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dc.contributor.authorValli, Haseeb
dc.contributor.authorAhmad, Shiraz
dc.contributor.authorFraser, James A
dc.contributor.authorJeevaratnam, Kamalan
dc.contributor.authorHuang, Christopher L-H
dc.date.accessioned2018-01-24T10:10:55Z
dc.date.available2018-01-24T10:10:55Z
dc.date.issued2017-12-01
dc.identifier.issn0958-0670
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/271054
dc.description.abstractNEW FINDINGS: What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherWiley
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHeart Atria
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectDisease Models, Animal
dc.subjectCardiac Pacing, Artificial
dc.subjectAge Factors
dc.subjectAction Potentials
dc.subjectHeart Rate
dc.subjectPhenotype
dc.subjectTime Factors
dc.subjectArrhythmias, Cardiac
dc.subjectGenetic Testing
dc.subjectIsolated Heart Preparation
dc.subjectPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
dc.titlePro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age.
dc.typeArticle
prism.endingPage1634
prism.issueIdentifier12
prism.publicationDate2017
prism.publicationNameExp Physiol
prism.startingPage1619
prism.volume102
dc.identifier.doi10.17863/CAM.18016
dc.identifier.doi10.17863/CAM.18016
dc.identifier.doi10.17863/CAM.18016
dcterms.dateAccepted2017-09-26
rioxxterms.versionofrecord10.1113/EP086589
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2017-12
dc.contributor.orcidFraser, James A [0000-0002-6505-1883]
dc.contributor.orcidJeevaratnam, Kamalan [0000-0002-6232-388X]
dc.contributor.orcidHuang, Christopher L-H [0000-0001-9553-6112]
dc.identifier.eissn1469-445X
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idMedical Research Council (MR/M001288/1)
pubs.funder-project-idWellcome Trust (105727/Z/14/Z)
pubs.funder-project-idBritish Heart Foundation (PG/15/12/31280)
cam.issuedOnline2017-10-29


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