Circulating Immune Cell Signature Analysis in HFpEF Across Species.

Abstract

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 <i>N</i>_ω-nitro-L-arginine methyl ester hydrochloride [L-NAME]), with one group additionally administered the anti-inflammatory agent nitro-oleic acid (NO₂-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, <i>CCL2</i> and <i>TNF</i>) 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.