QTc interval and ventricular action potential prolongation in the Mecp2Null/+ murine model of Rett syndrome

Hongwei Cheng, Ian Charles, Andrew F James, Ana P Abdala*, Jules C Hancox*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 Mecp2Null/+ female mice. ECG recordings from 12-13 month old female Mecp2Null/+ mice showed prolonged rate corrected QT (QTc) intervals compared to wild-type (WT) controls. Although Mecp2Null/+ animals exhibited longer periods of apnoea than did controls, no correlation between apnoea length and QTc interval was observed. Action potentials (APs) from Mecp2Null/+ myocytes had longer APD90 values than those from WT myocytes and showed augmented triangulation. Application of the investigational INa,Late inhibitor GS-6615 (eleclazine; 10 μM) reduced both APD90 and AP triangulation in Mecp2Null/+ and WT myocytes. These results constitute the first direct demonstration of delayed repolarization in Mecp2Null/+ myocytes and provide further evidence that GS-6615 may have potential as an intervention against QT prolongation in RTT.

Original languageEnglish
Article numbere15437
Number of pages12
JournalPhysiological Reports
Issue number19
Publication statusPublished - 5 Oct 2022

Bibliographical note

Funding Information:
The authors thank the British Heart Foundation for funding (PG/16/55/32277).

Publisher Copyright:
© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.


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