2. Academic Validation
  3. Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes

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

  • Biochem Biophys Rep. 2017 Jan 11;9:245-256. doi: 10.1016/j.bbrep.2017.01.002.
Yusuke Kuroda 1 2 3,  Shinsuke Yuasa 1,  Yasuhide Watanabe 4,  Shogo Ito 1,  Toru Egashira 1,  Tomohisa Seki 1,  Tetsuhisa Hattori 5,  Seiko Ohno 5 6,  Masaki Kodaira 1,  Tomoyuki Suzuki 1 2 3,  Hisayuki Hashimoto 1,  Shinichiro Okata 1,  Atsushi Tanaka 1,  Yoshiyasu Aizawa 1,  Mitsushige Murata 1 7,  Takeshi Aiba 8,  Naomasa Makita 9,  Tetsushi Furukawa 10,  Wataru Shimizu 11,  Itsuo Kodama 2,  Satoshi Ogawa 1,  Norito Kokubun 12,  Hitoshi Horigome 13,  Minoru Horie 5,  Kaichiro Kamiya 2,  Keiichi Fukuda 1
Affiliations

Affiliations

  • 1 Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
  • 2 Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Aichi, Japan.
  • 3 Department of Cardiology, Nagoya University Graduate School of Medicine, Aichi, Japan.
  • 4 Division of Pharmacological Science, Department of Health Science, Hamamatsu University School of Medicine, Shizuoka, Japan.
  • 5 Department of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan.
  • 6 Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Shiga, Japan.
  • 7 Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.
  • 8 Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
  • 9 Department of Molecular Pathophysiology-1, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
  • 10 Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
  • 11 Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
  • 12 Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
  • 13 Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
PMID: 28956012 DOI: 10.1016/j.bbrep.2017.01.002
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.

Keywords

Andersen-Tawil syndrome; Arrhythmia; Cardiomyocyte; iPS cell.

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