Hydrogen Sulfide and GLP-1 Combination Therapy to Treat HFpEF

Project Summary Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality, imposing a significant healthcare burden on 6.7 million Americans that is anticipated to increase to 8.5 million Americans by 2030. The lifetime risk of HF is 24% and 1 in 4 persons will develop HF in their lifetime. Heart failure with preserved ejection fraction (HFpEF) is the most prevalent from of HF in the United States. At present there are very limited treatments for HFpEF and the 5-year mortality rate is 50%. Hydrogen sulfide (H2S) is a potent endogenous signaling molecule that regulates cardiovascular homeostasis via regulation of vascular tone, systemic inflammation, redox balance, and metabolism. Glucagon-like peptide-1 agonists (GLP-1) are incretin analogues that promote insulin secretion, suppress glucagon release, slow gastric emptying, and increase satiety to promote weight loss and reduce blood glucose. Clinical trials of the GLP-1 agonist, semaglutide, demonstrated decreased hospitalizations and improvements in exercise capacity and quality of life in cardiometabolic HFpEF. While semaglutide meaningfully reduces disease burden, GLP-1 agonists have failed to reduce mortality in HFpEF patients. Clearly, there is a need for more potent therapies to treat HFpEF. Our preliminary data demonstrate that H2S donors ameliorate the severity of cardiometabolic HFpEF in preclinical rodent models to improve outcomes. Furthermore, we have discovered that combination therapy with an H2S donor + GLP-1 not only attenuates HFpEF disease severity, but completely halts disease progression and partially reverses cardiometabolic HFpEF. Our central hypothesis is that combination H2S + GLP-1 therapy results in potent synergistic benefits in cardiometabolic HFpEF via systemic metabolic, anti-inflammatory, antioxidant, antifibrotic, and vascular protective mechanisms to halt HFpEF disease progression. The proposed studies will first confirm the beneficial effects and elucidate the mechanistic actions of H2S donors + GLP-1 agonist therapy in a well-established rat model (i.e., ZSF1 obese) of severe cardiometabolic HFpEF. These studies will also refine dosing for both agents and define the mechanisms of action during the progression of HFpEF. Next, we will evaluate the efficacy of H2S donor + GLP-1 combination therapy in a clinically relevant porcine model (i.e., Gottingen "two-hit") of cardiometabolic HFpEF involving obesity and hypertension. Successful completion of the proposed studies will lead to a better understanding of the pathogenesis of HFpEF. This project will provide a strong foundation for the translation of novel pharmacological strategies to harness the cardioprotective actions of H2S to benefit patients with cardiometabolic HFpEF.