# Overcoming Exercise Intolerance in Veterans with Heart Failure: The Role of NO.

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2020 · —

## Abstract

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.
To date, studies concerning exercise intolerance in this patient group have failed to provide data linking
mechanisms with functional outcomes. Thus, a series of translational studies are proposed to comprehensively
quantify the relationship between NO bioavailability and SNS activity in this patient group, and relate these
mechanistic findings to the development of exercise intolerance and muscle fatigue in Veterans suffering from
HFrEF.
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. It is hypothesized that chronic AOx administration
(Vitamins C [1000mg], E [400 IU], and Alpha Lipoic Acid [600 mg], daily for 8 weeks) will reduce circulating free
radical levels, subsequently improving NO bioavailability and inhibiting of SNS activity, which will in turn improve
vascular function and exercising limb blood flow.
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. Is it hypothesized that chronic BH4
administration (10 mg/kg daily for 8 weeks) will improve NO bioavailability and inhibit SNS activity, which will in
turn improve vascular function and exercising limb blood flow.
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...

## Key facts

- **NIH application ID:** 9989670
- **Project number:** 5I01RX001311-04
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** D. Walter Wray
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989670

## Citation

> US National Institutes of Health, RePORTER application 9989670, Overcoming Exercise Intolerance in Veterans with Heart Failure: The Role of NO. (5I01RX001311-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989670. Licensed CC0.

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