Slow [Na] i Changes and Positive Feedback Between Membrane Potential and [Ca] i Underlie Intermittent Early Afterdepolarizations and Arrhythmias

Abstract

Background— Most cardiac arrhythmias occur intermittently. As a cellular precursor of lethal cardiac arrhythmias, early afterdepolarizations (EADs) during action potentials(APs) have been extensively investigated, and mechanisms for the occurrence of EADs on a beat-to-beat basis have been proposed. However, no previous study explains slow fluctuations in EADs, which may underlie intermittency of EAD trains and consequent arrhythmias. We hypothesize that the feedback of intracellular calcium and sodium concentrations ([Na] i and [Ca] i ) that influence membrane voltage (V) can explain EAD intermittency. Methods and Results— AP recordings in rabbit ventricular myocytes revealed intermittent EADs, with slow fluctuations between runs of APs with EADs present or absent. We then used dynamical systems analysis and detailed mathematical models of rabbit ventricular myocytes that replicate the observed behavior and investigated the underlying mechanism. We found that a dominance of inward Na–Ca exchanger current (I NCX ) over Ca-dependent inactivation of L-type Ca current (I CaL ) forms a positive feedback between [Ca] i and V, thus resulting in 2 stable AP states, with and without EADs (ie, bistability). Slow changes in [Na] i determine the transition between these 2 states, forming a bistable on–off switch of EADs. Tissue simulations showed that this bistable switch of cellular EADs provided both a trigger and a functional substrate for intermittent arrhythmias in homogeneous tissues. Conclusions— Our study demonstrates that the interaction among V, [Ca] i , and [Na] i causes slow on–off switching (or bistability) of AP duration in cardiac myocytes and EAD-mediated arrhythmias and suggests a novel possible mechanism for intermittency of cardiac arrhythmias.