Numerical Simulations Indicate I_K1Dynamic Clamp Can Unveil the Phenotype of Cardiomyocytes Derived from Induced Pluripotent Stem Cells

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are a virtually endless source of human cardiomyocytes, considerably used in vitro models to test drug toxicity. These cells express the major cardiac markers and ion channels, but they also result in a mix of incompletely mature cardiac cells that can be classified as atrial-like and ventricular-like cardiomyocytes. One of the most popular manipulations used to push towards more adult cardiac phenotypes is the dynamic clamp technique, based on virtual inward - rectifier potassium current (IK1) injection. In this exploratory in silico study, six different IK1 expressions have been virtually analyzed to classify hiPSC-CM phenotypes. Starting from the resulting action potential morphologies, we defined a mathematical criterion to estimate the efficacy of the injected IK1 current in terms of the threshold percentage of the current density required to obtain an hiPSC-CM physiological response. It was found that atrial IK1 formulations are more reliable than ventricular ones, with the Koivumäki IK1 formulation being the most appropriate since it requires the minimal current density to be injected.