Non-Equilibrium Reactivation of Na+ Current Drives Early Afterdepolarizations in Mouse Ventricle
Background—Early-afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca2+ current (ICaL) reactivation or sarcoplasmic reticulum (SR) Ca2+ release and Na+/Ca2+ exchange. In large mammals the positive action potential (AP) plateau promotes ICaL reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between ICaL and the repolarizing K+ currents. However, EADs are also frequent in the rapidly repolarizing mouse AP, which should not readily permit ICaL reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible CaMKIIδC-overexpressing mice (Tg), and via computational simulations.
Methods and Results—In Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated SR Ca2+ release, and initiated EADs below the ICaL activation range (-47±0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not Ranolazine), suggesting that SR Ca2+ release and Na+ current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated SR Ca2+ release and Na+/Ca2+ exchange shape late AP repolarization to favor non-equilibrium reactivation of INa, and thereby drive the EAD upstroke. AP clamp experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40-60 μM) for which lidocaine remains specific for inactivated Na+ channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that non-equilibrium INa dynamics underlie murine EADs.
Conclusions—Non-equilibrium reactivation of INa drives murine EADs.
- Received October 8, 2013.
- Revision received August 19, 2014.
- Accepted August 21, 2014.