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 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.

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