射血分数保留的心力衰竭（HFpEF）是一种异质性综合征，可能是由与合并症相关的重叠系统过程引起的。我们在一组表型良好的 HFpEF 患者中评估了独特的循环蛋白簇是否与基线和随访时的特定临床特征和功能状态相关。我们评估了 763 名随机化前血液样本中与心血管疾病和炎症相关的 368 种蛋白VITALITY-HFpEF（Vericiguat 改善 HFpEF 患者日常生活活动中的身体功能）参与者左心室射血分数≥45%，并且在 6 个月内发生心力衰竭失代偿事件。对蛋白质进行聚类，并通过线性回归估计它们与临床特征、基线和 24 周功能结果（堪萨斯城心肌病问卷身体限制评分、6 分钟步行距离 [6MWD] 和 Fried 衰弱表型）的关联。使用弹性网络回归得出蛋白质组总结复合材料，以预测 24 周功能结果的变化。确定了四个独特的蛋白质簇，包含 24、66、197 和 81 个蛋白质。在基线时，具有中心蛋白 caspase-3 和 Dickkopf 相关蛋白 1 的 2 个蛋白簇与虚弱程度增加相关，而以肿瘤坏死因子受体 1 作为中心蛋白的蛋白簇与较低的堪萨斯城心肌病问卷身体限制评分和更短的6MWD。相比之下，以蛋白 C 作为中心蛋白的簇与较少的脆弱性和较长的 6MWD 相关。 24周6MWD的增加与caspase-3蛋白簇呈负相关；蛋白 C 簇与 24 周时体弱程度减轻相关。基线蛋白质组总结综合预测了 24 周时观察到的堪萨斯城心肌病问卷体力限制评分和 6MWD 的变化（r=0.42 和 0.30；两者 P<0.001）。蛋白质组学区分与 HFpEF 相关的特定基线功能特征，并可能促进表型分析异质性疾病。这些蛋白质还提供了对 HFpEF 不同病理生理学的见解，以及哪些患者在随访期间可能会改善功能状态。URL：https://www.clinicaltrials.gov；唯一标识符：NCT03547583。

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that may emerge from overlapping systemic processes associated with comorbidities. We assessed whether unique clusters of circulating proteins are associated with specific clinical characteristics and functional status at baseline and follow-up in a well-phenotyped cohort of patients with HFpEF.We evaluated 368 proteins associated with cardiovascular disease and inflammation in prerandomization blood samples from 763 VITALITY-HFpEF (Vericiguat to Improve Physical Functioning in Daily Living Activities of Patients With HFpEF) participants who had a left ventricular ejection fraction ≥45% and a heart failure decompensation event within 6 months. Proteins were clustered, and their associations with clinical characteristics, baseline, and 24-week functional outcomes (Kansas City Cardiomyopathy Questionnaire Physical Limitation Score, 6-minute walk distance [6MWD], and Fried frailty phenotype) were estimated with linear regression. Elastic net regression was used to derive a proteomic summary composite to predict changes in 24-week functional outcomes.Four unique protein clusters were identified, containing 24, 66, 197, and 81 proteins. At baseline, 2 protein clusters with the hub proteins caspase-3 and Dickkopf-related protein 1 were associated with increased frailty, whereas the cluster with tumor necrosis factor receptor 1 as a hub protein was associated with lower Kansas City Cardiomyopathy Questionnaire Physical Limitation Score and shorter 6MWD. By contrast, the cluster with protein C as a hub protein was associated with less frailty and longer a 6MWD. The 24-week increase in 6MWD was negatively correlated with the protein cluster with caspase-3; the protein C cluster was correlated with less frailty at 24 weeks. The baseline proteomic summary composite predicted observed changes in Kansas City Cardiomyopathy Questionnaire Physical Limitation Score and 6MWD at 24 weeks (r=0.42 and 0.30; P<0.001 for both).Proteomics differentiate specific baseline functional traits associated with HFpEF and may facilitate phenotyping in a heterogeneous disease. These proteins also provide insights into the diverse pathophysiology of HFpEF and which patients may improve functional status during follow-up.URL: https://www.clinicaltrials.gov; Unique identifier: NCT03547583.