Computational modelling of cardiac fibroblast signalling reveals a key role for Ca²⁺ in driving atrial fibrillation‐associated fibrosis

Atrial fibrillation (AF) is the most common arrhythmia, characterized by irregular atrial electrical activity resulting in asynchronous atrial contraction. AF is accompanied by extensive structural remodelling of atria, including extracellular matrix expansion (fibrosis), which affects both AF maintenance and treatment outcomes. However, no fibrosis‐specific therapies are currently available for AF. To identify the prominent pathways in atrial fibroblasts (Fb) that modulate atrial fibrosis and arrhythmogenesis, we developed the first atrial Fb signalling network model. This expands on the well‐established ventricular model by integrating atrial‐relevant elements involved in fibrogenesis and/or differentially expressed in chronic AF ( vs . normal sinus rhythm) patients and connections based on experimental evidence in an Fb‐related context. Our findings indicate that under high profibrotic signals, e.g. angiotensin‐II (AngII) and transforming growth factor β, inhibition of Ca 2+ fluxes reduced the abundance of key fibrotic markers such as collagen I, collagen III, periostin, plasminogen activator inhibitor‐1, connective tissue growth factor and α‐smooth muscle actin, via modulation of the Ca 2+ /calmodulin‐dependent protein kinase II/Smad3 pathway and extra domain A of fibronectin via the calcineurin pathway. Mechanistically, we found that the Ca 2+ ‐dependent regulation of collagen I and III is primarily at the level of gene transcription, with collagen I and collagen III exhibiting similar dynamics in the Fb model. Overall, our study highlights the pivotal role of Ca 2+ signalling in the evolution of AF‐associated fibrogenesis and provides novel insights into potential anti‐AF therapeutic strategies targeting fibrotic responses. Future work will investigate in greater detail the upstream mechanisms driving Ca 2+ increases in atrial Fbs during AF. image Key points A fibroblast signalling network was developed incorporating new atrial‐informed elements and reactions to identify the prominent pathways that modulate atrial fibrosis and associated arrhythmogenesis, including atrial fibrillation (AF). The model was validated against experimental data in cardiac fibroblasts. For atrial‐specific validation, we focused on the model responses to AF‐relevant profibrotic inputs, i.e. angiotensin‐II (AngII) and transforming growth factor β (TGFβ). The analysis underscores the critical role of Ca 2+ signalling in mediating profibrotic responses under AF‐relevant stimuli, AngII and TGFβ and shows that Ca 2+ /calmodulin‐dependent protein kinase II/Smad3 and calcineurin mediate the Ca 2+ ‐dependent upregulation of key fibrotic markers.