Sossalla, Samuel Tobias

[["dc.bibliographiccitation.firstpage","102"],["dc.bibliographiccitation.journal","International Journal of Cardiology"],["dc.bibliographiccitation.lastpage","107"],["dc.bibliographiccitation.volume","272"],["dc.contributor.author","Bergau, Leonard"],["dc.contributor.author","Willems, Rik"],["dc.contributor.author","Sprenkeler, David J."],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Flevari, Panayota"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Katsaras, Dimitrios"],["dc.contributor.author","Kirova, Aleksandra"],["dc.contributor.author","Lehnart, Stephan E."],["dc.contributor.author","Lüthje, Lars"],["dc.contributor.author","Röver, Christian"],["dc.contributor.author","Seegers, Joachim"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Dunnink, Albert"],["dc.contributor.author","Sritharan, Rajevaa"],["dc.contributor.author","Tuinenburg, Anton E."],["dc.contributor.author","Vandenberk, Bert"],["dc.contributor.author","Vos, Marc A."],["dc.contributor.author","Wijers, Sofieke C."],["dc.contributor.author","Friede, Tim"],["dc.contributor.author","Zabel, Markus"],["dc.date.accessioned","2019-07-09T11:50:23Z"],["dc.date.available","2019-07-09T11:50:23Z"],["dc.date.issued","2018"],["dc.description.abstract","BACKGROUND AND OBJECTIVE: We prospectively investigated combinations of risk stratifiers including multiple EP diagnostics in a cohort study of ICD patients. METHODS: For 672 enrolled patients, we collected history, LVEF, EP study and T-wave alternans testing, 24-h Holter, NT-proBNP, and the eGFR. All-cause mortality and first appropriate ICD shock were predefined endpoints. RESULTS: The 635 patients included in the final analyses were 63 ± 13 years old, 81% were male, LVEF averaged 40 ± 14%, 20% were inducible at EP study, 63% had a primary prophylactic ICD. During follow-up over 4.3 ± 1.5 years, 108 patients died (4.0% per year), and appropriate shock therapy occurred in n = 96 (3.9% per year). In multivariate regression, age (p < 0.001), LVEF (p < 0.001), NYHA functional class (p = 0.007), eGFR (p = 0.024), a history of atrial fibrillation (p = 0.011), and NT-pro-BNP (p = 0.002) were predictors of mortality. LVEF (p = 0.002), inducibility at EP study (p = 0.007), and secondary prophylaxis (p = 0.002) were identified as independent predictors of appropriate shocks. A high annualized risk of shocks of about 10% per year was prevalent in the upper quintile of the shock score. In contrast, a low annual risk of shocks (1.8% per year) was found in the lower two quintiles of the shock score. The lower two quintiles of the mortality score featured an annual mortality <0.6%. CONCLUSIONS: In a prospective ICD patient cohort, a very good approximation of mortality versus arrhythmic risk was possible using a multivariable diagnostic strategy. EP stimulation is the best test to assess risk of arrhythmias resulting in ICD shocks."],["dc.identifier.doi","10.1016/j.ijcard.2018.06.103"],["dc.identifier.pmid","29983251"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15929"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59764"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.intern","In goescholar not merged with http://resolver.sub.uni-goettingen.de/purl?gs-1/15360 but duplicate"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/241526/EU//EUTRIGTREAT"],["dc.relation.issn","1874-1754"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.access","openAccess"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.subject.ddc","610"],["dc.subject.mesh","Aged"],["dc.subject.mesh","Aged, 80 and over"],["dc.subject.mesh","Arrhythmias, Cardiac"],["dc.subject.mesh","Cohort Studies"],["dc.subject.mesh","Death, Sudden, Cardiac"],["dc.subject.mesh","Defibrillators"],["dc.subject.mesh","Defibrillators, Implantable"],["dc.subject.mesh","Female"],["dc.subject.mesh","Follow-Up Studies"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Male"],["dc.subject.mesh","Middle Aged"],["dc.subject.mesh","Mortality"],["dc.subject.mesh","Multivariate Analysis"],["dc.subject.mesh","Natriuretic Peptide, Brain"],["dc.subject.mesh","Peptide Fragments"],["dc.subject.mesh","Prospective Studies"],["dc.subject.mesh","Risk Factors"],["dc.title","Differential multivariable risk prediction of appropriate shock versus competing mortality - A prospective cohort study to estimate benefits from ICD therapy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","Suppl. 1"],["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","40"],["dc.contributor.author","Eiringhaus, J."],["dc.contributor.author","Wuensche, C."],["dc.contributor.author","Herting, J."],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Fischer, T."],["dc.date.accessioned","2022-05-17T07:52:43Z"],["dc.date.available","2022-05-17T07:52:43Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1093/eurheartj/ehz745.0671"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/107986"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/319"],["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.conference","ESC Congress 2019 together with World Congress of Cardiology"],["dc.relation.eventend","2019-09-04"],["dc.relation.eventlocation","Paris"],["dc.relation.eventstart","2019-08-31"],["dc.relation.issn","0195-668X"],["dc.relation.issn","1522-9645"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.title","P3829 Antiarrhythmic effects of Sacubitrilat (LBQ657) on Ca2+ homeostasis in ventricular cardiomyocytes"],["dc.type","conference_paper"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","37"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Pabel, Stefanie Corinna"],["dc.contributor.author","Herting, J. Jonas"],["dc.contributor.author","Schotola, Hanna"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T10:10:28Z"],["dc.date.available","2018-11-07T10:10:28Z"],["dc.date.issued","2016"],["dc.format.extent","720"],["dc.identifier.isi","000383869503395"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39863"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.publisher.place","Oxford"],["dc.relation.eventlocation","Rome, ITALY"],["dc.relation.issn","1522-9645"],["dc.relation.issn","0195-668X"],["dc.title","Antiarrhythmic effects of dantrolene in human cardiomyocytes from patients with atrial fibrillation or heart failure"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1067"],["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.lastpage","1068"],["dc.bibliographiccitation.volume","36"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Mason, F."],["dc.contributor.author","Braun, I."],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel Tobias"],["dc.date.accessioned","2018-11-07T09:53:36Z"],["dc.date.available","2018-11-07T09:53:36Z"],["dc.date.issued","2015"],["dc.identifier.isi","000361205107171"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36361"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.publisher.place","Oxford"],["dc.relation.eventlocation","London, ENGLAND"],["dc.relation.issn","1522-9645"],["dc.relation.issn","0195-668X"],["dc.title","The combined effects of ranolazine and low dose dronedarone on atrial vs. ventricular electrophysiology; a novel therapeutic hope?"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["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","719"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Artificial Organs"],["dc.bibliographiccitation.lastpage","726"],["dc.bibliographiccitation.volume","40"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Kleinwächter, Astrid"],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Haverich, Axel"],["dc.contributor.author","Schmitto, Jan D."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2018-11-07T10:10:45Z"],["dc.date.available","2018-11-07T10:10:45Z"],["dc.date.issued","2016"],["dc.description.abstract","In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR-Ca2+ leak at the time of LVAD implantation (HF-Im) and heart transplantation (HF-Tx) and evaluated the effects of CaMKII-inhibition. Human left-ventricular cardiomyocytes were isolated, paced at 1Hz for 10 beats to ensure SR-Ca2+ loading and scanned for diastolic Ca2+ sparks (confocal microscopy). In HF-Im, the high diastolic spark frequency (CaSpF) of 0.76 +/- 0.12x100m(-1)xs(-1) could be reduced to 0.48 +/- 0.10x100m(-1)xs(-1) by CaMKII inhibition (AIP, 1M). The amplitude of Ca2+ sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR-Ca2+ leak (n cells/patients=76/6 vs. 108/6, P=0.08). In HF-Tx, we detected an even higher CaSpF of 1.00 +/- 0.10 100m(-1)xs(-1) and a higher SR-Ca2+ leak compared with HF-Im (increase by 81 +/- 33%, n cells/patients=156/7 vs. 130/7, P<0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 +/- 0.09 100m(-1)xs(-1,)P=0.06) and significantly reduced spark duration (n sparks/patients=58/3 vs. 159/3, P<0.05). Conclusively, the SR-Ca2+ leak was reduced by 69 +/- 12% in HF-Tx upon CaMKII inhibition (n cells/patients=53/3 vs. 91/3, P<0.05). These data show that the SR-Ca2+ leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR-Ca2+ leak in HF-Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation."],["dc.identifier.doi","10.1111/aor.12677"],["dc.identifier.isi","000383514300005"],["dc.identifier.pmid","26816346"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39920"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/136"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A03: Bedeutung CaMKII-abhängiger Mechanismen für die Arrhythmogenese bei Herzinsuffizienz"],["dc.relation.issn","1525-1594"],["dc.relation.issn","0160-564X"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.title","Inhibition of CaMKII Attenuates Progressing Disruption of Ca2+ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","184"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Cardiovascular Research"],["dc.bibliographiccitation.lastpage","196"],["dc.bibliographiccitation.volume","107"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Mason, Fleur E."],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Watanabe, Saera"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.contributor.author","Sprenger, Julia U."],["dc.contributor.author","Fan, Peidong"],["dc.contributor.author","Yao, Lina"],["dc.contributor.author","Popov, Aron-Frederik"],["dc.contributor.author","Danner, Bernhard C."],["dc.contributor.author","Schoendube, Friedrich"],["dc.contributor.author","Belardinelli, Luiz"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:43:42Z"],["dc.date.available","2017-09-07T11:43:42Z"],["dc.date.issued","2015"],["dc.description.abstract","Aims Enhanced cardiac late Na current (late I-Na) and increased sarcoplasmic reticulum (SR)-Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late I-Na and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and results In murine atrial CMs, SR-Ca2+-leak was increased by the late I-Na enhancer Anemonia sulcata toxin II (ATX-II). An inhibition of Ca2+/calmodulin-dependent protein kinase II (Autocamide-2-related inhibitory peptide), protein kinase A (H89), or late I-Na (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was not detected when either the Na+/Ca2+ exchanger was inhibited (KBR) or in CaMKIIdc-knockout mice. FRET measurements revealed increased cAMP levels upon ATX-II stimulation, which could be prevented by inhibition of adenylyl cyclases (ACs) 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA activation via an AC-dependent increase of cAMP levels. Western blots showed late I-Na-dependent hyperphosphorylation of CaMKII as well as PKA target sites at ryanodine receptor type-2 (-S2814 and -S2808) and phospholamban (-Thr17, -S16). Enhancement of late I-Na did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late I-Na activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased, whereas PKA inhibition reduced Ca2+-transient amplitude and load and additionally slowed Ca2+ elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late I-Na, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion Late I-Na exerts distinct effects on Ca2+ homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late I-Na represents a potential approach to attenuate CaMKII activation and decreases SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA system further increases the antiarrhythmic potential of late I-Na inhibition."],["dc.identifier.doi","10.1093/cvr/cvv153"],["dc.identifier.gro","3141867"],["dc.identifier.isi","000359088800021"],["dc.identifier.pmid","25990311"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1956"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/104"],["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.eissn","1755-3245"],["dc.relation.issn","0008-6363"],["dc.relation.issn","1755-3245"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.relation.workinggroup","RG Sossalla (Kardiovaskuläre experimentelle Elektrophysiologie und Bildgebung)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.title","Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","34"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Watanabe, S."],["dc.contributor.author","Popov, A. F."],["dc.contributor.author","Schoendube, F."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Maier, Lars. S."],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T09:21:37Z"],["dc.date.available","2018-11-07T09:21:37Z"],["dc.date.issued","2013"],["dc.format.extent","1102"],["dc.identifier.isi","000327744606564"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29149"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.publisher.place","Oxford"],["dc.relation.eventlocation","Amsterdam, NETHERLANDS"],["dc.relation.issn","1522-9645"],["dc.relation.issn","0195-668X"],["dc.title","An elevated late INa increases the diastolic SR-Ca-leak in atrial cardiomyocytes via a CaMKII-dependent mechanism"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1292"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","European Journal of Heart Failure"],["dc.bibliographiccitation.lastpage","1300"],["dc.bibliographiccitation.volume","16"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Eiringhaus, Jörg"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Foerster, Anna"],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Kleinwaechter, Astrid"],["dc.contributor.author","Ljubojevic, Senka"],["dc.contributor.author","Schmitto, Jan D."],["dc.contributor.author","Streckfuss-Boemeke, Katrin"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2017-09-07T11:45:23Z"],["dc.date.available","2017-09-07T11:45:23Z"],["dc.date.issued","2014"],["dc.description.abstract","AimsThe sarcoplasmic reticulum (SR) Ca2+ leak is an important pathomechanism in heart failure (HF). It has been suggested that Ca2+/calmodulin-dependent protein kinase II (CaMKII) is only relevant for the induction of the SR Ca2+ leak in non-ischaemic but not in ischaemic HF. Therefore, we investigated CaMKII and its targets as well as the functional effects of CaMKII inhibition in human ischaemic cardiomyopathy (ICM, n=37) and dilated cardiomyopathy (DCM, n=40). Methods and resultsWestern blots showed a significantly increased expression (by 549%) and autophosphorylation at Thr286 (by 129 +/- 29%, P<0.05 each) of CaMKII in HF compared with healthy myocardium. However, no significant difference could be detected in ICM compared with DCM as to the expression and autophosphorylation of CaMKII nor the phosphorylation of the target sites ryanodine receptor 2 (RyR2)-S2809, RyR2-S2815, and phospholamban-Thr17. Isolated human cardiomyocytes (CMs) of patients with DCM and ICM showed a similar frequency of diastolic Ca2+ sparks (confocal microscopy) as well as of major arrhythmic events (Ca2+ waves, spontaneous Ca2+ transients). Despite a slightly smaller size of Ca2+ sparks in DCM (P<0.01), the calculated SR Ca2+ leak [Ca2+ spark frequecy (CaSpF)xamplitudexwidthxduration] did not differ between CMs of ICM vs. DCM. Importantly, CaMKII inhibition by autocamide-2-related inhibitory peptide (AIP, 1 mu mol/L) reduced the SR Ca2+ leak by approximate to 80% in both aetiologies (P<0.05 each) and effectively decreased the ratio of arrhythmic cells (P<0.05). Conclusion

Functional and molecular measures of the SR Ca2+ leak are comparable in human ICM and DCM. CaMKII is equally responsible for the induction of the RyR2 leakiness' in both pathologies. Thus, CaMKII inhibition as a therapeutic measure may not be restricted to patients suffering from DCM but rather may be beneficial for the majority of HF patients."],["dc.identifier.doi","10.1002/ejhf.163"],["dc.identifier.gro","3142009"],["dc.identifier.isi","000345755200007"],["dc.identifier.pmid","25201344"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11676"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3534"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/15"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["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.eissn","1879-0844"],["dc.relation.issn","1388-9842"],["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.rights","CC BY-NC 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/3.0"],["dc.title","Ca2+/calmodulin-dependent protein kinase II equally induces sarcoplasmic reticulum Ca2+ leak in human ischaemic and dilated cardiomyopathy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]