Repolarization Reserve Evolves Dynamically During the Cardiac Action Potential Effects of Transient Outward Currents on Early Afterdepolarizations

Background Transient outward K currents (I-to) have been reported both to suppress and to facilitate early afterdepolarizations (EADs) when repolarization reserve is reduced. Here, we used the dynamic clamp technique to analyze how I-to 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 of 6 s, when native rabbit I-to is substantial. EADs disappeared when the pacing cycle length was shortened to 1 s, when I-to becomes negligible because of incomplete recovery from inactivation. During 6-s pacing cycle length, EADs were blocked by the I-to blocker 4-aminopyridine, but reappeared when a virtual current with appropriate I-to-like properties was reintroduced using the dynamic clamp (n=141 trials). During 1-s pacing cycle length in the absence of 4-aminopyridine, adding a virtual I-to-like current (n=1113 trials) caused EADs to reappear over a wide range of I-to conductance (0.005-0.15 nS/pF), particularly when inactivation kinetics were slow ((inact)20 ms) and the pedestal (noninactivating component) was small (<25% of peak I-to). Faster inactivation or larger pedestals tended to suppress EADs. Conclusions Repolarization reserve evolves dynamically during the cardiac action potential. Whereas sufficiently large I-to can suppress EADs, a wide range of intermediate I-to properties can promote EADs by influencing the temporal evolution of other currents affecting late repolarization reserve. These findings raise caution in targeting I-to as an antiarrhythmic strategy.