロファイリングに関する予備的な結果を得た。電気的ストーム家兎と健常家兎との比較にて、2倍以上の発現変化を示した遺伝子数は、右室心筋で155, 心室中隔心筋で124, 左室心筋で69であった。PDK4, SEPINE1, S100A8, acyl-CoA desaturase の4遺伝子が10倍以上の発現変化を示した。PDK4とSEPINE1は心室中隔心筋で、S100A8は右室心筋で強発現していた。一方で、acyl-CoA desaturase発現は、右室・左室心筋で著減していた。
実験計画の実施が遅延している主な理由として、電気的ストーム家兎モデルの作成・準備に少なくとも3か月という長い期間を要すること等が挙げられる。また、モデル動物の作成、経過観察、実験を長崎大学で行っているが、マンパワーが不足しており、研究課題の進捗は遅延せざるを得ない状況にある。
研究課題の遂行を効率的にするための人的補助が得られる見込みは小さい。代表者・分担者ともにエフォートを上げ、モデル動物の作成数を増やすことで、達成度の遅れを取り戻すよう取り組んでいく。 -
Grant number：18H02802 2018.4 - 2021.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
YAMAZAKI MASATOSHI
Authorship：Coinvestigator(s)
This study aimed to elucidate the mechanism of VF initiation and maintenance and depicting the 3D scroll waves that sustain VF. The goal is to construct the technical foundation for the clinical application of a new myocardial ablation technique. The applicants established a rabbit VF storm model where severe arrhythmia with repeated VF occurred and an implantable cardioverter-defibrillator was frequently triggered. When we implemented our proposed “phase dispersion analysis” during VF, we succeeded in continuously capturing the stump of a stable 3D scroll wave anchored in the septum.
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Rotors as Drivers of Torsades de Pointes and Ventricular Fibrillation
Grant number：17K09511 2017.4 - 2020.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
TSUJI Yukiomi
Authorship：Principal investigator
Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）
Electrophysiological mechanisms of ventricular tachycardia and fibrillation (VT/VF) were explored, using a rabbit model of electrical storm featuring multiple defibrillator-firings for repetitive VT/VF by electrical remodeling (QT-prolongation) due to chronic atrioventricular block. A vortex-like reentrant activity termed a rotor underlies VT and VF, but they have the rotor frequency and dynamics particular to themselves. VT resulted from a rotor in the distinctive manner, possibly explaining the ECG pattern of Torsades de Pointes (TdP), and VF was maintained by high frequency rotors which became stationary at the septum. Late Na-current enhancement due to neural Na-channel NaV1.8 upregulation was a major contributor to the substrate favoring rotors to form TdP. Cardiac metabolism-related enzyme X was strikingly upregulated at the septum, suggesting that septal myocardium remodeling may play a crucial role in the conversion to VF-driving stationary rotors.
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Arrhythmogenic gap junction remodeling in diseased hearts
Grant number：15K09078 2015.4 - 2018.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
Honjo Haruo
Authorship：Coinvestigator(s)
Arrhythmogenic remodeling of myocardial gap junctions was investigated using a transgenic mouse model with cardiac dysfunction/lethal ventricular arrhythmias, and a rabbit electrical storm model induced by sustained severe bradycardia. In diseased hearts, connexin43 expression was decreased in the intercalated disc region of ventricular myocytes, which was associated with a reduction of conduction velocity and an increase in the spatial heterogeneity of action potential repolarization, leading to increased susceptibility of reentrant ventricular tachyarrhythmias. In addition, the results suggested that the renin-angiotensin system and calmodulin/CAMKII are involved in arrhythmogenic gap junction remodeling in diseased hearts.
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Role of CaMKII in an experimental model of ventricular fibrillation storm
Grant number：26461074 2014.4 - 2017.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
TSUJI Yukiomi, MAKITA Naomasa, DOBREV Dobromir, NATTEL Stanley
Authorship：Principal investigator
Grant amount：\4940000 （ Direct Cost: \3800000 、 Indirect Cost：\1140000 ）
To elucidate mechanisms of ventricular tachycardia and fibrillation (VT/VF), we studied a rabbit model of electrical storm featuring multiple defibrillator-firings for repetitive VT/VF by electrical remodeling (QT-prolongation) due to chronic atrioventricular block. Optical mapping revealed that although a vortex-like reentrant activity called a rotor underlies both VT and VF, they have the rotor frequency and dynamics particular to themselves. VT resulted from a rotor in the distinctive manner, possibly explaining the ECG pattern of Torsades de Pointes (TdP), and VF was sustained by a high frequency stable rotor. Late Na-current was a major contributor to the substrate favoring TdP-related rotor, based on our findings that Na-channel Nav1.5 was hyperphosphorylated by Ca/calmodulin-dependent protein kinase II and that late Na-current blockade with lidocaine suppressed TdP. Conversion to a rapidly stationary rotor from a disease-specific rotor may be essential for VT-transition to VF.
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Grant number：24390199 2012.4 - 2016.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
MAKITA Naomasa, MAEMURA Koji, YOSHIURA Koichiro, TSUJI Yukiomi, ISHIKAWA Taisuke
Authorship：Coinvestigator(s)
1.We performed whole exome sequencing in 12 probands with Brugada syndrome (BrS), and found two novel responsible genes; peripheral neuronal Na channel α subunit (SCN10A), and T-type Ca channel α subunit (CACNA1H). Further screening these genes in 96 BrS cases revealed 6 rare variations in SCN10A, and 5 rare variations in CACNA1H, demonstrating that SCN10A and CACNA1H are the novel genes responsible for BrS.
2.We participated in the international collaborative GWAS which has identified two novel risk loci for BrS, SCN10A and HEY2, in addition to the well-established responsible gene SCN5A (Bezzina, Makita, et al. Nat Genet 2013). Four Japanese institutions including us performed a replication study using Japanese BrS samples. To further identify genetic risks for the lethal arrhythmias in BrS, we have focused on symptomatic BrS patients, and developed a consortium; Japanese BrS-GWAS. -
Genetic and functional basis of cardiac ion channelopathy
Grant number：22136007 2010.4 - 2015.3
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
MAKITA Naomasa, MAEMURA Koji, TSUJI Yukiomi, ISHIKAWA Taisuke
Authorship：Coinvestigator(s)
Recent genome-wide association studies have demonstrated an association between MYH6, the gene encoding α-myosin heavy chain (α-MHC), and sinus node function in the general population. We identified an in-frame 3-bp deletion predicted to delete one residue (delE933) at the highly conserved coiled-coil structure within the binding motif to myosin-binding protein C (MyBP-C) in one patient. Co-immunoprecipitation analysis revealed sarcomere impairments. The HL-1 stably expressing delE933 showed slower conduction velocity on than wild-type. Furthermore, targeted knock-down of MYH6 in zebrafish significantly reduced the heart rate, which was rescued by co-expressed wild-typeα-MHC but not by delE933. The novel MYH6 mutation delE933 causes both structural damage of the sarcomere and functional impairments on atrial action propagation. This report reinforces the relevance of MYH6 for sinus node function and identifies a novel pathophysiology underlying familial SSS
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Grant number：22590777 2010.4 - 2013.3
科学研究費助成事業 基盤研究(C)
辻 幸臣
Authorship：Principal investigator
Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）
心室頻拍・細動(VT/VF)といった致死的不整脈が繰り返し発生し、植込型除細動器(ICD)が頻回・連続作動する状態を電気的ストーム(Electrical Storm: 以下ES)と呼ぶ。ESは緊急の処置を要する重篤な状態であるばかりでなく、心機能低下や新たな不整脈惹起の原因となり生命予後にも重大な影響を及ぼしている。しかし、その病態・機序は明らかでない。我々は、ESを再現した実験モデル動物の作成に成功し、その病態を心筋細胞内カルシウム動態異常の観点から解析した。ESの発生により、リン酸化酵素カルモジュリンキナーゼ(CaMKII)活性が著しく亢進しカルシウム制御蛋白のリン酸化異常を引き起こす結果、心収縮・拡張障害やさらなる不整脈の発生が促進されることをつきとめた。
電位依存性Na+チャネル電流(INa)は心筋の興奮伝播速度を決定する重要な脱分極電流である。チャネルは開口後迅速に不活性化されその電流値はゼロに近づくが、持続する成分、遅延Na+電流(INa-L)が存在する。INa-Lは催不整脈電流で、その増加により活動電位持続時間が延長し早期後脱分極が惹起されやすくなる。Na+チャネル遺伝子変異によって引き起こされる先天性QT延長症候群3型だけでなく,心肥大や心不全といった後天的な病態心でもINa-Lが増加することが知られている。近年、CaMKIIによってNa+チャネルが過リン酸化されるとINa-Lが増加することが報告された。これらの所見より、CaMKII活性が亢進するESの病態にもINa-Lが深く関与し、INa-Lを標的とした治療戦略が有益な効果をもたらすかもしれないと考えられる。この仮説を検証するためINa-L遮断薬の抗不整脈効果を検討した。INa-L遮断薬がこの動物モデルのVT/VFを抑制すること、単離心室筋細胞で出現した早期・後期後脱分極を抑制することを観察した。以上の実験結果より、INa-L遮断が新たな治療戦略と成り得ることが示唆され、ESの病態に果たすINa-Lの役割を明らかにしていく必要がある。 -
Arrhythmogenic mechanism of gap junctional uncoupling
Grant number：20590860 2008 - 2010
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
HONJO Haruo, KAMIYA Kaichiro, TSUJI Yukiomi, KODAMA Itsuo
Authorship：Collaborating Investigator(s) (not designated on Grant-in-Aid)
Arrhythmogenic mechanisms of intercellular electrical uncoupling was investigated by optical mapping of purfued rabbit hearts. Pharmacological inhibition of myocardial gap junctions stabilized the dynamics of spiral-wave reentry and facilitated its perpetuation, whereas enhancement of gap junctional coupling destabilized spiral-wave reentry and promoted its early self-termination by compromising propagation of excitation waves with strong curvature near the rotation center. These results suggest that enhancement of gap junctional coupling could be a useful strategy for the treatment of life-threatening arrhythmias in diseased hearts with gap junctional remodeling.
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Grant number：19659203 2007 - 2008
科学研究費助成事業 萌芽研究
神谷 香一郎, 辻 幸臣
Authorship：Coinvestigator(s)
本研究の目的は、最新の心不全治療法である心臓再同期療法(CRT:Cardiac Resynchrozation Therapy)の普及に伴い顕在化してきた医療経済上の問題を克服する為、それに替わる細胞移植によるCRTの実用化をめざすことである。再生医学の進歩は循環器学の領域でもめざましく、骨格筋芽細胞および骨髄単核球細胞移植による重症虚血性心筋症患者に対する細胞移植、心筋再生による臨床治療が既に国内でもスタートしている。本研究では、この実用段階にある細胞移植療法を応用し、機械によるCRTに替わり、医療経済、QOL改善の点から優れた次世代CRTの開発を目的としている。
本年度は、不整脈発生モデルを用いて、骨格筋芽細胞を移植して非興奮部位を作成し、不整脈発生に及ぼす影響を観察した。その結果、不整脈発生は、心筋表面に直接移植用骨格筋芽細胞を注入しても、明らかな変化がないことを観察した。同様に、共同研究で移植用細胞群を組織内で集積させ、ペースメーカー機能を発揮させる試みを行った。磁性粒子をヒト骨格筋芽細胞にラベルし、新生児ラット心筋細胞と共培養した。磁石により骨格筋芽細胞をパターン化すると、非興奮部位の存在により、不整脈が容易に停止することを確認した。これらの成果は、平成21年3月の第73回日本循環器学会で発表された。移植用細胞をパターン化することが、細胞移植による不整脈停止機能あるいはペースメーカー機能を発揮する重要な要素と考え、今後の検討課題であると考えた。 -
反復する心室頻拍・細動(ストーム)の機序と除細動器頻回作動が引き起こす問題点
Grant number：18890081 2006 - 2007
科学研究費助成事業 若手研究(スタートアップ)
辻 幸臣
Authorship：Principal investigator
Grant amount：\2700000 （ Direct Cost: \2700000 ）
反復する心室頻拍・細動(Electrical Storm:ES)を呈する新しい動物モデルを確立した.独自に所有する慢性完全房室ブロック(CAVB)家兎モデルに植込み型除細動器(ICD)を植え込み,臨床症例と類似なESのエピソードを再現することが可能であった.ICD植込み手術を行い感染症などの合併症を有しなかったCAVB家兎(n=15)では,QTc間隔が延長し(0,21日目,185±10,226±11ms,P<0.05),非持続性心室頻拍が頻発した.その後,11羽(73%)がES(24時間以内に3回以上の心室細動エピソード)に進展した.ESは補充調律開始後35±9日目に出現し,82±8日の観察期間中14±4日間に認められた.QTc時間は,ES時に著名に延長した(271±12vs.219±10ms,P<0.05).ICD作動回数は,1羽あたり平均86±29回で総計1163回に及んだ.浸透圧ポンプを用い,カルモジュリン拮抗薬W-7を1週間持続投与したところ,用量依存性に心室頻拍・細動エピソードが減少し,ESが抑制された.CAVB家兎心室筋ではコントロールに比しカルモジュリンキナーゼIIの発現が増加した.ESを呈した家兎では,VFエピソードはあったがESに進展しなかった家兎に比し,その増加がより顕著であった.これらの実験結果から,カルモジュリン・カルモジュリンキナーゼ系細胞内シグナルがこの動物モデルのES発生に重要な役割を果たしていることが示唆された.Ca^<2+>ハンドリングの発現・機能変化,及び,カルモジュリンキナーゼ発現の程度によるCa^<2+>ハンドリングの変化の相違についての検討を現在継続している.本課題は,ESに関する初めての実験研究であり,これらの電気生理学的・分子生物学的変化の特徴から,重篤な不整脈についての理解を深めることができるとともにESの治療・管理に役立つと考えられる.
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Grant number：18590766 2006 - 2007
Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
INDEN Yasuya, MUROHARA Toyoaki, TSUJI Yukiomi, MAEDA Kengo
Authorship：Coinvestigator(s)
The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atrial structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure.Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses.Atrial fibrillation(AF) lasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits(mean duration of AF : 8.0 ± 1.4 seconds). Pioglitazone reduced the duration of AF(33 ± 0.2 seconds, P <.05)and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 ± 2 ms vs 41 ± 2 ms, P <.05) and atrial fibrosis(16.8% ± 0.8% vs 10.9% ± 0.7%, P <.05 ; control 1.6% ± 0.2%), effects comparable to those of candesartan(duration of AF : 3.0 ± 0.2 seconds ; activation time 44 ± 2 ms ; fibrosis : 9.4% ± 0.6%). Both pioglitazone and candesartan reduced transforming growth factor-al, tumor necrosis factor-o, and activated extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of pioglitazone or candesartan alone.
Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR u may be a potential therapeutic target for human AF.