Human and Murine Embryonic Stem Cell-Derived Cardiomyocytes Serve Together as a Valuable Model for Drug Safety Screening

Abstract

Aims: Screening of drug safety is typically performed in diverse non-human healthy species with an intact repolarization reserve. Nevertheless, these drugs are later applied in diseased humans with a reduced repolarization reserve. It would be optimal to set up a preclinical screening tool to estimate the proarrhythmic potential of drugs in human cardiac tissue with a reduced repolarization reserve in vitro. Methods and Results: In our study spontaneously beating human embryonic stem cell-derived cardiomyocytes clusters (hESCM) and murine ES cell-derived cardiomyocytes (mESCMs) were plated onto micro-electrode arrays (MEAs) to record the extracelluar field potentials (FPs) as well as effects of several antiarrhythmic drugs. In line with clinical observations the class III antiarrhythmic drugs (±)-sotalol, E4031 and class I antiarrhythmic drug quinidine led to a prolongation of the cardiac repolarization phase (FP duration, FPdur) and a decrease of the FP frequency. Verapamil (a class IV antiarrhythmic drug) decreased the FP frequency and shortened FPdur. Both, quinidine and verapamil, but not (±)-sotalol or E4031 decreased conduction velocities in hESCM clusters. Moreover, (±)-sotalol exerted stronger effects on FPdur in early developmental stages of hESCMs, as proof for a reduced repolarization reserve. The EC₅₀ of the (±)-sotalol-induced prolongation of the FPdur was higher in mESCMs than in hESCMs implying species-dependent differences in cardiac repolarization. Likewise, the incidence of drug-induced early recurrent depolarization (ERDs) was higher in mESCMs than hESCMs. Conclusion: The combined measurement of drug effects on FP parameters in hESCMs and mESCMs serves as a reliable in vitro model for preclinical studies of drug safety.