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

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 (dV/dt)(max) and latency), recovery (action potential duration (APD(90)) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)(max) and increased AP latency values in the Pgc-1β (−/−) hearts. APs observed prior to termination of the protocol showed lower (dV/dt)(max) and longer AP latencies, but indistinguishable APD(90) 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.