Hydrogen sulfide levels were 81% lower in HFpEF patients, and combining H₂S supplementation with a GLP-1/glucagon agonist synergistically improved heart function, exercise capacity, and cardiac fibrosis in animal models.
81% reduction in H₂SHydrogen sulfide levels were dramatically depleted in human HFpEF patients compared to healthy controls
What the researchers found
Hydrogen sulfide levels were reduced by 81% in human HFpEF patients and were similarly depleted in two rodent models of cardiometabolic HFpEF. This depletion was linked to reduced CSE enzyme expression and activity alongside increased SQR expression.
Genetic knockout of CSE in endothelial cells worsened HFpEF features including elevated E/e' ratio and left ventricular end-diastolic pressure, impaired aortic vasorelaxation, and increased mortality. Pharmacological H₂S supplementation restored bioavailability, improved diastolic function, and reduced cardiac fibrosis. Combining the H₂S donor DATS with the GLP-1/glucagon receptor agonist survodutide synergistically reduced obesity, improved diastolic function and exercise capacity, and decreased oxidative stress and cardiac fibrosis in ZSF1 obese rats.
Why it matters
HFpEF accounts for roughly half of all heart failure cases and has very limited treatment options. Identifying hydrogen sulfide deficiency as a contributing mechanism opens an entirely new therapeutic avenue. The synergistic benefit with GLP-1/glucagon agonism is particularly exciting because it suggests combination therapies could address both the metabolic and cardiac aspects of this complex disease.
How the study worked
The study used a translational approach spanning human patients and two preclinical models. H₂S bioavailability was measured in HFpEF patients and in two rodent HFpEF models: a 'two-hit' L-NAME plus high-fat diet mouse and the ZSF1 obese rat. Researchers used endothelial cell-specific CSE knockout mice to study loss of H₂S production, and tested pharmacological H₂S supplementation (JK-1 and DATS) alone and in combination with survodutide in the rat model.
What this study cannot tell us
This is a preprint (bioRxiv) that has not yet undergone peer review. The human data shows correlation between H₂S deficiency and HFpEF but cannot establish causation. The combination therapy was only tested in one animal model (ZSF1 rats). Specific dosing protocols and long-term safety of H₂S supplementation in humans remain unknown. The study does not provide human clinical trial data for the combination therapy.
How to read the evidence
This is a preprint combining human biomarker data with two preclinical animal models and genetic knockout experiments. While the translational approach is strong, the lack of peer review and absence of human interventional data limits the evidence grade.
When this study was published
Published as a preprint in 2025, this is cutting-edge research that has not yet undergone peer review. The findings should be interpreted with appropriate caution pending formal publication.
The bigger picture
This research adds hydrogen sulfide to the growing list of gaseous signaling molecules implicated in cardiovascular disease. It also connects the rapidly expanding GLP-1 drug class to heart failure treatment in a novel way — not just through metabolic improvements, but through synergistic interaction with H₂S pathways. This could lead to new combination therapy approaches for the millions of patients living with HFpEF worldwide.
Questions still open
- Can H₂S supplementation be safely and effectively delivered to human HFpEF patients, and through what route of administration?
- Would the synergistic benefit of H₂S plus GLP-1/glucagon agonism translate to human clinical outcomes?
- Could H₂S levels serve as a biomarker for identifying HFpEF patients most likely to benefit from targeted therapy?
Common questions
What is hydrogen sulfide and why does it matter for heart health?
What is HFpEF and why is it so hard to treat?
Read the original research
Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit with GLP-1/Glucagon Agonism.
bioRxiv : the preprint server for biology
Citation
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. (2025). Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit with GLP-1/Glucagon Agonism.. bioRxiv : the preprint server for biology. https://doi.org/10.1101/2024.09.16.613349