Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes

Yusuke Kuroda, Shinsuke Yuasa, Yasuhide Watanabe, Shogo Ito, Toru Egashira, Tomohisa Seki, Tetsuhisa Hattori, Seiko Ohno, Masaki Kodaira, Tomoyuki Suzuki, Hisayuki Hashimoto, Shinichiro Okata, Atsushi Tanaka, Yoshiyasu Aizawa, Mitsushige Murata, Takeshi Aiba, Naomasa Makita, Tetsushi Furukawa, Wataru Shimizu, Itsuo KodamaSatoshi Ogawa, Norito Kokubun, Hitoshi Horigome, Minoru Horie, Kaichiro Kamiya, Keiichi Fukuda

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Andersen-Tawil syndrome (ATS) is a rare inherited channelopathy. The cardiac phenotype in ATS is typified by a prominent U wave and ventricular arrhythmia. An effective treatment for this disease remains to be established. We reprogrammed somatic cells from three ATS patients to generate induced pluripotent stem cells (iPSCs). Multi-electrode arrays (MEAs) were used to record extracellular electrograms of iPSC-derived cardiomyocytes, revealing strong arrhythmic events in the ATS-iPSC-derived cardiomyocytes. Ca2+ imaging of cells loaded with the Ca2+ indicator Fluo-4 enabled us to examine intracellular Ca2+ handling properties, and we found a significantly higher incidence of irregular Ca2+ release in the ATS-iPSC-derived cardiomyocytes than in control-iPSC-derived cardiomyocytes. Drug testing using ATS-iPSC-derived cardiomyocytes further revealed that antiarrhythmic agent, flecainide, but not the sodium channel blocker, pilsicainide, significantly suppressed these irregular Ca2+ release and arrhythmic events, suggesting that flecainide's effect in these cardiac cells 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 cardiac ventricular myocytes confirmed that flecainide could directly affect the NCX current (INCX). ATS-iPSC-derived cardiomyocytes recapitulate abnormal electrophysiological phenotypes and flecainide suppresses the arrhythmic events through the modulation of INCX.

Original languageEnglish
Pages (from-to)245-256
Number of pages12
JournalBiochemistry and Biophysics Reports
Volume9
DOIs
Publication statusPublished - 2017 Mar 1

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Keywords

  • Andersen-Tawil syndrome
  • Arrhythmia
  • Cardiomyocyte
  • iPS cell

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kuroda, Y., Yuasa, S., Watanabe, Y., Ito, S., Egashira, T., Seki, T., Hattori, T., Ohno, S., Kodaira, M., Suzuki, T., Hashimoto, H., Okata, S., Tanaka, A., Aizawa, Y., Murata, M., Aiba, T., Makita, N., Furukawa, T., Shimizu, W., ... Fukuda, K. (2017). Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes. Biochemistry and Biophysics Reports, 9, 245-256. https://doi.org/10.1016/j.bbrep.2017.01.002