Identification of Genetic Background in Sudden Cardiac Death using Artificial Intelligence (AI)

• Project/Area Number: 19K08505
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: AIBA TAKESHI 国立研究開発法人国立循環器病研究センター, 病院, 部長 (40574348)
• Co-Investigator(Kenkyū-buntansha): 高橋 篤 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (50392014) ; 西村 邦宏 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (70397834)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 心臓突然死 / 心室細動 / 遺伝子 / 不整脈 / 心筋症 / イオンチャネル / 全エクソン解析 / 心室頻拍 / 突然死 / 心電図 / 遺伝多型 / リスク

Outline of Research at the Start

本研究は心臓突然死の主な原因である心室細動(VF)の発症リスクをゲノムレベルから評価することを目的とする。そのためにVF・心肺蘇生後の患者から得たゲノム試料を全エクソン解析（WES）とゲノムワイド関連解析(GWAS)により網羅的にVF発症に関連する変異・バリアント・多型(SNPs)を抽出する。さらに人工知能(AI)を利用し各バリアントやSNPs、臨床情報がVF発症リスクに最大となるの組み合わせを同定し、その点数(Polygenic Risk Score)を算出する。最終的には突然死リスクを評価できるGene panelの開発を目標とする。

Outline of Final Research Achievements

Genetic background of idiopathic ventricular fibrillation (IVF) is still controversial. Genetic testing in IVF therefore offers a modest but potentially significant diagnostic yield, identifying either rare monogenic causes of IVF or concealed arrhythmia syndromes where clinical evaluation has failed. In IVF patients, 15% had some pathogenic or likely pathogenic SNVs in genes associated with cardiovascular diseases, but many of these were not directly related to lethal ventricular arrhythmias but rather potential genes associated with cardiomyopathies and/or neuromuscular diseases. Future research should also be focused on identifying potential “polygenic” and nongenetic causes that likely underpin much of IVF.

Academic Significance and Societal Importance of the Research Achievements

突然の心室細動による心事故は若年者、働き盛りの成人に多いことから、社会や家族におよぼす影響は計り知れない。心臓突然死リスクの一つとして、遺伝学的異常を示すことで患者本人のみならず家族における突然死リスクを評価することが可能となる。特に若年における未診断あるいは原因不明の突然死を予防できることの社会的意義は大変大きい。

Research Products

• [Int'l Joint Research] AMC(オランダ)
• [Journal Article] Targeted deep sequencing analyses of long QT syndrome in a Japanese population (2022)
  • Author(s): NagataY、WatanabeR、EichhornC、OhnoS、AibaT、IshikawaT、NakanoY、AizawaY、HayashiKi、MurakoshiN、NakajimaT、YagiharaN、MishimaH、SudoT、HiguchiC、TakahashiA、SekineA、MakiyamaT、TanakaY、WatanabeA、TachibanaM、MoritaH、YoshiuraK-i、TsunodaT、WatanabeH、KurabayashiM、NogamiA、KiharaY、HorieM、ShimizuW、MakitaN、TanakaT
  • Journal Title: PLOS ONE Volume: 17 Issue: 12 Pages: e0277242-e0277242
  • DOI: 10.1371/journal.pone.0277242
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association Between Deleterious SCN5A Variants and Ventricular Septal Defect in Young Patients With Brugada Syndrome (2022)
  • Author(s): Suzuki Keisuke、Sonoda Keiko、Aoki Hisaaki、Nakamura Yuko、Watanabe Seiichi、Yoshida Yoko、Hoshino Kenji、Ozawa Junichi、Imamura Tomohiko、Aiba Takeshi、Kato Koichi、Makiyama Takeru、Kusano Kengo、Horie Minoru、Ohno Seiko
  • Journal Title: JACC: Clinical Electrophysiology Volume: 8 Issue: 3 Pages: 297-305
  • DOI: 10.1016/j.jacep.2022.01.007
  • Peer Reviewed / Open Access
• [Journal Article] Impact of cascade screening for catecholaminergic polymorphic ventricular tachycardia type 1 (2022)
  • Author(s): Shimamoto K, Ohno S, Kato K, Takayama K, Sonoda K, Fukuyama M, Makiyama T, Okamura S, Asakura K, Imanishi N, Kato Y, Sakaguchi H, Kamakura T, Wada M, Yamagata K, Ishibashi K, Inoue Y, Miyamoto K, Nagase S, Kusano K, Horie M, Aiba T.
  • Journal Title: Heart Volume: - Issue: 11 Pages: 2021-320220
  • DOI: 10.1136/heartjnl-2021-320220
  • Peer Reviewed / Open Access
• [Journal Article] An International Multicenter Cohort Study on β-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia (2022)
  • Author(s): Peltenburg, P. J. Kallas, D. Bos, J. M. Lieve, K. V. V. Franciosi, S. Roston, T. M. Denjoy, I. Sorensen, K. B. Ohno, S. Shimizu, W. Horie, M. Leenhardt, A. Ackerman, M. J. Sanatani, S. van der Werf, C. Wilde, A. A. M.
  • Journal Title: Circulation Volume: 145 Issue: 5 Pages: 333-344
  • DOI: 10.1161/circulationaha.121.056018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Case report of a ventricular fibrillation storm with a cardiac conduction disorder and HCN4 variant 18 years after ablation of atrial flutter (2022)
  • Author(s): Nakamura Toshihiro、Fukuzawa Koji、Aiba Takeshi、Ohno Seiko
  • Journal Title: European Heart Journal - Case Reports Volume: 6 Issue: 11 Pages: 1-6
  • DOI: 10.1093/ehjcr/ytac431
  • Peer Reviewed
• [Journal Article] Unusual Overlapping Cardiac Sarcoidosis and Long-QT Type 3 Induced Ventricular Fibrillation (2021)
  • Author(s): Nishikawa Tatsuya、Aiba Takeshi、Ueda Nobuhiko、Nakajima Kenzaburo、Yamada-Inoue Yuko、Kamakura Tsukasa、Wada Mitsuru、Yamagata Kenichiro、Ishibashi Kohei、Tateishi Emi、Kiso Keisuke、Ikeda Yoshihiko、Ishibashi-Ueda Hatsue、Miyamoto Koji、Nagase Satoshi、Noda Takashi、Kusano Kengo
  • Journal Title: Internal Medicine Volume: 60 Issue: 1 Pages: 85-89
  • DOI: 10.2169/internalmedicine.5018-20
  • NAID: 130007965451
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-01-01
  • Peer Reviewed / Open Access
• [Journal Article] Genotype-Phenotype Correlation of <i>SCN5A</i> Genotype in Patients With Brugada Syndrome and Arrhythmic Events: Insights From the SABRUS in 392 Probands (2021)
  • Author(s): Milman A、Behr ER.、Gray B、Aiba T, Belhassen B et al.
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 14 Issue: 5
  • DOI: 10.1161/circgen.120.003222
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare <i>KCNH2</i> Variants (2021)
  • Author(s): Kozek K, Wada Y, Makita N, Ishikawa T, Crotti L, Kroncke BM, et al.
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 14 Issue: 4
  • DOI: 10.1161/circgen.120.003289
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls (2020)
  • Author(s): 2.Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, et al.
  • Journal Title: Genetics in Medicine Volume: 23 Issue: 1 Pages: 47-58
  • DOI: 10.1038/s41436-020-00946-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families (2020)
  • Author(s): 3.Wijeyeratne YD, Tanck MW, Mizusawa Y, Batchvarov V, Barc J, Crotti L, et al.
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 13 Issue: 6
  • DOI: 10.1161/circgen.120.002911
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] First episode of ventricular fibrillation in an 84-year-old man with long-QT type 2 syndrome: A case report (2020)
  • Author(s): Miki Tomonori、Senoo Keitaro、Okura Takashi、Shiraishi Hirokazu、Shirayama Takeshi、Aiba Takeshi、Matoba Satoaki
  • Journal Title: Journal of Cardiology Cases Volume: 22 Issue: 6 Pages: 257-259
  • DOI: 10.1016/j.jccase.2020.07.012
  • Peer Reviewed / Open Access
• [Journal Article] Subcutaneous and transvenous implantable cardioverter defibrillator in high-risk long-QT syndrome type 3 associated with Val411Met mutation in SCN5A (2020)
  • Author(s): Yokoyama Yasuhiro、Aiba Takeshi、Ueda Nobuhiko、Nakajima Kenzaburo、Kamakura Tsukasa、Wada Mitsuru、Yamagata Kenichiro、Ishibashi Kohei、Inoue Yuko、Miyamoto Koji、Nagase Satoshi、Noda Takashi、Yasuda Satoshi、Shimizu Wataru、Kusano Kengo
  • Journal Title: Journal of Cardiology Cases Volume: 22 Issue: 5 Pages: 238-241
  • DOI: 10.1016/j.jccase.2020.07.007
  • Peer Reviewed / Open Access
• [Journal Article] An International Multicenter Evaluation of Type 5 Long QT Syndrome (2020)
  • Author(s): Roberts J.、Asaki S. Y、Mazzanti A, Bos J. M、Tuleta I、Muir Alison R.、Crotti L, Krahn A D.、Kutyifa V、Shoemaker M. B、Johnsrude CL.、Aiba T et al.
  • Journal Title: Circulation Volume: 141 Issue: 6 Pages: 429-439
  • DOI: 10.1161/circulationaha.119.043114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome (2020)
  • Author(s): Lahrouchi N, Tadros R, Crotti R, Mizusawa Y, Aiba T, K&auml;&auml;b S, Priori SG , Guicheney P, Tan HL, Newton-Cheh C ,Ackerman MJ, Schwartz PJ, Schulze-Bahr E , Probs Vt ,Horie M , Wilde AM, Tanck MT , Bezzina CR
  • Journal Title: Circulation Volume: -
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term prognosis of patients with J-wave syndrome. (2020)
  • Author(s): Kamakura T, Shinohara T, Yodogawa K, Murakoshi N, Morita H, Takahashi N, Inden Y, Shimizu W, Nogami A, Horie M, Aiba T, Kusano K.
  • Journal Title: Heart Volume: 106 Issue: 4 Pages: 299-306
  • DOI: 10.1136/heartjnl-2019-315007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Case reports of a c.475G>T, p.E159* lamin A/C mutation with a family history of conduction disorder, dilated cardiomyopathy and sudden cardiac death (2019)
  • Author(s): Yokokawa Tetsuro、Ichimura Shohei、Hijioka Naoko、Kaneshiro Takashi、Yoshihisa Akiomi、Kunii Hiroyuki、Nakazato Kazuhiko、Ishida Takafumi、Suzuki Osamu、Ohno Seiko、Aiba Takeshi、Ohtani Hiroshi、Takeishi Yasuchika
  • Journal Title: BMC Cardiovascular Disorders Volume: 19 Issue: 1 Pages: 298-298
  • DOI: 10.1186/s12872-019-01282-6
  • Peer Reviewed / Open Access
• [Journal Article] Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest (2019)
  • Author(s): van der Werf Christian、Lieve Krystien V、Seiko Ohno、Leenhardt Antoine、Ackerman Michael J、Wilde Arthur A、et al.
  • Journal Title: European Heart Journal Volume: 40 Issue: 35 Pages: 2953-2961
  • DOI: 10.1093/eurheartj/ehz309
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Risk stratification and Gene-guided treatment in patients with Long QT syndrome (2022)
  • Author(s): Aiba Takeshi
  • Organizer: THRS (Taiwan Heart Rhythm Society)
  • Int'l Joint Research / Invited
• [Presentation] Genetic basis sudden cardiac death in Japan (2021)
  • Author(s): Aiba Takeshi
  • Organizer: Korean Heart Rhythm Society (KHRS2021 Virtual)
  • Int'l Joint Research / Invited
• [Presentation] Prediction of Sudden Cardiac Death by Comprehensive Genetic Screening (2021)
  • Author(s): Aiba Takeshi
  • Organizer: European Society of Cardiology (ESC2021)
  • Int'l Joint Research / Invited