BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

1st Faculty of Medicine Charles University Prague Katerinska 1660 32 121 08 Prague Czech Republic

3rd Faculty of Medicine Charles University Prague Ruska 87 100 00 Prague Czech Republic

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Department of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic

Department of Biochemistry and Microbiology University of Chemistry and Technology Prague Technicka 5 166 28 Prague Czech Republic

Department of Cardiac Anesthesia Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Department of Cardiac Surgery Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Department of Cardiology Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Department of Informatics Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Department of Metabolism of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic

Department of Metabolomics Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic

Diabetes Centre Institute for Clinical and Experimental Medicine Videnska 1958 9 140 21 Prague Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital U Nemocnice 499 2 128 08 Prague Czech Republic

Research Unit for Rare Diseases Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Ke Karlovu 455 2 128 08 Prague Czech Republic

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