On-chip spatiotemporal electrophysiological analysis of human stem cell derived cardiomyocytes enables quantitative assessment of proarrhythmia in drug development

Yumiko Asahi, Tomoyo Hamada, Akihiro Hattori, Kenji Matsuura, Masao Odaka, Fumimasa Nomura, Tomoyuki Kaneko, Yasuyuki Abe, Kiyoshi Takasuna, Atsushi Sanbuissho, Kenji Yasuda

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Abstract

We examined a simultaneous combined spatiotemporal field potential duration (FPD) and cell-to-cell conduction time (CT) in lined-up shaped human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using an on-chip multielectrode array (MEA) system to evaluate two origins of lethal arrhythmia, repolarization and depolarization. The repolarization index, FPD, was prolonged by E-4031 and astemizole, and shortened by verapamil, flecainide and terfenadine at 10 times higher than therapeutic plasma concentrations of each drug, but it did not change after lidocaine treatment up to 100 μM. CT was increased by astemizol, flecainide, terfenadine, and lidocaine at equivalent concentrations of Nav1.5 IC50, suggesting that CT may be an index of cardiac depolarization because the increase in CT (i.e., decrease in cell-to-cell conduction speed) was relevant to Nav1.5 inhibition. Fluctuations (short-term variability; STV) of FPD and CT, STVFPD and STVCT also discriminated between torsadogenic and non-torsadogenic compounds with significant increases in their fluctuation values, enabling precise prediction of arrhythmogenic risk as potential new indices.

Original languageEnglish
Article number14536
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Spatio-Temporal Analysis
Cardiac Myocytes
Stem Cells
Terfenadine
Flecainide
Pharmaceutical Preparations
Lidocaine
Astemizole
Verapamil
Inhibitory Concentration 50
Cardiac Arrhythmias

ASJC Scopus subject areas

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On-chip spatiotemporal electrophysiological analysis of human stem cell derived cardiomyocytes enables quantitative assessment of proarrhythmia in drug development. / Asahi, Yumiko; Hamada, Tomoyo; Hattori, Akihiro; Matsuura, Kenji; Odaka, Masao; Nomura, Fumimasa; Kaneko, Tomoyuki; Abe, Yasuyuki; Takasuna, Kiyoshi; Sanbuissho, Atsushi; Yasuda, Kenji.

In: Scientific Reports, Vol. 8, No. 1, 14536, 01.12.2018.

Research output: Contribution to journalArticle

Asahi, Yumiko ; Hamada, Tomoyo ; Hattori, Akihiro ; Matsuura, Kenji ; Odaka, Masao ; Nomura, Fumimasa ; Kaneko, Tomoyuki ; Abe, Yasuyuki ; Takasuna, Kiyoshi ; Sanbuissho, Atsushi ; Yasuda, Kenji. / On-chip spatiotemporal electrophysiological analysis of human stem cell derived cardiomyocytes enables quantitative assessment of proarrhythmia in drug development. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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