Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β<sup>-/-</sup>) murine hearts.
Mechanisms of ageing and development
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Ahmad, S., Valli, H., Chadda, K. R., Cranley, J., Jeevaratnam, K., & Huang, C. (2018). Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β<sup>-/-</sup>) murine hearts.. Mechanisms of ageing and development, 173 92-103. https://doi.org/10.1016/j.mad.2018.05.004
Introduction: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors. Materials and Methods: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-γ coactivator-1β knockout (Pgc-1β-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA. Results and Discussion: Young and aged Pgc-1β-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1β-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (~157 vs. 120-130 V s-1), prolonged AP latencies (by ~20%) and shortened refractory periods (~58 vs. 51 ms) but similar AP durations (~50 ms at 90% recovery) compared to WT. However, Pgc-1β-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1β-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc-1β-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc-1β-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change.
Myocardium, Mitochondria, Heart, Animals, Mice, Knockout, Mice, Fibrosis, Action Potentials, Aging, Models, Cardiovascular, Arrhythmias, Cardiac, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Wellcome Trust, MRC, BHF, Sudden Adult Death Syndrome (SADS) UK society, and the Fundamental Research Grant Scheme (Ministry of Education, Malaysia)
British Heart Foundation (PG/14/79/31102)
WELLCOME TRUST (105727/Z/14/Z)
British Heart Foundation (PG/15/12/31280)
External DOI: https://doi.org/10.1016/j.mad.2018.05.004
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279445
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/