Beat-to-Beat Variability in Field Potential Duration in Human Embryonic Stem Cell-Derived Cardiomyocyte Clusters for Assessment of Arrhythmogenic Risk, and a Case Study of Its Application

Kazuto Yamazaki, Taro Hihara, Hiroshi Kato, Tatsuto Fukushima, Kazuyuki Fukushima, Tomohiko Taniguchi, Takashi Yoshinaga, Norimasa Miyamoto, Masashi Ito, Kohei Sawada

Biomarkers and Personalized Medicine CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Japan.
Biopharmaceutical Assessment CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Japan.
Global Discovery Research Neuroscience and General Medicine PCU, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Japan.
Next Generation Systems CFU, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Japan.

DOI: 10.4236/pp.2014.51017                

Abstract

We established a QT interval assessment system that uses human embryonic stem cell-derived cardiomyocyte clusters (hES-CMCs) in which the field potential duration (FPD) or corrected FPD (FPDc) was measured as an indicator of drug-induced QT interval prolongation. To investigate the applicability of the hES-CMC system to drug safety assessment, we investigated short-term variability in FPDc (STV_FPDc) (beat rate rhythmicity) as a marker of torsadogenic risk. We investigated the FPDc and STV_FPDc of hES-CMCs treated with hERG channel blockers (E-4031 or cisapride) or with our proprietary compounds X, Y, and Z. We also evaluated the electrocardiograms and hemodynamics of dogs treated with compound X, Y, or Z. The torsadogenic hERG channel blockers increased STV_FPDc and prolonged FPDc. Compounds X, Y, and Z had hERG inhibitory activity. Compound X prolonged FPDc with increased STV_FPDc, whereas compounds Y and Z tended to shorten FPDc in the hES-CMC system. In the in vivo canine study, compound X prolonged corrected QT (QTc), and compounds Y and Z tended to shorten QTc, showing a good correlation with the results in hES-CMCs. These findings suggest that combined assessment of FPDc and STV_FPDc in the hES-CMC system increases the predictability of torsadogenic risk.

Keywords

Human Embryonic Stem Cell-Derived Cardiomyocytes; Field Potential Duration; Short-Term Variability; QT Interval; Torsades de Pointes; Risk Assessment

Conflicts of Interest

The authors declare no conflicts of interest.

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