Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit with GLP-1/Glucagon Agonism
Authors: Doiron Jake E. , Elbatreek Mahmoud H. , Xia Huijing , Yu Xiaoman , Gehred Natalie D. , Gromova Tatiana , Chen Jingshu , Driver Ian H. , Muraoka Naoto , Jensen Martin , Shambhu Smitha , Tang W.H. Wilson , LaPenna Kyle B. , Sharp Thomas E. , Goodchild Traci T. , Xian Ming , Xu Shi , Quiriarte Heather , Allerton Timothy D. , Zagouras Alexia , Wilcox Jennifer , Shah Sanjiv J. , Pfeilschifter Josef , Beck Karl-Friedrich , Vondriska Thomas M. , Li Zhen , Lefer David J. 
Published: September 2024

ABSTRACTBackgroundHeart 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 (H2S) in HFpEF.ObjectivesThis study evaluated H2S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H2S on HFpEF severity through alterations in endogenous H2S production and pharmacological supplementation. We also evaluated the effects of the H2S donor, diallyl trisulfide (DATS) in combination with the GLP-1/glucagon receptor agonist, survodutide, in HFpEF.MethodsHFpEF patients and two rodent models of HFpEF (“two-hit” L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H2S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-γ-lyase (EC-CSE) knockout; (2) H2S donor, JK-1, supplementation. DATS and survodutide combination therapy was tested in ZSF1 obese rats.ResultsH2S 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 H2S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e’ ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H2S supplementation restored H2S 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.ConclusionsH2S deficiency is evident in HFpEF patients and conserved across multiple preclinical HFpEF models. Increasing H2S bioavailability improved cardiovascular function, while knockout of endogenous H2S production exacerbated HFpEF pathology and mortality. These results suggest H2S dysregulation contributes to HFpEF and increasing H2S bioavailability may represent a novel therapeutic strategy for HFpEF. Furthermore, our data demonstrate that combining H2S supplementation with GLP-1/glucagon receptor agonist may provide synergistic benefits in improving HFpEF outcomes.HighlightsH2S deficiency is evident in both human HFpEF patients and two clinically relevant models.Reduced H2S production by CSE and increased metabolism by SQR impair H2S bioavailability in HFpEF.Pharmacological H2S supplementation improves diastolic function and reduces cardiac fibrosis in HFpEF models.Targeting H2S dysregulation presents a novel therapeutic strategy for managing HFpEF.H2S synergizes with GLP-1/glucagon agonist and ameliorates HFpEF