Development of correction formula for frequency-dependent changes of field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets

[Speaker] Hiroko Izumi-Nakaseko:1
[Co-author] Yasunari Kanda:2, Yuji Nakamura:1, Mihoko Hagiwara-Nagasawa:1, Kentaro Ando:1, Atsuhiko T Naito:1, Yuko Sekino:1,3, Atsushi Sugiyama:1
1:Department of Pharmacology, Faculty of Medicine, Toho University, Japan, 2:Division of Pharmacology, National Institute of Health Sciences, Japan, 3:Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan

[Background] Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used in many studies to assess proarrhythmic risks of chemical compounds. In those studies, field potential durations (FPD) of hiPSC-CMs have been obtained under the spontaneous automaticity, which have been corrected by clinically-used Fridericia's and/or Bazett's formulae; however, the rationale for their use has not been well established.
[Methods] In the present study, we developed a novel correction formula for experiments using three lots of hiPSC-CMs. First, we analyzed the effect of beating rate on FPD in the hiPSC-CMs sheets using electrical stimuli with a HCN channel inhibitor zatebradine. The relationships between pacing cycle length and FPD in the presence and absence of zetabradine in each lot was fitted into linear and non-linear equations, and the correlation coefficients a in the equations were obtained. Next, we examined the relationship between the expression levels of ion channel genes and the electrophysiological properties in the cell sheets.
[Results] Zatebradine slowed the beating rate and allowed to analyze FPD changes at various pacing cycle lengths. Correlation coefficients a for FPD under various pacing cycle lengths in linear equation were calculated to be 0.09449, 0.07347 and 0.06594, whereas those in the non-linear equation were estimated to be 0.2384, 0.2198 and 0.1997 in the respective cell sheets. Each of these values was smaller than those clinically obtained. R2 value was greater in the non-linear equation than in the linear one in the respective lot. Expression levels of hKCNH2 and hKCNQ1 were significantly higher than those of hKCNE1, hKCNJ2 and hGJA1.
[Conclusions] Rate-dependent change in the repolarization period was smaller in the cell sheets than that reported on the human hearts, which can be partly explained by lower gene expression level of hKCNJ2 and hKCNE1. Non-linear equation for correcting FPD in the cell sheet; FPDc=FPD/RR0.22with RR given in second was obtained, which may make it feasible to assess net repolarization delay by various chemical compounds with a chronotropic action.
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