Reexcitation mechanisms in epicardial tissue: Role of Ito density heterogeneities and INa inactivation kinetics

Abstract

Dispersion of action potential repolarization is known to be an important arrhythmogenic factor in cardiopathies such as Brugada syndrome. In this work, we analyze the effect of a variation in sodium current ( I Na) inactivation and a heterogeneous rise of transient outward current ( I to) in the probability of reentry in epicardial tissue. We use the Luo–Rudy model of epicardial ventricular action potential to study wave propagation in a one-dimensional fiber. Spatial dispersion in repolarization is introduced by splitting the fiber into zones with different strength of I to. We then analyze the pro-arrhythmic effect of a variation in the relaxation time and steady-state of the sodium channel fast inactivating gate h. We quantify the probability of reentry measuring the percentage of reexcitations that occurs in 200 beats. We find that, for high stimulation rates, this percentage is negligible, but increases notably for pacing periods above 700 ms. Surprisingly, with decreasing I Na inactivation time, the percentage of reexcitations does not grow monotonically, but presents vulnerable windows, separated by values of the I Na inactivation speed-up where reexcitation does not occur. By increasing the strength of L-type calcium current I CaL above a certain threshold, reexcitation disappears. Finally, we show the formation of reentry in stimulated two-dimensional epicardial tissue with modified I Na kinetics and I to heterogeneity. Thus, we confirm that while I to dispersion is necessary for phase-2 reentry, altered sodium inactivation kinetics influences the probability of reexcitation in a highly nonlinear fashion.