This project will evaluate the impact of L-Citrulline, tetrahydrobiopterin (BH4), and atorvastatin administration on physical capacity and vascular function in Veterans with heart failure with preserved ejection fraction (HFpEF).

The hospital admission rate for Veterans with heart failure with a preserved ejection fraction (HFpEF) continues to rise within the VA Health Care System, making HF the number one reason for hospital discharge Additionally, readmission rates of Veterans with HF tend to be higher than the national average, emphasizing the shortcomings of current therapeutic strategies Indeed, while optimized pharmacotherapy has led to a declining mortality in heart failure with reduced ejection fraction (HFrEF) patients, similar therapies in patients with HFpEF have been unsuccessful in altering the natural history of the disease Clearly, alternative therapeutic approaches are needed to improve outcomes in this ever-growing Veteran patient group.

The clinical presentation of HFpEF continues to be defined by dyspnea upon exertion and severe exercise intolerance symptoms that are unlikely due to a simple deficit in cardiac mechanics Indeed, the contribution of vascular dysfunction to exercise intolerance in patients with HFpEF has recently been identified highlighting the importance of disease-related changes in the peripheral circulation to HFpEG pathophysiology. While the mechanisms responsible for vascular dysfunction in HFpEF have not been established, there is an emerging concept that chronic inflammation and the associated production of reactive oxygen species (ROS), stemming from HFpEF-associated comorbidities and inactivity, plays a crucial role. The proposed work seeks to address this important knowledge gap by examining the mechanisms linking inflammation, vascular health, and exercise tolerance in Veterans with HFpEF, and identifying which aspects of this cascade could be targeted to improve outcomes in this patient group.

In HFpEF, the peripheral vasculature represents an area that is particularly vulnerable to the harmful effects of circulating ROS due to the interaction with nitric oxide (NO). Indeed, following formation and release from the endothelium, the fate of NO is dictated to a large degree by the presence of ROS that catalyze the formation of peroxynitrite (ONOO-), thereby decreasing NO bioavailability. This deleterious effect on NO formation is amplified by ONOO--mediated oxidation of tetrahydrobiopterin (BH4), effectively "uncoupling" endothelial nitric oxide synthase (eNOS) and thus further diminishing NO production. Bioavailability of NO may also be diminished through reductions in precursor (L-Arginine/L-Citrulline) availability, such that a "substrate limitation" may also be present in patients with HFpEF.

While the potential of increased NO bioavailability to improve outcomes in patients with HFpEF has been increasingly recognized, results from clinical trials utilizing NO donors have been largely negative, suggesting a more comprehensive approach may be needed. Thus, the overall goal of the project is to evaluate the mechanisms responsible for vascular dysfunction and exercise intolerance in Veterans with HFpEF, which will be accomplished through selective pharmacologic targeting of distinct pathways known to regulate vascular NO signaling. The investigators have identified three discreet points in the cascade from inflammation to vascular dysfunction that may represent therapeutic targets for improving exercise tolerance in patients with HFpEF, and thus propose a series of integrative aims that will combine novel methodology with targeted pharmacologic interventions to selectively determine the importance of NO substrate, enzymatic cofactor bioavailability, and statin-induced mitigation of inflammation and ROS to disease-related changes in inflammation and NO signaling in HFpEF.

Inclusion Criteria:

• Age 18 years or older and able to give written informed consent.
• New York Heart Association (NYHA) functional class I, II, or III.
• Left Ventricular Ejection Fraction (LVEF) > 50%.
• Plasma Brain Natriuretic Peptide (BNP) equal to or greater than 150 pg/mL or NT-proBNP equal to or greater than 600 pg/mL at Visit 1, or a BNP equal to or great than 100 pg/mL (or NT-proBNP equal to or greater than 400 pg/mL) and a hospitalization for heart failure within the last 12 months.

Exclusion Criteria:

• History of hypersensitivity or allergy to any lipophilic statin.
• Prior EF <50%.
• NYHA Class IV.
• Patients with HFpEF secondary to significant uncorrected primary valvular disease.
• Active liver disease or unexplained persistent elevations in serum transaminase.
• Women who are pregnant or may become pregnant.
• Patients currently treated with antioxidants, nitrates, PDE-5 inhibitors, or statins.

A block randomization method will be used to randomize participants into equal groups and will be handled by investigational pharmacist.