Exercise and NO in HFrEF

August 1, 2025 updated by: VA Office of Research and Development

Overcoming Exercise Intolerance in Veterans With Heart Failure: The Role of NO

Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Heart failure with a reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease, now affects almost 6 million Americans. Within the VA Health Care System, HFrEF hospital admission rates continue to rise, and remain the number one reason for discharge from VA hospitals nationwide. Unfortunately, over one-third of all Veterans suffering from HFrEF die within two years of discharge despite optimized drug therapy, an unacceptably high number. This proposal is focused on how impaired muscle blood flow contributes to exercise intolerance in HFrEF, and on subsequently developing strategies for restoring exercise tolerance and slowing disease progression in this patient group. It is anticipated that knowledge gained from these studies will contribute to improved standard of care, quality of life, and prognosis in this VA patient group.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Heart failure with reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of the disease is an elevation in sympathetic nervous system (SNS) activity, which manifests peripherally as chronic vasoconstriction. In HFrEF patients, peripheral vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, premature skeletal muscle fatigue, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway. Thus, interventions focused on improving NO bioavailability may offer a new, unexplored strategy for inhibiting SNS overactivity in HFrEF, and thus represent a novel approach for improving and exercise tolerance.

Specific Aim 1 will utilize an oral antioxidant (AOx) cocktail to study whether disruptions in oxidative stress can favorably influence exercise tolerance in HFrEF patients.

Specific Aim 2 will examine the efficacy of oral tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), to improve exercise intolerance in HFrEF patients.

Specific Aim 3 will examine the therapeutic potential of aerobic, knee-extensor (KE) exercise training to improve skeletal muscle blood flow and thus exercise tolerance in HF patients. Importantly, this exercise modality produces a potent training stimulus without the significant cardiopulmonary stress that accompanies more traditional, whole-body exercise. It is proposed that 12 weeks of supervised KE training will increase NO bioavailability and inhibit SNS activity, which will in turn improve vascular function and exercising limb blood flow.

Specific Aim 4 will examine whether the interventional strategies in Aims 1-3 can improve adherence to an 8-week clinical cardiac rehabilitation program. It is hypothesized that chronic AOx consumption (Aim 1), BH4 consumption (Aim 2), and aerobic exercise training (Aim 3) interventions will reduce the rate of attrition from Phase II outpatient Cardiac Rehabilitation in HFrEF patients compared to patients that did not participate in an interventional phase of the study.

The investigators anticipate that disrupting this "vicious cycle" of vasoconstriction in HFrEF may improve overall vascular health to such a degree that significant improvements in exercise-related symptoms are realized, which could therefore improve enrollment in a cardiac rehabilitation program. In this context, findings from the proposed work may provide an important link between vascular and rehabilitative medicine, thus serving to refine current strategies for the treatment of Veterans with HFrEF, ultimately leading to enhanced quality of life in this cohort.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
68

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • United States
    • Utah
      • Salt Lake City, Utah, United States, 84148-0001
        • VA Salt Lake City Health Care System, Salt Lake City, UT

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

General Inclusion/Exclusion Criteria:

  • The study group will include subjects with a history of stable cardiomyopathy (ischemic and non-ischemic, >3 months duration, ages 45-75 yrs) despite a minimum of 6 weeks of optimal treatment.
  • Optimal therapy will be according to American Heart Association (AHA) /American College of Cardiology (ACC) and Heart Failure Society of America (HFSA) HF guidelines, including treatment with angiotensin-converting enzyme (ACE) and -blocker therapy (for at least 6 weeks), or have documented reason for variation, including medication intolerance, contraindication, patient preference, or personal physician's judgment.
  • Patient enrollment will be limited to those individuals with New York Heart Association (NYHA) class II and III symptoms, left ventricular ejection fraction <35% (LVEF), with no or minimal smoking history (<15 pk yrs), and without pacemakers.

Exclusion Criteria:

  • Patients with atrial fibrillation or HF believed to be secondary to atrial fibrillation will be excluded.
  • Patients with HF secondary to significant uncorrected primary valvular disease (except mitral regurgitation secondary to left ventricular dysfunction) will also be excluded.
  • Patients will be sedentary, defined here as no regular physical activity for at least the prior 6 months and current activity level will be documented by an activity questionnaire.
  • Patients must have no orthopedic limitations that would prohibit them from performing knee-extensor exercise.
  • Due to the typical age of patients with HF, all women will be postmenopausal (either natural or surgical) defined as a cessation of menses for at least 2 years, and in women without a uterus, follicle stimulating hormone (FSH) >40 IU/L.

  • Women currently taking hormone replacement therapy (HRT) will be excluded from the proposed studies due to the direct vascular effects of HRT Comorbidity Exclusion Criteria: Patients with significant non-cardiac comorbidities, which if present could alter the study results, will be excluded.

    • These include a diagnosis of Dementia
    • Severe chronic obstructive pulmonary disease (COPD)
    • Peripheral Vascular Disease
    • Anemia
    • Sleep-related Breathing Disorder
    • Severe Valvular Heart Disease
    • Diabetes (if on insulin therapy)
    • or End-stage Malignancy
  • The investigators will also exclude morbidly obese patients (BMI >40), patients with uncontrolled Hypertension (>160/100), Anemia (Hgb<9) and Severe Renal Insufficiency (individuals with creatinine clearance <30 by the Cockcroft-Gault formula).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Oral AOx
8 week oral antioxidant treatment
Dietary supplement: Antioxidant
Daily consumption of over-the-counter vitamins (600mg alpha lipoic acid, 1000mg vitamin c, 600IU vitamin E)
Placebo Comparator: Oral AOx (placebo)
Placebo for arm 1
Dietary supplement: Antioxidant
Daily consumption of over-the-counter vitamins (600mg alpha lipoic acid, 1000mg vitamin c, 600IU vitamin E)
Experimental: Oral BH4
8 week oral tetrahydrobiopterin treatment
Dietary supplement: Tetrahydrobiopterin (BH4)
Daily consumption of BH4 (10mg/kg)
Other Names:
  • Kuvan
Placebo Comparator: Oral BH4 (placebo)
Placebo for arm 3
Dietary supplement: Tetrahydrobiopterin (BH4)
Daily consumption of BH4 (10mg/kg)
Other Names:
  • Kuvan
Experimental: Ex training
8-week knee-extensor exercise training program
Other: Exercise training
Aerobic exercise training program (3x/week for 8 weeks, 1 hour per session)
Sham Comparator: Ex training (attn con)
Attention control for arm 5
Other: Exercise training
Aerobic exercise training program (3x/week for 8 weeks, 1 hour per session)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Blood Flow
Time Frame: four years
ultrasound Doppler
four years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
VA Office of Research and Development

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Utah

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: David W. Wray, PhD, VA Salt Lake City Health Care System, Salt Lake City, UT

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 31, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 31, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 27, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 27, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 2, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 6, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 1, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • F1311-R

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

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Heart Failure With Reduced Ejection Fraction

Clinical Trials on Antioxidant

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings