ORIGINAL RESEARCH article
Front. Cardiovasc. Med.
Sec. Cardiac Rhythmology
Volume 12 - 2025 | doi: 10.3389/fcvm.2025.1615574
This article is part of the Research TopicAtrial Fibrillation (AF) in Heart Failure with Preserved Ejection Fraction (HFpEF)View all 5 articles
Cellular Interactions and Ion Channel Signatures in Atrial Fibrillation Remodeling: Insights from Single-Cell Analysis and Machine Learning
Provisionally accepted
- 1The No. 1 Department of Gerontology, The Third Hospital of Mianyang, Sichuan Mental Health Center., Mianyang, China
- 2Renal Department, The Third Hospital of Mianyang, Sichuan Mental Health Center., Mianyang, China
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Abstract Background: Atrial structural and electrical remodeling are key mechanisms in atrial fibrillation (AF). However, the cellular interactions involved in structural remodeling and ion channel markers of electrical remodeling remain incompletely understood.Methods: Single-cell RNA sequencing (scRNA-seq) was employed to investigate structural remodeling at the cellular level in AF. After quality control and clustering using Seurat, principal component analysis (PCA) identified major cell types. Monocle was used for cell trajectory analysis, and CellChat for cell–cell communication. GO, KEGG, and GSEA analyses explored functional pathways. Ion channel-related genes from microarray datasets were analyzed using LASSO and SVM algorithms to identify AF-specific biomarkers, followed by drug enrichment analysis.Results: Five fibroblast subtypes were identified: embryonic fibroblasts (EF), actively proliferating fibroblasts (APF), smooth muscle cells (SMC), endothelial cells (EC), and leukocytes (LBCs). AF samples showed increased EF, APF, and LBCs, and decreased EC proportions compared to sinus rhythm (SR) controls. Trajectory analysis indicated that EF cells may differentiate into APF and SMC. Cell–cell interaction analysis revealed enhanced LAMININ and COLLAGEN signaling in EF cells and loss of EC signals such as GRN–SORT1 and AGRN–DAG1 in AF. Reduced NPPA–NPR1 signaling from SMC to EC was also observed, suggesting their role in AF maintenance.For electrical remodeling, two ion channel genes—ANO1 and GRIK2—were identified as AF signature genes with strong diagnostic value. Drug analysis revealed that phenytoin sodium may target EF cells, while ionomycin, DIDS, citalopram, and topiramate showed strong associations with ANO1 or GRIK2, suggesting potential for drug repurposing.Conclusion: This study highlights critical changes in fibroblast subtypes, differentiation patterns, and intercellular communication contributing to AF structural remodeling. ANO1 and GRIK2 serve as key biomarkers for electrical remodeling. The identification of existing drugs targeting these components offers promising therapeutic avenues for AF treatment.
Keywords: Atrial Fibrillation, structural remodeling, electrical remodeling, Single-Cell Analysis, machine learning
Received: 21 Apr 2025; Accepted: 30 Jul 2025.
Copyright: © 2025 He, Cheng, Wang, Zhan and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ya Zhan, Renal Department, The Third Hospital of Mianyang, Sichuan Mental Health Center., Mianyang, China
Yanqun Liu, The No. 1 Department of Gerontology, The Third Hospital of Mianyang, Sichuan Mental Health Center., Mianyang, China
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