SGLT2 inhibitor therapy is associated with IL-10/TGF-α/sVEGFR3 signalling and adipose tissue remodelling in advanced heart failure

Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardioprotective effects in heart failure (HF), yet the molecular mechanisms underlying these benefits remain incompletely understood. This study aimed to characterize cardioprotective effects of SGLT2i, changes of circulating growth and inflammatory factors, as well as adipose tissue gene expression, in subjects with advanced HF (stage D). Methods 27 subjects with HF undergoing cardiovascular surgery were included, comprising 17 subjects treated with SGLT2i and 10 untreated controls. Soluble factors were analysed using Luminex assay, and mRNA expression in subcutaneous (SAT) and epicardial adipose tissue (EAT) was assessed. Results Subjects receiving SGLT2i exhibited a non-significant trend toward lower BNP concentrations (329.1 ± 78.7 vs. 514.2 ± 103.8 pmol/L, p = 0.079) and increased circulatory levels of anti-inflammatory IL-10 (7.2 ± 0.4 vs. 5.8 ± 0.7 pg/mL, p = 0.025) and cardioprotective TGF-α (3.5 ± 0.3 vs. 2.7 ± 0.4 pg/mL, p = 0.039). sVEGFR3 levels (82.3 ± 4.7 vs. 63.3 ± 3.9 pg/mL, p = 0.010) were higher in SGLT2i, suggesting altered lymphangiogenic signalling. Transcriptomic analysis showed lower expression of genes associated with inflammation ( IL6 , CCL2 , CXCL2 ), cardiac hypertrophy ( PKFP , NAMPT ), fibrosis ( TNC , TNFAIP3 ), and cellular senescence ( ICAM1 , CDKN1A ), predominantly in SAT. Conclusions SGLT2i therapy in advanced HF was associated with higher circulating IL-10, TGF-α and sVEGFR3 levels and with a more favourable adipose tissue gene expression profile characterized by lower expression of genes related to inflammation, fibrosis, and cellular senescence. These findings identify molecular pathways associated with SGLT2i therapy that warrant further mechanistic investigation.