Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age.
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Valli, H., Ahmad, S., Fraser, J. A., Jeevaratnam, K., & Huang, C. L. (2017). Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age.. Experimental physiology, 102 (12), 1619-1634. https://doi.org/10.1113/EP086589
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.
Heart Atria, Animals, Mice, Inbred C57BL, Mice, Knockout, Disease Models, Animal, Cardiac Pacing, Artificial, Age Factors, Action Potentials, Heart Rate, Phenotype, Time Factors, Arrhythmias, Cardiac, Genetic Testing, Isolated Heart Preparation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Medical Research Council (MR/M001288/1)
British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
External DOI: https://doi.org/10.1113/EP086589
This record's URL: https://www.repository.cam.ac.uk/handle/1810/271054
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