Biophysical comparison of sodium currents in native cardiac myocytes and human induced pluripotent stem cell-derived cardiomyocytes

Abstract

Introduction: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for safety pharmacology and to investigate genetic diseases affecting cardiac ion channels. It is unclear whether adult myocytes or hiPSC-CMs are the better platform for cardiac safety pharmacology. We examined the biophysical and molecular properties of I_Na in adult myocytes and hiPSC-CMs.

Methods: hiPSC-CMs were plated at low density. Atrial and ventricular cells were obtained from dog hearts. Whole cell patch clamp was used to record I_Na.

Results: Voltage clamp recordings showed a large I_Na in all three cell types but different densities. Small differences in steady-state inactivation and recovery from inactivation were noted in the three cell types. Application of lidocaine to the three cell types showed a similar pattern of block of I_Na under voltage clamp; however, lidocaine produced different effects on AP waveform under current clamp. AP clamp experiments showed that application of ventricular or atrial cell waveforms to the same hiPSC-CM elicited a large I_Na while application of a sinoatrial node waveform elicited no I_Na. Molecular analysis of Na⁺ channel subunits showed SCN5A and SCN1B-4B were expressed in adult cells and iPSC-CMs. However, iPSC-CMs express both fetal (exon 6A) and adult (exon 6) isoforms of SCN5A.

Discussion: There are major differences in I_Na density and smaller differences in other biophysical properties of I_Na in adult atrial, ventricular, and hiPSC-CMs. The depolarized maximum diastolic potential coupled with the presence of phase 4 depolarization limits the contribution of I_Na in hiPSC-CM action potentials. Our results suggest that hiPSC-CMs may be useful for drug screening of Na⁺ channel inhibitors under voltage clamp but not current clamp.

Keywords: Action potentials; Atria; Depolarization; Electrophysiology; Sodium current; Stem cells; Ventricle.