Kneuer Jasmin Marga, Müller Marion, Erbe Stephan, Kokot Karoline Elizabeth, Rosch Sebastian, Müller-Kozarez Irina, Schröder Sophie Charlotte, Maeder Christina, Heitkamp Sarah Felicitas, Gaul Susanne, von Haehling Stephan, Tönjes Anke, Blüher Matthias, Lurz Philipp, Wachter Rolf, Klinke Anna, Laufs Ulrich, Boeckel Jes-Niels
Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany (J.M.K., S.E., K.E.K., I.M.-K., S.C.S., C.M., S.F.H., S.G., R.W., U.L., J.-N.B.).
Central German Heart Alliance (J.M.K., S.E., K.E.K., I.M.-K., S.C.S., C.M., S.F.H., S.G., R.W., U.L., J.-N.B.).
Circ Res. 2025 Aug 15;137(5):682-698. doi: 10.1161/CIRCRESAHA.125.326249. Epub 2025 Jul 25.
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical picture that is closely related to extracardiac comorbidities such as obesity, hypertension, and diabetes and is associated with chronic, low-grade systemic inflammation. Previous studies on myocardial biopsies of patients with HFpEF showed intramyocardial inflammatory activity, suggesting that the inflammatory processes in HFpEF are predominantly systemic and exhibit compartment-specific patterns.
We performed single-cell RNA sequencing of peripheral blood mononuclear cells of patients with HFpEF (n=6), patients with heart failure with reduced ejection fraction (HFrEF, n=8), and healthy controls (n=7), taking obesity status into account. For validation, bulk RNA sequencing was performed on whole blood samples. In parallel, the systemic immune cell response was investigated in an HFpEF mouse model (induced by a high-fat diet plus -nitro-L-arginine methyl ester hydrochloride [L-NAME]), with one group additionally administered the anti-inflammatory agent nitro-oleic acid (NO-OA).
Analysis of human peripheral blood mononuclear cells revealed an HFpEF-specific inflammatory fingerprint, which manifested in obesity-related increased expression of cytokine signaling genes (eg, and ) and obesity-independent increases in mitochondrial-associated activity. In the mouse model, HFpEF animals showed a comparable increase in inflammatory markers, with treatment with nitro-oleic acid leading to a partial normalization of immunologic signatures and a significant improvement in diastolic function.
Our results demonstrate that the immune cells of patients with HFpEF are characterized by a distinct transcriptional immune signature that differs from that of patients with HFrEF analyzed in this study. The conserved immunologic signatures between the human and murine data sets analyzed here, and the beneficial effect of nitro-oleic acid in the preclinical model induced by high-fat diet and L-NAME, provide translational insights and generate hypotheses for personalized interventions in HFpEF.
射血分数保留的心力衰竭（HFpEF）是一种异质性临床表现，与肥胖、高血压和糖尿病等心外合并症密切相关，并与慢性低度全身炎症有关。先前对HFpEF患者心肌活检的研究显示心肌内存在炎症活动，这表明HFpEF中的炎症过程主要是全身性的，并呈现出特定区域的模式。
我们对HFpEF患者（n = 6）、射血分数降低的心力衰竭（HFrEF，n = 8）患者和健康对照者（n = 7）的外周血单个核细胞进行了单细胞RNA测序，同时考虑了肥胖状态。为进行验证，对全血样本进行了批量RNA测序。同时，在HFpEF小鼠模型（由高脂饮食加盐酸 - 硝基 - L - 精氨酸甲酯 [L - NAME] 诱导）中研究全身免疫细胞反应，其中一组额外给予抗炎剂硝基油酸（NO - OA）。
对人类外周血单个核细胞的分析揭示了HFpEF特异性炎症特征，表现为细胞因子信号基因（如 和 ）与肥胖相关的表达增加以及与肥胖无关的线粒体相关活性增加。在小鼠模型中，HFpEF动物的炎症标志物有类似增加，用硝基油酸治疗导致免疫特征部分正常化以及舒张功能显著改善。
我们的结果表明，HFpEF患者的免疫细胞具有独特的转录免疫特征，与本研究中分析的HFrEF患者不同。此处分析的人类和小鼠数据集之间保守的免疫特征，以及硝基油酸在高脂饮食和L - NAME诱导的临床前模型中的有益作用，为HFpEF的个性化干预提供了转化见解并产生了假设。
