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

ABSTRACT Background Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H 2 S) in HFpEF. Objectives This study evaluated H 2 S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H 2 S on HFpEF severity through alterations in endogenous H 2 S production and pharmacological supplementation. We also evaluated the effects of the H 2 S donor, diallyl trisulfide (DATS) in combination with the GLP-1/glucagon receptor agonist, survodutide, in HFpEF. Methods HFpEF patients and two rodent models of HFpEF (“two-hit” L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H 2 S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-γ-lyase (EC-CSE) knockout; (2) H 2 S donor, JK-1, supplementation. DATS and survodutide combination therapy was tested in ZSF1 obese rats. Results H 2 S levels were significantly reduced (i.e., 81%) in human HFpEF patients and in both preclinical HFpEF models. This depletion was associated with reduced CSE expression and activity, and increased SQR expression. Genetic knockout of H 2 S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e’ ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H 2 S supplementation restored H 2 S bioavailability, improved diastolic function and attenuated cardiac fibrosis corroborating an improved HFpEF phenotype. DATS synergized with survodutide to attenuate obesity, improve diastolic function, exercise capacity, and reduce oxidative stress and cardiac fibrosis. Conclusions H 2 S deficiency is evident in HFpEF patients and conserved across multiple preclinical HFpEF models. Increasing H 2 S bioavailability improved cardiovascular function, while knockout of endogenous H 2 S production exacerbated HFpEF pathology and mortality. These results suggest H 2 S dysregulation contributes to HFpEF and increasing H 2 S bioavailability may represent a novel therapeutic strategy for HFpEF. Furthermore, our data demonstrate that combining H 2 S supplementation with GLP-1/glucagon receptor agonist may provide synergistic benefits in improving HFpEF outcomes. Highlights H 2 S deficiency is evident in both human HFpEF patients and two clinically relevant models. Reduced H 2 S production by CSE and increased metabolism by SQR impair H 2 S bioavailability in HFpEF. Pharmacological H 2 S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models. Targeting H 2 S dysregulation presents a novel therapeutic strategy for managing HFpEF. H 2 S synergizes with GLP-1/glucagon agonist and ameliorates HFpEF