Automatic optimization of an in silico model of human iPSC derived cardiomyocytes recapitulating calcium handling abnormalities

Abstract

<p>The growing importance of human induced pluripotent stem cell-derived cardiomyoyctes (hiPSC-CMs), as patient-specific and disease-specific models for studying cellular cardiac electrophysiology or for preliminary cardiotoxicity tests, generated better understanding of hiPSC-CM biophysical mechanisms and great amount of action potential and calcium transient data. In this paper, we propose a new hiPSC-CM in silico model, with particular attention to Ca<sup>2+</sup> handling. We used (i) the hiPSC-CM Paci2013 model as starting point, (ii) a new dataset of Ca<sup>2+</sup> transient measurements to tune the parameters of the inward and outward Ca<sup>2+</sup> fluxes of sarcoplasmic reticulum, and (iii) an automatic parameter optimization to fit action potentials and Ca<sup>2+</sup> transients. The Paci2018 model simulates, together with the typical hiPSC-CM spontaneous action potentials, more refined Ca<sup>2+</sup> transients and delayed afterdepolarizations-like abnormalities, which the old Paci2013 was not able to predict due to its mathematical formulation. The Paci2018 model was validated against (i) the same current blocking experiments used to validate the Paci2013 model, and (ii) recently published data about effects of different extracellular ionic concentrations. In conclusion, we present a new and more versatile in silico model, which will provide a platform for modeling the effects of drugs or mutations that affect Ca<sup>2+</sup> handling in hiPSC-CMs.</p>