Nitrite Supplementation in Long COVID Patients

Potential benefits of a nitrate-rich juice supplement to improve skeletal muscle function and associated physical capacity will be studied in patients with Long COVID. Consenting patients with Long-COVID will be randomized to receive Beet-It nitrate beverage group versus a nitrate-depleted placebo beverage. Both groups will receive physical therapy at the long COVID Clinic at VAPHS with therapeutic goals to improve strength, balance, inspiratory, and aerobic capabilities. Physical therapy will last for 2 weeks and include 2 or 3 sessions with a physical therapist a week depending on each individual's exercise tolerance. These sessions can take place on-site or at home (or a hybrid combination) All participants will undergo functional assessments and tissue assessments before and after the 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: We will conduct a pilot randomized controlled trial to study the benefits of nitrate-rich beetroot juice versus placebo in 30 Veterans with a diagnosis of Long COVID. All participants will receive a daily study juice intervention for 2 weeks. All participants will be encouraged to participate in the standard physical therapy program in the Long COVID clinic.

Aim 1: To study the efficacy of nitrate-rich juice supplementation to reduce fatigability as measured by rating of perceived exertion (RPE) during submaximal steady-state 1.5 mile per hour walking after two weeks of treatment in patients with Long Covid. Walking efficiency (VO2 per kg) will also be assessed in association with fatigability.

Aim 2: To study the benefits of nitrate-rich juice supplementation to increase cardiorespiratory fitness (peak oxygen utilization \[VO2\], VO2 at anaerobic threshold (VAT), 400-meter corridor walk (400MCW), short physical performance battery (SPPB) in patients with Long COVID after two weeks of treatment.

Aim 3: To explore the utility of nitrate-rich juice supplementation to enhance skeletal muscle mitochondrial respiration in patients with Long COVID as measured by ex vivo Oroboros analysis.

Eligibility Criteria:
Inclusion Criteria:

* Veterans with prior COVID-19, with residual symptoms of long COVID including increased fatigability.
* Inclusion limited to age 18 and over

Exclusion Criteria:

* Blood pressure \<110/60 mmHg, either systolic or diastolic value which may affect participant safety during assessments will be at the discretion of the study physician
* 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 in men or hemoglobin \<10.0 g/dL in women)
* Unstable psychiatric diagnosis
* Clinically significant alcohol intake 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.
* Suicidal ideations
* Unwilling to hold Viagra-like drugs (i.e. Viagra, Cialis, Levitra, other phosphodiesterase inhibitors)
* Involved in another greater than minimal risk study
* Other clinically unstable medical condition as determined by the study physician