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bioRxiv · 10.1101/2025.09.16.676656

Embryonic Atrial Injury Programs an Anti-Fibrotic Atrial Fibrillation Substrate

Xin, F.·Wang, H.·Zhao, X.·Xu, X.·Cao, J.·Zhang, K.·Zhang, Y.·Tian, J.·Jia, Y.·Sun, C.·Liang, Y.·Chen, X.·Wang, J.
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Abstract

Atrial myopathy is associated with atrial fibrillation in adults, yet the role of embryonic atrial injury in predisposing individuals to atrial fibrillation remains unclear. Using an inducible, cardiomyocyte-specific diphtheria toxin A-mediated injury mouse model, we found that injured embryonic atria exhibited upregulation of apoptosis and TNF signaling pathways, alongside downregulation of calcium handling and atrial fibrillation-associated genes. Single-cell RNA sequencing revealed two distinct cardiomyocyte populations with differential injury responses. Importantly, although myofibroblasts increased in the fibroblast population, these cells displayed an extracellular matrix gene expression profile distinct from the pro-fibrotic phenotype typically observed in fibrillating adult atria and showed no evidence of fibrosis. Concurrently, monocytes/macrophages were activated and showed upregulated expression of the anti-fibrotic factor GPNMB. These findings suggest that adaptive tissue remodeling is counterintuitively prevented from progressing to fibrosis, potentially through GPNMB-mediated mechanisms. This study elucidates molecular pathways linking developmental atrial injury to myopathy and proposes novel strategies to attenuate atrial fibrillation progression.

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Xin, F., Wang, H., Zhao, X., Xu, X., Cao, J., Zhang, K., Zhang, Y., Tian, J., Jia, Y., Sun, C., Liang, Y., Chen, X., Wang, J.. 2025-09-17. Embryonic Atrial Injury Programs an Anti-Fibrotic Atrial Fibrillation Substrate. https://doi.org/10.1101/2025.09.16.676656

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