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Rate-Dependent Role of I Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance

hal.structure.identifierUniversité de Montréal [UdeM]
dc.contributor.authorAGUILAR, Martin
hal.structure.identifierBristol-Myers Squibb Company
dc.contributor.authorFENG, Jianlin
hal.structure.identifierModélisation et calculs pour l'électrophysiologie cardiaque [CARMEN]
dc.contributor.authorVIGMOND, Edward
hal.structure.identifierUniversité de Montréal [UdeM]
dc.contributor.authorCOMTOIS, Philippe
hal.structure.identifierUniversité de Montréal [UdeM]
dc.contributor.authorNATTEL, Stanley
dc.date.accessioned2024-04-04T02:51:20Z
dc.date.available2024-04-04T02:51:20Z
dc.date.issued2017-05
dc.identifier.issn0006-3495
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/191982
dc.description.abstractEnThe atrial-specific ultrarapid delayed rectifier K+ current (IKur) inactivates slowly but completely at depolarized voltages. The consequences for IKur rate-dependence have not been analyzed in detail and currently available mathematical action-potential (AP) models do not take into account experimentally observed IKur inactivation dynamics. Here, we developed an updated formulation of IKur inactivation that accurately reproduces time-, voltage-, and frequency-dependent inactivation. We then modified the human atrial cardiomyocyte Courtemanche AP model to incorporate realistic IKur inactivation properties. Despite markedly different inactivation dynamics, there was no difference in AP parameters across a wide range of stimulation frequencies between the original and updated models. Using the updated model, we showed that, under physiological stimulation conditions, IKur does not inactivate significantly even at high atrial rates because the transmembrane potential spends little time at voltages associated with inactivation. Thus, channel dynamics are determined principally by activation kinetics. IKur magnitude decreases at higher rates because of AP changes that reduce IKur activation. Nevertheless, the relative contribution of IKur to AP repolarization increases at higher frequencies because of reduced activation of the rapid delayed-rectifier current IKr. Consequently, IKur block produces dose-dependent termination of simulated atrial fibrillation (AF) in the absence of AF-induced electrical remodeling. The inclusion of AF-related ionic remodeling stabilizes simulated AF and greatly reduces the predicted antiarrhythmic efficacy of IKur block. Our results explain a range of experimental observations, including recently reported positive rate-dependent IKur-blocking effects on human atrial APs, and provide insights relevant to the potential value of IKur as an antiarrhythmic target for the treatment of AF.
dc.language.isoen
dc.publisherBiophysical Society
dc.title.enRate-Dependent Role of I Kur in Human Atrial Repolarization and Atrial Fibrillation Maintenance
dc.typeArticle de revue
dc.identifier.doi10.1016/j.bpj.2017.03.022
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire
bordeaux.journalBiophysical Journal
bordeaux.page1997-2010
bordeaux.volume112
bordeaux.hal.laboratoriesInstitut de Mathématiques de Bordeaux (IMB) - UMR 5251*
bordeaux.issue9
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionBordeaux INP
bordeaux.institutionCNRS
bordeaux.peerReviewedoui
hal.identifierhal-02885667
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-02885667v1
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Biophysical%20Journal&rft.date=2017-05&rft.volume=112&rft.issue=9&rft.spage=1997-2010&rft.epage=1997-2010&rft.eissn=0006-3495&rft.issn=0006-3495&rft.au=AGUILAR,%20Martin&FENG,%20Jianlin&VIGMOND,%20Edward&COMTOIS,%20Philippe&NATTEL,%20Stanley&rft.genre=article


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