Mason, Fleur E.

[["dc.bibliographiccitation.firstpage","95"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","106"],["dc.bibliographiccitation.volume","94"],["dc.contributor.author","Hartmann, Nico H."],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Braun, Inga"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Schotola, Hanna"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Danner, Bernhard C."],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Belardinelli, Luiz"],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:44:54Z"],["dc.date.available","2017-09-07T11:44:54Z"],["dc.date.issued","2016"],["dc.description.abstract","Introduction: Pharmacological rhythm control of atrial fibrillation (AF) in patients with structural heart disease is limited. Ranolazine in combination with low dose dronedarone remarkably reduced AF-burden in the phase II HARMONY trial. We thus aimed to investigate the possible mechanisms underlying these results. Methods and results: Patch clamp experiments revealed that ranolazine (5 mu M), low-dose dronedarone (0.3 mu M), and the combination significantly prolonged action potential duration (APD(90)) in atrial myocytes from patients in sinus rhythm (prolongation by 23.5 +/- 0.1%, 31.7 +/- 0.1% and 25.6 +/- 0.1% respectively). Most importantly, in atrial myocytes from patients with AF ranolazine alone, but more the combination with dronedarone, also prolonged the typically abbreviated APD(90) (prolongation by 21.6 +/- 0.1% and 31.9 +/- 0.1% respectively). It was clearly observed that neither ranolazine, dronedarone nor the combination significantly changed the APD or contractility and twitch force in ventricular myocytes or trabeculae from patients with heart failure (HF). Interestingly ranolazine, and more so the combination, but not dronedarone alone, caused hyperpolarization of the resting membrane potential in cardiomyocytes from AF. As measured by confocal microscopy (Fluo-3), ranolazine, dronedarone and the combination significantly suppressed diastolic sarcoplasmic reticulum (SR) Ca2+ leak in myocytes from sinus rhythm (reduction by ranolazine: 89.0 +/- 30.7%, dronedarone: 75.6 +/- 27.4% and combination: 78.0 +/- 272%), in myocytes from AF (reduction by ranolazine: 67.6 +/- 33.7%, dronedarone: 86.5 +/- 31.7% and combination: 81.0 +/- 33.3%), as well as in myocytes from HF (reduction by ranolazine: 64.8 +/- 26.5% and dronedarone: 65.9 +/- 29.3%). Conclusions: Electrophysiological measurements during exposure to ranolazine alone or in combination with low-dose dronedarone showed APD prolongation, cellular hyperpolarization and reduced SR Ca2+ leak in human atrial myocytes. The combined inhibitory effects on various currents, in particular Na+ and K+ currents, may explain the anti-AF effects observed in the HARMONY trial. Therefore, the combination of ranolazine and dronedarone, but also ranolazine alone, may be promising new treatment options for AF, especially in patients with HF, and merit further clinical investigation. (C) 2016 Elsevier Ltd. All rights reserved."],["dc.identifier.doi","10.1016/j.yjmcc.2016.03.012"],["dc.identifier.gro","3141690"],["dc.identifier.isi","000376839000011"],["dc.identifier.pmid","27056421"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/8938"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/146"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.eissn","1095-8584"],["dc.relation.issn","0022-2828"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.relation.workinggroup","RG Voigt (Molecular Pharmacology)"],["dc.title","The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4816"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","22"],["dc.contributor.affiliation","Wagner, Michael; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, michael_wagner@tu-dresden.de\t\t \r\n\t\t Klinik für Innere Medizin und Kardiologie, Dresden Heart Center, Dresden University of Technology, 01307 Dresden, Germany, michael_wagner@tu-dresden.de"],["dc.contributor.affiliation","Sadek, Mirna S.; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, mirna.sadeks@gmail.com"],["dc.contributor.affiliation","Dybkova, Nataliya; \t\t \r\n\t\t Clinic for Cardiology & Pneumology, University of Göttingen, 37075 Göttingen, Germany, ndybkov@med.uni-goettingen.de\t\t \r\n\t\t DZHK (German Centre for Cardiovascular Research), 10785 Berlin, Germany, ndybkov@med.uni-goettingen.de"],["dc.contributor.affiliation","Mason, Fleur E.; \t\t \r\n\t\t Clinic for Cardiology & Pneumology, University of Göttingen, 37075 Göttingen, Germany, fleur.mason@med.uni-goettingen.de\t\t \r\n\t\t DZHK (German Centre for Cardiovascular Research), 10785 Berlin, Germany, fleur.mason@med.uni-goettingen.de"],["dc.contributor.affiliation","Klehr, Johann; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, johann.klehr@tu-dresden.de"],["dc.contributor.affiliation","Firneburg, Rebecca; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, rebecca.firneburg@tu-dresden.de"],["dc.contributor.affiliation","Cachorro, Eleder; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, eleder.cachorro_puente@tu-dresden.de"],["dc.contributor.affiliation","Richter, Kurt; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, kurt.richter@outlook.de\t\t \r\n\t\t Klinik für Innere Medizin und Kardiologie, Dresden Heart Center, Dresden University of Technology, 01307 Dresden, Germany, kurt.richter@outlook.de"],["dc.contributor.affiliation","Klapproth, Erik; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, erik.klapproth@tu-dresden.de"],["dc.contributor.affiliation","Kuenzel, Stephan R.; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, Stephan.kuenzel@tu-dresden.de"],["dc.contributor.affiliation","Lorenz, Kristina; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Julius-Maximilians-Universität Würzburg, 97078 Würzburg, Germany, lorenz@toxi.uni-wuerzburg.de\t\t \r\n\t\t Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44139 Dortmund, Germany, lorenz@toxi.uni-wuerzburg.de"],["dc.contributor.affiliation","Heijman, Jordi; \t\t \r\n\t\t Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine, and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands, Jordi.heijman@maastrichtuniversity.nl"],["dc.contributor.affiliation","Dobrev, Dobromir; \t\t \r\n\t\t Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, 45147 Essen, Germany, Dobromir.dobrev@uk-essen.de\t\t \r\n\t\t Montréal Heart Institute, Research Center, University de Montréal, Montréal, QC H1T 1C8, Canada, Dobromir.dobrev@uk-essen.de\t\t \r\n\t\t Department of Molecular Physiology Biophysics, Baylor College of Medicine, Houston, TX 77030, USA, Dobromir.dobrev@uk-essen.de"],["dc.contributor.affiliation","El-Armouche, Ali; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, ali.el-armouche@tu-dresden.de"],["dc.contributor.affiliation","Sossalla, Samuel; \t\t \r\n\t\t Clinic for Cardiology & Pneumology, University of Göttingen, 37075 Göttingen, Germany, samuel.sossalla@ukr.de\t\t \r\n\t\t DZHK (German Centre for Cardiovascular Research), 10785 Berlin, Germany, samuel.sossalla@ukr.de\t\t \r\n\t\t Department of Internal Medicine II, University Hospital Regensburg, 93042 Regensburg, Germany, samuel.sossalla@ukr.de"],["dc.contributor.affiliation","Kämmerer, Susanne; \t\t \r\n\t\t Department of Pharmacology and Toxicology, Dresden University of Technology, 01307 Dresden, Germany, susanne.kaemmerer@tu-dresden.de"],["dc.contributor.author","Wagner, Michael"],["dc.contributor.author","Sadek, Mirna S."],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Klehr, Johann"],["dc.contributor.author","Firneburg, Rebecca"],["dc.contributor.author","Cachorro, Eleder"],["dc.contributor.author","Richter, Kurt"],["dc.contributor.author","Klapproth, Erik"],["dc.contributor.author","Kämmerer, Susanne"],["dc.contributor.author","Kuenzel, Stephan R."],["dc.contributor.author","Lorenz, Kristina"],["dc.contributor.author","Heijman, Jordi"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2021-06-01T09:42:36Z"],["dc.date.available","2021-06-01T09:42:36Z"],["dc.date.issued","2021"],["dc.date.updated","2022-11-11T13:15:11Z"],["dc.description.abstract","Background: Phosphodiesterases (PDE) critically regulate myocardial cAMP and cGMP levels. PDE2 is stimulated by cGMP to hydrolyze cAMP, mediating a negative crosstalk between both pathways. PDE2 upregulation in heart failure contributes to desensitization to β-adrenergic overstimulation. After isoprenaline (ISO) injections, PDE2 overexpressing mice (PDE2 OE) were protected against ventricular arrhythmia. Here, we investigate the mechanisms underlying the effects of PDE2 OE on susceptibility to arrhythmias. Methods: Cellular arrhythmia, ion currents, and Ca2+-sparks were assessed in ventricular cardiomyocytes from PDE2 OE and WT littermates. Results: Under basal conditions, action potential (AP) morphology were similar in PDE2 OE and WT. ISO stimulation significantly increased the incidence of afterdepolarizations and spontaneous APs in WT, which was markedly reduced in PDE2 OE. The ISO-induced increase in ICaL seen in WT was prevented in PDE2 OE. Moreover, the ISO-induced, Epac- and CaMKII-dependent increase in INaL and Ca2+-spark frequency was blunted in PDE2 OE, while the effect of direct Epac activation was similar in both groups. Finally, PDE2 inhibition facilitated arrhythmic events in ex vivo perfused WT hearts after reperfusion injury. Conclusion: Higher PDE2 abundance protects against ISO-induced cardiac arrhythmia by preventing the Epac- and CaMKII-mediated increases of cellular triggers. Thus, activating myocardial PDE2 may represent a novel intracellular anti-arrhythmic therapeutic strategy in HF."],["dc.description.sponsorship","German Research Foundation"],["dc.identifier.doi","10.3390/ijms22094816"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85300"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.publisher","MDPI"],["dc.relation.eissn","1422-0067"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0/"],["dc.title","Cellular Mechanisms of the Anti-Arrhythmic Effect of Cardiac PDE2 Overexpression"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]