摘要
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.
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.
