{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:50:11Z","timestamp":1782877811641,"version":"3.54.5"},"reference-count":52,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2018,10,13]],"date-time":"2018-10-13T00:00:00Z","timestamp":1539388800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["FS\/12\/10\/29265"],"award-info":[{"award-number":["FS\/12\/10\/29265"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The sinoatrial node (SAN) is the primary pacemaker of the heart. SAN dysfunction, or \u2018sick sinus syndrome\u2019, can cause excessively slow heart rates and pauses, leading to exercise limitation and syncope, currently treated by implantation of an electronic pacemaker.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>\u2018Biopacemaking\u2019 utilises gene therapy to restore pacemaker activity by manipulating gene expression. Overexpressing the HCN pacemaker ion channel has been widely used with limited success.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We utilised bradycardic rat subsidiary atrial pacemaker tissue to evaluate alternative gene targets: the Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchanger NCX1, and the transcription factors TBX3 and TBX18 known to be involved in SAN embryonic development.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>TBX18 overexpression restored normal SAN function, as assessed by increased rate, improved heart rate stability and restoration of isoprenaline response. TBX3 and NCX1 were not effective in accelerating the rate of subsidiary atrial pacemaker tissue.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Gene therapy targeting TBX18 could therefore have the potential to restore pacemaker function in human sick sinus syndrome obviating electronic pacemakers.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The sinoatrial node (SAN) is the primary pacemaker of the heart. Disease of the SAN, sick sinus syndrome, causes heart rate instability in the form of bradycardia and pauses, leading to exercise limitation and syncope. Biopacemaking aims to restore pacemaker activity by manipulating gene expression, and approaches utilising HCN channel overexpression have been widely used. We evaluated alternative gene targets for biopacemaking to restore normal SAN pacemaker physiology within bradycardic subsidiary atrial pacemaker (SAP) tissue, using the Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchanger NCX1, and the transcription factors TBX3 and TBX18. TBX18 expression in SAP tissue restored normal SAN function, as assessed by increased rate (SAN 267.5\u00a0\u00b1\u00a013.6\u00a0bpm, SAP 144.1\u00a0\u00b1\u00a08.6\u00a0bpm, SAP\u2010TBX18 214.4\u00a0\u00b1\u00a014.4\u00a0bpm; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), improved heart rate stability (standard deviation of RR intervals fell from 39.3\u00a0\u00b1\u00a07.2\u00a0ms to 6.9\u00a0\u00b1\u00a00.8\u00a0ms, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; root mean square of successive differences of RR intervals fell from 41.7\u00a0\u00b1\u00a08.2\u00a0ms to 6.1\u00a0\u00b1\u00a01.2\u00a0ms, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; standard deviation of points perpendicular to the line of identity of Poincar\u00e9 plots (SD1) fell from 29.5\u00a0\u00b1\u00a05.8\u00a0ms to 7.9\u00a0\u00b1\u00a02.0\u00a0ms, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and restoration of isoprenaline response (increases in rates of SAN 65.5\u00a0\u00b1\u00a01.3%, SAP 28.4\u00a0\u00b1\u00a03.4% and SAP\u2010TBX18 103.3\u00a0\u00b1\u00a010.2%; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). These changes were driven by a TBX18\u2010induced switch in the dominant HCN isoform in SAP tissue, with a significant upregulation of HCN2 (from 1.01\u00a0\u00d7\u00a010<jats:sup>\u22125<\/jats:sup>\u00a0\u00b1\u00a02.2\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup> to 2.8\u00a0\u00d7\u00a010<jats:sup>\u22125<\/jats:sup>\u00a0\u00b1\u00a04.3\u00a0\u00d7\u00a010<jats:sup>\u22126<\/jats:sup> arbitrary units, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Biophysically detailed computer modelling incorporating isoform\u2010specific HCN channel electrophysiology confirmed that the measured changes in HCN abundance could account for the observed changes in beating rates. TBX3 and NCX1 were not effective in accelerating the rate of SAP tissue.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp276508","type":"journal-article","created":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T06:40:04Z","timestamp":1538030404000},"page":"6141-6155","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3795-8178","authenticated-orcid":false,"given":"M.","family":"Choudhury","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Black","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"D'Souza","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Yanni","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Dobrzynski","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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