https://doi.org/10.1007/s00392-025-02625-4
1Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland; 2Universitätsmedizin der Johannes Gutenberg-Universität Mainz Zentrum für Kardiologie Mainz, Deutschland; 3Institute of Veterinary Pathology, Leipzig University Faculty of Veterinary Medicine Leipzig, Deutschland; 4Universitätsklinikum Leipzig Klinik und Poliklinik für Kardiologie Leipzig, Deutschland; 5Herzzentrum Leipzig - Universität Leipzig Klinik für Innere Medizin/Kardiologie Leipzig, Deutschland
Background: Adipose tissue alterations, especially epicardial fat (Ef), have been proposed as key pathological drivers in the transition of mere obesity into developing heart failure with preserved ejection fraction (HFpEF). However, little data is available that looked at Ef of HFpEF on a molecular level. Therefore, within the prospective SLIM-HFpEF study (NCT04886713) we aimed to investigate the role of Ef in obese HFpEF patients.
Methods: Ef, pericardial fat (Pf) and subcutaneous fat (Sf) were harvested intraoperatively in patients undergoing isolated coronary artery bypass graft surgery (Fig. 1A). Histological analysis as well as bulk RNA sequencing were performed. Patients were stratified in a HFpEF group (HFpEF defined according to the HFA-PEFF algorithm and body mass index [BMI] ≥30 kg/m²) and in a lean (BMI <30 kg/m²) and obese (BMI ≥30 kg/m²) control group.
Results: Overall 11 HFpEF (median age 74 [IQR 67, 78] years, BMI 32 [31, 35] kg/m², NT-proBNP 554 [474, 614] pg/ml), 10 obese (age 65 [62, 67] years, BMI 32 [31, 33] kg/m², NT-proBNP 74 [68, 87] pg/ml) and 12 lean control patients (age 67 [63, 74] years, BMI 26 [25, 28] kg/m², NT-proBNP 141 [47, 180] pg/ml) were included.
RNA sequencing was successfully performed in 6 HFpEF, 5 obese and 7 lean control patients. Differential gene expression analysis showed a minimal overlap between all three tissues of only 4% (Fig. 1B). Between HFpEF and obese control patients there were only 23 and 15 genes differentially expressed in Pf and Sf, respectively. However, there were 369 genes differently expressed in Ef between HFpEF and obese control patients (Fig. 1C). Pathway analysis suggested those genes being associated with various potentially dismal pathways of metabolic efficiency, immune cell activation and cardiovascular haemostasis (Fig. 1D and E).
On histological analysis CD3+ and CD8+ cells were observed in Ef of obese patients with a significant increase in patients with HFpEF as compared to mere obese controls (Fig. 1F, p=0.007 and p=0.001, respectively) indicating an accumulation and infiltration of adipose tissue with cytotoxic T cells in the Ef of HFpEF patients.
Conclusion: Ef, Pf and Sf share a distinct RNA expression profile. In HFpEF patients, Ef, the adipose tissue nearest to the heart, shows a dysregulation of immune cell activation, metabolic efficiency and cardiovascular homeostasis and is adversely affected by infiltration and accumulation of CD3+ and CD8+ cells likely referring to cytotoxic T-cells. This change in Ef immunological and metabolic state might explain the transition from mere obesity to a HFpEF specific phenotype. Acknowledging this could pave the way for novel therapeutic targets.