High-throughput cardiac safety evaluation and multi-parameter arrhythmia profiling of cardiomyocytes using microelectrode arrays.
Microelectrode arrays (MEAs) recording extracellular field potentials of human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) provide a rich data set for functional assessment of drug response. The aim of this work is the development of a method for a systematic analysis of arrhythmia using MEAs, with emphasis on the development of six parameters accounting for different types of cardiomyocyte signal irregularities. We describe a software approach to carry out such analysis automatically including generation of a heat map that enables quick visualization of arrhythmic liability of compounds. We also implemented signal processing techniques for reliable extraction of the repolarization peak for field potential duration (FPD) measurement even from recordings with low signal to noise ratios. We measured hiPS-CM's on a 48 well MEA system with 5minute recordings at multiple time points (0.5, 1, 2 and 4h) after drug exposure. We evaluated concentration responses for seven compounds with a combination of hERG, QT and clinical proarrhythmia properties: Verapamil, Ranolazine, Flecainide, Amiodarone, Ouabain, Cisapride, and Terfenadine. The predictive utility of MEA parameters as surrogates of these clinical effects were examined. The beat rate and FPD results exhibited good correlations with previous MEA studies in stem cell derived cardiomyocytes and clinical data. The six-parameter arrhythmia assessment exhibited excellent predictive agreement with the known arrhythmogenic potential of the tested compounds, and holds promise as a new method to predict arrhythmic liability.
['Gilchrist|Kristin H|KH|', 'Lewis|Gregory F|GF|', 'Gay|Elaine A|EA|', 'Sellgren|Katelyn L|KL|', 'Grego|Sonia|S|']
D001145:Arrhythmias, Cardiac D057205:Automation, Laboratory D002454:Cell Differentiation D002478:Cells, Cultured D004305:Dose-Response Relationship, Drug D004867:Equipment Design D006339:Heart Rate D057166:High-Throughput Screening Assays D006801:Humans D057026:Induced Pluripotent Stem Cells D008564:Membrane Potentials D008839:Microelectrodes D032383:Myocytes, Cardiac D018570:Risk Assessment D012815:Signal Processing, Computer-Assisted D059629:Signal-To-Noise Ratio D012984:Software D013997:Time Factors D018675:Toxicity Tests
Arrhythmia Microelectrode array Field potential duration Automated analysis Human induced pluripotent stem cell-derived cardiomyocytes QT prolongation