A titin truncating variant linked to atrial fibrillation increases atrial profibrotic signalling and cholinergic sensitivity
Year: 2026
Type: article
Abstract: AIMS: Titin truncating variants (TTNtv) are a major genetic cause of dilated cardiomyopathy (DCM), accounting for approximately 25% of familial cases. 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. METHODS AND RESULTS: We introduced a patient-associated TTNtv (TTN c.59926+1G>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-β1, consistent with activation of profibrotic signalling. Together, these findings indicate that a TTNtv can cause intrinsic atrial electrical instability and promote pro-fibrotic signalling. CONCLUSION: 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.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvag112
Authors: Max J Cumberland, Albert Dasí, Naeramit Sontayananon, Alan D Marcus, Alex R Qin, Leto Riebel, Jonas Euchner, Amar J Azad, Caitlin Hall, Christopher O’Shea, James G W Smith, Charikleia Papadopoulou, Eric A Miska, Davor Pavlovic, Ellis Patrick, James J H Chong, Paulus Kirchhof, Chris Denning, Benjamin Davies, Blanca Rodriguez, Andrew P Holmes, Katja Gehmlich
Institutions: The University of Sydney, Westmead Institute for Medical Research, University of Birmingham, British Heart Foundation, University of Oxford, University of Warwick, University of East Anglia, Norwich Research Park, University of Cambridge, Royal Papworth Hospital, Universität Hamburg, University Medical Center Hamburg-Eppendorf, German Centre for Cardiovascular Research, University of Nottingham, Centre for Human Genetics
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,329
Funders: Royal Papworth Hospital NHS Foundation Trust, U.S. Department of Energy, AstraZeneca, Wellcome Trust, UK Research and Innovation, National Institute for Health and Care Research, British Heart Foundation, Academy of Medical Sciences, National Centre for the Replacement, Refinement and Reduction of Animals in Research, University of Birmingham, National Heart Foundation of Australia, Bupa Health Foundation, Barwon Health Foundation, Office of Science, Horizon 2020 Framework Programme, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Argonne National Laboratory
Awards: G102163711, G107546177, G1288919872, G1313983767, The interactions between filamin C and small heat-shock proteins in cardiac mechanosignalling, G1664757510, G1770046676, G2041042888, G2287611682, G2321842562, G238625183, G262962599, G3075337988, G307780719, G3294912903, 3D heart models to understand genetic and pathway related factors that drive electromechanical physiology in humans, G3980162340, G4038303151, G4347984473, G4444112550, G4651254044, Understanding the mechano-signalling role of the Z-disc in the pathogenesis of hypertrophic cardiomyopathy (HeartDisc). (Joint funding with the German Centre for Cardiovascular Research and the Dutch Heart Foundation), Human in silico clinical trials in post myocardial infarction: mechanistic investigations into phenotypic electromechanical variability and response to treatment, G498139845, G5197532807, G5199502960, G5429897984, G5830010515, G5904151224, Accelerator Award, G5959846095, G602094861, G6187274708, G6205868633, G6848031779, G6918803902, G7154628268, G7267802120, G7277019853, G747216417, Defining the mechanistic importance of CD73 in promoting carotid body-mediated hypertension and cardiac arrhythmia in response to pathological hypoxia, G7817698619, G8020985458, Human in silico clinical trials in post myocardial infarction: mechanistic investigations into phenotypic electromechanical variability and response to treatment, CompBioMedX: Computational Biomedicine at the Exascale, G899502808, Harnessing regenerative therapies and spatial biology to advance cardiovascular disease prevention and treatment., G969889393, G993149817
OpenAlex ID: W7162540445