Abstract
Introduction: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors.
Materials and methods: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-y coactivator-1 beta knockout (Pgc-1 beta(-/-)) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA.
Results and discussion: Young and aged Pgc-1 beta(-/-) showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1 beta(-/-) hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)(max) (similar to 157 vs. 120-130 V s(-1)), prolonged AP latencies (by-20%) and shortened refractory periods (similar to 58 vs. 51 ms) but similar AP durations (-50 ms at 90% recovery) compared to WT. However, Pgc-1 beta(-/-) genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1 beta(-/-) ventricles displayed similar dependences of AP latency upon (dV/dt)(max) resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1 beta(-/-) and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1 beta(-/-) phenotypes by altering AP conduction through reducing (dV/dt)(max), and causing age-dependent fibrotic change.