Nguyen, T. P., Singh, N., Xie, Y., Qu, Z. & Weiss, J. N. Repolarization Reserve Evolves Dynamically During the Cardiac Action Potential: Effects of Transient Outward Currents on Early Afterdepolarizations. Circulation: Arrhythmia and Electrophysiology (2015). doi:10.1161/CIRCEP.114.002451

Background — Transient outward K currents (Ito) have been reported both to suppress and facilitate early afterdepolarizations (EADs) when repolarization reserve is reduced. Here we used the dynamic clamp technique to analyze how Ito accounts for these paradoxical effects on EADs by influencing the dynamic evolution of repolarization reserve during the action potential.

Methods and Results — Isolated patch-clamped rabbit ventricular myocytes were exposed to either oxidative stress (H2O2) or hypokalemia to induce bradycardia-dependent EADs at a long pacing cycle length (PCL) of 6 s, when native rabbit Ito is substantial. EADs disappeared when the PCL was shortened to 1 s, when Ito becomes negligible due to incomplete recovery from inactivation. During 6-s PCL, EADs were blocked by the Ito blocker 4-aminopyridine, but reappeared when a virtual current with appropriate Ito-like properties was reintroduced using the dynamic clamp (n=141 trials). During 1-s PCL in the absence of 4-aminopyridine, adding a virtual Ito-like current (n=1,113 trials) caused EADs to reappear over a wide range of Ito conductance (0.005-0.15 nS/pF), particularly when inactivation kinetics were slow (τinact≥20 ms) and the pedestal (non-inactivating component) was small (<25% of peak Ito). Faster inactivation or larger pedestals tended to suppress EADs.

Conclusions — Repolarization reserve evolves dynamically during the cardiac action potential. Whereas sufficiently large Ito can suppress EADs, a wide range of intermediate Ito properties can promote EADs by influencing the temporal evolution of other currents affecting late repolarization reserve. These findings raise caution in targeting Ito as an antiarrhythmic strategy.