Abstract
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 agedependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting efects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fbrotic 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 fbrosis (both: p<0.001). Ventricles also showed increased fbrosis 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 fndings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fbrotic change for the frst time, adding activation abnormalities to established recovery abnormalities in LQTS3. These fndings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients.