Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC125
Age-dependent effects on atrial arrhythmogenicity in Scn5a+/- murine hearts
L. Guzadhur1,2, W. Jiang3, K. Jeevaratnam2, R. Duehmke1, S. Pearcey2, A. Grace1, M. Lei4, C. L. Huang2
1. Biochemistry, University of Cambridge, Cambridge, United Kingdom. 2. Physiology, Development & Neuroscience, University of Cambridge, Cambridge, United Kingdom. 3. Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi Province, China. 4. School of Clinical and Laboratory Sciences, University of Manchester, Manchester, United Kingdom.
Recent clinical studies associate both ageing and mutations in the gene encoding the cardiac Na+ channel, SCN5A, with atrial arrhythmogenicity. Atrial action potential initiation, propagation and recovery were compared in young (3 month) and aged (12 month), wild-type (WT) and loss-of-function Scn5a+/- murine hearts previously used to model Brugada Syndrome. Multi-electrode array recordings assessed the spatial propagation and duration of intrinsic electrical activity in superfused atrial preparations. Bipolar electrogram recordings (BEGs) measured basic cycle lengths (BCLs) in Langendorff preparations. Durations of electrogram activity (EGDs), during regular (S1) and extrasystolic (S2) stimulation during programmed electrical stimulation (PES), provided both EGD ratios and atrial effective refractory periods (AERPs). Finally, monophasic recordings measured action potential durations (APDs). Systematic statistical explorations for independent and interacting effects of age and the Scn5a+/- condition demonstrated that young and aged Scn5a+/- mice showed increased intrinsic BCLs as well as slowed propagation of atrial excitation relative to the corresponding WT with the greatest effects in the aged Scn5a+/-. However, the aged Scn5a+/- showed normal APDs, EGDs and EGD ratios, increased AERPs, and smaller APD/AERP ratios. In contrast, the young Scn5a+/- showed prolonged electrograms and APDs as well as greater EGD and APD/AERP ratios, measures previously used to assess arrhythmic tendency. In conclusion the Scn5a+/- condition exerts effects upon measures of atrial arrhythmogenicity that overlap with those recently described for the gain-of-function Scn5a+/ΔKPQ condition, but which produce their maximum effects in young rather than aged animals.
Where applicable, experiments conform with Society ethical requirements