Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1β hearts

Ahmad, Shiraz; Valli, Haseeb; Edling, Charlotte; Grace, Andrew; Jeevaratnam, Kamalan; Huang, Christopher
December 2017
Pflugers Archiv European Journal of Physiology;Dec2017, Vol. 469 Issue 12, p1579
Academic Journal
A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β ( Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (d V/d t) and latency), recovery (action potential duration (APD) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (d V/d t) and increased AP latency values in the Pgc-1β hearts. APs observed prior to termination of the protocol showed lower (d V/d t) and longer AP latencies, but indistinguishable APD and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β and WT hearts showed similar limiting gradients. However, Pgc-1β hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β hearts. Pgc-1β hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.


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