Abstract
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 (APD90) 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 APD90 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.
Highlights
Following the successful mechanistic and mathematical description of the cardiac action potential and its propagation, cardiac electrophysiology has increasingly focused upon the physiological mechanisms underlying arrhythmia [19]
Each procedure began with a programmed electrical stimulation protocol interposing extrasystolic (S2) stimuli at successively decremented intervals following trains of eight regular (S1) stimuli applied at a 125 ms basic cycle length (BCL)
Overall ventricular electrical activity through the S1S2 protocol was monitored by the ECG recordings. Analysis of these initial recordings yielded ventricular effective refractory periods (VERPs) that indicated the extent to which BCLs could be decreased in the succeeding experiments
Summary
Following the successful mechanistic and mathematical description of the cardiac action potential and its propagation, cardiac electrophysiology has increasingly focused upon the physiological mechanisms underlying arrhythmia [19]. The prevalence of atrial fibrillation rises from ~ 4% of individuals aged 60–70 to ~ 20% at > 80 years [54], while the incidence of sudden cardiac death attributable to ventricular arrhythmias is eight times higher in 75- than 50-year-old individuals [8]. Metabolic abnormalities associated with chronic, age-dependent, conditions including obesity, insulin resistance, diabetes mellitus and heart failure accentuate arrhythmic risk, independently of any ischaemic changes arising from associated coronary vascular effects [1, 28, 51]. These situations are accompanied by cardiomyocyte energetic and mitochondrial dysfunction, itself an independent arrhythmic risk factor [2].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
