Slow [Na⁺]_i dynamics impacts arrhythmogenesis and spiral wave reentry in cardiac myocyte ionic model

Accumulation of intracellular Na⁺ is gaining recognition as an important regulator of cardiac myocyte electrophysiology. The intracellular Na⁺ concentration can be an important determinant of the cardiac action potential duration, can modulate the tissue-level conduction of excitation waves, and can alter vulnerability to arrhythmias. Mathematical models of cardiac electrophysiology often incorporate a dynamic intracellular Na⁺ concentration, which changes much more slowly than the remaining variables. We investigated the dependence of several arrhythmogenesis-related factors on [Na⁺]_i in a mathematical model of the human atrial action potential. In cell simulations, we found that [Na⁺]_i accumulation stabilizes the action potential duration to variations in several conductances and that the slow dynamics of [Na⁺]_i impacts bifurcations to pro-arrhythmic afterdepolarizations, causing intermittency between different rhythms. In long-lasting tissue simulations of spiral wave reentry, [Na⁺]_i becomes spatially heterogeneous with a decreased area around the spiral wave rotation center. This heterogeneous region forms a functional anchor, resulting in diminished meandering of the spiral wave. Our findings suggest that slow, physiological, rate-dependent variations in [Na⁺]_i may play complex roles in cellular and tissue-level cardiac dynamics.