Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β^-/- hearts: effects of age.

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.