Abstract
IntroductionAgeing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF). Materials and methodsAtrial arrhythmogenesis was investigated in Langendorff-perfused young (3–4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β−/−) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES). Results and discussionThe Pgc-1β−/− genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β−/− hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β−/− hearts. Pgc-1β−/− hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β−/− hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β−/− hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.
Highlights
Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF)
Simultaneous ECG and intracellular microelectrode readings were recorded from Langendorff perfused wild type (WT) and Pgc-1β−/− hearts and the presence or otherwise of an arrhythmic substrate was correlated with structural changes at the organ level
Volume conductor ECGs and intracellular action potential (AP) recordings were first obtained from Langendorff perfused hearts during regular pacing at a basic cycle length (BCL) of 125 ms (8 Hz) mimicking murine resting heart rates, enabling quantification of occurrence of spontaneous arrhythmia and electrophysiological characterisation under conditions of baseline activity
Summary
Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF). Materials and methods: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3–4 month) and aged (> 12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β−/−) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES). It is clear that AF is a dynamic process, which at its inception is characterised by fleeting episodes of the abnormal rhythm triggered by focal ectopic activity in the pulmonary vein sleeves (Haïssaguerre et al, 1998). With time, these episodes become more protracted and eventually permanent through progressive electrical and structural remodeling producing a tissue substrate itself conducive to arrhythmia maintenance. Treatment in these latter stages is far less efficacious (Cappato et al, 2010), highlighting the need to target therapies to the upstream processes
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