Dominant ionic currents in rabbit ventricular action potential dynamics

TL;DR

This study uses Sobol sensitivity analysis on the Shannon model of rabbit ventricular myocytes to identify key ionic currents influencing action potential variability, enabling simplified yet accurate personalized cardiac models.

Contribution

It introduces a global sensitivity analysis approach to identify dominant parameters, leading to a reduced model that retains predictive accuracy for cardiac action potential features.

Findings

IClb is the most influential current affecting AP variability.

A reduced model with six key parameters captures over 90% of biomarker variance.

The approach enhances personalized cardiac modeling and drug response prediction.

Abstract

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.