Inferring ion channel block from rabbit Purkinje fiber action potential recordings

Abstract

Mathematical action potential (AP) models describe the changes in the membrane voltage due to a complex interplay between ionic currents, and their interactions with drug compounds. These models can guide preclinical risk assessments for drug-induced cardiac arrhythmia and extract more information from animal-based experiments. The rabbit Purkinje fiber has been used in preclinical studies, as it includes the major currents present in human ventricular myocytes. A recently proposed mathematical AP model of the rabbit Purkinje fiber, combined with ion channel screening data, predicted drug effects on AP changes, with an agreement of up to 80 % (Mohr et al., 2022). To explain the 20 % mismatch, we first improve the original AP model by re-calibrating its parameters to fit control AP traces. Subsequently we test our inference method in terms of uncertainty quantification of the control parameters. Finally, we compare the calibrated model and the original model in terms of prediction of AP %-changes induced by reference drug compounds with well-studied channel block properties and low measurement error (sd < 10). Preliminary results indicate that after calibrating the ionic conductances, the correlation between observed and predicted %-change in APD50 (APD90) increased from −0.1 (0.04) to 0.43 (0.34). We are currently working on fitting model predictions to experimental AP changes in the presence of a new set of compounds, to infer the block of various ion channels, in terms of 50 % inhibitory concentration (IC50). The aim is to perform an experimental test for any computationally inferred IC50s which have not been measured, particularly for those drug compounds whose action potential changes are not explained by the existing ion channel screening data.