# Novel Approaches for Improving Vascular Function in Veterans with HFpEF

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2021 · —

## Abstract

PROJECT SUMMARY: Heart failure with preserved ejection fraction (HFpEF) accounts for greater than 50% of
the 6 million HF cases nationwide, and the prevalence relative to heart failure with reduced ejection fraction
(HFrEF) continues to rise at a rate of 1% per year, presenting an imminent need for further research addressing
the pathophysiology of this pervasive disease. The clinical presentation of HFpEF is defined by dyspnea upon
exertion and severe exercise intolerance, symptoms that are likely due, at least in part, to disease-related
changes in the peripheral circulation. While the mechanisms responsible for vascular dysfunction in HFpEF have
not been established, chronic inflammation and associated production of reactive oxygen species (ROS),
stemming from HFpEF-associated comorbidities and inactivity, appear to play a crucial role. The peripheral
vasculature of this patient group represents an area that is particularly vulnerable to the harmful effects of ROS,
which interact with, and reduce bioavailability of, nitric oxide (NO). The proposed work thus seeks to examine
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 physical capacity and vascular function
in this patient group. Using a randomized, double-blind, crossover design, a series of experiments are proposed
that will combine novel methodology with targeted pharmacologic interventions to selectively determine the
importance of NO substrate, enzymatic cofactor bioavailability, and inflammation/ROS to disease-related
changes in NO signalling in HFpEF. Specific Aim 1 will test the hypothesis that chronic enteral L-Citrulline
administration (100mg/kg) will increase NO substrate, leading to an increase in NO bioavailability and a
subsequent improvement in vascular function. Specific Aim 2 will explore whether administration of
tetrahydrobiopterin (BH4), an essential cofactor for endothelial NO synthase, can improve enzymatic coupling
and therefore restore vascular function in patients with HFpEF. Specific Aim 3 will evaluate the potential
pleiotropic properties of atorvastatin, a HMG CoA reductase inhibitor, to reduce inflammation and oxidative
stress, leading to improvement in physical capacity and vascular function. Each Specific Aim will combine in vivo
and ex vivo assessments to comprehensively determine the impact of the proposed interventions on the cascade
of inflammation, oxidative stress and exercise intolerance in this patient group. Upon completion, it is anticipated
that the proposed work focused on developing a better understanding of the mechanisms that contribute to
impaired peripheral vascular function in HFpEF, and pinpointing novel strategies to alleviate vascular dysfunction
and promote physical cpacity, will translate directly into an improved ability to perform activities of daily living,
which is likely to lead to improved quality of life ...

## Key facts

- **NIH application ID:** 10123187
- **Project number:** 1I01CX002152-01A1
- **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:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123187

## Citation

> US National Institutes of Health, RePORTER application 10123187, Novel Approaches for Improving Vascular Function in Veterans with HFpEF (1I01CX002152-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123187. Licensed CC0.

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