Optimization of the O'Hara-Rudy Model of Human Ventricular Action Potential with Respect to Electrolyte Concentrations and Rate Dependence

The 'Comprehensive In vitro Proarrhythmia Assay' (CiPA) initiative proposes a new mechanistic, model-informed, approach to cardiac safety assessment of new drugs, an approach made possible by a deeper understanding of the ionic currents that play a role in QTc prolongation and in the development of torsades de pointes (TdP). In defining a new paradigm in the field of cardiac safety the proarrhythmic risk would be primarily assessed using preclinical in vitro and in silico human models. In this scenario the best cellular computer model(s) would have to be selected and if necessary improved. The aim of this study has been the upgrade of the most updated human ventricular cell model in order to: 1) correct its response to [Ca2+]°changes; 2) replicate the steady state action potential duration (APD) rate dependency and 3) the S1S2 APD restitution. The presented model has been validated against the same experimental data used for the original one, in order to verify its consistency and enforce its integration in the use of in silico models for predicting clinical risk of drug-induced arrhythmias.