Background: Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca2+ current (ICaL) reactivation or sarcoplasmic reticulum Ca2+ release and Na+/Ca2+ exchange. In large mammals the positive action potential 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 action potential, 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 calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations. Methods and Results: In Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum 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 sarcoplasmic reticulum Ca2+ release and Na+ current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca2+ release and Na+/Ca2+ exchange shape late action potential repolarization to favor nonequilibrium reactivation of INa and thereby drive the EAD upstroke. Action potential clamp experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40-60 μmol/L) for which lidocaine remains specific for inactivated Na+ channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium INa dynamics underlie murine EADs. Conclusions: Nonequilibrium reactivation of INa drives murine EADs.
- Arrhythmias, cardiac
- Calcium/calmodulin-dependent protein kinase type 2
- Sodium-calcium exchanger 1
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)