SGLT2 Inhibitors Exert Anti-inflammatory and Antioxidant Effects in Epicardial Adipose Tissue of Severe Heart Failure Subjects

The exact mechanisms behind cardioprotective effects of SGLT-2 inhibitors (SGLT-2i) are still not fully elucidated. Using complex transcriptomic, metabolomic and immunochemical methods we analysed epicardial (EAT) and subcutaneous (SAT) adipose tissue of patients with severe heart failure treated with SGLT-2i in order to identify possible cardioprotective pathways. Twenty six subjects with severe heart failure with reduced ejection fraction (NYHA III-IV) treated with SGLT-2i (18 with type 2 diabetes mellitus - T2DM) and 26 age-, BMI- and left ventricular ejection fraction-matched control subjects (8 with T2DM) scheduled for heart transplantation or mechanical support implantation were included into the study. The complex analysis of EAT and SAT included liquid chromatography in combination with mass spectrometry for metabolomics, RT-qPCR for transcriptomics and flow cytometry and immunochemistry for detection of immune cells and mitochondria. Compared with controls, EAT of SGLT-2i subjects showed marked reduction in allover immune cell infiltration along with a decrease in Th1 and Th2 cells and mRNA levels of macrophage marker ADGRE1. This was not the case for SAT, where only reduced mRNA levels of inflammatory markers including IL6 and MCP1 were detected. Moreover, mitochondrial staining revealed improvement of mitochondrial morphology in EAT of SGLT-2i group accompanied by decreased oxidative stress. Finally, enhanced enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests reduced disposition to ferroptosis (iron-dependent lipid peroxidation-regulated cell death) further contributing to decreased oxidative stress in EAT of SGLT-2i subjects. In conclusion, SGLT-2i treatment is associated with reduced inflammation and oxidative stress in EAT, which could at least partially explain their cardioprotective effects. Disclosure M.Mraz: None. I.Pleyerova: None. K.Rosolová: None. P.Novodvorsky: Advisory Panel; Sanofi, Boehringer-Ingelheim, Consultant; Novo Nordisk, Merck & Co., Inc., Novartis, Speaker's Bureau; Novo Nordisk, Sanofi, Eli Lilly and Company, KRKA, Mundipharma, Abbott. P.Ivak: Consultant; Abbott, Other Relationship; Abbott. V.Melenovsky: None. I.Netuka: Board Member; LeviticusCardio Ltd., Consultant; Abbott, CARMAT SA, Other Relationship; Abbott, CARMAT SA, Stock/Shareholder; LeviticusCardio Ltd. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. B.Kasperova: None. S.Stemberkova: None. P.Svoboda: None. D.Hlavácek: None. J.Mahrík: None. O.Kuda: None. T.Cajka: None. L.Tomanová: None. Funding NV19-02-00118; National Institute for Research of Metabolic and Cardiovascular Diseases (EXCELES, LX22NPO5104) Funded by the European Union - Next Generation EU; Ministry of Health, Czech Republic Conceptual Development of Research Organization Institute