Pabel, Steffen

[["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","1690"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","European Journal of Heart Failure"],["dc.bibliographiccitation.lastpage","1700"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Wagner, Stefan"],["dc.contributor.author","Bollenberg, Hannah"],["dc.contributor.author","Bengel, Philipp"],["dc.contributor.author","Kovács, Árpád"],["dc.contributor.author","Schach, Christian"],["dc.contributor.author","Tirilomis, Petros"],["dc.contributor.author","Mustroph, Julian"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Fischer, Thomas"],["dc.contributor.author","Van Linthout, Sophie"],["dc.contributor.author","Tschöpe, Carsten"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hamdani, Nazha"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2019-02-19T13:12:22Z"],["dc.date.available","2019-02-19T13:12:22Z"],["dc.date.issued","2018"],["dc.description.abstract","Aims Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium. Methods and results In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected. Conclusion Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial."],["dc.identifier.doi","10.1002/ejhf.1328"],["dc.identifier.pmid","30328645"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57583"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/239"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt"],["dc.relation.issn","1879-0844"],["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.title","Empagliflozin directly improves diastolic function in human heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","412"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Heart Rhythm"],["dc.bibliographiccitation.lastpage","419"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Hartmann, Nico H."],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Schatter, Felix"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Schotola, Hanna"],["dc.contributor.author","Danner, Bernhard C."],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Fischer, Andre"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:52:35Z"],["dc.date.available","2017-09-07T11:52:35Z"],["dc.date.issued","2016"],["dc.identifier.doi","10.1016/j.hrthm.2016.09.014"],["dc.identifier.gro","3144963"],["dc.identifier.pmid","27650424"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2646"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/300"],["dc.notes.intern","Crossref Import"],["dc.notes.status","public"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","1547-5271"],["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.title","Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1673"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","European Journal of Heart Failure"],["dc.bibliographiccitation.lastpage","1685"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Saadatmand, Alireza"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Weber, Silvio"],["dc.contributor.author","Wang, Yansong"],["dc.contributor.author","Köhn, Maja"],["dc.contributor.author","Tirilomis, Theodor"],["dc.contributor.author","Ljubojevic, Senka"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2019-02-18T13:43:31Z"],["dc.date.available","2019-02-18T13:43:31Z"],["dc.date.issued","2018"],["dc.description.abstract","Background Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII-dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown. Methods and results Human myocardium from three groups of patients was investigated: (i) healthy controls (non-failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end-stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor-1 (I-1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1-disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load. Conclusion This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach."],["dc.identifier.doi","10.1002/ejhf.1297"],["dc.identifier.pmid","30191648"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57579"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/232"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt"],["dc.relation.issn","1879-0844"],["dc.relation.workinggroup","RG El-Armouche"],["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.title","Activation of protein phosphatase 1 by a selective phosphatase disrupting peptide reduces sarcoplasmic reticulum Ca2+ leak in human heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1728"],["dc.bibliographiccitation.issue","13"],["dc.bibliographiccitation.journal","Cardiovascular Research"],["dc.bibliographiccitation.lastpage","1737"],["dc.bibliographiccitation.volume","114"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Tirilomis, Petros"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Fischer, Thomas H"],["dc.contributor.author","Bengel, Philipp"],["dc.contributor.author","Tirilomis, Theodoros"],["dc.contributor.author","Ljubojevic, Senka"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Ellenberger, David"],["dc.contributor.author","Wagner, Stefan"],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Maier, Lars S"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2020-12-10T18:18:48Z"],["dc.date.available","2020-12-10T18:18:48Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1093/cvr/cvy152"],["dc.identifier.pmid","29931291"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/75097"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/294"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A11: Absolute Arrhythmie bei Vorhofflimmern - ein neuer Mechanismus, der zu einer Störung von Ca2+-Homöostase und elektrischer Stabilität in der Transition zur Herzinsuffizienz führt"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["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.title","Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1440"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","EP Europace"],["dc.bibliographiccitation.lastpage","1448"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Hartmann, Nico H."],["dc.contributor.author","Ellenberger, David"],["dc.contributor.author","Friedrich, Martin"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Zabel, Markus"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:44:40Z"],["dc.date.available","2017-09-07T11:44:40Z"],["dc.date.issued","2016"],["dc.description.abstract","Aims Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca2+ leak is arrhythmogenic, it could represent a cellular basis for this paradox. Methods/Results We evaluated the SR Ca2+ leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca2+ spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men (P < 0.05). As Ca2+ spark width and duration were similar in women and men, this difference in CaSpF did not yet translate into a significant difference of the calculated SR Ca2+ leak between both sexes at this stage of disease (P < 0.14). Epifluorescence measurements (Fura2-AM) revealed comparable Ca2+ cycling properties (diastolic Ca2+ levels, amplitude of systolic Ca2+ transients, SR Ca2+ load) in patients of both sexes suffering from Hy. Additionally, the increased diastolic CaSpF in male patients with Hy did not yet translate into an elevated ratio of cells showing arrhythmic events (Ca2+ waves, spontaneous Ca2+ transients) (P < 0.77). In the transition to HF, both sexes showed an increase of the CaSpF (P, 0.05) and the sex dependence was even more pronounced. Female patients had a 69 +/- 10% lower SR Ca2+ leak (P < 0.05), which now even translated into a lower ratio of arrhythmic cells in female HF patients compared with men (P < 0.001). Conclusion These data show that the SR Ca2+ leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca2+ leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca2+ leak."],["dc.identifier.doi","10.1093/europace/euv313"],["dc.identifier.gro","3141624"],["dc.identifier.isi","000387007900027"],["dc.identifier.pmid","26493982"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2455"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/96"],["dc.language.iso","en"],["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 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","1099-5129"],["dc.relation.issn","1532-2092"],["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.title","Sex-dependent alterations of Ca2+ cycling in human cardiac hypertrophy and heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]