Cardiomyocyte functional screening: interrogating comparative electrophysiology of high-throughput model cell systems

Abstract

Cardiac arrhythmias of both atrial and ventricular origin are an important feature of cardiovascular disease. Novel antiarrhythmic therapies are required to overcome current drug limitations related to effectiveness and pro-arrhythmia risk in some contexts. Cardiomyocyte culture models provide a high-throughput platform for screening antiarrhythmic compounds, but comparative information about electrophysiological properties of commonly used types of cardiomyocyte preparations is lacking. Standardization of cultured cardiomyocyte microelectrode array (MEA) experimentation is required for its application as a high-throughput platform for antiarrhythmic drug development. The aim of this study was to directly compare the electrophysiological properties and responses to isoproterenol of three commonly used cardiac cultures. Neonatal rat ventricular myocytes (NRVMs), immortalized atrial HL-1 cells, and custom-generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured on microelectrode arrays for 48–120 h. Extracellular field potentials were recorded, and conduction velocity was mapped in the presence/absence of the β-adrenoceptor agonist isoproterenol (1 µM). Field potential amplitude and conduction velocity were greatest in NRVMs and did not differ in cardiomyocytes isolated from male/female hearts. Both NRVMs and hiPSC-CMs exhibited longer field potential durations with rate dependence and were responsive to isoproterenol. In contrast, HL-1 cells exhibited slower conduction and shorter field potential durations and did not respond to 1 µM isoproterenol. This is the first study to compare the intrinsic electrophysiologic properties of cultured cardiomyocyte preparations commonly used for in vitro electrophysiology assessment. These findings offer important comparative data to inform methodological approaches in the use of MEA and other techniques relating to cardiomyocyte functional screening investigations of particular relevance to arrhythmogenesis.

Negative chronotropic and inotropic effects of lubiprostone on iPS cell-derived cardiomyocytes via activation of CFTR

“…The changes in the beating rate and contraction ratio of the FCMs and ACMs treated with these compounds were also similar to those of the iPS-CMs. The response of CMs treated with these chemical compounds is consistent with that reported in previous studies [49][50][51]. Therefore, our results indicate that iPS-CMs have the physiological functional characteristics of native CMs.…”

Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies

“…The potential for scalability of hiPSC-CMs in 3D culture 215 together with the recent characterization of comparative electrophysiology 216 offer a unique platform for high-throughput phenotypic screening of drugs and assaying for cardiotoxicity. In a recent study, 21 FDA-approved tyrosine kinase inhibitors (TKIs) were screened for cardiotoxicity using hiPSC-CMs derived from 11 healthy individuals and 2 patients undergoing cancer treatment 217 .…”

An improved procedure for isolating adult mouse cardiomyocytes for epicardial activation mapping

“…Cardiomyocytes are terminally differentiated cells and thus cannot proliferate in response to injury and death. Although some atrial cardiac cell lines, such as AT‐1 and HL‐1, 1 and human ventricular cardiac cell lines, such as AC16, 2 have been used in in vitro studies, their characteristics are not identical to mature cardiomyocytes 3 …”

“…Although some atrial cardiac cell lines, such as AT‐1 and HL‐1, 1 and human ventricular cardiac cell lines, such as AC16, 2 have been used in in vitro studies, their characteristics are not identical to mature cardiomyocytes. 3 Therefore, these cell lines are not ideal for studying cardiomyocyte physiology and pathophysiology in vitro .…”