Aims Immune cell alterations may play a role in the development of atrial fibrillation (AF). Our objective was to comprehensively characterize immune cells in AF, and investigate the potential mechanisms. Methods and Results Single-cell RNA sequencing and multicolor flow cytometry revealed that T cells constituted the most significant subset alterations in AF, and senescent CD8+ T cells were AF-associated subset. Senescent CD8+ T cells increased in both peripheral veins (p < 0.0001) and the left atria (p < 0.05) in patients with AF compared to non-AF control. Senescent CD8+ T cells were independently associated with AF prevalence (odds ratio = 2.876, p < 0.05) and postprocedural recurrence (hazard ratio = 22.955, p < 0.0001) using a cross-sectional study and a subsequent prospective cohort study. Senescent CD8+ T cells secreted an increased amount of interferon (IFN)-γ, which induces Ca2+ handling abnormalities in human induced pluripotent stem cell-derived atrial cardiomyocytes, and translated into an increased susceptibility to AF assessed by heart optical mapping. Conclusions An increased amount of senescent CD8+ T cells may be a hallmark of the immune senescence phenotype in AF and potentially serve as a valid biomarker for assessing prevalence and postprocedural recurrence of AF. By connecting immune senescence with electrophysiological disturbances in AF, this research provides a potential mechanism for the involvement of senescent CD8+ T cells in proarrhythmic calcium disorders and suggests novel avenues for developing new immune-modulatory and senolytic therapies for AF.

中文翻译：

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衰老的 CD8+ T 细胞：心房颤动的新危险因素


目的 免疫细胞改变可能在心房颤动 （AF） 的发生中发挥作用。我们的目的是全面表征 AF 中的免疫细胞，并研究潜在的机制。方法和结果 单细胞 RNA 测序和多色流式细胞术显示，T 细胞构成了 AF 中最重要的亚群改变，衰老的 CD8+ T 细胞是 AF 相关的亚群。与非 AF 对照相比，AF 患者外周静脉 （p < 0.0001） 和左心房 （p < 0.05） 的衰老 CD8 + T 细胞增加。使用横断面研究和随后的前瞻性队列研究，衰老的 CD8 + T 细胞与 AF 患病率 （比值比 = 2.876，p < 0.05） 和术后复发 （风险比 = 22.955，p < 0.0001） 独立相关。衰老的 CD8+ T 细胞分泌增加的干扰素 （IFN）-γ，这会导致人诱导的多能干细胞来源的心房心肌细胞的 Ca2+ 处理异常，并转化为通过心脏光学标测评估的对 AF 的易感性增加。结论衰老 CD8+ T 细胞数量的增加可能是 AF 免疫衰老表型的标志，并可能作为评估 AF 患病率和术后复发的有效生物标志物。通过将免疫衰老与 AF 中的电生理紊乱联系起来，这项研究为衰老 CD8 + T 细胞参与致心律失常钙疾病提供了潜在机制，并为开发新的 AF 免疫调节和免疫溶解疗法提出了新的途径。