Numerical Simulations Indicate IK1 Dynamic Clamp Can Unveil the Phenotype of Cardiomyocytes Derived from Induced Pluripotent Stem Cells

Sofia Botti1, Chiara Bartolucci2, Claudia Altomare3, Lucio Barile3, Rolf Krause4, Luca Pavarino1, Stefano Severi2
1University of Pavia, 2University of Bologna, 3Cardiocentro Ticino Institute - EOC, 4Euler Institute - USI


Introduction: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are an endless source of human CMs, resulting in a mix of atrial-like (AL) and ventricular-like (VL) cardiomyocytes. A useful tool to improve action potential (AP) measurements in hiPSC-CMs is the Dynamic Clamp (DC) technique, based on virtual inward - rectifier potassium current (IK1) injection. The aim of this in silico study is to analyse six different IK1 expressions in a virtual DC procedure in order to classify hiPSC-CM AL and VL phenotypes. Methods: The Paci2013 ionic model was used to simulate the ionic membrane currents and the AP of AL and VL hiPSC-CMs. In this computational set, the virtual DC was carried out by suppressing the native IK1 and testing six additional IK1 formulations available in the literature, using the Ten Tusscher, Grandi, Fink, O'Hara-Rudy, Koivumaki and Courtemanche ionic models, rescaled in order to obtain the same outward current peak. Results: For each IK1 formulation considered, the AP morphology is absolutely non physiological for low percentages of the injected current, while it becomes physiological for higher densities. Using a mathematical criterion based on the number of AP inflections, we obtain the threshold percentages of the current density, defined as the minimal amount of injected IK1 required to obtain a physiological AP. Conclusion: Keeping in mind that we are considering non-native currents, we claim that the most appropriate IK1 formulation is the one that minimizes the threshold percentage, i.e. the Koivumaki formulation.