TY - JOUR
T1 - Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes
AU - Kuroda, Yusuke
AU - Yuasa, Shinsuke
AU - Watanabe, Yasuhide
AU - Ito, Shogo
AU - Egashira, Toru
AU - Seki, Tomohisa
AU - Hattori, Tetsuhisa
AU - Ohno, Seiko
AU - Kodaira, Masaki
AU - Suzuki, Tomoyuki
AU - Hashimoto, Hisayuki
AU - Okata, Shinichiro
AU - Tanaka, Atsushi
AU - Aizawa, Yoshiyasu
AU - Murata, Mitsushige
AU - Aiba, Takeshi
AU - Makita, Naomasa
AU - Furukawa, Tetsushi
AU - Shimizu, Wataru
AU - Kodama, Itsuo
AU - Ogawa, Satoshi
AU - Kokubun, Norito
AU - Horigome, Hitoshi
AU - Horie, Minoru
AU - Kamiya, Kaichiro
AU - Fukuda, Keiichi
N1 - Funding Information:
The authors thank all the laboratory members for their critical comments and helpful discussions. The authors thank Drs. I. Komuro, H. Morita and A. Naito (University of Tokyo) for helpful discussions. This study was supported, in part, by research grants from the Program for Intractable Diseases Research utilizing Disease-specific iPS cells from Japan Agency for Medical Research and development, AMED, Grants-in-Aid for Scientific Research (JSPS KAKENHI Grant Number: 26670408, 15H01521, 16H050304, 16K15415), a Health Labour Sciences Research Grant, the New Energy and Industrial Technology Development Organization, and the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation, Suzuken Memorial Foundation and Keio University Medical Science Fund.
Publisher Copyright:
© 2017 The Authors
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - Andersen-Tawil syndrome
KW - Arrhythmia
KW - Cardiomyocyte
KW - iPS cell
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U2 - 10.1016/j.bbrep.2017.01.002
DO - 10.1016/j.bbrep.2017.01.002
M3 - Article
AN - SCOPUS:85009965903
SN - 2405-5808
VL - 9
SP - 245
EP - 256
JO - Biochemistry and Biophysics Reports
JF - Biochemistry and Biophysics Reports
ER -