克隆造血 [clonal hematopoiesis (CH)] 由多种非恶性引发基因突变所致，可以导致免疫细胞功能异常和慢性疾病，并与心力衰竭 (heart failure, HF) 伴随收缩功能降低 [heart failure with reduced ejection fraction (HFpEF)]患者的恶化预后有关。然而，CH在伴随舒张功能保留 [heart failure with preserved ejection fraction (HFpEF)]的患者预后中的作用尚未得到充分研究。本研究旨在描述HFpEF患者中的CH情况并阐明其在小鼠模型中的因果作用。通过使用20个候选CH驱动基因面板和变异等位基因频率截断为0.5%进行超深度纠错测序，确定了一个包含81例HFpEF患者 (平均年龄71±6岁；射出分数63±5%)和36例没有HFpEF诊断的对照组 (平均年龄74±7岁；射出分数61.5±8%) 的CH队列。与对照组相比，HFpEF患者中存在富集的TET2介导的CH情况 (分别为12%和0%，P=0.02)。在HFpEF队列中，与无CH的患者相比，具有CH的患者在E/e' (14.9 versus 11.7，P=0.0096)和E/A (1.69 versus 0.89，P=0.0206) 方面表现出更为严重的舒张功能障碍。CH与舒张功能恶化的关联在包含59名HFpEF个体的验证队列中得到证实。此外，在年龄≥70岁的HFpEF患者中，与无CH的HFpEF患者相比，具有CH的患者的5年心血管相关住院率的预后更差 (风险比为5.06，P=0.042)。为了研究CH在HFpEF中的因果作用，正常小鼠进行了Tet2野生型或Tet2缺陷骨髓的细胞移植，并随后接受高脂饮食/L-NAME (Nω-硝基-L-精氨酸甲酯)联合治疗以诱导HFpEF特征。这个Tet2-CH模型与Tet2野生型条件相比，通过心重/胫骨长度和心肌细胞大小的心脏肥厚、通过E/e'和左心室舒张末压力的舒张功能障碍以及通过心脏纤维化显示出更严重的HFpEF特征。CH与HFpEF患者的心功能和预后恶化相关，并且Tet2介导的CH小鼠实验模型呈现出更明显的HFpEF特征。

Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model.Using a panel of 20 candidate CH driver genes and a variant allele frequency cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%).Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of 59 individuals with HFpEF. In accordance, patients with HFpEF with CH and age ≥70 years exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF without CH and age ≥70 years. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition.CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.