Pasquale Paolisso, Lucia Scisciola, Manuela Giovanna Basilicata, Emanuela Salviati, Marta Belmonte, Leen Delrue, Giuseppe Comentale, Pasquale Policastro, Marco Redivo, Linda Piras, Francesco Zito, Marco Coli, Raffaella Mistrulli, Rashmi Joshi, Emanuele Gallinoro, Luca Bergamaschi, Carmine Pizzi, Filip Casselman, Bernard Stockman, Giovanna Aquino, Antonio Pio Montella, Michele Torella, Marisa De Feo, Emanuele Pilato, Jozef Bartunek, Eduardo Maria Somella, Pietro Campiglia, Raffaele Marfella, Marc Vanderheyden, Giuseppe Paolisso, Emanuele Barbato, Giovanni Melina, Michelangela Barbieri
Sodium-glucose cotransporter 2 inhibitor (SGLT2i) exerts pleiotropic metabolic and anti-inflammatory effects, but its role in calcific aortic valve stenosis (CAVS) is unclear. In this multicenter prospective study, 83 patients with severe CAVS undergoing surgical aortic valve replacement were stratified by SGLT2i use. Explanted valve tissue and plasma were analyzed using transcriptomics, circulating biomarkers, and metabolomics, including MALDI-MSI. SGLT2i therapy was associated with reduced valvular expression of SGLT1/2, GLUT4, and NHE, increased PPARα, decreased PPARγ, attenuation of inflammatory signaling (lower NF-κB and IL-6), and oxidative stress response (higher SOD2). Extracellular matrix turnover and fibrocalcific remodeling enzymes (MMP-9 and MMP-12) were also reduced. Metabolomic profiling demonstrated distinct clustering, with enrichment of amino acid and redox pathways in SGLT2i users. These findings suggest that SGLT2i therapy is associated with coordinated molecular and metabolic reprogramming of the valvular microenvironment, supporting a potential disease-modifying role in CAVS.