Degree

Doctor of Philosophy (PhD)

Department

Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Heart failure (HF) is defined as a condition where the heart cannot pump enough blood to meet the body’s needs. There are 3 subtypes of HF based on left ventricular ejection fraction.  Heart failure with preserved ejection fraction (HFpEF) is the predominant phenotype of HF, representing over 50% of all HF cases. The increase in the prevalence of HFpEF is associated with aging demographics, an increase in risk factors associated with HFpEF, and emerging novel therapies. Clinical trials have largely failed to improve outcomes due to the heterogeneous nature of HFpEF and complex pathophysiology. Exercise intolerance is a hallmark of HFpEF and is strongly associated with an increase in the rate of hospitalization, poor prognosis, and poor quality of life. Patients with cardiometabolic HFpEF exhibit concomitant comorbidities such as obesity, diabetes, and hypertension. HFpEF is characterized by concentric left ventricular hypertrophy, elevated end-diastolic pressure, and myocardial relaxation, which contribute to impaired diastolic function. HFpEF patients also exhibit extracardiac dysfunction, including skeletal muscle dysfunction, vascular dysfunction, and visceral adiposity. All these factors reflect the systemic nature of HFpEF and contribute to exercise intolerance. To date, there are no targeted pharmacological therapies that improve HFpEF prognosis, making HFpEF an unmet need in cardiovascular care.

In this context, exercise training has emerged as a compelling non-pharmacological intervention for HFpEF, which includes improving peak oxygen uptake, six-minute walk distance, ventilatory threshold, endothelial function, cardiorespiratory fitness, and quality of life. Consequently, the American Heart Association (AHA)/American College of Cardiology (ACC) recommends exercise training as a Class 1 recommendation (level of evidence A) in patients with HF, regardless of phenotype. However, the cardiac metabolic adaptations to exercise in HFpEF remain poorly understood.

In parallel, hydrogen sulfide (H2S), an endogenous gaseous signaling molecule, has emerged as a novel cardioprotective therapeutic with potent antioxidant, anti-fibrotic, and mitochondrial regulatory actions. Patients with HFpEF have an 80% reduction in H2S bioavailability according to recent reports. SG-1002, a dietary H₂S donor, has shown promise in HFpEF, yet its mechanism of action remains unclear

The objective of this preclinical study is to independently investigate the role of voluntary wheel running exercise and hydrogen sulfide therapy (SG1002) for the treatment of HFpEF. To test our hypotheses, we used the two-hit mouse model of cardiometabolic HFpEF with HFD and L-NAME. In these independent studies, after induction of HFpEF at 5 weeks, they were subjected to voluntary wheel running exercise and SG1002 therapy for an additional 5 weeks, respectively.

Our results demonstrated that voluntary exercise training in HFpEF significantly improved exercise capacity, enhanced mitochondrial coupling, and bioenergetic efficiency. Exercise therapy also reduced cardiac hypertrophy. Our results also showed increased mitochondrial coupling and decreased lipolysis. These results underscore the central role of adipose–cardiac metabolic crosstalk in reducing myocardial lipid overload in HFpEF. Similarly, hydrogen sulfide donor therapy (SG1002) increased circulating H2S and sulfane sulfur in HFpEF mice. This therapy improved the respiratory control ratio and reduced cardiac hypertrophy. Mechanistically, SG1002 upregulates SERCA2 and downregulates Phospholamban expression in the calcium signaling pathway, thereby promoting sarcoplasmic reticulum Ca2+ release and improving myocardial relaxation.

These findings highlight the therapeutic potential of exercise therapy and SG1002 treatment in cardiometabolic HFpEF. Future studies are focused on evaluating the combined effects of exercise training and SG1002 therapy to address the heterogeneity of HFpEF.

Date

3-26-2026

Committee Chair

Francis, Joseph

LSU Acknowledgement

1

LSU Accessibility Acknowledgment

1

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