1Universitätsklinikum Leipzig Klinik und Poliklinik für Kardiologie Leipzig, Deutschland; 2Herzzentrum Leipzig - Universität Leipzig Klinik für Innere Medizin/Kardiologie Leipzig, Deutschland; 3University of Leipzig Medical Center Medical Department III – Endocrinology, Nephrology, Rheumatology Leipzig, Deutschland; 4Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland
Heart failure with preserved ejection fraction (HFpEF) is a growing public health problem with increasing incidence and prevalence, which is accompanied by activation of the immune system. Obesity is strongly associated with the development and progression of HFpEF. However there are also lean HFpEF patients. Here, we aim to characterize immune cell-specific activation comparing HFpEF patients with and without obesity to characterize the heart failure-specific contribution to HFpEF.
Single cell sequencing of (n=61,082) immune cells of lean and obese individuals as well as lean and obese HFpEF patients was performed. Characterisation of the immune cell types revealed obese individuals to have less B cells (Healthy lean: 8.0%, Healthy obese: 4.7%, HFpEF lean: 14.4%, HFpEF obese: 5.6%) and more CD16+ monocytes (Healthy lean: 2.9%, Healthy obese: 5.4%, HFpEF lean: 3.5%, HFpEF obese: 4.7%) compared to the lean individuals. HFpEF patients have further more NK cells (Healthy lean: 9.1%, Healthy obese: 8.8%, HFpEF lean: 15.2%, HFpEF obese: 14.3%) and less progenitor cells (Healthy lean: 0.17%, Healthy obese: 0.13%, HFpEF lean: 0.09%, HFpEF obese: 0.08%) compared to obese and lean controls. The HFpEF-specific increase in NK cells was independent of obesity.
On a metabolic level, immune cells of lean and obese HFpEF patients are characterized by oxidative phosphorylation as top upregulated metabolic pathway compared to lean healthy individuals. Indeed, genes related to mitochondrial activation such as ATP5F1E, NDUFA1 and MT-ND4L are already upregulated in obese healthy individuals without HFpEF.
Inflammatory genes, such as TNFα or CCL5 were upregulated in lean and obese HFpEF patients compared to healthy individuals whereby strongest upregulation was seen in obese HFpEF patients compared to lean HFpEF patients. The observed increase of these genes may contribute to an enhanced immune cell activation in HFpEF patients.
Together this study shows that circulating immune cells derived from obese patients with and without HFpEF have altered phenotypes. HFpEF patients are characterized by more NK cells and an increased inflammatory gene activation independent of obesity. Metabolic genes on the other hand were already upregulated in obese healthy individuals but further enhanced by HFpEF. These data provide a rich source for identification of signatures of immune cells contributing to HFpEF.