Screening with hiPSC-CMs and low-impedance microelectrode arrays accurately identified drug-induced arrhythmias, detecting early afterdepolarizations in 33% and 40% of sotalol and quinidine samples.
Does the use of hiPSC-CMs combined with a low-impedance microelectrode array accurately detect drug-induced arrhythmias?
The combination of hiPSC-CMs and low-impedance microelectrode arrays provides a sensitive and robust platform for preclinical screening of drug-induced arrhythmias.
BACKGROUND: Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. METHODS AND RESULTS: Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. CONCLUSIONS: We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.
Navarrete et al. (Tue,) conducted a other in Drug-induced arrhythmia. Comprehensive panel of drugs (including sotalol and quinidine) vs. Untreated controls was evaluated on Early afterdepolarizations and ectopic beats. Screening with hiPSC-CMs and low-impedance microelectrode arrays accurately identified drug-induced arrhythmias, detecting early afterdepolarizations in 33% and 40% of sotalol and quinidine samples.
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