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.
SGLT2-Inhibitors and Molecular Signatures of Aortic Valve Remodeling in Severe Aortic Stenosis / Paolisso, P., Scisciola, L., Giovanna Basilicata, M., Salviati, E., Belmonte, M., Delrue, L., Comentale, G., Policastro, P., Redivo, M., Piras, L., Zito, F., Coli, M., Mistrulli, R., Joshi, R., Gallinoro, E., Bergamaschi, L., Pizzi, C., Casselman, F., Stockman, B., Aquino, G., et al.. - In: JACC. BASIC TO TRANSLATIONAL SCIENCE. - ISSN 2452-302X. - (2026). [10.1016/j.jacbts.2026.101658]
SGLT2-Inhibitors and Molecular Signatures of Aortic Valve Remodeling in Severe Aortic Stenosis
Pasquale Paolisso;Marta Belmonte;Pasquale Policastro;Marco Redivo;Linda Piras;Marco Coli;Raffaella Mistrulli;Emanuele Barbato;Giovanni Melina;Linda Piras
2026
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
