TITLE:
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
AUTHORS:
Kazuto Yamazaki, Taro Hihara, Hiroshi Kato, Tatsuto Fukushima, Kazuyuki Fukushima, Tomohiko Taniguchi, Takashi Yoshinaga, Norimasa Miyamoto, Masashi Ito, Kohei Sawada
KEYWORDS:
Human Embryonic Stem Cell-Derived Cardiomyocytes; Field Potential Duration; Short-Term Variability; QT Interval; Torsades de Pointes; Risk Assessment
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.5 No.1,
January
23,
2014
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 (STVFPDc) (beat rate
rhythmicity) as a marker of torsadogenic risk. We investigated
the FPDc and STVFPDc 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 STVFPDc and prolonged FPDc. Compounds X, Y, and Z had hERG inhibitory activity.
Compound X prolonged FPDc
with increased STVFPDc, 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 STVFPDc in the hES-CMC system increases the predictability of torsadogenic
risk.