Screening Drug-Induced Arrhythmia Using Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes and Low-Impedance Microelectrode Arrays

Abstract

Background Drug-induced arrhythmia is the most common cause 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 upon industry-standard, preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. Human iPSC-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 (EBs) exposed to a comprehensive panel of drugs at 65 to 95 days post-induction 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 (EADs) and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared to negligible EADs and ectopic beats in untreated controls. Conclusions We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with 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. We believe that this system holds 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.

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: Disease mechanisms and pharmacological rescue

“…The increased susceptibility to drug-induced arrhythmias of JLNS 1781A/A -and JLNS 478-2T/TCMs is likely a direct consequence of impaired I Ks and concomitant reduction of the repolarization reserve (49). One promising application of hiPSC-CMs is screening for proarrhythmic side effects of certain drugs (50,51). JLNS hiPSC-CMs may be particularly suited to this purpose because of their extraordinary sensitivity.…”

A near-infrared fluorescent voltage-sensitive dye allows for moderate-throughput electrophysiological analyses of human induced pluripotent stem cell-derived cardiomyocytes

“…However, a major impediment to realizing the full potential of stem cell-based models is the laborintensive nature of standard electrophysiological approaches. CMs differentiated from human iPSC are heterogeneous in nature, comprising nodal-, atrial-, and ventricular-like phenotypes, based on the morphology, duration, upstroke velocity, and MDP of their respective APs (4,5,7,11,17). Currently, the patch-clamp technique is the gold-standard method that allows for distinguishing chamber-specific lineages.…”

“…We could not precisely distinguish between nodal-and atrial-like CMs. Nodal-like iPSC-CMs generally represent the smallest fraction (ϳ10%) of stem cellderived CM subgroups (4,5,7,11,17).…”

Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance

“…Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are known to express multiple cardiac ion channels, profiles of which can be similar to those in human intact heart (Ma et al, 2011;Navarrete et al, 2013). In order to evaluate the utility of hiPSC-CMs as a tool for detecting drug-induced electrophysiological modifications, the effects of various drugs and chemical compounds have been assessed on the action potential waveform of single hiPSC-CM (Gibson et al, 2014;Peng et al, 2010) as well as the field potential configuration of two-dimensional cell sheets of hiPSC-CMs (Harris et al, 2013;Mehta et al, 2013;Nakamura et al, 2014;Nozaki et al, 2014;Uesugi et al, 2014).…”