Evidence map›Paper›PMID 25249569›Full record

ArticleCirculation research2014

Hyperphosphorylation of RyRs underlies triggered activity in transgenic rabbit model of LQT2 syndrome.

Dmitry Terentyev, Colin M Rees, Weiyan Li, Leroy L Cooper, Hitesh K Jindal, Xuwen Peng, Yichun Lu, Radmila Terentyeva, Katja E Odening, Jean Daley and 4 more

Abstract read
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In one paragraph

Article in Circulation research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.

0numbers the graph read from it
0cells of the map it votes in
47citing papers in PubMed
4.1field-weighted citation impact, top 5% of its field
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

47 citing papers in PubMed, 70 citations in OpenAlex.

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  17. MCU overexpression evokes disparate dose-dependent effects on mito-ROS and spontaneous CaAmerican journal of physiology. Heart and circulatory physiology · 2021
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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

14 authors at 2 institutions in 1 country.

Dmitry TerentyevFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.). dmitry_terentyev@brown.edu gideon_koren@brown.edu.
Colin M ReesFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Weiyan LiFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Leroy L CooperFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Hitesh K JindalFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Xuwen PengFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Yichun LuFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Radmila TerentyevaFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Katja E OdeningFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Jean DaleyFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Kamana BistFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Bum-Rak ChoiFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Alain KarmaFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.).
Gideon KorenFrom the Department of Medicine, Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence (D.T., W.L., L.L.C., H.K.J., Y.L., R.T., J.D., K.B., B.-R.C., G.K.); Physics Department, Center for Interdisciplinary Research on Complex Systems, Northeastern University, Boston, MA (C.M.R., A.K.); Department of Comparative Medicine, Pennsylvania State University College of Medicine, Hershey (X.P.); and Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany (K.E.O.). dmitry_terentyev@brown.edu gideon_koren@brown.edu.
Northeastern University · USPennsylvania State University · US

Funding

A Multi-Scale Approach to Cardiac Arrhythmia: from the Molecule to the OrganR01HL110791 · NHLBI · RHODE ISLAND HOSPITAL · PI KOREN, GIDEON · 2013 to 2017
$7.3M
Brown CardioPulmonary Research Training ProgramT32HL094300 · NHLBI · RHODE ISLAND HOSPITAL · PI KOREN, GIDEON · 2008 to 2012
$2.2M
NHLBI NIH HHS 5T32HL094300-05NHLBI NIH HHS R01 HL0460005-23NHLBI NIH HHS R01 HL110791NHLBI NIH HHS R01 HL110791-01A1NHLBI NIH HHS T32 HL094300
6 · The paper itself

Abstract

rationaleLoss-of-function mutations in human ether go-go (HERG) potassium channels underlie long QT syndrome type 2 (LQT2) and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasma membrane-related pathways involved in arrhythmogenesis in long QT syndrome, whereas proarrhythmic changes in intracellular Ca(2+) handling remained unexplored.

objectiveWe investigated the remodeling of Ca(2+) homeostasis in ventricular cardiomyocytes derived from transgenic rabbit model of LQT2 to determine whether these changes contribute to triggered activity in the form of early after depolarizations (EADs). METHODS AND

resultsConfocal Ca(2+) imaging revealed decrease in amplitude of Ca(2+) transients and sarcoplasmic reticulum Ca(2+) content in LQT2 myocytes. Experiments using sarcoplasmic reticulum-entrapped Ca(2+) indicator demonstrated enhanced ryanodine receptor (RyR)-mediated sarcoplasmic reticulum Ca(2+) leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes versus controls. Coimmunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with β-adrenergic agonist isoproterenol resulted in prolongation of the plateau of action potentials accompanied by aberrant Ca(2+) releases and EADs, which were abolished by inhibition of Ca(2+)/calmodulin-dependent protein kinase type 2. Computer simulations showed that late aberrant Ca(2+) releases caused by RyR hyperactivity promote EADs and underlie the enhanced triggered activity through increased forward mode of Na(+)/Ca(2+) exchanger type 1.

conclusionsHyperactive, hyperphosphorylated RyRs because of reduced local phosphatase activity enhance triggered activity in LQT2 syndrome. EADs are promoted by aberrant RyR-mediated Ca(2+) releases that are present despite a reduction of sarcoplasmic reticulum content. Those releases increase forward mode Na(+)/Ca(2+) exchanger type 1, thereby slowing repolarization and enabling L-type Ca(2+) current reactivation.

Indexed as

Action PotentialsProtein Processing, Post-TranslationalAnimalsAnimals, Genetically ModifiedCalcium-Calmodulin-Dependent Protein Kinase Type 2Calcium Channels, L-TypeCalcium SignalingCells, CulturedERG1 Potassium ChannelEther-A-Go-Go Potassium ChannelsHeart VentriclesHumansLong QT SyndromeMyocytes, CardiacPhosphorylationProtein Phosphatase 1Calcium-Calmodulin-Dependent Protein Kinase Type 2Calcium Channels, L-TypeERG1 Potassium ChannelEther-A-Go-Go Potassium ChannelsKCNH2 protein, humanProtein Phosphatase 1Protein Phosphatase 2Ryanodine Receptor Calcium Release ChannelSodium-Calcium Exchangerarrhythmias, cardiaccalcium releaselong QT syndromeprotein phosphataseryanodine receptor

Identifiers

PMID25249569
PMCPMC4406222
OpenAlexW2103036074

What OpenQuestion holds

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Read underepoch 390

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.