Calibration of an in‐silico Human Ventricular Action Potential Model to Detect Proarrhythmic Liabilities

Abstract

In‐silico models of human ventricular action potentials (APs) are useful for defining the roles of specific ionic currents on cardiac repolarization and integrating drug effects on multiple cardiac ionic currents. To provide utility in defining proarrhythmic risk, these models need to be adequately benchmarked regarding their ability to generate cellular proarrhythmia. The present studies calibrated the proarrhythmic liabilities of blocking single and multiple ionic currents using ventricular APs from the O'Hara‐Rudy (ORd) model based on delayed repolarization and early afterdepolarization (EAD) activity.An endocardial cell model paced at a cycle length (CL) of 4 sec was used to reconstruct AP changes; the maximal conductance of IKr (hERG current), along with IKs, ICaL, INaL, and Na/K pump current were reduced (both individually and in concert with IKr).Decreasing IKr conductance caused AP prolongation and typically required 150‐250+ beats to reach steady‐state responses when no EADs were present. EADs were first observed when IKr was reduced by 85%; additional IKr block yielded APs with patterns of 1‐6+ EADs. When concurrently blocking IKr, EADs were less prevalent when inward currents (either ICaL or INaL) were reduced, and more prominent when outward currents (either NA/K pump or IKs) were reduced.In conclusion, in the ORd model, a) EAD activity is typically oscillatory (even after several minutes of simulated pacing), often with no stabilized, steady state rate or pattern, b) EAD activity is present only with substantial IKr block, is reduced with concomitant block of inward ICaL and INaL, and is increased by reducing IKs or Na/K pump current.This research was supported by AbbVie.