2026-07-25T03:54:46Zhttps://repisalud.isciii.es/rest/oai/request
oai:repisalud.isciii.es:20.500.12105/276012026-07-17T00:16:40Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud author Simon-Chica, Ana author Quintanilla, Jorge G author Torroja, Carlos author Couselo-Seijas, Marinela author Toda, Haruka author Lee, Peter author Benguria, Alberto author Revilla, Concepción author Redondo-Rodríguez, Andrés author Alfonso-Almazán, José Manuel author García-Escolano, Alba author Marina-Breysse, Manuel author Galán-Arriola, Carlos author Vera-Pedrosa, María Linarejos author La Rosa, Giulio author Dopazo, Ana author Sánchez-Cabo, Fátima author García-Torrent, María Jesús author Ortega-Hernández, Adriana author Ibáñez, Borja author Núñez, Estefanía author Gómez-Garre, Dulcenombre author Morillo, Carlos author Greiner, Joachim author Kohl, Peter author Pérez-Villacastín, Julián author Pérez-Castellano, Nicasio author Jalife, José author Domínguez, Javier author Vázquez, Jesús author Carnero-Alcázar, Manuel author Filgueiras-Rama, David 2026-07-16T11:59:22Z 2026-07-16T11:59:22Z 2026-03-13 Circ Res. 2026 Mar 13;138(6):e326291. CIRCULATION RESEARCH 41664919 https://hdl.handle.net/20.500.12105/27601 Nonmyocytes may contribute to regional adaptive changes during persistent atrial fibrillation (PsAF), favoring its perpetuation. We aimed to investigate the differential features of fibroblast and macrophage populations within individual-specific atrial regions associated with PsAF maintenance. The study was conducted in 2 pig models of PsAF with and without infarct-related substrate (N=27 and N=27, respectively) and further validated in humans with PsAF (N=20). Sham-operated pigs (N=9), healthy animals (N=4), and patients in sinus rhythm (N=7) were used as comparative controls. In pigs, in vivo high-density instantaneous frequency modulation maps were used to identify atrial regions associated with PsAF maintenance (drivers). Regional cellular composition and phenotypic states of fibroblast and myeloid lineages were determined using flow cytometry, single-cell RNA sequencing, immunohistochemistry, and proteomic analyses. The functional relevance of driver regions was further studied in patients with symptomatic PsAF undergoing ablation. Flow cytometry and single-cell RNA sequencing analyses were performed in tissue samples of the left atrial appendage in a complementary cohort of patients with PsAF undergoing thoracoscopic-guided ablation. PsAF terminated acutely in 12 of 14 pigs undergoing mapping and ablation of driver regions. In humans, driver ablation was associated with 90% AF-freedom (on/off antiarrhythmic drugs) after 2 years of follow-up. Samples from nonablated pigs revealed a phenotypic shift towards ACTA2 (actin alpha 2)-fibroblasts and PTX3 (pentraxin 3)-fibroblasts during PsAF. Although ACTA2-fibroblasts were highly preserved in human samples, paired comparisons in pig samples showed that PTX3-fibroblasts were enriched only in driver regions. PsAF also showed changes in myeloid cells towards inflammatory profiles. However, regional analysis revealed that, in both humans and pigs with PsAF, driver regions were enriched in cardiac resident macrophages with transcriptomic and proteomic profiles favoring cardiomyocyte homeostasis and cell survival. PsAF shows differential regional changes in fibroblast and myeloid populations with distinctive gene signatures in areas that drive the overall arrhythmia. eng atrial appendage atrial fibrillation fibroblasts macrophages Cardiac Macrophages and Fibroblasts Modulate Atrial Fibrillation Maintenance. research article 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 URL https://repisalud.isciii.es/bitstreams/d736d8bc-7e06-41ca-90c5-413d875e0b53/download File MD5 dc09dcd891c63d5a6e0b338d40211d3b 10960736 application/pdf Cardiac Macrophages and Fibroblasts_Circ Res_2026.pdf