耐力运动与心房颤动（AF）的风险增加相关。我们先前证实了在小鼠中通过剧烈运动引起的不利心房重塑和AF易感性需要感应力敏感和促炎性细胞因子肿瘤坏死因子（TNF）。这些由TNF介导的效应的细胞和机制基础尚不清楚。我们研究了TNF在心房心肌细胞或内皮细胞中的割除，在此中进行了心脏对6周剧烈游泳训练的反应的研究。无论是心房心肌细胞还是内皮细胞的TNF割除，对于通过运动训练引起的心率、自主神经张力或左室结构与功能的变化均无影响。然而，心房心肌细胞中的Tnf割除能够预防来自运动训练的心房肥大、纤维化和巨噬细胞浸润以及传导减慢和AF易感性的发生。相比之下，内皮细胞特异性割除仅减少了训练后引起的心房肥大。与Tnf割除的细胞特异性效应一致，心房心肌细胞中TNF的丧失能够阻止p38MAPKinase的激活，这是TNF信号传导的过程中应变依赖性的下游介体，而不会影响根据运动引起的心房压力评估的心房拉伸。尽管TNF在先天免疫反应和炎症中的作用已被证实，但无论急性还是慢性运动训练均未引起可测量的NLRP3炎症小体活化。我们的发现表明，通过剧烈运动引起的不利心房重塑和AF易感与心房心肌细胞中的TNF存在相关性，而内皮源性的TNF的影响仅限于肥大调节。我们讨论了TNF的细胞自主效应和心房之间的细胞相互作用对心房的影响的意义。 耐力运动与心房颤动（AF）相关，而小鼠模型显示剧烈运动训练促进心房肥大、纤维化、炎症和AF易感，这些需要感应力敏感的炎症细胞因子肿瘤坏死因子（TNF）。我们证明心房心肌细胞中的Tnf割除完全保护免受运动引起的心房变化的影响，而内皮特异性割除仅可以预防心房肥大。由于心房充盈压力在运动期间显著增加，且大多数与AF相关的临床情况（高血压、心力衰竭、瓣膜/代谢性疾病）也是如此，我们讨论了心房拉伸如何介导TNF的细胞自主效应和心房的致心律失常组织变化。 © 2023作者。由牛津大学出版社代表欧洲心脏病学学会出版。保留所有权利。如需权限，请发送电子邮件至：journals.permissions@oup.com。

Endurance exercise is associated with an increased risk of atrial fibrillation (AF). We previously established that adverse atrial remodeling and AF susceptibility induced by intense exercise in mice requires the mechanosensitive and pro-inflammatory cytokine tumor necrosis factor (TNF). The cellular and mechanistic basis for these TNF-mediated effects is unknown.We studied the impact of TNF excision, in either atrial cardiomyocytes or endothelial cells (using Cre-recombinase expression controlled by Nppa or Tie2 promoters, respectively), on the cardiac responses to six weeks of intense swim exercise training. TNF ablation, in either cell type, had no impact on the changes in heart rate, autonomic tone or left ventricular structure and function induced by exercise training. Tnf excision in atrial cardiomyocytes did, however, prevent atrial hypertrophy, fibrosis, and macrophage infiltration as well as conduction slowing and increased AF susceptibility arising from exercise training. By contrast, endothelial-specific excision only reduced the training-induced atrial hypertrophy. Consistent with these cell-specific effects of Tnf excision, the loss of TNF in cardiomyocytes was able to prevent the activation of p38MAPKinase, a strain-dependent downstream mediator of TNF signaling, without affecting the atrial stretch as assessed by atrial pressures induced by exercise. Despite TNF's established role in innate immune responses and inflammation, neither acute nor chronic exercise training caused measurable NLRP3 inflammasome activation.Our findings demonstrate that adverse atrial remodeling and AF vulnerability induced by intense exercise requires TNF in atrial cardiomyocytes whereas the impact of endothelial-derived TNF is limited to hypertrophy modulation. The implications of the cell autonomous effects of TNF and crosstalk between cells in the atria are discussed.Endurance sport is associated with atrial fibrillation (AF) and mouse models show intense exercise training promotes atrial hypertrophy, fibrosis, inflammation, and AF vulnerability, which requires the mechanosensitive inflammatory cytokine tumor necrosis factor (TNF). We demonstrate that Tnf ablation in atrial cardiomyocytes protects fully against atrial changes induced by exercise, whereas endothelial-specific ablation only prevents atrial hypertrophy. Since atrial filling pressures increase markedly during exercise and most clinical conditions linked to AF (hypertension, heart failure, valvular/metabolic diseases), we discuss how atrial stretch may mediate cell autonomous effects of TNF and arrhythmogenic tissue changes in the atria.© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.