Abstract
Rett Syndrome (RTT) is a congenital, X-chromosome-linked developmental disorder characterized by developmental delay, dysautonomia, and breathing irregularities. RTT is also associated with sudden death and QT intervals are prolonged in some RTT patients. Most individuals with RTT have mutations in the MECP2 gene. Whilst there is some evidence for QT prolongation in mouse models of RTT, there is comparatively little information on how loss of Mecp2 function affects ventricular action potentials (APs) and, to-date, none on ventricular APs from female RTT mice. Accordingly, the present study was conducted to determine ECG and ventricular AP characteristics of Mecp2(Null/+) female mice. ECG recordings from 12-13 month old female Mecp2(Null/+) mice showed prolonged rate corrected QT (QTc) intervals compared to wild-type (WT) controls. Although Mecp2(Null/+) animals exhibited longer periods of apnoea than did controls, no correlation between apnoea length and QT(c) interval was observed. Action potentials (APs) from Mecp2(Null/+) myocytes had longer APD(90) values than those from WT myocytes and showed augmented triangulation. Application of the investigational I(Na,Late) inhibitor GS-6615 (eleclazine; 10 μM) reduced both APD(90) and AP triangulation in Mecp2(Null/+) and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2(Null/+) myocytes and provide further evidence that GS-6615 may have potential as an intervention against QT prolongation in RTT.