{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:07:00Z","timestamp":1785283620841,"version":"3.55.0"},"reference-count":66,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:00:00Z","timestamp":1653004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/16\/55\/32277"],"award-info":[{"award-number":["PG\/16\/55\/32277"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome (RTT) is a severe developmental disorder that is strongly linked to mutations in the MECP2 gene. RTT has been associated with sudden unexplained death and ECG QT interval prolongation. There are mixed reports regarding QT prolongation in mouse models of RTT, with some evidence that loss of Mecp2 function enhances cardiac late Na current, INa,Late. The present study was undertaken in order to investigate both ECG and ventricular AP characteristics in the Mecp2Null\/Y male murine RTT model and to interrogate both fast INa and INa,Late in myocytes from the model. ECG recordings from 8\u201310-week-old Mecp2Null\/Y male mice revealed prolongation of the QT and rate corrected QT (QTc) intervals and QRS widening compared to wild-type (WT) controls. Action potentials (APs) from Mecp2Null\/Y myocytes exhibited longer APD75 and APD90 values, increased triangulation and instability. INa,Late was also significantly larger in Mecp2Null\/Y than WT myocytes and was insensitive to the Nav1.8 inhibitor A-803467. Selective recordings of fast INa revealed a decrease in peak current amplitude without significant voltage shifts in activation or inactivation V0.5. Fast INa \u2018window current\u2019 was reduced in RTT myocytes; small but significant alterations of inactivation and reactivation time-courses were detected. Effects of two INa,Late inhibitors, ranolazine and GS-6615 (eleclazine), were investigated. Treatment with 30 \u00b5M ranolazine produced similar levels of inhibition of INa,Late in WT and Mecp2Null\/Y myocytes, but produced ventricular AP prolongation not abbreviation. In contrast, 10 \u00b5M GS-6615 both inhibited INa,Late and shortened ventricular AP duration. The observed changes in INa and INa,Late can account for the corresponding ECG changes in this RTT model. GS-6615 merits further investigation as a potential treatment for QT prolongation in RTT.<\/jats:p>","DOI":"10.3390\/ijms23105735","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T13:56:12Z","timestamp":1653054972000},"page":"5735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome"],"prefix":"10.3390","volume":"23","author":[{"given":"Hongwei","family":"Cheng","sequence":"first","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Charles","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2035-9489","authenticated-orcid":false,"given":"Andrew F.","family":"James","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana P.","family":"Abdala","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jules C.","family":"Hancox","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience, University of Bristol, University Walk, Bristol BS8 1TD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s10354-016-0492-8","article-title":"On a remarkable syndrome of cerebral atrophy associated with hyperammonaemia in childhood","volume":"166","author":"Rett","year":"2016","journal-title":"Wien. 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