Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit With GLP-1/Glucagon Agonism.

Heart failure with preserved ejection fraction (HFpEF) presents significant treatment challenges. We assessed hydrogen sulfide (HS) bioavailability in HFpEF patients and 2 animal models: the "2-hit" L-NAME + high-fat diet mouse model and ZSF1 obese rats. HS levels were significantly reduced in patients and both models, linked to decreased cystathionine-γ-lyase expression and increased sulfide quinone oxidoreductase. Cystathionine-γ-lyase knockout worsened HFpEF, whereas pharmacological supplementation with an HS donor improved diastolic function and reduced cardiac fibrosis. HS supplement synergized with GLP-1/glucagon agonist and ameliorated HFpEF. These findings suggest that enhancing HS bioavailability may provide a novel therapeutic strategy for HFpEF.