Glycoursodeoxycholic acid 3 sulfate sodium links hemodynamics and bile acid metabolism in aortic stenosis

Aortic stenosis (AS) involves aortic obstruction, pressure overload, reduced cardiac output, and impaired organ arterial hemodynamics. Many patients remain at risk of rehospitalization or death after transcatheter aortic valve replacement (TAVR) due to unclear mechanisms. Our previous studies linked bile acids (BAs) metabolism to heart-other organ crosstalk, but the BAs-hemodynamics interplay in AS remains unclear. To investigate metabolic abnormalities in AS, focusing on the role of BA metabolism in AS pathogenesis and the underlying mechanisms. An acute canine model of AS was established via intra-aortic balloon catheter-induced transverse aortic obstruction (ITAO). Computational fluid dynamics (CFD) simulation was performed to assess the arterial hemodynamics of the aorta and other organs. Untargeted/targeted metabolomics and transcriptomics were performed in ITAO and deleting ITAO (deITAO) canines. The findings were validated in 33 controls and 30 AS patients. Metabolic predictive performance was assessed by the area under the receiver-operating characteristic (AUROC) curve. Transcriptomic and western blot analyses were used to assess the effects of glycoursodeoxycholic acid (GUDCA) and glycoursodeoxycholic acid 3 sulfate sodium (GUDCA-3S) on isoproterenol (ISO)-induced myocardial remodeling. ITAO replicated AS hemodynamics (reduced cardiac output, increased aortic velocity), reversed post-deITAO. CFD revealed that ITAO increased organ (e.g., liver) artery pressure, improved after deITAO. Untargeted metabolomics identified 1583 differentially abundant metabolites; transcriptomics revealed 291 DEGs enriched in BA biosynthesis. Targeted BA analysis revealed that GUDCA-3S was elevated in ITAO canines, correlated with aortic velocity (R = -0.4822, P = 0.0002) and BNP (R = 0.3836, P = 0.0019) in AS patients, and exhibited superior AS diagnostic performance (AUROC = 0.844, P < 0.001). Reduced aortic flow upregulated hepatic SULT2A1, driving GUDCA sulfonation to GUDCA-3S and weakening GUDCA's cardioprotection by impairing IL-17/NF-κB signaling inhibition in ISO-induced cardiomyocytes. BA metabolism dysfunction responds to cardiac hemodynamic changes, with GUDCA-3S linking cardiac hemodynamics and BA metabolism in AS.