Aims Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to: 1) Evaluate AF-susceptibility and senescence-marker expression in rat models of aging and myocardial infarction (MI); 2) Study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI-rats; 3) Assess senescence markers in human atrial tissue as a function of age and the presence of AF. Methods and Results AF-susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital-PCR or RT-qPCR (mRNA). A previously-validated senolytic combination, dasatinib and quercetin (D + Q), (or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment-assignment. Burst pacing-induced AF was seen in 100% of aged rats, 87.5% of young MI-rats and 10% of young-control rats (P≤0.001 vs. each). Conduction velocity was slower in aged (both left atrium, LA and right atrium, RA) and young-MI (LA) rats versus young-control rats (P≤0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young-MI (LA) versus young-control rats (P < 0.05 for each). Senolytic therapy reduced AF-inducibility in MI-rats (from 8/9 rats, 89% in MI-vehicle, to 0/9 rats, 0% in MI-D + Q, P < 0.001) and attenuated LA-fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence-markers were upregulated in older (≥ 70 years) and longstanding-AF patients versus individuals ≤ 60 and sinus-rhythm controls respectively. Conclusions Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

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细胞衰老在与心脏病理学相关的原颤心房重构中的作用

细胞衰老是一种与压力相关或衰老的反应，据信会导致许多心脏疾病。然而，其在心房颤动（AF）中的作用尚不清楚。年龄是房颤风险最重要的决定因素。本研究旨在： 1) 评估衰老和心肌梗塞 (MI) 大鼠模型中的 AF 易感性和衰老标志物表达；2) 研究衰老细胞治疗对 MI 大鼠心房基质减轻衰老细胞负担的作用；3) 评估人类心房组织中的衰老标志物作为年龄和 AF 存在的函数。方法和结果通过程序化电刺激研究房颤敏感性。通过免疫印迹或免疫荧光（蛋白质）以及数字 PCR 或 RT-qPCR（mRNA）评估基因和蛋白质表达。从假手术或 MI 手术时到 28 天后，给予先前验证的 senolytic 组合达沙替尼和槲皮素 (D + Q)（或相应的载体）。实验是在对治疗分配不知情的情况下进行的。突发起搏诱发的 AF 在 100% 的老年大鼠、87.5% 的年轻 MI 大鼠和 10% 的年轻对照大鼠中观察到（P≤0.001）。与年轻对照大鼠相比，老年大鼠（左心房，LA 和右心房，RA）和年轻 MI（LA）大鼠的传导速度较慢（P≤0.001）。与年轻对照大鼠相比，老年大鼠（LA 和 RA）和年轻 MI（LA）的心房纤维化程度更高（均 P < 0.05）。Senolytic 疗法降低了 MI 大鼠中的 AF 诱导性（从 MI 载体中的 8/9 大鼠，89％，到 MI-D + Q 中的 0/9 大鼠，0％，P < 0.001）并减轻了 LA 纤维化。双重染色表明 D + Q 通过清除衰老的肌成纤维细胞和内皮细胞发挥作用。在人类心房中，老年（≥ 70 岁）和长期房颤患者的衰老标志物分别与≤ 60 岁的个体和窦性心律对照者相比上调。结论 我们的结果表明细胞衰老在 AF 病理生理学中具有潜在的重要作用。调节细胞衰老可能为房颤的新治疗方法提供基础。