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

  • Author(s): Nguyen, TP
  • Singh, N
  • Xie, Y
  • Qu, Z
  • Weiss, JN
  • et al.
Abstract

© 2015 American Heart Association, Inc. Background - Transient outward K currents (Ito) 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 Itoaccounts 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 Itois substantial. EADs disappeared when the pacing cycle length was shortened to 1 s, when Itobecomes negligible because of incomplete recovery from inactivation. During 6-s pacing cycle length, EADs were blocked by the Itoblocker 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 pacing cycle length in the absence of 4-aminopyridine, adding a virtual Ito-like current (n=1113 trials) caused EADs to reappear over a wide range of Itoconductance (0.005-0.15 nS/pF), particularly when inactivation kinetics were slow (τinact≥20 ms) and the pedestal (noninactivating 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 Itocan suppress EADs, a wide range of intermediate Itoproperties can promote EADs by influencing the temporal evolution of other currents affecting late repolarization reserve. These findings raise caution in targeting Itoas an antiarrhythmic strategy.

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