Atrial arrhythmogenesis in a murine model of mitochondrial insufficiency

Age-related atrial arrhythmias including atrial fibrillation are frequently encountered in clinical practice and are associated with significant mortality and morbidity. A putative role for chronic mitochondrial impairment in their pathogenesis was investigated using a murine model with homozygous deficiency of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1 β (Pgc-1β-/-). Pgc-1β regulates mitochondrial biogenesis and function, and unlike other murine models of mitochondrial dysfunction Pgc-1β-/- mice have a mild cardiac phenotype, devoid of confounding contractile dysfunction. All experiments were performed in young (12-16 weeks) and aged (>52 weeks) Pgc-1β-/- mice and compared to aged-matched wild type (WT) controls. Sharp microelectrode recordings of cellular action potentials (AP) in a whole-heart Langendorff-perfused system revealed that the Pgc-1β-/- genotype was associated with an atrial arrhythmic phenotype that progressed with age. Young and aged Pgc-1β-/- hearts showed evidence of slowed AP conduction at the cellular level, through deficits in maximum rates of AP depolarization (dV/dt)max, and at the tissue level through prolonged AP latencies. Action potential duration (APD) was also significantly shorter in Pgc-1β-/- hearts at high heart rates. APD restitution has been linked to the pathogenesis of ventricular fibrillation and more recently AF. However in the present work the incidence of alternans or steepness of the restitution curves did not correlate with arrhythmic tendency. Loose patch clamp measurements demonstrated that Pgc-1β−/− atria had significantly lower inward Na+ currents than that of WT preparations, correlating to the differences in (dV/dt)max values. No differences in delayed outward (K+) currents were evident. Morphometric analysis revealed that Pgc-1β deficiency was associated with accelerated fibrosis, with aged Pgc-1β-/- hearts displaying the greatest fibrotic change. The Pgc-1β-/- murine model of chronic mitochondrial impairment results in an age-related atrial arrhythmic phenotype through adverse electrical and structural remodelling producing an atrial substrate promoting AP reentry and arrhythmia persistence.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Valli, Haseeb

Advisor dc:contributor.advisor

• Huang, Christopher

• Atrial fibrillation
• arrhythmia
• mitochondrial
• metabolic
• peroxisome proliferator-activated receptor γ coactivator-1 β
• Pgc-1β

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ecf60a00-fe01-4111-a089-46c64ee3bdcd/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.41673

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/294568