Ranolazine Prevents Phase-3 Early Afterdepolarizations in Human Atrial Myocytes by Inhibiting Na Current Non-Equilibrium Reactivation

Abstract

Background: We have previously shown that non-equilibrium reactivation of the Na current (INa) drives Isoproterenol-induced phase-3 early afterdepolarizations (EADs) in failing mouse ventricular myocytes. EAD initiation is secondary to potentiated sarcoplasmic reticulum Ca release and enhanced Na/Ca exchange (NCX), and can be abolished by the INa blocker tetrodotoxin, but not by the selective (in ventricles) late INa blocker ranolazine.Aim. Since repolarization in human atrial myocytes is relatively rapid and potently modulated by Ca (as in mouse ventricle), we investigate whether the same EAD mechanism may occur in human atria. Indeed, phase-3 EADs have been suggested to underlie re-initiation of atrial fibrillation (AF) after termination upon autonomic stimuli - well recognized AF triggers.Methods: We integrated a Markov model of INa (also describing the channel interaction with ranolazine, similar to work by Clancy) in our human atrial myocyte model. To recapitulate experimental results, we simulated rapid cell pacing (10 Hz) in the presence of Acetylcholine (0.1 μM) and Isoproterenol (1 μM), and assessed EAD occurrence upon return to sinus rhythm (1 Hz).Results: Cellular Ca overload during fast pacing results in a transient period of hyper-contractility after return to sinus rhythm. Here, fast repolarization and enhanced NCX facilitate INa reactivation via the canonical gating mode (i.e., not late INa burst mode), which drives EAD initiation. Notably, in action potential clamp experiments, an EAD waveform elicits a lidocaine-sensitive inward current during the EAD upstroke in pig atrial cells. Simulating ranolazine administration reduces peak INa and leads to a faster repolarization, during which INa fails to reactivate.Conclusions: Our simulations suggest that non-equilibrium INa reactivation critically contributes to arrhythmias in human atrial myocytes. Ranolazine might be beneficial in this context by blocking peak (not late) atrial INa.