Maier, Lars Siegfried

[["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","115"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Tirilomis, Petros"],["dc.contributor.author","Stehle, Thea"],["dc.contributor.author","Mustroph, Julian"],["dc.contributor.author","Knierim, Maria"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Bengel, Philipp"],["dc.contributor.author","Holzamer, Andreas"],["dc.contributor.author","Hilker, Michael"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2020-12-10T14:10:25Z"],["dc.date.available","2020-12-10T14:10:25Z"],["dc.date.issued","2020"],["dc.description.abstract","Pharmacologic approaches for the treatment of atrial arrhythmias are limited due to side effects and low efficacy. Thus, the identification of new antiarrhythmic targets is of clinical interest. Recent genome studies suggested an involvement of SCN10A sodium channels (NaV1.8) in atrial electrophysiology. This study investigated the role and involvement of NaV1.8 (SCN10A) in arrhythmia generation in the human atria and in mice lacking NaV1.8. NaV1.8 mRNA and protein were detected in human atrial myocardium at a significant higher level compared to ventricular myocardium. Expression of NaV1.8 and NaV1.5 did not differ between myocardium from patients with atrial fibrillation and sinus rhythm. To determine the electrophysiological role of NaV1.8, we investigated isolated human atrial cardiomyocytes from patients with sinus rhythm stimulated with isoproterenol. Inhibition of NaV1.8 by A-803467 or PF-01247324 showed no effects on the human atrial action potential. However, we found that NaV1.8 significantly contributes to late Na+ current and consequently to an increased proarrhythmogenic diastolic sarcoplasmic reticulum Ca2+ leak in human atrial cardiomyocytes. Selective pharmacological inhibition of NaV1.8 potently reduced late Na+ current, proarrhythmic diastolic Ca2+ release, delayed afterdepolarizations as well as spontaneous action potentials. These findings could be confirmed in murine atrial cardiomyocytes from wild-type mice and also compared to SCN10A−/− mice (genetic ablation of NaV1.8). Pharmacological NaV1.8 inhibition showed no effects in SCN10A−/− mice. Importantly, in vivo experiments in SCN10A−/− mice showed that genetic ablation of NaV1.8 protects against atrial fibrillation induction. This study demonstrates that NaV1.8 is expressed in the murine and human atria and contributes to late Na+ current generation and cellular arrhythmogenesis. Blocking NaV1.8 selectively counteracts this pathomechanism and protects against atrial arrhythmias. Thus, our translational study reveals a new selective therapeutic target for treating atrial arrhythmias."],["dc.identifier.doi","10.1007/s00395-020-0780-8"],["dc.identifier.pmid","32078054"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/70756"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/349"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["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.rights","CC BY 4.0"],["dc.title","Inhibition of NaV1.8 prevents atrial arrhythmogenesis in human and mice"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","385"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","108"],["dc.contributor.author","Sag, Can Martin"],["dc.contributor.author","Wolff, Hendrik Andreas"],["dc.contributor.author","Neumann, Kay"],["dc.contributor.author","Opiela, Marie-Kristin"],["dc.contributor.author","Zhang, J."],["dc.contributor.author","Steuer, Felicia"],["dc.contributor.author","Sowa, Thomas"],["dc.contributor.author","Gupta, Shamindra"],["dc.contributor.author","Schirmer, Markus"],["dc.contributor.author","Huenlich, Mark"],["dc.contributor.author","Rave-Fraenk, Margret"],["dc.contributor.author","Hess, Clemens Friedrich"],["dc.contributor.author","Anderson, Mark E."],["dc.contributor.author","Shah, Ajay M."],["dc.contributor.author","Christiansen, Hans"],["dc.contributor.author","Maier, Lars S."],["dc.date.accessioned","2018-11-07T09:19:46Z"],["dc.date.available","2018-11-07T09:19:46Z"],["dc.date.issued","2013"],["dc.description.abstract","Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after similar to 1 h) as well as chronically (after similar to 1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction."],["dc.identifier.doi","10.1007/s00395-013-0385-6"],["dc.identifier.isi","000324877000001"],["dc.identifier.pmid","24068185"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10300"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/28721"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/51"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["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","0300-8428"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII"],["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"]]

[["dc.bibliographiccitation.firstpage","267"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Clinical Research in Cardiology"],["dc.bibliographiccitation.lastpage","276"],["dc.bibliographiccitation.volume","99"],["dc.contributor.author","Jacobshagen, Claudius"],["dc.contributor.author","Pelster, Theresa"],["dc.contributor.author","Pax, Anja"],["dc.contributor.author","Horn, Wiebke"],["dc.contributor.author","Schmidt-Schweda, Stephan"],["dc.contributor.author","Unsoeld, Bernhard W."],["dc.contributor.author","Seidler, Tim"],["dc.contributor.author","Wagner, Stephan"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.date.accessioned","2017-09-07T11:46:04Z"],["dc.date.available","2017-09-07T11:46:04Z"],["dc.date.issued","2010"],["dc.description.abstract","Post-cardiac arrest myocardial dysfunction is a common phenomenon after return of spontaneous circulation (ROSC) and contributes to hemodynamic instability and low survival rates after cardiac arrest. Mild hypothermia for 24 h after ROSC has been shown to significantly improve neurologic recovery and survival rates. In the present study we investigate the influence of therapeutic hypothermia on hemodynamic parameters in resuscitated patients and on contractility in failing human myocardium. We analyzed hemodynamic data from 200 cardiac arrest survivors during the hypothermia period. The initial LVEF was 32.6 +/- A 1.2% indicating a significantly impaired LV function. During hypothermia induction, the infusion rate of epinephrine could be significantly reduced from 9.1 +/- A 1.3 mu g/min [arrival intensive care unit (ICU) 35.4A degrees C] to 4.6 +/- A 1.0 mu g/min (34A degrees C) and 2.8 +/- A 0.5 mu g/min (33A degrees C). The dobutamine and norepinephrine application rates were not changed significantly. The mean arterial blood pressure remained stable. The mean heart rate significantly decreased from 91.8 +/- A 1.7 bpm (arrival ICU) to 77.3 +/- A 1.5 bpm (34A degrees C) and 70.3 +/- A 1.4 bpm (33A degrees C). In vitro we investigated the effect of hypothermia on isolated ventricular muscle strips from explanted failing human hearts. With decreasing temperature, the contractility increased to a maximum of 168 +/- A 23% at 27A degrees C (n = 16, P < 0.05). Positive inotropic response to hypothermia was accompanied by moderately increased rapid cooling contractures as a measure of sarcoplasmic reticulum (SR) Ca(2+) content, but can be elicited even when the SR Ca(2+) release is blocked in the presence of ryanodine. Contraction and relaxation kinetics are prolonged with hypothermia, indicating increased Ca(2+) sensitivity as the main mechanism responsible for inotropy. In conclusion, mild hypothermia stabilizes hemodynamics in cardiac arrest survivors which might contribute to improved survival rates in these patients. Mechanistically, we demonstrate that hypothermia improves contractility in failing human myocardium most likely by increasing Ca(2+)-sensitivity."],["dc.identifier.doi","10.1007/s00392-010-0113-2"],["dc.identifier.gro","3142931"],["dc.identifier.isi","000277014600001"],["dc.identifier.pmid","20130890"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/4240"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/389"],["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.publisher","Springer"],["dc.publisher.place","Heidelberg"],["dc.relation.issn","1861-0684"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Effects of mild hypothermia on hemodynamics in cardiac arrest survivors and isolated failing human myocardium"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","345"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Clinical Research in Cardiology"],["dc.bibliographiccitation.lastpage","352"],["dc.bibliographiccitation.volume","98"],["dc.contributor.author","Maier, Lars. S."],["dc.contributor.author","Baumhaekel, Magnus"],["dc.contributor.author","Boehm, Michael"],["dc.date.accessioned","2018-11-07T08:29:01Z"],["dc.date.available","2018-11-07T08:29:01Z"],["dc.date.issued","2009"],["dc.description.abstract","The article summarizes the results of clinical trials in the field of cardiovascular medicine, which were presented during the Hotline Sessions at the annual meeting of the American College of Cardiology in Orlando, USA, from 28th March to 31st March 2009. The data were presented by leading experts in the field with relevant positions within the trials. Unpublished reports should be considered as preliminary data as the analysis may change in the final publications. The summaries presented in the manuscript were generated from the oral presentations and provide the readers with the comprehensive information on the results of the latest clinical trials in cardiovascular medicine."],["dc.identifier.doi","10.1007/s00392-009-0023-3"],["dc.identifier.isi","000267217400002"],["dc.identifier.pmid","19430713"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6724"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/16551"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Dr Dietrich Steinkopff Verlag"],["dc.relation.issn","1861-0684"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Hotline sessions presented at the American College of Cardiology Congress 2009"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.subtype","letter_note"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1150"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.lastpage","U215"],["dc.bibliographiccitation.volume","107"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Fluschnik, Nina"],["dc.contributor.author","Schotola, Hanna"],["dc.contributor.author","Ort, Katharina R."],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Schulte, Timo"],["dc.contributor.author","Wittkoepper, Katrin"],["dc.contributor.author","Renner, André"],["dc.contributor.author","Schmitto, Jan D."],["dc.contributor.author","Gummert, Jan"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Maier, Lars S."],["dc.date.accessioned","2017-09-07T11:45:15Z"],["dc.date.available","2017-09-07T11:45:15Z"],["dc.date.issued","2010"],["dc.description.abstract","Rationale: Heart failure (HF) is known to be associated with increased Ca2+/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium. Objective: We sought to investigate detailed CaMKII delta expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility. Methods and Results: Expression analysis revealed that CaMKII delta, both cytosolic delta(C) and nuclear delta(B) splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca2+ loading. This was confirmed in isolated myocytes by a reduced SR Ca2+ spark frequency and hence SR Ca2+ leak, resulting in increased SR Ca2+ load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca2+ leak, was found to be markedly reduced in KN-93-treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae. Conclusions: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKII delta expression is increased. The mechanism proposed consists of a reduced SR Ca2+ leak and consequently increased SR Ca2+ load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation. (Circ Res. 2010;107:1150-1161.)"],["dc.identifier.doi","10.1161/CIRCRESAHA.110.220418"],["dc.identifier.gro","3142840"],["dc.identifier.isi","000283583400015"],["dc.identifier.pmid","20814023"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6154"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/288"],["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.publisher","Lippincott Williams & Wilkins"],["dc.relation.issn","0009-7330"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Inhibition of Elevated Ca2+/Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","359"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Clinical Research in Cardiology"],["dc.bibliographiccitation.lastpage","368"],["dc.bibliographiccitation.volume","99"],["dc.contributor.author","Sohns, Christian"],["dc.contributor.author","Sossalla, Samuel T."],["dc.contributor.author","Schmitto, Jan Dieter"],["dc.contributor.author","Jacobshagen, Claudius"],["dc.contributor.author","Raab, Bjoern-Werner"],["dc.contributor.author","Obenauer, Silvia"],["dc.contributor.author","Maier, Lars. S."],["dc.date.accessioned","2018-11-07T08:42:29Z"],["dc.date.available","2018-11-07T08:42:29Z"],["dc.date.issued","2010"],["dc.description.abstract","Hypertrophic obstructive cardiomyopathy (HOCM) is treated by surgical myectomy or transcoronary ablation of septal hypertrophy (TASH). The aim of this study was to visualize the feasibility, success and short-term results of TASH on the basis of cardiac MRI (CMR) in comparison with cardiac catheterization and echocardiography. In this in vivo study, nine patients with HOCM were treated with TASH. Patients were evaluated by transthoracic echocardiography, invasive cardiac angiography and CMR. Follow-up examinations were carried out after 1, 3 and 12 months. MR imaging was performed on a 1.5-T scanner. All images were processed using the semiautomatic Argus software and were evaluated by an attending thoracic radiologist and cardiologist. The echocardiographic pressure gradient (at rest) was 69.3 +/- A 15.3 mmHg before and 22.1 +/- A 5.7 mmHg after TASH (P < 0.01, n = 9). The flux acceleration over the aortic valve examined (V (max)) was 5.1 +/- A 0.6 m/s before and 3.4 +/- A 0.3 m/s after the TASH procedure (P < 0.05). Also, there was a decrease of septum thickness from 22.0 +/- A 1.2 to 20.2 +/- A 1.0 mm (P < 0.05) after 6 +/- A 3 weeks. The invasively assessed pressure gradient at rest was reduced from 63.7 +/- A 15.2 to 21.2 +/- A 11.1 mmHg (P < 0.01) and the post-extrasystolic gradient was reduced from 138.9 +/- A 12.7 to 45.6 +/- A 16.5 mmHg (P < 0.01). All differences as well as the quantity of injected ethanol were plotted against the size or amount of scar tissue as assessed in the MRI. There was a statistically significant correlation between the post-extrasystolic gradient decrease and the amount of scar tissue (P = 0.03, r (2) = 0.5). In addition, the correlation between the quantity of ethanol and scar tissue area was highly significant (P < 0.01, r (2) = 0.6), whereas the values for the gradient deviation (P = 0.10, r (2) = 0.34), Delta V (max) (P = 0.12, r (2) = 0.31), as well as the gradient at rest (P = 0.27, r (2) = 0.17) were not significant. TASH was consistently effective in reducing the gradient in all patients with HOCM. In contrast to the variables investigated by echocardiography, the invasively measured post-extrasystolic gradient correlated much better with the amount of scar tissue as assessed by CMR. We conclude that the optimal modality to visualize the TASH effect seems to be a combination of CMR and the invasive identification of the post-extrasystolic gradient."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG) [MA 1982/2-2, MA 1982/4-1]"],["dc.identifier.doi","10.1007/s00392-010-0128-8"],["dc.identifier.isi","000278089000002"],["dc.identifier.pmid","20503122"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/4241"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19712"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","Heidelberg"],["dc.relation.issn","1861-0684"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Visualization of transcoronary ablation of septal hypertrophy in patients with hypertrophic obstructive cardiomyopathy: a comparison between cardiac MRI, invasive measurements and echocardiography"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","263"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.lastpage","272"],["dc.bibliographiccitation.volume","106"],["dc.contributor.author","Sossalla, Samuel"],["dc.contributor.author","Maurer, Ulrike"],["dc.contributor.author","Schotola, Hanna"],["dc.contributor.author","Hartmann, Nico H."],["dc.contributor.author","Didie, Michael"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Jacobshagen, Claudius"],["dc.contributor.author","Wagner, Stefan"],["dc.contributor.author","Maier, Lars S."],["dc.date.accessioned","2017-09-07T11:44:20Z"],["dc.date.available","2017-09-07T11:44:20Z"],["dc.date.issued","2011"],["dc.description.abstract","Transgenic (TG) Ca2+/calmodulin-dependent protein kinase II (CaMKII) delta(C) mice develop systolic heart failure (HF). CaMKII regulates intracellular Ca2+ handling proteins as well as sarcolemmal Na+ channels. We hypothesized that CaMKII also contributes to diastolic dysfunction and arrhythmias via augmentation of the late Na+ current (late I (Na)) in early HF (8-week-old TG mice). Echocardiography revealed severe diastolic dysfunction in addition to decreased systolic ejection fraction. Premature arrhythmogenic contractions (PACs) in isolated isometrically twitching papillary muscles only occurred in TG preparations (5 vs. 0, P < 0.05) which could be completely terminated when treated with the late I (Na) inhibitor ranolazine (Ran, 5 mu mol/L). Force-frequency relationships revealed significantly reduced twitch force amplitudes in TG papillary muscles. Most importantly, diastolic tension increased with raising frequencies to a greater extent in TG papillary muscles compared to WT specimen (at 10 Hz: 3.7 +/- A 0.4 vs. 2.5 +/- A 0.3 mN/mm(2); P < 0.05). Addition of Ran improved diastolic dysfunction to 2.1 +/- A 0.2 mN/mm(2) (at 10 Hz; P < 0.05) without negative inotropic effects. Mechanistically, the late I (Na) was markedly elevated in myocytes isolated from TG mice and could be completely reversed by Ran. In conclusion, our results show for the first time that TG CaMKII delta(C) overexpression induces diastolic dysfunction and arrhythmogenic triggers possibly via an enhanced late I (Na). Inhibition of elevated late I (Na) had beneficial effects on arrhythmias as well as diastolic function in papillary muscles from CaMKII delta(C) TG mice. Thus, late I (Na) inhibition appears to be a promising option for diastolic dysfunction and arrhythmias in HF where CaMKII is found to be increased."],["dc.identifier.doi","10.1007/s00395-010-0136-x"],["dc.identifier.gro","3142765"],["dc.identifier.isi","000286934300008"],["dc.identifier.pmid","21174213"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/7315"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/205"],["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.publisher","Springer"],["dc.publisher.place","Heidelberg"],["dc.relation.issn","0300-8428"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Diastolic dysfunction and arrhythmias caused by overexpression of CaMKII delta(C) can be reversed by inhibition of late Na+ current"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","617"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Clinical Investigation"],["dc.bibliographiccitation.lastpage","626"],["dc.bibliographiccitation.volume","120"],["dc.contributor.author","Wittoepper, Katrin"],["dc.contributor.author","Fabritz, Larissa"],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Ort, Katharina R."],["dc.contributor.author","Grefe, Clemens"],["dc.contributor.author","Unsoeld, Bernhard W."],["dc.contributor.author","Kirchhof, Paulus"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Eschenhagen, Thomas"],["dc.contributor.author","El-Armouche, Ali"],["dc.date.accessioned","2017-09-07T11:46:09Z"],["dc.date.available","2017-09-07T11:46:09Z"],["dc.date.issued","2010"],["dc.description.abstract","Phosphatase inhibitor-1 (I-1) is a distal amplifier element of P-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTG(I-1c) mice) on an I-1-deficient background. Young adult dTG(I-1c) mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTG(I-1c) mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca(2+) sparks in isolated myocytes. Aged dTG(I-1c) mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-I mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1(S67A)). In conclusion, conditional expression of I-1c or I-1(S67A) enhanced steady-state phosphorylation of 2 key Ca(2+)-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure."],["dc.identifier.doi","10.1172/JCI40545"],["dc.identifier.gro","3142974"],["dc.identifier.isi","000274040000020"],["dc.identifier.pmid","20071777"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6149"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/437"],["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.publisher","Amer Soc Clinical Investigation Inc"],["dc.relation.issn","0021-9738"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","179"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Clinical Research in Cardiology"],["dc.bibliographiccitation.lastpage","184"],["dc.bibliographiccitation.volume","102"],["dc.contributor.author","Rasenack, Eva C. L."],["dc.contributor.author","Oehler, Martin"],["dc.contributor.author","Elsaesser, Albrecht"],["dc.contributor.author","Schilling, Meinhard"],["dc.contributor.author","Maier, Lars. S."],["dc.date.accessioned","2018-11-07T09:27:51Z"],["dc.date.available","2018-11-07T09:27:51Z"],["dc.date.issued","2013"],["dc.description.abstract","Electrocardiogram (ECG) assessment plays a crucial role in patients presenting with chest pain and suspected acute coronary syndrome (ACS). In a pilot study, we previously evaluated a capacitive ECG system (cECG) as a novel ECG technique for a fast and simple ECG assessment in patients with ST-elevation myocardial infarction (STEMI). In a next step, the sensitivity and specificity of this novel ECG technique have to be assessed in patients with ACS. The Fast Infarction Diagnosis ECG Trial (FIDET) is a prospective, bi-center, observer-blinded noninferiority study to evaluate the cECG compared to the conventional ECG (kECG) in the clinical practice for ECG assessment in consecutive patients presenting with suspected ACS. In 250 patients who were admitted to the hospital, because of an ACS [including STEMI and non-ST-elevation acute coronary syndrome (NSTE-ACS)], both a kECG and a cECG recording were performed within a time lag of less than 10 min. The primary end point will be sensitivity and specificity of the cECG compared to the kECG in diagnosing a STEMI with a margin of noninferiority of 7.5 %. Secondary end points include sensitivity and specificity of the cECG compared to the kECG in diagnosing an NSTE-ACS, safety of the cECG system (adverse event, serious adverse event and suspected unexpected serious adverse reaction), parameters of the ECG measurement (PQ-interval, QT-interval, ST-amplitude and heart rate) and measurement duration of the two methods. FIDET is designed as a noninferiority study to show that a novel cECG system is suitable for the diagnosis of myocardial infarction in the clinical context and might even have benefits, for example by offering a faster and easier ECG assessment."],["dc.identifier.doi","10.1007/s00392-012-0512-7"],["dc.identifier.isi","000314883200002"],["dc.identifier.pmid","23052332"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10298"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/30635"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","Heidelberg"],["dc.relation.issn","1861-0684"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Evaluation of a novel portable capacitive ECG system in the clinical practice for a fast and simple ECG assessment in patients presenting with chest pain: FIDET (Fast Infarction Diagnosis ECG Trial)"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","555"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Circulation Research"],["dc.bibliographiccitation.lastpage","565"],["dc.bibliographiccitation.volume","108"],["dc.contributor.author","Wagner, Stefan"],["dc.contributor.author","Ruff, Hanna M."],["dc.contributor.author","Weber, Sarah L."],["dc.contributor.author","Bellmann, Sarah"],["dc.contributor.author","Sowa, Thomas"],["dc.contributor.author","Schulte, Timo"],["dc.contributor.author","Anderson, Mark E."],["dc.contributor.author","Grandi, Eleonora"],["dc.contributor.author","Bers, Donald M."],["dc.contributor.author","Backs, Johannes"],["dc.contributor.author","Belardinelli, Luiz"],["dc.contributor.author","Maier, Lars. S."],["dc.date.accessioned","2018-11-07T08:58:14Z"],["dc.date.available","2018-11-07T08:58:14Z"],["dc.date.issued","2011"],["dc.description.abstract","Rationale: In heart failure, Ca/calmodulin kinase (CaMK) II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late I-Na leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation. Objective: We tested whether CaMKII delta is required for ROS-dependent late I-Na regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved. Methods and Results: 40 mu mol/L H2O2 significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free [Ca](i) (5 mmol/L BAPTA/1 mmol/L Br-2-BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 mu mol/L), the H2O2-dependent CaMKII oxidation and autophosphorylation was abolished. H2O2 significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H2O2 increased late I-Na (whole cell patch-clamp). This increase was abolished in CaMKII delta(-/-) myocytes. H2O2-induced [Na](i) and [Ca](i) accumulation (SBFI [sodium-binding benzofuran isophthalate] and Indo-1 epifluorescence) was significantly slowed in CaMKII delta(-/-) myocytes (versus WT). CaMKII delta(-/-) myocytes developed significantly less H2O2-induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late I-Na, [Na](i) and [Ca](i) accumulation) were obtained by overexpression of CaMKII delta in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 mu mol/L KN93 or 0.1 mu mol/L AIP [autocamtide 2-related inhibitory peptide]). Conclusions: Free [Ca](i) and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKII delta enhances late I-Na, which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression. (Circ Res. 2011; 108: 555-565.)"],["dc.identifier.doi","10.1161/CIRCRESAHA.110.221911"],["dc.identifier.isi","000287963900009"],["dc.identifier.pmid","21252154"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/7822"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/23593"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Lippincott Williams & Wilkins"],["dc.relation.issn","0009-7330"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Reactive Oxygen Species-Activated Ca/Calmodulin Kinase II delta Is Required for Late I-Na Augmentation Leading to Cellular Na and Ca Overload"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]