Predicting risk by assessing substrate and trigger for drug-induced arrhythmia

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07106
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Chuo University
• Principal Investigator: Murakami Shingo 中央大学, 理工学部, 教授 (40437314)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 薬物誘発性不整脈 / L型カルシウムチャネル / シミュレーション / EAD

Outline of Final Research Achievements

In the present study, to predict the different risks of drug-induced arrhythmia under various IKr blockers, we investigated the mechanism of pharmacological effects on the repolarization reserve and early afterdepolarization (EAD) by using the O'Hara-Rudy human ventricular myocyte model, three drug models (amiodarone, bepridil, terfenadine), and hypothetical drug models. We rigorously redefined repolarization reserve and constructed a new quantitative risk assessment method based on this redefinition. In addition, it was shown that the difference of the drug effect on L-type calcium current (ICaL) affected the generation frequency of EAD. Based on the mechanisms identified above, we proposed a protocol for risk prediction and confirmed its validity.

Free Research Field

医工学

Academic Significance and Societal Importance of the Research Achievements

薬物誘発性不整脈は新規薬物開発コストの上昇の一因であり、新規薬物開発や臨床における安全性や社会的コストの面からも、薬物誘発性不整脈の正確な予測が必要とされている。従来の薬物誘発性不整脈の機序の説明では、薬物の副作用でIKr阻害により活動電位や心電図上のQTが延長することでTorsades de pointes（多型性心室頻拍）が発生するとしてきた。しかし、近年の多数の擬陽性の実例より、IKr阻害と薬物誘発性不整脈発生の危険性の関連性がそれほど高くないことが判明している。本研究では単純なIKr阻害だけでない新たな薬物誘発性不整脈の危険性の予測方法を提案することができた。