Atrial arrhythmogenicity in aged Scn5a+/a†KPQ mice modeling long QT type 3 syndrome and its relationship to Na+ channel expression and cardiac conduction

Recent studies have reported that human mutations in Nav1.5 predispose to early age onset atrial arrhythmia. The present experiments accordingly assess atrial arrhythmogenicity in aging Scn5a+/a dagger KPQ mice modeling long QT3 syndrome in relationship to cardiac Na+ channel, Nav1.5, expression. Atrial electrophysiological properties in isolated Langendorff-perfused hearts from 3- and 12-month-old wild type (WT), and Scn5a+/a dagger KPQ mice were assessed using programmed electrical stimulation and their Nav1.5 expression assessed by Western blot. Cardiac conduction properties were assessed electrocardiographically in intact anesthetized animals. Monophasic action potential recordings demonstrated increased atrial arrhythmogenicity specifically in aged Scn5a+/Delta KPQ hearts. These showed greater action potential duration/refractory period ratios but lower atrial Nav1.5 expression levels than aged WT mice. Atrial Nav1.5 levels were higher in young Scn5a+/Delta KPQ than young WT. These levels increased with age in WT but not Scn5a+/Delta KPQ. Both young and aged Scn5a+/Delta KPQ mice showed lower heart rates and longer PR intervals than their WT counterparts. Young Scn5a+/Delta KPQ mice showed longer QT and QTc intervals than young WT. Aged Scn5a+/Delta KPQ showed longer QRS durations than aged WT. PR intervals were prolonged and QT intervals were shortened in young relative to aged WT. In contrast, ECG parameters were similar between young and aged Scn5a+/Delta KPQ. Aged murine Scn5a+/Delta KPQ hearts thus exhibit an increased atrial arrhythmogenicity. The differing Nav1.5 expression and electrocardiographic indicators of slowed cardiac conduction between Scn5a+/Delta KPQ and WT, which show further variations associated with aging, may contribute toward atrial arrhythmia in aged Scn5a+/Delta KPQ hearts.