Evidence map›Paper›PMID 25236710›Full record

ArticleCirculation. Arrhythmia and electrophysiology2014

Nonequilibrium reactivation of Na+ current drives early afterdepolarizations in mouse ventricle.

Andrew G Edwards, Eleonora Grandi, Johan E Hake, Sonia Patel, Pan Li, Shigeki Miyamoto, Jeffrey H Omens, Joan Heller Brown, Donald M Bers, Andrew D McCulloch

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In one paragraph

Article in Circulation. Arrhythmia and electrophysiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.

0numbers the graph read from it
0cells of the map it votes in
33citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

33 citing papers in PubMed.

  1. Article
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  5. Role of ryanodine receptor cooperativity in CaThe Journal of physiology · 2024
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  11. CaMKIIδC Drives Early Adaptive CaCirculation research · 2020
    Article
  12. Genetic Loss ofCirculation. Arrhythmia and electrophysiology · 2020
    Article
  13. Article
  14. Quantitative systems models illuminate arrhythmia mechanisms in heart failure: Role of the NaWiley interdisciplinary reviews. Systems biology and medicine · 2019
    Review
  15. A Mathematical Model of the Human Cardiac NaThe Journal of membrane biology · 2019
    Article
  16. Article
  17. Article
  18. A privileged role for neuronal NaThe Journal of general physiology · 2018
    Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Andrew G EdwardsFrom 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.
Eleonora GrandiFrom 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.).
Johan E HakeFrom 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.).
Sonia PatelFrom 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.).
Pan LiFrom 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.).
Shigeki MiyamotoFrom 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.).
Jeffrey H OmensFrom 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.).
Joan Heller BrownFrom 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.).
Donald M BersFrom 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.).
Andrew D McCullochFrom 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.).

Funding

Vinculin and Talin in Cardiocyte Integrity and AdhesionP01HL046345 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI KNOWLTON, KIRK U · 1992 to 2011
$25.0M
Program AdministrationP01HL080101 · NHLBI · UNIVERSITY OF CALIFORNIA AT DAVIS · PI BERS, DONALD M · 2006 to 2015
$23.4M
National Biomedical Computation Resource - Competitive Revision SupplementP41GM103426 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI AMARO, ROMMIE E · 2012 to 2019
$14.0M
The Virtual Physiological Rat ProjectP50GM094503 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BEARD, DANIEL A · 2011 to 2015
$11.6M
Systems Biology CoreP01HL098053 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI POWELL, FRANK L. · 2010 to 2014
$10.2M
Phospholemman and Na-Pump Function in Cardiac MyocytesR01HL081562 · NHLBI · UNIVERSITY OF CALIFORNIA AT DAVIS · PI BERS, DONALD M · 2005 to 2018
$5.3M
Multi-scale Systems Model of Murine Heart FailureR01HL105242 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BERS, DONALD M, MCCULLOCH, ANDREW D. · 2012 to 2016
$3.5M
Multi-Scale Modeling of the Failing Heart for Cardiac Rysynchronization TherapyR01HL096544 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MCCULLOCH, ANDREW D. · 2009 to 2013
$1.8M
Modeling Cytosolic and Nuclear Ca2+ and IP3 Signaling in Ventricular MyocytesR03EB014593 · NIBIB · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MCCULLOCH, ANDREW D. · 2013 to 2014
$153k
NHLBI NIH HHS P01 HL046345NHLBI NIH HHS P01 HL080101NHLBI NIH HHS P01-HL080101NHLBI NIH HHS P01-HL098053NHLBI NIH HHS R01 HL081562NHLBI NIH HHS R01 HL096544NHLBI NIH HHS R01 HL105242NHLBI NIH HHS R01-HL105242NHLBI NIH HHS R01-HL96544NIBIB NIH HHS R03 EB014593NIGMS NIH HHS P41 GM103426NIGMS NIH HHS P41-GM103426NIGMS NIH HHS P50 GM094503NIGMS NIH HHS P50-GM094503
6 · The paper itself

Abstract

backgroundEarly 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. METHODS AND

resultsIn 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.

conclusionsNonequilibrium reactivation of INa drives murine EADs.

Indexed as

Ventricular FunctionAction PotentialsAdrenergic beta-AntagonistsAnimalsCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2Computer SimulationFemaleHeart VentriclesMaleMice, TransgenicModels, CardiovascularMyocytes, CardiacSarcoplasmic ReticulumSarcoplasmic Reticulum Calcium-Transporting ATPasesSodiumAdrenergic beta-AntagonistsCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2Camk2d protein, mouseSarcoplasmic Reticulum Calcium-Transporting ATPasesSodiumSodium-Calcium ExchangerSodium Channel Blockersarrhythmiascalcium/calmodulin-dependent protein kinase type 2cardiacelectrophysiologysodium-calcium exchanger 1

Identifiers

PMID25236710
PMCPMC4301603

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.