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 (IK1). 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 IK1. Without injection of IK1, our hiPSC-CMs showed nodal-like spontaneous beating, but injection of an in silico IK1 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 IKl, 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.