Analysis of drug-induced long QT syndrome using iPS cell-derived cardiomyocytes of inherited arrhythmic patients

2016 Fiscal Year Final Research Report

• Project/Area Number: 25461051
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Nagoya University
• Principal Investigator: NIWA RYOKO 名古屋大学, 環境医学研究所, 研究員 (00216467)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: 遺伝性不整脈 / iPS細胞 / 薬物誘発性 / QT延長症候群 / イオンチャネル

Outline of Final Research Achievements

This study aimed to investigate cardiac pathogenesis and effective treatment in Andersen syndrome, a rare inherited channelopathy, using specific induced pluripotent stem cell (iPSC).
We reprogrammed somatic cells from three ATS patients carrying the KCNJ2 mutations to generate iPSCs. Multi-electrode arrays (MEAs) revealed strong arrhythmic events in the ATS-iPSC-derived cardiomyocytes. Using Ca2+ imaging, we found a significantly higher incidence of irregular Ca2+ release in the ATS-iPSC-derived cardiomyocytes. Flecainide, but not the sodium channel blocker, pilsicainide, suppressed these irregular Ca2+ release and arrhythmias, suggesting that the effect was not via sodium channels blocking. A reverse-mode Na+/Ca2+exchanger (NCX) inhibitor, KB-R7943, was also found to suppress the irregular Ca2+ release, and whole-cell voltage clamping of isolated guinea-pig ventricular myocytes confirmed that flecainide directly affect the NCX current.

Free Research Field

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