Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts

Introduction: 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). Results and discussion: The 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) , prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD ) but shortened APD 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.We acknowledge financial support from the Medical Research Council (MR/M001288/1), the Wellcome Trust (105727/Z/14/Z), British Heart Foundation (PG/14/79/31102 and PG/15/12/31280), Sudden Arrhythmic Death Syndrome (SADS) UK, The McVeigh Benefaction and the Fundamental Research Grant Scheme, Ministry of Education, Malaysia (FRGS/2/2014/SKK01/PERDANA/02/1)