Global Sensitivity Analysis of Arrhythmic Risk Biomarkers in Cardiac Single Cell Models

Abstract

Global sensitivity analysis is critical in understanding the role of ionic currents variability in modulating cellular electrophysiological properties of ventricular myocytes as well as in assessing the cardiac single cell arrhythmic risk biomarkers. This work involves a systematic investigation into the sensitivity of various preclinical cellular biomarkers of arrhythmic risk to changes in ionic current conductances and kinetics. We compare local and global sensitivity analysis approaches. The nonlinearity of the system is confirmed to play an important role when considering the effect of parameters on markers that involve information from different frequencies. In the case of such biomarkers as action potential duration (APD), maxima Cai and Nai concentrations, we find no significant changes in the overall order of the parameters' significance between local and global sensitivity studies. However, even for these single frequency markers we are able to give a more precise relative contribution of each parameter. Importantly, in the case of maximum S1-S2 slope marker, which integrates the information across a spectrum of frequencies of electrical stimuli, we find significant changes in the order of parameters as compared to the previously used methods for studying the sensitivity of cellular biomarkers. Moreover, the models consistently identify the L-type Calcium current (ICaL) as one of the dominant currents affecting the plateau of the action potential. Furthermore, in consistence with experimental data, the simulation results show that variation in conductances and kinetics of other channels does not affect the significance of ICaL's contribution. We demonstrate the critical role of global (vs local) sensitivity analysis in providing insights into the sensitivity of preclinical biomarkers, and hence mechanisms of repolarization and their rate dependence.