https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Leipzig Klinik und Poliklinik für Kardiologie Leipzig, Deutschland; 2Herz- und Diabeteszentrum NRW Agnes Wittenborg Institut für translationale Herz-Kreislaufforschung Bad Oeynhausen, Deutschland; 3Medical Department III – Endocrinology, Nephrology, Rheumatology University of Leipzig Medical Center Leipzig, Deutschland; 4Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland; 5Herz- und Diabeteszentrum NRW Allgemeine und Interventionelle Kardiologie/Angiologie Bad Oeynhausen, Deutschland
Heart failure (HF) is a growing public health problem with increasing incidence and prevalence associated with immune system activation. In HFrEF, the activation of immune cells is mainly mediated by monocytes, whereas this is not yet understood in HFpEF patients. HFpEF is associated with obesity but also occurs in lean patients. Immune cell-specific activation was studied in HFpEF (n=6) and HFrEF (n=8) patients and controls (n=7) with and without obesity, and in a HFpEF mouse model (HFD + L-NAME, n=5) treated with nitro-oleic acid (NO2-OA), a compound shown to improve diastolic dysfunction in HFpEF.
Single-cell sequencing of immune cells revealed distinct activation patterns between HFrEF and HFpEF. In contrast to HFrEF, HFpEF was not associated with an increased monocyte count or monocyte-driven inflammatory activation. Instead, HFpEF patients displayed an increase in NK cells, independent of obesity. Immune cells from HFpEF patients and mice exhibited inflammatory activation, which was most pronounced in obese HFpEF.
At the metabolic level, mitochondrial activation was detected in obese healthy individuals and was further amplified in both lean and obese HFpEF patients. Oxidative phosphorylation emerged as the most strongly regulated metabolic pathway in immune cells from HFpEF patients compared to lean healthy controls. Similarly, mice with HFpEF or obesity exhibited metabolic activation, highlighting a consistent link between HFpEF and metabolic dysregulation.
Therapeutic intervention with NO2-OA significantly reduced immune cell activation. Immune cell composition in NO2-OA-treated HFpEF mice resembled that of lean control mice, and metabolic activation was attenuated.
In conclusion, HFrEF is characterized by monocyte-driven inflammatory activation, whereas HFpEF exhibits NK cell-driven inflammation, independent of obesity. Inflammatory and metabolic activation of NK and T cells define HFpEF at the cellular level. NO2-OA effectively reduced inflammatory and metabolic alterations in obese HFpEF mice, its potential as a therapeutic strategy for HFpEF warrants further investigation.