Pro‐arrhythmic atrial phenotypes in incrementally paced murine Pgc1β−/− hearts: effects of age

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 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. This article is protected by copyright. All rights reserved