Novel Approaches for Improving Vascular Function in Veterans With HFpEF

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).

Study Overview

• Status: Recruiting
• Conditions: Inflammation; HFpEF - Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: L-Citrulline; Drug: Placebo for L-Citrulline; Drug: BH4; Drug: Placebo for BH4; Drug: Atorvastatin; Drug: Placebo for Atorvastatin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: D. W. Wray; Phone Number: 858-205-3078; Email: walter.wray@hsc.utah.edu
• Study Contact Backup: Name: Misti Seppi; Phone Number: 435-714-1516; Email: misti.seppi@hsc.utah.edu

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84128
      • Recruiting
      • George E. Whalen VA Medical Center
      • Contact: Walter Wray; Phone Number: 858-205-3078; Email: walter.wray@hsc.utah.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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) ≥150 pg/mL or NT-proBNP ≥600 pg/mL at Visit 1, or a BNP ≥100 pg/mL (or NT-proBNP ≥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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: L-Citrulline, Then Placebo; Participants will receive a 90-day supply of L-Citrulline and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.	Drug: L-Citrulline; 100 mg tablet; Drug: Placebo for L-Citrulline; L-Citrulline-matched Placebo tablet
Experimental: BH4, Then Placebo; Participants will receive a 90-day supply of BH4 and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.	Drug: BH4; 10mg/kg; Other Names: sapropterin dihydrochloride; Kuvan®; Drug: Placebo for BH4; BH4-matched Placebo
Experimental: Atorvastatin, Then Placebo; Participants will receive a 90-day supply of Atorvastatin and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Placebo and perform baseline and follow-up assessments as above.	Drug: Atorvastatin; 10 mg tablet; Other Names: Lipitor®; Drug: Placebo for Atorvastatin; Atorvastatin-matched Placebo
Experimental: Placebo, Then L-Citrulline; Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of L-Citrulline and perform baseline and follow-up assessments as above.	Drug: L-Citrulline; 100 mg tablet; Drug: Placebo for L-Citrulline; L-Citrulline-matched Placebo tablet
Experimental: Placebo, Then BH4; Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of BH4 and perform baseline and follow-up assessments as above.	Drug: BH4; 10mg/kg; Other Names: sapropterin dihydrochloride; Kuvan®; Drug: Placebo for BH4; BH4-matched Placebo
Experimental: Placebo, Then Atorvastatin; Participants will receive a 90-day supply of Placebo and perform baseline assessments of resting arterial blood pressure, ECT, arterial elasticity/pulse contour analysis, flow-mediated vasodilation and passive limb movement procedures. Participants will return to the laboratory for up to 5 additional study visits (days 10, 20, 30, 60, and 90) and repeat the experimental protocol. After a two-week washout period, participants will receive a 90-day supply of Atorvastatin and perform baseline and follow-up assessments as above.	Drug: Atorvastatin; 10 mg tablet; Other Names: Lipitor®; Drug: Placebo for Atorvastatin; Atorvastatin-matched Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow-mediated dilation (FMD)	Peak change in brachial artery diameter (%)	Baseline, Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Passive Limb Movement (PLM)	Peak change in leg blood flow (ml/min)	Baseline, Day 90

Collaborators and Investigators

• Sponsor: D. Walter Wray
• Collaborators: US Department of Veterans Affairs

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2021
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2030

Study Registration Dates

• First Submitted: March 8, 2024
• First Submitted That Met QC Criteria: March 8, 2024
• First Posted (Actual): March 15, 2024

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: exercise tolerance; nitric oxide; HFpEF; vascular health
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: 138675

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No