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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Huang, CL 
Valli, H 
Ahmad, S 
Chadda, KR 
Al-Hadithi, ABAK 

Abstract

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.

Description

Keywords

peroxisome proliferator activated receptor-γ coactivator-1 (PGC-1), atrial, action potential, wavelength, cardiac conduction, cardiac arrhythmias, atrial fibrillation

Journal Title

Mechanisms of Ageing and Development

Conference Name

Journal ISSN

0047-6374
1872-6216

Volume Title

167

Publisher

Elsevier
Sponsorship
British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
Medical Research Council (MR/M001288/1)
British Heart Foundation (PG/15/12/31280)
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).