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Atrial fibrillation (AF) frequently occurs in DCM patients carrying TTNtv and may precede overt ventricular dysfunction, suggesting an atrial-specific disease mechanism. How TTNtv increase susceptibility to AF, particularly in the absence of established DCM, remains incompletely understood. This study aimed to define the cellular and molecular mechanisms by which a clinically relevant TTNtv predisposes to atrial arrhythmogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We introduced a patient-associated TTNtv (TTN c.59926+1G&amp;gt;A) into human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-CMs). TTNtv hiPSC-CMs exhibited proarrhythmic electrophysiological alterations, including increased spontaneous beating frequency, abnormal sodium channel kinetics, and heightened sensitivity to cholinergic agonists. In silico simulations demonstrated that heightened cholinergic sensitivity was sufficient to trigger AF under conditions of sinus tachycardia. RNA sequencing revealed dysregulation of sarcomere assembly and extracellular matrix pathways, and TTNtv hiPSC-CMs showed structurally shortened sarcomeres. Engineered heart tissues composed of TTNtv hiPSC-CMs co-cultured with cardiac fibroblasts demonstrated reduced contractile force and increased secretion of collagen, fibronectin-1 and TGF-\u03b21, consistent with activation of profibrotic signalling. Together, these findings indicate that a TTNtv can cause intrinsic atrial electrical instability and promote pro-fibrotic signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results identify atrial electrophysiological abnormalities and profibrotic remodelling as key mechanisms by which TTNtv increase AF risk, even in the absence of overt DCM. These findings support a primary atrial contribution to TTNtv-associated arrhythmogenesis and provide mechanistic insight into AF as an early clinical manifestation in carriers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag112","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T06:06:11Z","timestamp":1779861971000},"page":"1206-1223","source":"Crossref","is-referenced-by-count":4,"title":["A titin truncating variant linked to atrial fibrillation increases atrial profibrotic signalling and cholinergic sensitivity"],"prefix":"10.1093","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7124-5390","authenticated-orcid":false,"given":"Max J","family":"Cumberland","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Science, School of Medical Sciences, University of Birmingham , Edgbaston B15 2TT ,","place":["UK"]},{"name":"Centre for Heart Research, The Westmead Institute for Medical Research , University of Sydney, 176 Hawkesbury Road, Westmead, NSW 2145 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8649-8203","authenticated-orcid":false,"given":"Albert","family":"Das\u00ed","sequence":"additional","affiliation":[{"name":"Department of Computer Science, British Heart Foundation Centre of Research Excellence Oxford, University of Oxford , Oxford ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naeramit","family":"Sontayananon","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Radcliffe Department of Medicine, and British Heart Foundation Centre of Research Excellence Oxford, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan D","family":"Marcus","sequence":"additional","affiliation":[{"name":"Centre for Heart Research, The Westmead Institute for Medical Research , University of Sydney, 176 Hawkesbury Road, Westmead, NSW 2145 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex R","family":"Qin","sequence":"additional","affiliation":[{"name":"Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney , Sydney, New South Wales ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5774-2406","authenticated-orcid":false,"given":"Leto","family":"Riebel","sequence":"additional","affiliation":[{"name":"Department of Computer Science, British Heart Foundation Centre of Research Excellence Oxford, University of Oxford , Oxford ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Euchner","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, School of Medical Sciences, University of Birmingham , Edgbaston B15 2TT ,","place":["UK"]},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), The Universities of Birmingham and Nottingham , The Midlands B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amar J","family":"Azad","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, School of Medical Sciences, University of Birmingham , Edgbaston B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlin","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, School of Medical Sciences, University of Birmingham , Edgbaston B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"O\u2019Shea","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, School of Medical Sciences, University of Birmingham , Edgbaston B15 2TT ,","place":["UK"]},{"name":"Heart Rhythm Research Group, University of Warwick , Coventry CV2 2DX ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James G W","family":"Smith","sequence":"additional","affiliation":[{"name":"Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park , Norwich NR4 7UQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charikleia","family":"Papadopoulou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge , Sanger Building, 80 Tennis Ct Rd, Cambridge CB2 1GA, UK"},{"name":"Royal Papworth Hospital , Papworth Rd, Trumpington, Cambridge CB2 0AY, U K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A","family":"Miska","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge , Sanger Building, 80 Tennis Ct Rd, Cambridge CB2 1GA, UK"},{"name":"Royal Papworth Hospital , Papworth Rd, Trumpington, Cambridge CB2 0AY, U K"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3171-3551","authenticated-orcid":false,"given":"Davor","family":"Pavlovic","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Science, School of Medical Sciences, University of Birmingham , Edgbaston B15 2TT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellis","family":"Patrick","sequence":"additional","affiliation":[{"name":"Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney , Sydney, New South Wales ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J H","family":"Chong","sequence":"additional","affiliation":[{"name":"Centre for Heart Research, The Westmead Institute for Medical Research , University of Sydney, 176 Hawkesbury Road, Westmead, NSW 2145 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