Testing the limits of cardiac electrophysiology models through systematic variation of current

Mathematical models of the electrical response of cardiac cells are used to help develop an understanding of the electrophysiological properties of cardiac cells. Increasingly complex models are being developed in an effort to enhance the biological fidelity of the models and potentially increase their ability to predict electrical dynamics observed in vivo and in vitro. However, as the models increase in size, they have a tendency to become unstable and are highly sensitive to changes in established parameters. This means that such models might be unable to accurately predict person-to-person variability, dynamical changes due to disease pathologies that alter ionic currents, or the effect of treatment with antiarrhythmics. In this paper, we test the predictive limits of two mathematical models by altering the conductance of Ca²⁺, Na⁺, and K⁺ channels. We assess changes in action potential duration (APD), rate dependence, hysteresis, dynamical behavior, and restitution as conductance is varied. We find model predictions of abrupt changes in measured quantities and differences in the predictions of the two models that might be missed in a less systematic approach. These features can be compared to experimental observations to help assess the fidelity of the models.