Abstract
Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1 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 (12-16weeks) and aged (>52weeks), wild type (WT) (n=5 and 8) and Pgc-1(-/-) (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 1-adrenergic (intraperitoneal dobutamine 3mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1(-/-) 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-1(-/-) mice. Moreover, Pgc-1(-/-) 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-1(-/-) mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QT(c) 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-1(-/-) systems in widespread cardiac regions.