title: Nonequilibrium reactivation of Na+ current drives early afterdepolarizations in mouse ventricle.
abstract: BACKGROUND
  Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca(2+) current (ICaL) reactivation or sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) 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.
  
  
  RESULTS
  In Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca(2+) 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 Ca(2+) release and Na(+) current (INa), but not late INa, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca(2+) release and Na(+)/Ca(2+) 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.
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.). agedwards@ucsd.edu.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Edwards
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Eleonora
authors.initials: E
authors.lastname: Grandi
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Johan E
authors.initials: JE
authors.lastname: Hake
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Sonia
authors.initials: S
authors.lastname: Patel
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Omens
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Joan
authors.initials: J
authors.lastname: Heller Brown
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.affiliation: From the Department of Bioengineering (A.G.E., S.P., J.H.O., A.D.M.), Department of Pharmacology (S.M., J.H.B.), University of California, San Diego, La Jolla; Department of Pharmacology, University of California, Davis (E.G., D.M.B.); and Simula Research Laboratory, Center for Biomedical Computing, Lysaker, Oslo, Norway (J.E.H., P.L.).
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
mesh_terms: D000200:Action Potentials; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors; D016276:Ventricular Function
chemical_list: D000319:Adrenergic beta-Antagonists; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517673:Camk2d protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: arrhythmias; calcium/calmodulin-dependent protein kinase type 2; cardiac; electrophysiology; sodium-calcium exchanger 1