Potential benefits of a nitrate juice supplement to improve skeletal muscle function andassociated physical capacity will be studied in patients with Long COVID. Consentingpatients with Long-COVID will be randomized to receive Beet-It nitrate beverage groupversus a nitrate-depleted placebo beverage. Both groups will receive physical therapy atthe long COVID Clinic at VAPHS with therapeutic goals to improve strength, balance,inspiratory, and aerobic capabilities. Physical therapy will last for 2 weeks and include2 or 3 sessions with a physical therapist a week depending on each individual's exercisetolerance. These sessions can take place on-site or at home (or a hybrid combination) Allparticipants will undergo functional assessments and tissue assessments before and afterthe 14-day study intervention.
In a proof of concept pilot, the investigators will study 30 Veterans with long COVID,
comparing 15 who consume two weeks of daily nitrate-rich beetroot juice versus matched
Veterans who consume a nitrate-depleted placebo. Nitrate is metabolized to increase
cellular nitric oxide once it is ingested. Nitric oxide (NO) is a signaling molecule that
contributes to numerous physiological functions, including enhanced skeletal muscle
mitochondrial respiration, which may thereby lead to decreased fatigability and increased
physical function. NO is commonly produced from the conversion of the amino acid
L-arginine to L-citrulline in the presence of oxygen. However, inorganic nitrate provided
as a dietary supplement can serve as an additional substrate for bioactive nitrite and
downstream NO, particularly during the ischemic stress of exercise. In this study,
consenting patients with Long-COVID will be randomized to receive Beet-It nitrate
beverage group as a source of inorganic nitrites and NO, versus a nitrate-depleted
placebo beverage. Both groups will undergo simultaneous physical therapy. Primary
endpoints center on meaningful clinical changes, including fatigability (i.e., rating of
perceived exertion during steady-state walking), cardiorespiratory fitness (i.e., peak
oxygen utilization [VO2] as well as submaximal VO2 at anaerobic threshold [VAT]). In
addition, serology and skeletal muscle assessments will include nitrate and nitrite
levels and mitochondrial respiration to analyze nitrite-mediated mechanisms underlying
functional changes.
Principal investigator Daniel Forman, MD has developed expertise in nitrite therapeutics
using nitrite capsule supplements for older sedentary adults in relation to sedentariness
and heart failure. This SPiRE proposal focuses nitrite therapeutics to both younger and
older adults with long COVID.
Aims: To conduct a pilot randomized controlled trial to study the benefits of beetroot
juice versus placebo in 30 Veterans with prior COVID-19 infection and who have been left
with residual symptoms of long COVID. All participants will receive a daily study juice
intervention for 2 weeks in association with physical therapy with a standardized
exercise regimen designed to increase strength and aerobic function.
- Aim 1: To study the efficacy of nitrite supplementation to reduce fatigability over
two weeks as measured by rating of perceived exertion (RPE) during submaximal
steady-state 1.5 mile per hour walking. Walking efficiency (VO2 per kg) will also be
assessed during steady-state walking.
- Aim 2: To study the benefits of nitrite supplementation to increase
cardiorespiratory fitness (peak oxygen utilization [VO2], VO2 at anaerobic threshold
(VAT), 400 meter walk test (400MWT), and short physical performance battery (SPPB)
after two weeks.
- Aim 3: To explore the utility of nitrite supplementation to enhance skeletal muscle
mitochondrial respiration in long COVID patients as measured by ex vivo Oroboros
analysis.
Dietary Supplement: 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK)
The investigators propose to study the benefits nitrite therapeutics, using nitrate-rich
beetroot juice to increase serum nitrite. The investigators hypothesize that increased
nitrite will improve functional metrics and reduce fatigability in Veterans with long
COVID as a result of enhanced skeletal muscle mitochondrial respiration. Participant will
receive 210 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days
vs the placebo.
Inclusion Criteria:
- Veterans with prior COVID-19, with residual symptoms of long COVID including
increased fatigability (i.e., RPE 10 during steady-state walking and reduced
physical activity (<8 Mets/day)).
- Inclusion limited to age 18 and over
Exclusion Criteria:
- Blood pressure <110/60 mmHg, either systolic or diastolic value
- Unable to hold warfarin, novel oral anticoagulants (NOACs) or aspirin for 3 days
prior to muscle biopsy, or to hold thienopyridine medications for 5 days prior to
muscle biopsy
- Current use of organic nitrates or phosphodiesterase type 5 (PDE5) inhibitors
- Orthopedic or other chronic condition which limits physical activity or functional
testing assessments
- End-stage disease
- Dementia or other reason unable to give informed consent
- Anemia (hemoglobin <11.0 g/dL or <10.0 g/dL)
- Unstable psychiatric diagnosis
- Clinically significant alcohol intake (CAGE score 2 or >) or substance abuse
- Chronic use of oral corticosteroids or medications that affect muscle function
- Use of anti-bacterial mouthwash or antacids that confound the nitrate/nitrite/NO
pathway.
- Involved in another greater than minimal risk study
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Pittsburgh, Pennsylvania, United States
Investigator: Scott B Dreisbach, MS BS
Contact: 412-360-2371
scott.dreisbach@va.gov
Investigator: Daniel E Forman, MD
Daniel E Forman, MD
(412) 360-2917
Daniel.Forman@va.gov
Daniel E Forman, MD, Principal Investigator
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA