Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure

• Published in: Cardiovascular diabetology Vol. 23; no. 1; pp. 223 - 17
• Main Authors: Kasperova, Barbora Judita, Mraz, Milos, Svoboda, Petr, Hlavacek, Daniel, Kratochvilova, Helena, Modos, Istvan, Vrzackova, Nikola, Ivak, Peter, Janovska, Petra, Kobets, Tatyana, Mahrik, Jakub, Riecan, Martin, Steiner Mrazova, Lenka, Stranecky, Viktor, Netuka, Ivan, Cajka, Tomas, Kuda, Ondrej, Melenovsky, Vojtech, Stemberkova Hubackova, Sona, Haluzik, Martin
• Format: Journal Article
• Language: English
• Published: England BioMed Central 28.06.2024; BMC
• Subjects: Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Architects; Biomarkers - blood; Body fat; Body mass index; Cardiovascular disease; Cardiovascular diseases; Congestive heart failure; Coronary vessels; Cytokines; Data analysis; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Ejection fraction; Epicardial Adipose Tissue; Ether lipids; Female; Ferroptosis; Flow cytometry; Gene expression; Glucose; Health risks; Heart diseases; Heart failure; Heart Failure - drug therapy; Heart Failure - metabolism; Heart Failure - physiopathology; Heart transplantation; Heart transplants; Humans; Inflammation; Inflammation Mediators - metabolism; Lipid metabolism; Lymphocytes; Male; Metabolomics; Middle Aged; Mortality; Obesity; Oleic acid; Oxidative stress; Patients; Pericardium - drug effects; Pericardium - metabolism; Severity of Illness Index; Sodium; Sodium-glucose cotransporter; Sodium-glucose cotransporter 2 inhibitors; Sodium-Glucose Transporter 2 Inhibitors - adverse effects; Sodium-Glucose Transporter 2 Inhibitors - pharmacology; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Stroke Volume - drug effects; Treatment Outcome; Ventricular Function, Left - drug effects; United States > US; Germany; Heart failure; Ether lipids; Inflammation; Adipose tissue; Sodium-glucose cotransporter 2 inhibitors
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-024-02298-9

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. 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/m , 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. 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. 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.