Variability of the Field Potential Duration of Stem Cell-Derived Cardiomyocytes is a Proarrhythmic Indicator

Abstract

The effect of drugs on the extracellular field potential of stem cell cardiomyocytes is one of the three components of the new Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative promoted by the FDA to assess the proarrhythmic potential of new drugs. The cells are used to confirm in silico predictions based on the IC50s for channel block of the major cardiac channels and to detect effects that would not have been anticipated by the simulations. Here we investigated whether drug-dependent beat-to-beat variations in the field potential duration (FPD) of Cor.4U cells is a predictor of torsadogenic risk. We quantified variability using the coefficient of variation (CV) of thirty consecutive FPDs. Experiments were performed at 35°C in the absence of serum. Spontaneous electrical activity was recorded after 30 min drug exposure. Drugs were added in incremental concentrations in the range of the clinical exposure levels. The measured CV of five vehicle control wells was 2.4 ± 0.2%. A clear distinction between torsadogenic and non-torsadogenic drugs was detected based on the slope of the functional relationship between CV and FPD. Safe drugs like verapamil and nifedipine showed a negative slope of −0.029 %CV/ms and −0.011 %CV/ms, respectively. Prolongation of FPD in the presence of torsadogenic drugs was associated with an increase in variability as indicated by the positive slopes for quinidine (0.025), terfenadine (0.044), E-4031 (0.097), dofetilide (0.132) and sotalol (0.231). For moxifloxacin the FPD was markedly increased, but this change was not associated with a significant increase in variability (slope = 0.009 %CV/ms). This result is consistent with moxifloxacin's relatively safe clinical profile and demonstrates that the FPD CV proarrhythmia marker may distinguish between safe and unsafe QT prolonging drugs.