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Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts.

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Ahmad, Shiraz 
Valli, Haseeb 
Salvage, Samantha C 
Grace, Andrew A 
Jeevaratnam, Kamalan  ORCID logo


Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12-16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc-1β-/- (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1-adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1β-/- genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino-atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc-1β-/- mice. Moreover, Pgc-1β-/- mice displayed electrocardiographic features consistent with the existence of a pro-arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc-1β-/- mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc-1β-/- systems in widespread cardiac regions.



cardiac arrhythmias, cardiac conduction, electrocardiogram, ECG, peroxisome proliferator activated receptor-γ-coactivator-1 (PGC-1), Aging, Animals, Electrocardiography, Gene Expression Regulation, Mice, Mice, Knockout, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

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Clin Exp Pharmacol Physiol

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British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
Medical Research Council (MR/M001288/1)