SGLT2 inhibitors and molecular signatures of aortic valve remodeling in severe aortic stenosis: the Valve-AS study
M Belmonte, L Scisciola, M G Basilicata, P Paolisso, L Delrue, M Torella, M De Feo, E Pilato, P Campiglia, R Marfella, M Vanderheyden, G Paolisso, G Melina, E Barbato, M BarbieriAbstract
Background
Degenerative aortic stenosis (AS) is an active fibrocalcific disease with no pharmacological therapy proven to slow its progression.SGLT2 inhibitors exert pleiotropic effects, but their role in valvular heart disease remains poorly defined.
Purpose
To quantify SGLT2 expression in explanted human aortic valve leaflets and to compare molecular and metabolic signatures between SGLT2i users and those receiving other glucose-lowering therapies.Secondary objectives included associations with valvular and circulating biomarkers of inflammation, fibrosis, oxidative stress, and calcification.
Methods
In this international multicenter prospective study, consecutive patients with severe AS referred for SAVR were enrolled (Jul 2024-Aug 2025). Based on antidiabetic therapy at admission, patients were stratified into SGLT2i and non-SGLT2i users.Intraoperative peripheral venous blood samples and explanted aortic valve leaflets were collected.Valvular gene expression of metabolic, inflammatory, fibrotic, oxidative stress, and calcification-related markers were assessed by RT-PCR, while circulating biomarkers by ELISA.Global metabolomic profiling and MALDI-MSI were performed on explanted aortic valve to characterize metabolic signatures and their spatial distribution within the stenotic valve.
Results
The study population included 83 patients, of whom 21 (25.3%) were treated with SGLT2i. Clinical characteristics, surgical risk, echocardiographic parameters, and coronary artery disease burden were comparable between groups.SGLT2i users exhibited significantly lower valvular expression of SGLT2 and SGLT1 (p<0.001), GLUT4, and NHE (p<0.05) compared to non-SGLT2i users, while GLUT1 remained unchanged. Metabolic regulators showed increased PPARα (p<0.001) and reduced PPARγ expression (p<0.05).Inflammatory signaling was attenuated in SGLT2i users, with lower valvular NF-κB and IL-6 expression and reduced circulating IL-6 (p<0.001), alongside increased SOD2 expression (p<0.05).Fibrotic markers did not differ between groups; however, circulating Serpin-4 was higher (p<0.05), while MR-proADM, PINP, and NT-proBNP were lower (p<0.05) in SGLT2i users. MMP-9 and MMP-12 were significantly reduced in SGLT2i users (p<0.05).Global metabolomic profiling revealed a distinct metabolic segregation between groups. 34 metabolites within aminoacid, purine, phospholipid and glutathione pathways were differentially modulated.SGLT2i users exhibited enrichment of aminoacid and redox metabolites, while non-SGLT2i users showed elevated phospholipid derivatives.Altered purine intermediates indicated modified nucleotide turnover.
Conclusions
SGLT2i therapy is associated with distinct molecular and metabolic signatures in human calcific aortic valve tissue, suggesting therapy-related metabolic reprogramming of the valvular microenvironment and providing translational evidence supporting a potential role of SGLT2-related pathways in AS pathobiology.