Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1205-1213 |
| Number of pages | 9 |
| Journal | Circulation: Arrhythmia and Electrophysiology |
| Volume | 7 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2014 |
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Keywords
- Arrhythmias, cardiac
- Calcium/calmodulin-dependent protein kinase type 2
- Electrophysiology
- Sodium-calcium exchanger 1
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
Cite this
Nonequilibrium reactivation of Na+ current drives early afterdepolarizations in mouse ventricle. / Edwards, Andrew G.; Grandi, Eleonora; Hake, Johan E.; Patel, Sonia; Li, Pan; Miyamoto, Shigeki; Omens, Jeffrey H.; Brown, Joan Heller; Bers, Donald M.; McCulloch, Andrew D.
In: Circulation: Arrhythmia and Electrophysiology, Vol. 7, No. 6, 01.12.2014, p. 1205-1213.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nonequilibrium reactivation of Na+ current drives early afterdepolarizations in mouse ventricle
AU - Edwards, Andrew G.
AU - Grandi, Eleonora
AU - Hake, Johan E.
AU - Patel, Sonia
AU - Li, Pan
AU - Miyamoto, Shigeki
AU - Omens, Jeffrey H.
AU - Brown, Joan Heller
AU - Bers, Donald M.
AU - McCulloch, Andrew D.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
KW - Arrhythmias, cardiac
KW - Calcium/calmodulin-dependent protein kinase type 2
KW - Electrophysiology
KW - Sodium-calcium exchanger 1
UR - http://www.scopus.com/inward/record.url?scp=84924612571&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924612571&partnerID=8YFLogxK
U2 - 10.1161/CIRCEP.113.001666
DO - 10.1161/CIRCEP.113.001666
M3 - Article
C2 - 25236710
AN - SCOPUS:84924612571
VL - 7
SP - 1205
EP - 1213
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
SN - 1941-3149
IS - 6
ER -