The elucidation of mechanisms underlying triggered activity in inheritable lethal arrhythmias: in silico predictions

2018 Fiscal Year Final Research Report

• Project/Area Number: 16KT0194
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Kanazawa Medical University (2018); Osaka University (2016-2017)
• Principal Investigator: TSUMOTO Kunichika 金沢医科大学, 医学部, 准教授 (70353331)
• Co-Investigator(Kenkyū-buntansha): 倉智 嘉久 大阪大学, 医学系研究科, 教授 (30142011) ; 芦原 貴司 滋賀医科大学, 医学部, 講師 (80396259)
• Project Period (FY): 2016-07-19 – 2019-03-31
• Keywords: 生理学 / 循環器・高血圧 / 細胞・組織 / 生物物理 / 興奮伝播 / 心筋細胞 / 活動電位

Outline of Final Research Achievements

It is believed that arrhythmias in patients with long QT syndrome, heart failure, and Brugada syndrome are caused by a triggered activity that preceded the arrhythmia onset. For instance, cardiac action potential with transient depolarizations that occurs during action potential (AP) phase 2 to 3 (early afterdepolarization) is a typical example of the triggered activity. Furthermore, an AP shortening followed by re-excitation, which is referred to as phase-2 reentry, is the triggering mechanism of ventricular fibrillation in the Brugada syndrome. We showed that a combination of selective reduction of cardiac sodium channel expression from the lateral membrane in each cardiomyocyte and spatial dispersion of sodium channel expression in the ventricle is responsible for phase-2 reentry mechanism. Furthermore, we elucidated that reactivation of L-type calcium channel current accompanying excessive prolongation of AP leads to the development of early afterdepolarization.

Free Research Field

生理学一般

Academic Significance and Societal Importance of the Research Achievements

心室頻拍や心室細動といった心室性不整脈は、突然死をもたらす。これらの致死性不整脈の発生に先行して、発症のきっかけとなる応答（トリガー）が発生する。このトリガーの発生を予測し、抑止できれば、心臓突然死の危険性を低減できる。本研究では、不整脈トリガーの発生機序を解明し、新たな不整脈発生予測法の開発に資する重要な成果を得た。本成果は、致死性不整脈の誘発制御理論の確立に向けた礎となる。