Research Project 1 - Allerton

Project Summary Heart failure with preserved ejection fraction (HFpEF) will soon become the predominant form of heart failure. Patients with cardiometabolic HFpEF have multiple co-morbidities including obesity, hypertension, and diabetes. The primary symptom of HFpEF is exercise intolerance. Skeletal muscle metabolic dysfunction and hypoperfusion are cited as major causes of exercise intolerance in HFpEF. Patients with cardiometabolic HFpEF have worse exercise intolerance and survival outcomes than people with other forms of HFpEF. Hydrogen sulfide (H2S) is a gaseous signaling molecule important for metabolic and cardiovascular health. In skeletal muscle, 3- mercaptopyruvate sulfurtransferase (3-MST) in myocytes produces mitochondrial H2S, while cystathionine-γ- lyase (CSE) in the endothelium supplies microvascular H2S. Our preliminary studies demonstrate in patients and animals with HFpEF severe H2S dysregulation. In humans with HFpEF, circulating plasma H2S bioavailability is reduced by 80%. Animal models demonstrate a similar reduction in circulating H2S but also show a significant reduction in skeletal muscle H2S along with a reduction in the expression of the H2S-producing enzyme 3-MST. The loss of H2S induces metabolic inefficiency in metabolizing important fuels for exercise. H2S donor therapy increases H2S bioavailability and restores skeletal muscle metabolic function in animal models of HFpEF. These preliminary studies demonstrate that H2S is involved in the physiological response to exercise in HFpEF. Our central hypothesis is that reductions in H2S synthesis and bioavailability lead to impaired skeletal muscle metabolism and exercise intolerance in cardiometabolic HFpEF. Using novel H2S detection methods we will investigate the impact of skeletal muscle 3-MST and endothelial cell CSE on exercise intolerance during progression of cardiometabolic HFpEF. We will determine the role of H2S on skeletal muscle metabolism and mitochondrial function during cardiometabolic. The long-term objective of our proposed studies is to understand how H2S contributes to skeletal muscle function and metabolism in HFpEF.