{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T07:22:20Z","timestamp":1792826540248,"version":"4.5.0"},"reference-count":69,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Research Council","award":["714866,899422"],"award-info":[{"award-number":["714866,899422"]}]},{"name":"Health Holland","award":["LentiPace II"],"award-info":[{"award-number":["LentiPace II"]}]},{"name":"Horizon 2020 Eurostars","award":["E114245,E115484"],"award-info":[{"award-number":["E114245,E115484"]}]},{"name":"Dutch Research Council Open Technology Program","award":["18485"],"award-info":[{"award-number":["18485"]}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"crossref","award":["OCENW.GROOT.2019.029"],"award-info":[{"award-number":["OCENW.GROOT.2019.029"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100018703","name":"European Innovation Council","doi-asserted-by":"crossref","award":["101099608"],"award-info":[{"award-number":["101099608"]}],"id":[{"id":"10.13039\/100018703","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:p>Gene therapy\u2013based biological pacemakers have been proposed as an alternative to their hardware-based counterparts. In this context, short-term ectopic expression of the T-box transcription factor 18 (TBX18) in the ventricle has been reported to generate potent, short-term pacemaker function in various animal models. Here, we investigated the impact of adeno-associated virus\u2013mediated (AAV-mediated), long-term expression of TBX18 and compared the outcomes with those of the pacemaker ion channel hyperpolarization-activated cyclic nucleotide-gated potassium and sodium channel 2 (Hcn2). Our findings revealed that CMV-driven ectopic TBX18 expression in mouse hearts led to severe cardiac fibrosis. At lower, nonfibrogenic levels, TBX18 maintained its transcriptional function but failed to induce pacemaker phenotypes. TBX18-expressing cells showed suppressed expression of key working myocardial genes, but the pacemaker gene program was not induced. Electrophysiological studies showed abnormal automaticity in TBX18-expressing cells, combined with prolonged repolarization and various current changes. However, no hyperpolarization-activated funny current was detected. In a complete atrioventricular block rat model, AAV-mediated Hcn2 expression induced robust ectopic pacemaker activity in the presence of isoproterenol, whereas TBX18 expression neither generated such activity nor augmented Hcn2-mediated pacing. In conclusion, at functionally nonfibrogenic levels, TBX18 is neither sufficient nor necessary to induce pacemaker activity. In contrast, Hcn2 generates reliable pacing, making it a more viable candidate for biological pacemaker development.<\/jats:p>","DOI":"10.1172\/jci190632","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:00:15Z","timestamp":1781193615000},"source":"Crossref","is-referenced-by-count":2,"title":["AAV-mediated long-term TBX18 expression causes cardiac fibrosis and fails to induce pacemaker activity in rodents"],"prefix":"10.1172","volume":"136","author":[{"given":"Jianan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde R.","family":"Rivaud","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, 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