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
  • 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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