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However, the molecular mechanisms underlying this site\u2010specificity remain poorly understood. Here, we present a comparative single\u2010cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber\u2010specific properties of the main cell types.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Single\u2010cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10\u00d7 genomics. The AF mice model was created using<jats:italic>Tbx5<\/jats:italic>knockout mice. Validation experiments were performed by glutathione S\u2010transferase pull\u2010down assays, coimmunoprecipitation (Co\u2010IP), cleavage assays and shear stress experiments in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up\u2010regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down\u2010regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (<jats:italic>Tbx5<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1297","type":"journal-article","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T01:19:03Z","timestamp":1686187143000},"source":"Crossref","is-referenced-by-count":17,"title":["Single\u2010cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial 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