Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β<sup>-/-</sup> hearts: effects of age.
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Publication Date
2017-12Journal Title
Experimental physiology
ISSN
0958-0670
Publisher
Wiley-Blackwell
Volume
102
Issue
12
Pages
1619-1634
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print-Electronic
Metadata
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Valli, H., Ahmad, S., Fraser, J., Jeevaratnam, K., & Huang, C. (2017). Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β<sup>-/-</sup> hearts: effects of age.. Experimental physiology, 102 (12), 1619-1634. https://doi.org/10.1113/ep086589
Abstract
Atrial arrhythmias, most commonly manifesting as atrial fibrillation (AF),
represent a major clinical problem. AF incidences increase with both age and conditions
associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in
young (12-16 week) and aged (>52 week), WT and peroxisome proliferator receptor
gamma co-activator 1β-deficient (Pgc-1β-/-), Langendorff-perfused hearts, previously
used to model mitochondrial energetic disorder. Electrophysiological explorations were
performed using simultaneous whole-heart electrocardiogram and intracellular atrial
action potential (AP) recordings. Two stimulation protocols were employed: an S1S2
protocol which imposed extrasystolic stimuli at successively decremented intervals
following regular pulse trains and a regular pacing protocol at successively incremented
Disclaimer: This is a confidential document.
frequencies. Aged Pgc-1β-/- hearts showed greater atrial arrhythmogenicity, presenting
as atrial tachycardia and ectopic activity. Maximum rates of AP depolarisation,
(dV/dt )max, were reduced in Pgc-1β-/- hearts. AP latencies were increased by the Pgc-
1β-/- genotype with an added interactive effect of age. In contrast, AP durations to 90%
recovery (APD90) were shorter in Pgc-1β-/- hearts despite similar atrial effective
recovery periods amongst the different groups. These findings accompanied paradoxical
decreases in alternans incidence and duration in the aged and Pgc-1β-/- hearts. Limiting
slopes of restitution curves of APD90 against diastolic interval were correspondingly
interactively reduced by Pgc1β-/- genotype and age. In contrast, reduced AP
wavelengths were associated with Pgc-1β-/- genotype both independently, and
interacting with age, through the basic cycle lengths explored, with the aged Pgc-1β-/-
showing the shortest wavelengths. These findings thus implicate AP wavelength in
possible mechanisms for the atrial arrhythmic changes reported here.
Keywords
Heart Atria, Animals, Mice, Inbred C57BL, Mice, Knockout, Disease Models, Animal, Cardiac Pacing, Artificial, Age Factors, Action Potentials, Heart Rate, Phenotype, Time Factors, Arrhythmias, Cardiac, Genetic Testing, Isolated Heart Preparation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Sponsorship
British Heart Foundation (PG/14/79/31102)
MRC (MR/M001288/1)
WELLCOME TRUST (105727/Z/14/Z)
British Heart Foundation (PG/15/12/31280)
Identifiers
External DOI: https://doi.org/10.1113/ep086589
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271054
Rights
Attribution 4.0 International, Attribution 4.0 International
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