{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T09:35:08Z","timestamp":1772789708608,"version":"3.50.1"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Atrial fibrillation (AF) is the most common cardiac arrhythmia, linked to greater risk of heart failure, stroke and death. Inflammation has been connected to AF emergence, however mechanisms of inflammation-caused AF remain thus far elusive, leading to a lack of mechanism-based treatments. An isogenic, 3D tissue model containing hiPSC-derived atrial-like cardiomyocytes (aCM), cardiac fibroblasts (cfb), and cardiac macrophages was engineered using custom injection-molded pillar devices. Electrophysiological changes were examined via sharp electrode recordings, calcium imaging, and multi-electrode assays. Gene function was interrogated using siRNA knock-down, lentiviral overexpression, and pharmacological modulation. In silico tissue and whole-heart models validated findings under simulated stress and heterogeneous conditions. Activation of M1 macrophages led to a 50% reduction in contraction amplitude, action potential spike amplitude (aCM+cfb+M1: 61.3 mV \u00b113.9\n                    <jats:italic>vs<\/jats:italic>\n                    control: 71.6 mV \u00b114.5, p\u2009&amp;lt;\u20090.01) and increased beat irregularity (M1: 150.7% \u00b1 388.9\n                    <jats:italic>vs<\/jats:italic>\n                    control, p\u2009&amp;lt;\u20090.001). Calcium transient amplitude was reduced (12.3 a.u. \u00b1 14.7, p\u2009&amp;lt;\u20090.05) and upstroke velocity slowed. SCN5A knock-down reduced contraction amplitude (\u221251.9% \u00b1 37.2, p\u2009&amp;lt;\u20090.01) without inducing arrhythmias, whereas combined GJA5 and ATP1A1 knock-down induced significant irregularity (403% \u00b1 371.3, p\u2009&amp;lt;\u20090.001), increased conduction heterogeneity (+18%), and reduced velocity (\u221252.4%). In silico modeling confirmed that paired 50% downregulation of sodium-potassium pump and tissue conductivity induced AF under tachycardia even without ectopic activity. This work reveals a novel, inflammation-driven mechanism for AF initiation. Combined downregulation of GJA5 (connexin 40) and ATP1A1 (NaK ATPase) disrupted intercellular connectivity and ion flux, establishing a substrate for arrhythmogenesis. These results were robust across\n                    <jats:italic>in vitro<\/jats:italic>\n                    , genetic\/pharmacological, and in silico models, defining new avenues for translational intervention.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1719392","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T06:45:18Z","timestamp":1772779518000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["GJA5 and ATP1A1 perturbations recapitulate inflammation-related beat irregularities in iPSC-based atrial myocardium tissue model"],"prefix":"10.3389","volume":"16","author":[{"given":"Thomas","family":"Hutschalik","sequence":"first","affiliation":[{"name":"Ncardia Services B.V.","place":["Leiden, Netherlands"]},{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht","place":["Maastricht, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert","family":"Das\u00ed","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leto L.","family":"Riebel","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maury","family":"Wiendels","sequence":"additional","affiliation":[{"name":"Anatomy and Embryology, Leiden University Medical Center (LUMC)","place":["Leiden, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederikus","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Digital Standardization and Licensing Research, Intellectual Property and Standards, Royal Philips","place":["Eindhoven, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas J. A. M.","family":"Beckers","sequence":"additional","affiliation":[{"name":"Department of Digital Standardization and Licensing Research, Intellectual Property and Standards, Royal Philips","place":["Eindhoven, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koen C.","family":"Kriege","sequence":"additional","affiliation":[{"name":"Department of Digital Standardization and Licensing Research, Intellectual Property and Standards, Royal Philips","place":["Eindhoven, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne M.","family":"Valster","sequence":"additional","affiliation":[{"name":"Department of Digital Standardization and Licensing Research, Intellectual Property and Standards, Royal Philips","place":["Eindhoven, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland C. M.","family":"Vulders","sequence":"additional","affiliation":[{"name":"Department of Digital Standardization and Licensing Research, Intellectual Property and Standards, Royal Philips","place":["Eindhoven, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ozan","family":"\u00d6zg\u00fcl","sequence":"additional","affiliation":[{"name":"Department of Physiology, Cardiovascular Research Institute Maastricht","place":["Maastricht, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R\u00e9mi","family":"Peyronnet","sequence":"additional","affiliation":[{"name":"Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg Bad Krozingen, and Faculty of Medicine, University of Freiburg","place":["Freiburg, Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blanca","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of 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