Sodium Current Analysis in Myocytes Obtained from Human Induced Pluripotent Stem Cells and Native Adult Heart

Background: The proposed Comprehensive in Vitro Pro-Arrhythmia Assay (CiPA) initiative aims to examine proarrhythmic drug effects on multiple cardiac ion channels in adult cardiac tissue as well as in human-induced pluripotent stem cell-derived (hiPSC) cardiomyocytes. In this study, we examined the biophysical properties of INa in hiPSC myocytes and compared them to adult canine atrial and ventricular myocytes. Methods: Left atrial and ventricular myocytes were isolated from dog hearts, whereas hiPSC myocytes were obtained from commercially available sources. Action potential recordings from all tissue types were made using high resistance electrodes. Patch clamp techniques were used to record INa from single cells. Results: Analysis of the action potential characteristics showed a higher upstroke velocity in atrial and ventricular tissue (185.4±18.4 and 183.3±14.2 V/s, respectively) compared to hiPSC (33.1±3.3 V/s) beating clusters. Voltage clamp recordings of fast INa showed that current density was lower in hiPSC myocytes compared with atrial and ventricular myocytes (−25.8±4.28 pA/pF vs. −119.6±6.7 pA/pF and −70.0±9.28 pA/pF, respectively, p<0.05). Steady state-inactivation was also significantly different between the 3 cardiac tissue types with atrial cells showing the most negative V½ and ventricular cells showing the least negative. Application of the INa blocker lidocaine (100 µM) resulted in a differential effect on Vmax and INa blockade with atrial tissue and hiPSC showing the greatest reduction in both parameters whereas ventricular tissue showing the smallest reduction. Conclusions: These data show that the density of INa in hiPSC myocytes was much lower compared to native myocytes. In addition, the response of hiPSC cells to a prototypical sodium channel blocker indicates caution should be exercised when comparing the results obtained in these cells to native ventricular cells.