The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3.
Chadda, Karan R
den Uijl, Ingrid
Al-Hadithi, Ali Bak
Springer Science and Business Media LLC
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Chadda, K. R., Ahmad, S., Valli, H., den Uijl, I., Al-Hadithi, A. B., Salvage, S., Grace, A., et al. (2017). The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3.. Sci Rep, 7 (1), 11070. https://doi.org/10.1038/s41598-017-11210-3
Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/ΔKPQ interacted in increasing incidences of repolarisation alternans (p = 0.02). Dobutamine increased ventricular rate (p < 0.001) and reduced both atrioventricular conduction (PR segment-p = 0.02; PR interval-p = 0.02) and incidences of repolarisation alternans (p < 0.001) in all mice. However, in Scn5a+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fibrotic change for the first time, adding activation abnormalities to established recovery abnormalities in LQTS3. These findings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients.
Animals, Humans, Mice, Long QT Syndrome, Disease Models, Animal, Fibrosis, Adrenergic Agents, Heart Function Tests, Electrocardiography, Aging, Phenotype, Cardiac Conduction System Disease
Medical Research Council (MR/M001288/1)
Wellcome Trust (105727/Z/14/Z)
British Heart Foundation (None)
External DOI: https://doi.org/10.1038/s41598-017-11210-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/282883
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/