Dominant ionic currents in rabbit ventricular action potential dynamics

Mathematical models of cardiac cell electrical activity include numerous parameters, making calibration to experimental data and individual-specific modeling challenging. This study applies Sobol sensitivity analysis, a global variance-decomposition method, to identify the most influential parameters in the Shannon model of rabbit ventricular myocyte action potential (AP). The analysis highlights the background chloride current (IClb) as the dominant determinant of AP variability. Additionally, the inward rectifier potassium current (IK1), fast/slow delayed rectifier potassium currents (IKr, IKs), sodium-calcium exchanger current (INaCa), the slow component of the transient outward potassium current (Itos), and L-type calcium current (ICaL) significantly affect AP biomarkers, including duration, plateau potential, and resting potential. Exploiting these results, a hierarchical reduction of the model is performed and demonstrates that retaining only six key parameters can capture sufficiently well individual biomarkers, with a coefficient of determination exceeding 0.9 for selected cases. These findings improve the utility of the Shannon model for personalized simulations, aiding applications like digital twins and drug response predictions in biomedical research.Author summary: In our study, we explored the complexity of a mathematical model used to understand the electrical activity of rabbit ventricular cells. Such models involve many parameters, which makes it difficult to match them with experimental data or to personalize them for individual cells. To address this, we used a method for global sensitivity analysis to identify which ion current parameters have the most impact on the action potential output of the model. Our analysis shows that the background chloride current is the main factor influencing the variability of the rabbit ventricular action potential. Other important currents include the inward rectifier potassium current, various potassium currents, sodium-calcium exchanger current, the slow component of the transient outward potassium current, and the L-type calcium current. These factors play a significant role in determining key features of the action potential, such as its duration, plateau potential, and resting potential. Based on these results, we proposed a sequence of simplified models obtained by retaining variability in a few most influential parameters while fixing the rest to appropriate constant values. This approach is also applicable to other mathematical models of cardiac action potentials and can make them more useful for personalized simulations, and in areas like digital twins and predicting drug responses in biomedical research.