Cardiotoxicity screening of illicit drugs and new psychoactive substances (NPS) in human iPSC-derived cardiomyocytes using microelectrode array (MEA) recordings

The use of recreational drugs, including new psychoactive substances (NPS), is paralleled by emergency department visits of drug users with severe cardiotoxicity. Drug-induced cardiotoxicity can be the (secondary) result of increased norepinephrine blood concentrations, but data on potential drug-induced direct effects on cardiomyocyte function are scarce. The presence of hundreds of NPS therefore calls for efficient screening models to assess direct cardiotoxicity. We investigated effects of four reference compounds (3-30 nM dofetilide, nifedipine and isoproterenol, and 1-10 mu M mexiletine) and six recreational drugs (0.01-100 mu M cocaine, 0.01-1000 mu M amphetamine, MDMA, 4-fluoroamphetamine, alpha-PVP and MDPV) on cardiomyocyte function (beat rate, spike amplitude and field potential duration (FPD approximate to QT interval in ECGs)), using Pluricyte (R) human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes cultured on ready-to-use CardioPlate (TM) multi-well microelectrode arrays (mwMEAs). Moreover, the effects of exposure to recreational drugs on cell viability were assessed. Effects of reference compounds were in accordance with the literature, indicating the presence of hERG potassium (dofetilide), sodium (mexiletine) and calcium (nifedipine) channels and alpha-adrenergic receptors (isoproterenol). All recreational drugs decreased the spike amplitude at 10-100 mu M. All amphetamine-type stimulants and alpha-PVP decreased the beat rate at 300 mu M, while cocaine and MDPV did so at 10 mu M and 30 mu M, respectively. All drugs increased the FPD, however at varying concentrations. MDMA, MDPV and amphetamine affected cardiomyocyte function at concentrations relevant for human exposure, while other drugs affected cardiomyocyte function only at higher concentrations ( >= 10 mu M). Cell viability was only mildly affected at concentrations well above the lowest concentrations affecting cardiomyocyte function. We demonstrate that MEA recordings of hiPSC-derived cardiomyocytes enable screening for acute, direct effects on cardiomyocyte function. Our data further indicate that tachycardia in patients exposed to recreational drugs is likely due to indirect drug effects, while prolonged repolarization periods (prolonged QT(c) interval) could (partly) result from direct drug effects on cardiomyocyte function.