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dc.contributor.authorSkibsbye Lasse
dc.contributor.authorJespersen Thomas
dc.contributor.authorChrist Torsten
dc.contributor.authorMaleckar Mary M
dc.contributor.authorvan den Brink Jonas
dc.contributor.authorTavi Pasi
dc.contributor.authorKoivumäki Jussi T
dc.date.accessioned2017-03-07T08:34:02Z
dc.date.available2017-03-07T08:34:02Z
dc.date.issued2016
dc.identifier10.1016/j.yjmcc.2016.10.009fi_FI
dc.identifier.issn0022-2828
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/449
dc.descriptionArticle
dc.description.abstractBackground Refractoriness of cardiac cells limits maximum frequency of electrical activity and protects the heart from tonic contractions. Short refractory periods support major arrhythmogenic substrates and augmentation of refractoriness is therefore seen as a main mechanism of antiarrhythmic drugs. Cardiomyocyte excitability depends on availability of sodium channels, which involves both time- and voltage-dependent recovery from inactivation. This study therefore aims to characterise how sodium channel inactivation affects refractoriness in human atria. Methods and results Steady-state activation and inactivation parameters of sodium channels measured in vitro in isolated human atrial cardiomyocytes were used to parameterise a mathematical human atrial cell model. Action potential data were acquired from human atrial trabeculae of patients in either sinus rhythm or chronic atrial fibrillation. The ex vivo measurements of action potential duration, effective refractory period and resting membrane potential were well-replicated in simulations using this new in silico model. Notably, the voltage threshold potential at which refractoriness was observed was not different between sinus rhythm and chronic atrial fibrillation tissues and was neither affected by changes in frequency (1 vs. 3 Hz). Conclusions Our results suggest a preferentially voltage-dependent, rather than time-dependent, effect with respect to refractoriness at physiologically relevant rates in human atria. However, as the resting membrane potential is hyperpolarized in chronic atrial fibrillation, the voltage-dependence of excitability dominates, profoundly increasing the risk for arrhythmia re-initiation and maintenance in fibrillating atria. Our results thereby highlight resting membrane potential as a potential target in pharmacological management of chronic atrial fibrillation.fi_FI
dc.language.isoengfi_FI
dc.publisherElsevier BVfi_FI
dc.relation.ispartofseriesJOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
dc.relation.urihttp://dx.doi.org/10.1016/j.yjmcc.2016.10.009fi_FI
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/fi_FI
dc.subjectElectrophysiologyfi_FI
dc.subjectRefractory periodfi_FI
dc.subjectIon channelsfi_FI
dc.subjectAtrial fibrillationfi_FI
dc.subjectMathematical modelingfi_FI
dc.titleRefractoriness in human atria: Time and voltage dependence of sodium channel availabilityfi_FI
dc.typehttp://purl.org/eprint/type/JournalArticle
dc.description.versionfinal draftfi_FI
dc.contributor.departmentA.I. Virtanen -instituutti / Bioteknologia ja molekulaarinen lääketiede
uef.solecris.id43272651
eprint.statushttp://purl.org/eprint/status/PeerReviewedfi_FI
dc.type.publicationinfo:eu-repo/semantics/article
dc.rights.accessrights© Elsevier BVfi_FI
uef.citationinfo.pages26-34
dc.relation.doi10.1016/j.yjmcc.2016.10.009
dc.description.reviewstatushttp://purl.org/eprint/status/PeerReviewed
dc.relation.issn0022-2828
dc.relation.volume101


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