Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte hypertrophy, and cardiac phospholamban phosphorylation were T cell dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the inositol-requiring enzyme 1α/X-box–binding protein 1 (IRE1α/XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1α/XBP1 activation was restored after withdrawal of the 2 comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrated that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF were T cell dependent and that reversible dysregulation of the T cell IRE1α/XBP1 axis was a T cell signature of HFpEF.

中文翻译：

---

受损的 T 细胞 IRE1α/XBP1 信号传导在射血分数保留的实验性心力衰竭中引导炎症


射血分数保留的心力衰竭（HFpEF）是一种普遍存在的综合征，治疗选择有限，而且人们对免疫病理生理学知之甚少。使用诱导肥胖和高血压的心脏代谢 HFpEF 的 2 次打击临床前模型，我们发现心脏 T 细胞浸润和淋巴扩张与心脏病理学同时发生，并且舒张功能障碍、心肌细胞肥大和心脏受磷蛋白磷酸化是 T 细胞依赖性的。心脏浸润 T 细胞不限于心脏抗原，其独特特征是未折叠蛋白反应中肌醇需求酶 1α/X-box 结合蛋白 1 (IRE1α/XBP1) 臂的激活受损。值得注意的是，T 细胞中 XBP1 的选择性消融增强了它们在临床前 HFpEF 小鼠心脏和淋巴器官中的持久性。此外，在去除引起 HFpEF 的 2 种合并症后，T 细胞 IRE1α/XBP1 激活恢复，导致心脏病理学部分改善。我们的结果表明，临床前 HFpEF 中的舒张功能障碍和心肌细胞肥大是 T 细胞依赖性的，并且 T 细胞 IRE1α/XBP1 轴的可逆失调是 HFpEF 的 T 细胞特征。