Abstract
IntroductionAgeing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors. Materials and methodsPro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β−/−) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA. Results and discussionYoung and aged Pgc-1β−/− showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (∼157 vs. 120–130 V s-1), prolonged AP latencies (by ∼20%) and shortened refractory periods (∼58 vs. 51 ms) but similar AP durations (∼50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β−/− 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-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β−/− phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.
Highlights
Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors
The young wild type (WT) and young Pgc-1β−/− groups consisted of mice aged between 3–4 months; animals aged greater than 12 months were used for the aged WT and aged Pgc-1β−/− groups respectively
They explored and characterised effects of the Pgc-1β−/ − genotype and ageing upon arrhythmic properties at the organ level in Langendorff-perfused murine hearts during both regular pacing and programmed electrical stimulation (PES). These findings were correlated with cellular electrophysiological quantifications of action potential (AP) activation and propagation, as well as recovery characteristics, and morphometric assessments of age-related structural change, features previously implicated in arrhythmic substrate
Summary
Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors. Young and aged WT ventricles displayed distinct, but Pgc-1β−/− ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT Cardiovascular disease is the leading worldwide cause of mortality Half such cases are attributable to sudden cardiac death (SCD) (Go et al, 2013), often following ventricular arrhythmias. Growing evidence links such arrhythmias to energetic dysfunction seen in both ageing and agerelated conditions including obesity, diabetes mellitus and heart failure (Hookana et al, 2011; Kucharska-Newton et al, 2010; Yeung et al, 2012) The latter constitute risk factors for SCD independent of any underlying coronary artery disease (Adabag et al, 2015; Yeung et al, 2012). Ageing itself is associated with an increased incidence of cardiac rhythm disturbances including both pathological bradycardic rhythms as well as atrial and ventricular tachy-arrhythmias (Bradshaw et al, 2014; Deo and Albert, 2012; Go et al, 2001), though the underlying mechanisms remain unclear
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