Ahmad, Shakil

[["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","6586"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Bengel, Philipp"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Tirilomis, Petros"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Hartmann, Nico Horst"],["dc.contributor.author","A. Mohamed, Belal"],["dc.contributor.author","Krekeler, Miriam Celine"],["dc.contributor.author","Maurer, Wiebke"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Trum, Maximilian"],["dc.contributor.author","Sossalla, Samuel Tobias"],["dc.date.accessioned","2021-12-01T09:20:52Z"],["dc.date.available","2021-12-01T09:20:52Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract An interplay between Ca 2+ /calmodulin-dependent protein kinase IIδc (CaMKIIδc) and late Na + current (I NaL ) is known to induce arrhythmias in the failing heart. Here, we elucidate the role of the sodium channel isoform Na V 1.8 for CaMKIIδc-dependent proarrhythmia. In a CRISPR-Cas9-generated human iPSC-cardiomyocyte homozygous knock-out of Na V 1.8, we demonstrate that Na V 1.8 contributes to I NaL formation. In addition, we reveal a direct interaction between Na V 1.8 and CaMKIIδc in cardiomyocytes isolated from patients with heart failure (HF). Using specific blockers of Na V 1.8 and CaMKIIδc, we show that Na V 1.8-driven I NaL is CaMKIIδc-dependent and that Na V 1.8-inhibtion reduces diastolic SR-Ca 2+ leak in human failing cardiomyocytes. Moreover, increased mortality of CaMKIIδc-overexpressing HF mice is reduced when a Na V 1.8 knock-out is introduced. Cellular and in vivo experiments reveal reduced ventricular arrhythmias without changes in HF progression. Our work therefore identifies a proarrhythmic CaMKIIδc downstream target which may constitute a prognostic and antiarrhythmic strategy."],["dc.identifier.doi","10.1038/s41467-021-26690-1"],["dc.identifier.pii","26690"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/94290"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/412"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-478"],["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","2041-1723"],["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 Toischer (Kardiales Remodeling)"],["dc.rights","CC BY 4.0"],["dc.title","Detrimental proarrhythmogenic interaction of Ca2+/calmodulin-dependent protein kinase II and NaV1.8 in heart failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","154"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","ESC Heart Failure"],["dc.bibliographiccitation.lastpage","163"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Tirilomis, Petros"],["dc.contributor.author","Pabel, Steffen"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Molina, Cristina E."],["dc.contributor.author","Tirilomis, Theodoros"],["dc.contributor.author","Kutschka, Ingo"],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuss, Gerd"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2019-02-26T11:03:53Z"],["dc.date.available","2019-02-26T11:03:53Z"],["dc.date.issued","2019"],["dc.description.abstract","Aims In hypertrophy and heart failure, the proarrhythmic persistent Na+ current (INaL) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel NaV1.8 in human hypertrophied myocardium. Methods and results Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of NaV1.8 mRNA (2.34fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, NaV1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent INaL was significantly reduced after addition of novel NaV1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of NaV1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca2+ leak and SR-Ca2+ spark frequency after exposure to both NaV1.8 inhibitors."],["dc.identifier.doi","10.1002/ehf2.12378"],["dc.identifier.pmid","30378291"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57615"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/242"],["dc.language.iso","en"],["dc.notes.status","final"],["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-NC 4.0"],["dc.title","The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Der Internist"],["dc.bibliographiccitation.volume","57"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Tirilomis, P."],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Pabel, Stefanie Corinna"],["dc.contributor.author","Stevens, E."],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T10:15:51Z"],["dc.date.available","2018-11-07T10:15:51Z"],["dc.date.issued","2016"],["dc.format.extent","S20"],["dc.identifier.isi","000375417500034"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40899"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.issn","1432-1289"],["dc.relation.issn","0020-9554"],["dc.title","Role of sodium channel Nav1.8 for arrhythmogenesis in the human failing heart"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","35"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","46"],["dc.bibliographiccitation.volume","144"],["dc.contributor.author","Bengel, Philipp"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Tirilomis, Petros"],["dc.contributor.author","Trum, Maximilian"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Wagner, Stefan"],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel"],["dc.date.accessioned","2021-04-14T08:25:53Z"],["dc.date.available","2021-04-14T08:25:53Z"],["dc.date.issued","2020"],["dc.identifier.doi","10.1016/j.yjmcc.2020.05.002"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81759"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation.issn","0022-2828"],["dc.title","Contribution of the neuronal sodium channel NaV1.8 to sodium- and calcium-dependent cellular proarrhythmia"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Heart Journal"],["dc.bibliographiccitation.volume","36"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T09:53:36Z"],["dc.date.available","2018-11-07T09:53:36Z"],["dc.date.issued","2015"],["dc.format.extent","1038"],["dc.identifier.isi","000361205107065"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/36360"],["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","Evidence and role of the neuronal sodium channel Nav1.8 in the human failing heart"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["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.journal","European Heart Journal"],["dc.bibliographiccitation.volume","37"],["dc.contributor.author","Dybkova, Nataliya"],["dc.contributor.author","Ahmad, Shakil"],["dc.contributor.author","Hartmann, Nico"],["dc.contributor.author","Tirilomis, P."],["dc.contributor.author","Pabel, Stefanie Corinna"],["dc.contributor.author","Stevens, E."],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Sossalla, Samuel T."],["dc.date.accessioned","2018-11-07T10:10:27Z"],["dc.date.available","2018-11-07T10:10:27Z"],["dc.date.issued","2016"],["dc.format.extent","617"],["dc.identifier.isi","000383869503054"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39861"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.publisher.place","Oxford"],["dc.relation.conference","Congress of the European-Society-of-Cardiology (ESC)"],["dc.relation.eventlocation","Rome, ITALY"],["dc.relation.issn","1522-9645"],["dc.relation.issn","0195-668X"],["dc.title","SCN10A/Nav1.8 channels contribute to arrhythmogenesis in the human failing heart"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]