Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts
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Authors
Valli, H
Ahmad, S
Chadda, KR
Al-Hadithi, ABAK
Grace, Andrew
Jeevaratnam, K
Publication Date
2017-10-01Journal Title
Mechanisms of Ageing and Development
ISSN
0047-6374
Publisher
Elsevier
Volume
167
Pages
30-45
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Huang, C., Valli, H., Ahmad, S., Chadda, K., Al-Hadithi, A., Grace, A., & Jeevaratnam, K. (2017). Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts. Mechanisms of Ageing and Development, 167 30-45. https://doi.org/10.1016/j.mad.2017.09.002
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.
Keywords
peroxisome proliferator activated receptor-γ coactivator-1 (PGC-1), atrial, action potential, wavelength, cardiac conduction, cardiac arrhythmias, atrial fibrillation
Sponsorship
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).
Funder references
British Heart Foundation (None)
Wellcome Trust (105727/Z/14/Z)
Medical Research Council (MR/M001288/1)
British Heart Foundation (PG/15/12/31280)
Identifiers
External DOI: https://doi.org/10.1016/j.mad.2017.09.002
This record's URL: https://www.repository.cam.ac.uk/handle/1810/274851
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