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dc.contributor.authorAhmad, Shirazen
dc.contributor.authorValli, Haseeben
dc.contributor.authorChadda, Karan Ren
dc.contributor.authorCranley, Jamesen
dc.contributor.authorJeevaratnam, Kamalanen
dc.contributor.authorHuang, Christopheren
dc.date.accessioned2018-09-05T12:44:01Z
dc.date.available2018-09-05T12:44:01Z
dc.date.issued2018-07en
dc.identifier.issn0047-6374
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279445
dc.description.abstractIntroduction: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors. Materials and Methods: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA. Results and Discussion: Young and aged Pgc-1β-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (~157 vs. 120-130 V s-1), prolonged AP latencies (by ~20%) and shortened refractory periods (~58 vs. 51 ms) but similar AP durations (~50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.
dc.description.sponsorshipWellcome Trust, MRC, BHF, Sudden Adult Death Syndrome (SADS) UK society, and the Fundamental Research Grant Scheme (Ministry of Education, Malaysia)
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherElsevier
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectMyocardiumen
dc.subjectMitochondria, Hearten
dc.subjectAnimalsen
dc.subjectMice, Knockouten
dc.subjectMiceen
dc.subjectFibrosisen
dc.subjectAction Potentialsen
dc.subjectAgingen
dc.subjectModels, Cardiovascularen
dc.subjectArrhythmias, Cardiacen
dc.subjectPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaen
dc.titleVentricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β<sup>-/-</sup>) murine hearts.en
dc.typeArticle
prism.endingPage103
prism.publicationDate2018en
prism.publicationNameMechanisms of ageing and developmenten
prism.startingPage92
prism.volume173en
dc.identifier.doi10.17863/CAM.26819
dcterms.dateAccepted2018-05-11en
rioxxterms.versionofrecord10.1016/j.mad.2018.05.004en
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2018-07en
dc.contributor.orcidChadda, Karan R [0000-0002-8060-8408]
dc.contributor.orcidJeevaratnam, Kamalan [0000-0002-6232-388X]
dc.contributor.orcidHuang, Christopher [0000-0001-9553-6112]
dc.identifier.eissn1872-6216
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/M001288/1)
pubs.funder-project-idBritish Heart Foundation (PG/14/79/31102)
pubs.funder-project-idWELLCOME TRUST (105727/Z/14/Z)
pubs.funder-project-idBritish Heart Foundation (PG/15/12/31280)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)