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In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo<jats:italic>,<\/jats:italic> dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.<\/jats:p>","DOI":"10.1007\/s00395-023-01022-0","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T11:01:50Z","timestamp":1704279710000},"page":"93-112","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Acute antiarrhythmic effects of SGLT2 inhibitors\u2013dapagliflozin lowers the excitability of atrial cardiomyocytes"],"prefix":"10.1007","volume":"119","author":[{"given":"Amelie","family":"Paasche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Wiedmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fitzwilliam","family":"Seibertz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Herlt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo L.","family":"Blochberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"J\u00e1vorszky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Weirauch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timon","family":"Seeger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje","family":"Blank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Haefeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawa","family":"Arif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Warnecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Karck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Voigt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Frey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5897-237X","authenticated-orcid":false,"given":"Constanze","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,3]]},"reference":[{"key":"1022_CR1","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1111\/j.1749-6632.2009.05086.x","volume":"1188","author":"C Antzelevitch","year":"2010","unstructured":"Antzelevitch C, Burashnikov A (2010) Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation. 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All other authors declare that they have no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study protocol involving human tissue samples was approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University (Germany; S-017\/2013) and was conducted in accordance with the 1964 Declaration of Helsinki. Human induced pluripotent stem cell (hiPSC) line UMGi014-C clone 14 (isWT1.14) was derived from dermal fibroblasts of a healthy male donor and experimental protocols were approved by the ethics committee of the University Medical Center G\u00f6ttingen (10\/9\/15). All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals adopted by the US National Institutes of Health (NIH publication No. 86\u201323, revised 1985), with EU Directive 2010\/63\/EU, with the current version of the German Law on the Protection of Animals, and the ARRIVE guidelines. The study protocol was approved by the local Animal Welfare Committee (Regierungspr\u00e4sidium Karlsruhe, Germany, reference numbers\u00a0G-165\/19; G-67\/20; G-229\/21).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent was obtained from all individual participants included in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}