Use of FDSS/μCell imaging platform for preclinical cardiac electrophysiology safety screening of compounds in human induced pluripotent stem cell-derived cardiomyocytes

FDSS/μCell is a high-speed acquisition imaging platform (Hamamatsu Ltd., Hamamatsu, Japan) that allows for simultaneous high-throughput reading under controlled conditions. We evaluated the Ca2 + transients or optical membrane potential changes of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (iCells) in the presence or absence of 44 pharmacological agents known to interfere with cardiac ion channels (e.g., hERG, IKs, NaV1.5, CaV1.2). We tested two Ca2 +-sensitive fluorescence dyes (Codex ACTOne® and EarlyTox®) and a membrane potential dye (FLIPR® membrane potential dye). We were able to quantify and report drug-induced early-after depolarizations (EAD)-like waveforms, cardiomyocyte ectopic beats and changes in beating rate from a subgroup of pharmacological agents acting acutely (within a 1-hour period). Cardiovascular drugs, such as dofetilide and d,l-sotalol, exhibited EAD-like signals at 3 nM and 10 μM, respectively. CNS drugs, such as haloperidol and sertindole, exhibited EAD-like signals and ectopic beats at 30 nM and 1 μM, respectively. Other drugs, such as astemizole, solifenacin, and moxifloxacin, exhibited similar arrhythmias at 30 nM, 3 μM and 300 μM, respectively. Our data suggest that the membrane potential and intracellular Ca2 + signal are tightly coupled, supporting the idea that the EAD-like signals reported are the accurate representation of an EAD signal of the cardiac action potential. Finally, the EAD-like Ca2 + signal was well correlated to clinically-relevant concentrations where Torsade de Pointes (TdPs) arrhythmias were noted in healthy volunteers treated orally with some of the compounds we tested, as reported in PharmaPendium®.