Elucidation of novel pathophysiology underlysing lethal arrhythmia due to mutations in cardiac ion transporters

• Project/Area Number: 15H04823
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagasaki University
• Principal Investigator: MAKITA Naomasa 長崎大学, 医歯薬学総合研究科(医学系), 教授 (00312356)
• Co-Investigator(Kenkyū-buntansha): 吉浦 孝一郎 長崎大学, 原爆後障害医療研究所, 教授 (00304931) ; 牧山 武 京都大学, 医学研究科, 助教 (30528302) ; 渡邊 泰秀 浜松医科大学, 医学部, 教授 (50305380)
• Research Collaborator: ISHIKAWA Taisuke
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: Na-Ca交換体 / トランスポータ / 早期再分極症候群 / QT短縮症候群 / 遺伝子変異 / 心臓突然死 / J波 / パッチクランプ / ゲノム編集 / 致死性不整脈 / コンピュータシミュレーション / Na/Ca交換体 / 心室細動 / カルモジュリン / 内科 / 分子心臓学

Outline of Final Research Achievements

By using target exon panel sequencing for 450 cardiac disease-related genes, we identified, for the first time, 12 mutations in SLC8A1, the gene encoding for cardiac Na/Ca exchanger (NCX1) in patients with idiopathic ventricular fibrillation associated with QT shortening and J waves on ECG. Mutant NCX1 transiently expressed in COS-7 cells exhibited significantly reduced NCX1 current compared with wild-type NCX1, and impaired 45Ca uptake. Akthough it has been generally accepted that most inherited lethal arrhythmia are attributable to the mutations in cardiac ion channel genes, our study clear demonstrates that there is a distinct inherited lethal arrhythmia entity asociated with mutations in cardiac transporter genes.

Academic Significance and Societal Importance of the Research Achievements

心臓突然死にはこれまで様々な心電図マーカーが報告され、器質的心疾患のない心室細動（特発性心室細動）の原因遺伝子にもいくつかの原因遺伝子が報告されてきた。しかし変異の判明率は低いため、特発性心室細動の分子病態の全体像はつかめておらず、遺伝子解析の結果を予後予測や突然死予防に応用することはできていなかった。今回我々はQT短縮とJ波を特徴とする特発性心室細動に、これまで全く知られていなかった心臓のトランスポーターの変異を同定し、新たな致死性不整脈の疾患範疇を解明した。今後この疾患の分子病態をさらに解析することで、心臓突然死の発症前予知と予防を推進できると期待している。

Research Products

• [Int'l Joint Research] INSERM(フランス)
• [Journal Article] Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients (2019)
  • Author(s): Shimizu Wataru、Makimoto Hisaki、Yamagata Kenichiro、Kamakura Tsukasa、Wada Mitsuru、Miyamoto Koji、Inoue-Yamada Yuko、Okamura Hideo、Ishibashi Kohei、Noda Takashi、Nagase Satoshi、Miyazaki Aya、Sakaguchi Heima、Shiraishi Isao、Makiyama Takeru、Ohno Seiko、Itoh Hideki、et al
  • Journal Title: JAMA Cardiology Volume: in press Issue: 3 Pages: 246-254
  • DOI: 10.1001/jamacardio.2018.4925
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical Manifestations and Long-Term Mortality in <i>Lamin A/C</i> Mutation Carriers From a Japanese Multicenter Registry (2018)
  • Author(s): 14.Nakajima K, Aiba T, Makiyama T, Nishiuchi S, Ohno S, Kato K, Yamamoto Y, Doi T, Shizuta S, Onoue K, Yagihara N, Ishikawa T, Watanabe I, Kawakami H, Oginosawa Y, Murakoshi N, Nogami A, Aonuma K, Saito Y, Kimura T, Yasuda S, Makita N, Shimizu W, Horie M, Kusano K.
  • Journal Title: Circulation Journal Volume: 82 Issue: 11 Pages: 2707-2714
  • DOI: 10.1253/circj.CJ-18-0339
  • NAID: 40021697176
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-10-25
  • Peer Reviewed / Open Access
• [Journal Article] HCN4 Gene Polymorphisms Are Associated With Occurrence of Tachycardia-Induced Cardiomyopathy in Patients With Atrial Fibrillation (2018)
  • Author(s): Nakano Yukiko、Ochi Hidenori、Sairaku Akinori、Onohara Yuko、Tokuyama Takehito、Motoda Chikaaki、Matsumura Hiroya、Tomomori Shunsuke、Amioka Michitaka、Hironobe Naoya、Ohkubo Yousaku、Okamura Shou、Makita Naomasa、Yoshida Yukihiko、Chayama Kazuaki、Kihara Yasuki
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 11 Issue: 7 Pages: 1-7
  • DOI: 10.1161/circgen.117.001980
  • Peer Reviewed
• [Journal Article] HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node (2018)
  • Author(s): Kozasa Yuko、Nakashima Noriyuki、Ito Masayuki、Ishikawa Taisuke、Kimoto Hiroki、Ushijima Kazuo、Makita Naomasa、Takano Makoto
  • Journal Title: The Journal of Physiology Volume: 596 Issue: 5 Pages: 809-825
  • DOI: 10.1113/jp275303
  • Peer Reviewed / Open Access
• [Journal Article] Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants (2018)
  • Author(s): Gray B., Hasdemir C., Ingles J., Aiba T., Makita N., Probst V., Wilde A. A. M., Newbury-Ecob R., Sheppard M. N., Semsarian C., Sy R. W., Behr E. R.
  • Journal Title: Heart Rhythm Volume: 15 Issue: 7 Pages: 1051-1057
  • DOI: 10.1016/j.hrthm.2018.03.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Allele-specific Ablation Rescues Electrophysiological Abnormalities in a Human iPS Cell Model of Long-QT Syndrome with a CALM2 Mutation. (2017)
  • Author(s): Yamamoto Y, Horie M, et al.
  • Journal Title: Human Molecular Genetics Volume: 印刷中 Issue: 9 Pages: 1670-1677
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genotype-phenotype correlation of SCN5A mutation for clinical and electrocardiographic characteristics of probands with Brugada syndrome: Japanese Multicenter Registry. (2017)
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  • 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] A novel de novo calmodulin mutation in a 6-year-old boy who experienced an aborted cardiac arrest (2017)
  • Author(s): Takahashi K, Ishikawa T, Makita N, Takefuta K, Nabeshima T, Nakayashiro M
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• [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
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• [Journal Article] Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death. (2017)
  • Author(s): Oshima Y, Yamamoto T, Ishikawa T, Mishima H, Matsusue A, Umehara T, Murase T, Abe Y, Kubo SI, Yoshiura KI, Makita N, Ikematsu K.
  • Journal Title: J Hum Genet. Volume: 62 Issue: 11 Pages: 989-995
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  • 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] Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes. (2017)
  • Author(s): Kuroda Y, Yuasa S, Watanabe Y, Ito S, Egashira T, ・・・Horie M, Kamiya K, Fukuda K.
  • Journal Title: Biochemistry and Biophysics Reports Volume: 9 Pages: 245-256
  • DOI: 10.1016/j.bbrep.2017.01.002
  • 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
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  • Peer Reviewed / Open Access
• [Journal Article] Letter to the Editor (2017)
  • Author(s): Ishikawa T, Makita N, Aoki H, Saida Y
  • Journal Title: J Vet Intern Med Volume: 31 Issue: 4 Pages: 967-968
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  • Peer Reviewed / Open Access
• [Journal Article] The Phenotypic Spectrum of a Mutation&nbsp;Hotspot Responsible for the&nbsp;Short QT Syndrome (2017)
  • Author(s): Hu D, Li Y, Zhang J, Pfeiffer R, Gollob MH, Healey J, Harrell DT, Makita N, Abe H, Sun Y, Guo J, Zhang L, Yan G, Mah D, Walsh EP, Leopold HB, Giustetto C, Gaita F, Zienciuk-Krajka A, Mazzanti A, Priori SG, Antzelevitch C, Barajas-Martinez H.
  • Journal Title: JACC: Clinical Electrophysiology Volume: 印刷中 Issue: 7 Pages: 727-743
  • DOI: 10.1016/j.jacep.2016.11.013
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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] Partial IK1 blockade destabilizes spiral wave rotation center without inducing wave breakup and facilitates termination of reentrant arrhythmias in ventricles (2016)
  • Author(s): Kushiyama Y, Honjo H, Niwa R, Takanari H, Yamazaki M, Takemoto Y, Sakuma I, Kodama I, Kamiya K
  • Journal Title: American Journal of Physiology Heart and Circulatory Physiology Volume: 311 Issue: 1 Pages: 750-758
  • DOI: 10.1038/srep34198
  • NAID: 120005946586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reply: Search for Evidence-Based Medicine for Brugada Syndrome: The Complex Network of the Brugada Syndrome (2016)
  • Author(s): Nademanee K, Raju H, De Noronha S, Papadakis M, Robinson L, Rothery S, Makita N, Kowase S, Boonmee N, Vitayakritsirikul V, Ratanarapee S, Sharma S, van der Wal A. C. Christiansen M, Tan H. L, Wilde A. A, Nogami A, Sheppard M. N, Veerakul G, Behr E. R.
  • Journal Title: J Am Coll Cardiol Volume: 67 Issue: 13 Pages: 1658-1659
  • DOI: 10.1016/j.jacc.2016.01.032
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inherited bradyarrhythmia: A diverse genetic background. (2016)
  • Author(s): Ishikawa T, Tsuji Y, Makita N
  • Journal Title: Journal of Arrhythmia Volume: 印刷中 Issue: 5 Pages: 352-358
  • DOI: 10.1016/j.joa.2015.09.009
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeted resequencing identifies TRPM4 as a major gene predisposing to progressive familial heart block type I. (2016)
  • Author(s): Daumy X, Amarouch MY, Lindenbaum P, Bonnaud S, Charpentier E, Bianchi B, Nafzger S, Baron E, Fouchard S, Thollet A, Kyndt F, Barc J, Le Scouarnec S, Makita N, Le Marec H, Dina C, Gourraud JB, Probst V, Abriel H, Redon R, Schott JJ.
  • Journal Title: Int J Cardiol Volume: 207 Pages: 349-358
  • DOI: 10.1016/j.ijcard.2016.01.052
  • Peer Reviewed / Int'l Joint Research
• [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] Prognostic Significance of Premature Ventricular Contractions without Obvious Heart Diseases Determined by Standard 12-Lead Electrocardiography Considering their Morphology. (2016)
  • Author(s): Haruta D, Akahoshi M, Hida A, Sera N, Imaizumi M, Ichimaru S, Nakashima E, Takahashi I, Ohishi W, Fukae S, Maemura K.
  • Journal Title: Ann Noninvasive Electrocardiol. Volume: 印刷中 Issue: 2 Pages: 142-151
  • DOI: 10.1111/anec.12275
  • Peer Reviewed
• [Journal Article] Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction. (2016)
  • Author(s): Chen J, Makiyama T, Wuriyanghai Y, Ohno S, Sasaki K, Hayano M, Harita T, Nishiuchi S, Yamamoto Y, Ueyama T, Shimizu A, Horie M, Kimura T.
  • Journal Title: Heart Rhythm Volume: 13(1) Issue: 1 Pages: 289-298
  • DOI: 10.1016/j.hrthm.2015.08.021
  • 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] LMNA cardiomyopathy detected in Japanese arrhythmogenic right ventricular cardiomyopathy cohort. (2016)
  • Author(s): Kato K, Takahashi N, Fujii Y, Umehara A, Nishiuchi S, Makiyama T, Ohno S, Horie M
  • Journal Title: J Cardiol Volume: 印刷中 Issue: 4 Pages: 346-51
  • DOI: 10.1016/j.jjcc.2015.10.013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel SCN10A variants associated with Brugada syndrome (2016)
  • Author(s): Fukuyama M, Ohno S, Makiyama T, Horie M
  • Journal Title: Europace. Volume: 印刷中 Issue: 3 Pages: 520-529
  • DOI: 10.1093/cvr/cvv042
  • Peer Reviewed
• [Journal Article] Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome. (2015)
  • Author(s): Harrell DT, Ashihara T, Ishikawa T, et al.
  • Journal Title: International Journal of Cardiology. Volume: 190 Pages: 393-402
  • DOI: 10.1016/j.ijcard.2015.04.090
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation. (2015)
  • Author(s): Hayashi K, Konno T, Tada H, Tani S, Liu L, Fujino N, Nohara A, Hodatsu A, Tsuda T, Tanaka Y, Kawashiri MA, Ino H, Makita N, Yamagishi M.
  • Journal Title: Circ Arrhythm Electrophysiol. Volume: 8 Issue: 5 Pages: 1095-1104
  • DOI: 10.1161/circep.114.002519
  • Peer Reviewed / Open Access
• [Journal Article] A novel mutation in alpha-myosin heavy chain gene is associated with sick sinus syndrome (2015)
  • Author(s): Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 8 Issue: 2 Pages: 400-108
  • DOI: 10.1161/circep.114.002534
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Molecular Mechanisms Underlying Urate-Induced Enhancement of Kv1.5 Channel Expression in HL-1 Atrial Myocytes (2015)
  • Author(s): Maharani N, Ting YK, Cheng J, Hasegawa A, Kurata Y, Li P, Nakayama Y, Ninomiya H, Ikeda N, Morikawa K, Yamamoto K, Makita N, Yamashita T, Shirayoshi Y, Hisatome I.
  • Journal Title: Circulation Journal Volume: 79 Issue: 12 Pages: 2659-2668
  • DOI: 10.1253/circj.CJ-15-0416
  • NAID: 130005110934
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome (2015)
  • Author(s): Nademanee K, Raju H, de Noronha SV, Papadakis M, Robinson L, Rothery S, Makita N, Kowase S, Boonmee N, Vitayakritsirikul V, Ratanarapee S, Sharma S, van der Wal AC, Christiansen M, Tan HL, Wilde AA, Nogami A, Sheppard MN, Veerakul G, Behr ER
  • Journal Title: J Am Coll Cardiol Volume: 66(18) Issue: 18 Pages: 1976-1986
  • DOI: 10.1016/j.jacc.2015.08.862
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Relationships Between Clinical Characteristics and Decreased Plakoglobin and Connexin 43 Expressions in Myocardial Biopsies From Patients With Arrhythmogenic Right Ventricular Cardiomyopathy (2015)
  • Author(s): Yoshida T, Kawano H, Kusumoto S, Fukae S, Koga S, Ikeda S, Koide Y, Abe K, Hayashi T, Maemura K.
  • Journal Title: International Heart Journal Volume: 56 Issue: 6 Pages: 626-631
  • DOI: 10.1536/ihj.15-144
  • NAID: 130005113062
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Effective Management of Atrioventricular Interval for Paroxysmal Atrial Fibrillation That Developed After DDDR Pacemaker Implantation in a Sick Sinus Syndrome Patient (2015)
  • Author(s): Tasaki H, Ashizawa N, Nagao S, Fukushima K, Furukawa R, Fukae S, Maemura K.
  • Journal Title: International Heart Journal Volume: 56 Issue: 5 Pages: 558-563
  • DOI: 10.1536/ihj.15-008
  • NAID: 130005102113
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Asymmetry of parental origin in Long QT syndrome. Preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. (2015)
  • Author(s): Itoh H, Berthet M, Fressart V, Denjoy I, Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Shimizu W, Wilde AAM, Schulze-Bahr E, Horie M, Tezenas du Montcel S, Guicheney P.
  • Journal Title: European Journal of Human Genetics Volume: - Issue: 8 Pages: 1160-6
  • DOI: 10.1038/ejhg.2015.257
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 不整脈症候群で心臓が構造的に正常な患者における心筋症の原因遺伝子変異の特定 (2018)
  • Author(s): 八木原伸江, 渡部裕, 蒔田直昌, 堀江稔, 清水渉, 大野聖子, 長谷川奏恵, 相庭武司, 田中敏博, 角田達彦, 重水大智, 徹 南野
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] CaMKII as a target for novel therapy to treat lethal ventricular tachyarrhythmias. (2018)
  • Author(s): 辻幸臣, 蒔田直昌
  • Organizer: 第57回日本生体医工学学会大会
• [Presentation] CALM2関連性QT延長症候群iPSCモデルにおいて、l-cis-diltiazemは遅延したL型calciumチャネルの不活性化をさらに強める (2018)
  • Author(s): 横井文香, 牧山武, 山本雄大, 張田健志, Yimin Wuriyanghai, 早野護, 西内英, 糀谷泰彦, 廣瀬紗也子, 高景山, 大野聖子, 豊田太, 吉田善紀, 蒔田直昌, 堀江稔, 木村剛
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Torsadogenic Action Of Late Na+ Current In Experimental Electrical Storm (2018)
  • Author(s): Yamazaki M., Tsuji Y. , Niwa R., Tomii N., Arafune T., Honjo H., Dobrev D., Nattel S., Kodama I., Sakuma I., Makita N.
  • Organizer: The 39th Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Single Cell Electrophysiological Analysis of Human iPS Cell-Derived Cardiomyocytes Generated from Long-QT Syndrome Patients Carrying a CALM2 Mutation Using a Membrane Voltage Imaging System (2018)
  • Author(s): Yamamoto Y., Makiyama T, Wuriyanghai Y., Kohjitani H., Hirose S., Gao J, Kashiwa A., Kimura T., Ishikawa T., Motomura H., Makita N, Ohno S., Chonabayashi K., Yoshida Y., Suda K., Horie M
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] The inactivation of L-type Ca2+ Channel was impaired in Human iPS Cell Model of Long-QT Syndrome with CALM2-D134H Mutation. (2018)
  • Author(s): Yamamoto Y., Makiyama T., Harita T., Hayano M., Nishiuchi S., Wuriyanghai Y., Kohjitani H., Hirose S., Yokoi F., Ishikawa T., Ohno S., Chonabayashi K., Suda K., Yoshida Y., Horie M., Makita N., Kimura T.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Duration Predicts Events In Caucasians With E1784K-SCN5A: The E1784K International Consortium (2018)
  • Author(s): Wijeyeratne Y. , Makita N. et al
  • Organizer: The 39th Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms of Electrical Storm Associated With QT Prolongation: Successful Mapping of Torsades de Pointes in Rabbits (2018)
  • Author(s): Tsuji Y., Yamazaki M., Niwa R., Tomii N., Arafune T., Honjo H., Dobrev D., Nattel S., Kodama I., Sakuma I., Makita N
  • Organizer: American Heart Association Annual Scientific Sessions 2018
  • Int'l Joint Research / Invited
• [Presentation] HCN4 Polymorphisms and Tachycardia Induced Cardiomyopathy (2018)
  • Author(s): Nakano Y., Ochi H., Onohara Y., Sairaku A., Tokuyama T., Motoda C., Matsumura H., Tomomori S., Amioka M., Hironobe N., Ohkubo Y., Okamura S., Makita N., Yoshida Y., Chayama K., Kihara Y.
  • Organizer: The 65th Annual Meeting of the Japan Heart Rhythm Society
• [Presentation] Clinical Manifestations and Long-term Mortality in Lamin A/C Mutation Carriers from the Japanese Multicenter Registry (2018)
  • Author(s): Nakajima K., Aiba T., Makiyama T., Nishiuchi S., Ohno S., Doi T., Shizuta S., Onoue K., Yagihara N., Ishikawa T., Watanabe I., Oginosawa Y., Nogami A., Aonuma K., Saitoh Y., Kimura T., Makita N., Shimizu W., Horie M., Kusano K.
  • Organizer: The 65th Annual Meeting of the Japan Heart Rhythm Society
• [Presentation] Genotype-Dependent Differences in Short QT Syndrome (2018)
  • Author(s): Makita N.
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Atrial Conduction Defects Caused by a Connexin45 Mutation (2018)
  • Author(s): Makita N.
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Novel Arrhythmia Syndrome Associated with Gap Junction Mutations (2018)
  • Author(s): Makita N.
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Clinical and Genetic Basis of Calmodulinopathy (2018)
  • Author(s): Makita N.
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Pathophysiology of Inherited Arrhythmias Associated with Ca Handling Abnormality (2018)
  • Author(s): Makita N.
  • Organizer: The 65th Annual Meeting of the Japan Heart Rhythm Society
  • Invited
• [Presentation] Mutation Hot-spot-based Risk Stratification In Long QT Syndrome Type 1: Data From A Nationwide Japanese LQT Registry (2018)
  • Author(s): Kashiwa A., Aiba T., Makimoto H., Yamagata K. , Keiko S. , Yagihara N., Watanabe H. , Ohno S., Hayashi K. , Sumitomo N., Yoshinaga M. , Morita H., Miyamoto Y. , Makita N. , Horie M., Yasuda S., Kusano K., Shimizu W. , The_Japanese_LQTS_registry_investigators.
  • Organizer: The 39th Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Cardiac Connexin Syndrome: A New Inherited Cardiac Conduction Disease Entity with Distinct Electrophysiological and Extracardiac Manifestations. (2018)
  • Author(s): Ishikawa T., Seki A., Hagiwara N., Makita N.
  • Organizer: 第82回日本循環器学会学術大会
• [Presentation] Rare Coding Variants in Genes Other Than SCN5A Are Minimal Genetic Burden on the Prognosis of Brugada Syndrome (2018)
  • Author(s): Ishikawa T., Mishima H., Ohno S., T. Aiba, Nakano Y., Aizawa Y., Nakajima T., Hayashi K., Murakoshi N., Yagihara N., Kimoto H., Makiyama T., Watanabe H., Morita H., Yoshiura K., Nogami A., Shimizu W., Horie M., Tanaka T., Makita N.
  • Organizer: The 65th Annual Meeting of the Japan Heart Rhythm Society
• [Presentation] Lack Of Genotype-phenotype Correlation In Brugada Syndrome And Sudden Arrhythmic Death Syndrome Families With Reported Pathogenic SCN1B Variants (2018)
  • Author(s): Gray B. , Hasdemir C. , Ingles J. , Aiba T., Makita N. , PROBST V. , Wilde A., Semsarian C. , Sy R., Behr E.
  • Organizer: The 39th Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Mutations in Desmin Gene Uncover Phenotypic Overlap between Progressive Cardiac Conduction Defect with Muscular Dystrophy and Cardiomyopathy (2017)
  • Author(s): 木本浩貴, 石川泰輔, 町田紘子, 森田宏, 住友直方, 中村一文, 伊藤浩, バーク・ジュリアン, ショット・ジョンジャック, 蒔田直昌.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Calmodulin Mutations Responsible for Long QT Syndrome and Functional Rescue using a CRISPR/Cas9 System (2017)
  • Author(s): 蒔田直昌.
  • Organizer: 第94回日本生理学会大会
  • Invited
• [Presentation] ブルガダ症候群の予後予測を目指す変異心筋Naチャネルの機能解析 (2017)
  • Author(s): 下河舞子, 木本浩貴, 石川泰輔, 蒔田直昌.
  • Organizer: 第68回西日本生理学会
• [Presentation] lL-cis-Diltiazem Ameliorates Impaired Calcium Channel Inactivation in a Patient-Specific Stem Cell Model of Long-QT Syndrome with a Calmodulin Mutation (2017)
  • Author(s): Yokoi F, Makiyama T, Harita T, Yamamoto Y, Hayano M, Nishiuchi S, Kohjitani H, Wuriyanghai Y, Hirose S, Toyoda F, Yoshida Y, Makita N, Horie M, Kimura T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Sasaki K, Wuriyanghai Y, Nishiuchi S, Kohjitani H, Hirose S, Ishikawa T, Motomura H, Ohno S, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] CALM2-D134H Mutation Associated With Long-QT Syndrome Delayed Inactivation of L-type Ca2+ Currents in Human iPS Cells Derived Cardiomyocytes. (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Yokoi F, Ishikawa T, Ohno S, Chonabayashi K, Suda K, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: American Heart Association Annual Scientific Session 2017
  • Int'l Joint Research
• [Presentation] CALM2-D134H Mutation Associated with Long-QT Syndrome Prevents Inactivation of L-type Ca2+ Currents in Human iPS Cell Derived Cardiomyocytes. (2017)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Yokoi F, Ishikawa T, Ohno S, Chinabayashi K, Suda K, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Genotype-Phenotype Correlation of SCN5A Mutations for the Clinical and Electrocardiographic Characteristics of Probands with Brugada Syndrome: A Japanese Multicenter Registry (2017)
  • Author(s): Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y, Takagi M, Makiyama T, Ohno S, Fukuda K, Watanabe H, Morita H, Hayashi K, Fukushima-Kusano K, Kamakura S, Yasuda S, Ogawa H, Y. M, Kapplinger J, Ackerman M, Shimizu W.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers (2017)
  • Author(s): Nishiuchi S, Makiyama T, Aiba T, Nakajima K, Ishikawa T, Murakoshi N, Watanabe H, Ohno S, Doi T, Shizuta S, Minamino T, Saito Y, Oginosawa Y, Nogami A, Aonuma K, Kusano K, Makita N, Shimizu W, Horie M, Kimura T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Sosiety Scientific Session
  • Int'l Joint Research
• [Presentation] 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
• [Presentation] Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers in Japan (2017)
  • Author(s): Nishiuchi S, Aiba T, Makiyama T, Nakajima K, Yagihara N, Ishikawa T, Onoue K, Murakoshi N, Watanabe I, Ohkubo K, Watanabe H, Ohno S, Doi T, Shizuta S, Minamino T, Saito Y, Oginosawa Y, Nogami A, Aonuma K, Kusano K, Makita N, Shimizu W, Horie M, Kimura T.
  • Organizer: American Heart Association Annual Scientific Session 2017
  • Int'l Joint Research
• [Presentation] De novo and Familial Connexin45 Mutant R75H Causes Progressive Atrioventricular Block Associated with Craniofacial and Dentodigital Dysmorphisms (2017)
  • Author(s): Makita N, Seki A, Ishikawa T, Dawmy X, Mishima H, Barc J, Sasaki R, Nishii K, Saito K, Urano M, Ohno S, Otsuki S, Kimoto H, Baruteau A, Aurelie T, Swanny F, St?phanie B, Parent P, Shibata Y, Perrin JJ, Le Marec H, Hagiwara N, Mercier S, Horie M, Probst V, Yoshiura K, Redon R, Schott J, J.
  • Organizer: Printemps de la Cardiologie Recherche Fondamentale et Clinique
  • Int'l Joint Research / Invited
• [Presentation] Brugada Syndrome: Basic and Clinical Updates, Advancement of Basic Research (2017)
  • Author(s): Makita N.
  • Organizer: 13th Annual Congress European Cardiac Arrhythmia Society
  • Int'l Joint Research / Invited
• [Presentation] Genetic Mutation of Brugada Syndrome (2017)
  • Author(s): Makita N.
  • Organizer: Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Genetic and Biophysical Basis of Calmodulinopathy, and Functional Rescue by Genome-Editing in Patient-Derived iPS Cardiomyocytes (2017)
  • Author(s): Makita N.
  • Organizer: 20th International Symposium on Calcium Binding Proteins and Calcium Function in Health and Disease
  • Int'l Joint Research / Invited
• [Presentation] Multinational genome-wide association study in long QT syndrome identifies a role for common genetic variation in disease susceptibility and points to a polygenic architecture in mutation-negative cases (2017)
  • Author(s): Lahrouchi N, Makita N, et al.
  • Organizer: Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research
• [Presentation] Mutation in L-type Calcium Channel Cav1.3 (CACNA1D) Underlying a Consanguineous Family Associated with Congenital AV Block and Deaf-Blindness (2017)
  • Author(s): Kimoto H, Ishikawa T, Mishima H, Hasdemir C, Yoshiura K, Makita N.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Sick sinus syndrome caused by HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular non-compaction (2017)
  • Author(s): Ishikawa T, Ohno S, Murakami T, Yoshida K, Fukuoka T, Mishima H, Kimoto H, Aiba T, Nogami A, Sumitomo N, Shimizu W, Horigome H, Yoshiura KI, Horie M, Makita N.
  • Organizer: Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research
• [Presentation] Genetics of Familial Atrial Fibrillation (2017)
  • Author(s): Ishikawa T, Makita N.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Progressive Cardiac Conduction Defect and Sick Sinus Syndrome as Sodium Channelopathy (2017)
  • Author(s): Ishikawa T.
  • Organizer: The 10th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Mutation Spot-sensitive Clinical Features and Risk of Life-threatening Arrhythmia in Long QT Syndrome Type 1 in Japan (2017)
  • Author(s): Aiba T, Makimoto H, Yagihara N, Watanabe H, Ohno S, Hayashi K, Sumitomo N, Yoshinaga M, Morita H, Miyamoto Y, Makita N, Horie M, Yasuda S, Kusano K, Shimizu W.
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Electrophysiological Features of Patient-specific Human-induced Pluripotent Stem Cell-derived Cardiomyocytes Carrying the SCN5A-D1275N Mutation (2016)
  • Author(s): 早野 護、牧山 武
  • Organizer: 日本循環器学会
  • Place of Presentation: 仙台、仙台国際会議場
  • Year and Date: 2016-03-18
  • Invited
• [Presentation] 歯牙骨格形成異常を合併する洞不全症候群に固定されたコネキシン45遺伝子変異と機能異常 (2016)
  • Author(s): 木本浩貴, 石川泰輔, 西井明子, 斎藤加代子, 三嶋博之, 大槻早紀, 辻幸臣, 吉浦孝一郎, 萩原誠久, 蒔田直昌.
  • Organizer: 第67回西日本生理学会
• [Presentation] Naチャネル遺伝子のバリエーションと致死性不整脈の罹患性との関連 (2016)
  • Author(s): 蒔田直昌, 石川泰輔.
  • Organizer: 第93回日本生理学会大会
• [Presentation] 心臓刺激伝導系と心室の電気的興奮現象のマルチスケールシミュレーション研究 (2016)
  • Author(s): 稲田慎, ハーレルダニエル, 原口亮, 芦原貴司, 相庭武司, 山下富義, 柴田仁太郎, 池田隆徳, 三井和幸, 蒔田直昌, 本荘晴朗, ボエットマーク, 中沢一雄.
  • Organizer: 第93回日本生理学会大会
• [Presentation] ECG Screening of 1-month-old Infants May Prevent Out-of-hospital Cardiac Arrest in Infancy (2016)
  • Author(s): Yoshinaga M, Ohno S, Ushinohama H, Sato S, Miyamoto T, Tauchi N, Horigome H, Sumitomo N, Shiraishi H, Ichida F, Hata T, Nomura Y, Horie M, Makita N, Nagashima M.
  • Organizer: American Heat Association Scientific Meeting 2016
  • Int'l Joint Research
• [Presentation] Modeling of long-QT syndrome associated with a calmodulin mutation using human induced pluripotent stem cells (2016)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Sasaki K, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Cheng J, Ishikawa T, Ohno S, Yoshida Y, Horie M, Makita N, Kimura T.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Utility of QT dynamics for identyfying genetic testing candidates in children with borderline QT interval prolongation (2016)
  • Author(s): Takahashi K, Makita N, Shimizu W.
  • Organizer: 第80回日本循環器学会学術集会
• [Presentation] Novel de novo Calmodulin Mutation in a Pre-school boy Experiencing Aborted Cardiac Arrest (2016)
  • Author(s): Takahashi K, Makita N.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Conditional knockout mice recapitulated two families with congenital AV block and sick sinus syndrome with a novel connexin 45 mutation. (2016)
  • Author(s): Nishii A, Ishikawa T, Daumy X, Urano M, Saito K, Baruteau A, Nishii K, Shibata Y, Kobayashi Y, Redon R, Schott JJ, Probst V, Hagiwara N, Makita N.
  • Organizer: 第80回日本循環器学会学術集会
• [Presentation] Catheter Ablation of Brugada Syndrome：Further Evidence of Conduction Delay in the Right Ventricular Subepicardium as Mechanism of Brugada ECG and Ventricular Fibrillation (2016)
  • Author(s): Nakagawa H, Sakamoto Y, Yamashiro K, Takagi M, Kusano K, Noda T, Yamazaki M, Honjo H, Makita N, Tsuchiya T, Hoogeudiik MG, Nademanee K.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Common genetic variants at SCN5A, SCN10A, and HEY2 are associated with cardiac conduction disturbance in patients with Brugada syndrome (2016)
  • Author(s): Murakoshi N, Xu D, Nogami A, Makita N, Sekiguchi Y, Kurosaki K, Kowase S, Naruse Y, Aonuma K.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Overview of Genes Related to Cardiac Conduction (2016)
  • Author(s): Makita N.
  • Organizer: Korean Heart Rhythm Society 8th Annual Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Genetic Background of Inherited Bradyarrhythmia (2016)
  • Author(s): Makita N.
  • Organizer: Korean Heart Rhythm Society 8th Annual Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Dose-Sensitive Relationship of an SCN10A Pore Mutation and Enhancer SNPs Identified in a Brugada Syndrome Family with Different Expressivity (2016)
  • Author(s): Ishikawa T, Ohkubo K, Yamaguchi R, Harrell DT, Tsuji Y, Watanabe I, Makita N.
  • Organizer: 第80回日本循環器学会学術集会
• [Presentation] Broader Genetic Spectrum of Familial Atrial Arrhythmias Involving Rare Variations in the Common Arrhythmia-Susceptible Genes (2016)
  • Author(s): Ishikawa T, Mishima H, Ohno S, Harrell DT, Tsuji Y, Yoshiura K, Horie M, Makita N.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] Selective therapeutic targeting of ion channel rare variants predisposing to lone atrial fibrillation (2016)
  • Author(s): Hayashi K, Fujino N, Tsuda T, Tanaka Y, Ino H, Makita N, Yamagishi M.
  • Organizer: 第63回日本不整脈心電学会学術大会
• [Presentation] International Calmodulinopathy Registry (ICaMR) (2016)
  • Author(s): Crotti L, Makita N.
  • Organizer: American Heart Association's Scientific Sessions
  • Int'l Joint Research
• [Presentation] 睡眠・サーカディアンリズムと循環器疾患～体内時計の視点から～ (2015)
  • Author(s): 前村浩二
  • Organizer: 第25回日本循環薬理学会
  • Place of Presentation: 奈良市、東大寺総合文化センター
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] SCN5A and ventricular arrhythmias (2015)
  • Author(s): Makita N
  • Organizer: Asian Pacific Heart Rhythm Society,
  • Place of Presentation: Melbourne, Australia.
  • Year and Date: 2015-11-22
  • Int'l Joint Research / Invited
• [Presentation] Cardiac Sodium Channel Mutation Associated With Epinephrine-Induced QT Prolongation and Sinus Node Dysfunction, (2015)
  • Author(s): 陳 嘉容、牧山 武
  • Organizer: 日本不整脈学会／日本心電学会
  • Place of Presentation: 京都、京都国際会議場
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] New genes for Progressive Cardiac Conduction Disease. (2015)
  • Author(s): Makita N
  • Organizer: Heart Rhythm Society
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-05-14
  • Int'l Joint Research / Invited
• [Presentation] Structural and Electrophysiological Characteristic of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes, (2015)
  • Author(s): 牧山 武
  • Organizer: 日本循環器学会
  • Place of Presentation: 大阪、大阪国際会議場
  • Year and Date: 2015-04-24
  • Invited
• [Presentation] Genetic Backgrounds of Patients with Clinically Diagnosed Idiopathic Ventricular Fibrillation (2015)
  • Author(s): 糀谷 泰彦、牧山 武
  • Organizer: 日本循環器学会
  • Place of Presentation: 大阪、大阪国際会議場
  • Year and Date: 2015-04-24
  • Invited
• [Book] 標準生理学 第9版 (2019)
  • Author(s): 蒔田直昌 （本間 研一 編）
  • Total Pages: 1172
  • Publisher: 医学書院
  • ISBN: 9784260034296
• [Book] 循環器内科専門医バイブル (2018)
  • Author(s): 辻幸臣・蒔田直昌(小室一成・平尾見三 編）
  • Total Pages: 376
  • Publisher: 中山書店
  • ISBN: 9784521745855
• [Book] 循環器科の心電図: ECG for Cardiologists (2018)
  • Author(s): 石川泰輔 蒔田直昌(村川裕二 編）
  • Total Pages: 215
  • Publisher: 南江堂
  • ISBN: 9784524237913
• [Book] 不整脈症候群－遺伝子変異から不整脈治療を捉えるー (2015)
  • Author(s): 蒔田直昌
  • Total Pages: 196
  • Publisher: 南江堂
• [Book] 不整脈診療クリニカルクエスチョン200 (2015)
  • Author(s): 蒔田直昌
  • Total Pages: 333
  • Publisher: 診断と治療社