Real-time simulation of IK1 in cardiomyocytes derived from human induced pluripotent stem cells

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are widely used in studying basic mechanisms of ventricular arrhythmias. However, their action potential profile-and thereby the profile of individual ionic currents active during that action potential-difers substantially from that of native human cardiomyocytes, which is largely due to an almost negligible expression of the inward rectifier potassium current (I_K1). We attempted to ´normalize´ the action potential profile of our hiPSC-CMs through real-time simulation of the lacking hi in the dynamic clamp configuration of the perforated patch clamp technique, which allows the injection of a voltage-dependent in silico I_K1. Without injection of I_K1, our hiPSC-CMs showed nodal-like spontaneous beating, but injection of an in silico I_K1 unmasked their ventricular-like nature. Proarrhythmic action potential changes were observed upon real-time simulation of both loss-of-function and gain-of-function mutations in I_Kl, as associated with Andersen-Tawil syndrome type 1 and short QT syndrome type 3, respectively. We conclude that injection of in silico hi makes the hiPSC-CM a more reliable model for investigating mechanisms underlying ventricular arrhythmias.