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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
17
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 140 ml per day of Beet-It nitrate beverage for 16 mmol of nitrate/day for 14 days vs the placebo.
Participants randomized to the placebo arm will receive 210 ml of nitrate-depleted beverage (cranberry juice) per day for 14 days.
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
Pittsburgh, Pennsylvania, United States
Fatigability
Rating of Rate of Perceived Exertion (RPE) during the 5th minute of a 5-min of a 1.5 mile per hour steady-state treadmill walking test is used as an assessment of fatigability. RPE scale is from 6 (no physical exertion) - 20 (maximal exertion/very hard).
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Walking Efficiency
Walking efficiency (VO2/kg) is assessed by incorporating VO2 assessments during the 5-min steady-state walking protocol. This is assessed using cardiopulmonary exercise testing (CPET) equipment. A lower VO2 for the same functional workload indicates improved efficiency.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
400m Corridor Walk Test (400MCW)
This test measures the amount of time it takes the participant to walk a 400-meter course to assess cardiovascular and pulmonary fitness or to predict adverse outcomes such as mobility disability.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Short Performance Physical Battery (SPPB)
The SPPB is a test of balance, gait, strength, and endurance that combines gait speed, chair stand and balance tests. SPPB scaled score ranges from 0 - 12. Scores of 0 indicate that the participant is unable/barely able to perform the tasks, while 12 indicates they completed all tasks optimally.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Mitochondrial Respiration
To determine the impact of nitrite-rich juice supplementation on skeletal muscle mitochondrial respiration on patients with Long COVID, muscle biopsy of the vastus lateralis will be completed at baseline and following 2 weeks of supplementation. At each time point muscle respiratory capacity will be measured using the Oroboros-2k system. The main outcome will be state 3 respiration (maxOXPHOS, pmol/mg/min wet.wt.). Data will be reported as Mean +/- standard deviation.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Peak oxygen utilization (VO2) non-normalized
Peak VO2 (ml/min) non-normalized to weight will be collected using symptom-limited cardiopulmonary exercise testing (CPET).
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
VO2 at anaerobic threshold (AT) non-normalized
VO2 (ml/min) non-normalized at AT will be assessed using symptom-limited CPET. The VO2 at AT for the general population occurs at approximately 50-60% of the peak VO2.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Veterans RAND-12 (VR-12)
The Veterans RAND-12 (VR-12) is a brief, multi-use, self-administered health survey comprised of 12 items. The instrument is primarily used to measure health related quality of life, to estimate disease burden, and to evaluate disease-specific benchmarks. There are two score components: a Physical Component Score a Mental Component Score. The scores are a standardized t-score with mean of 50 and standard deviation of 10.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Peak oxygen utilization (VO2) normalized to weight
Peak VO2 will be collected using symptom-limited cardiopulmonary exercise testing (CPET). The average sedentary male will achieve a peak VO2 of approximately 35 to 40 mL/kg/min. The average sedentary female will score a VO2 max of between 27 and 30 mL/kg/min.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Serum Nitrate
5 ml of blood will be collected from participants and spun down using a centrifuge to separate the plasma from the rest of the blood. Serological sampling is completed at baseline and at final visit. Serum nitrite (µmol/L) and nitrate levels (µmol/L) will be measured at baseline and after the study intervention to evaluate the successful metabolism of nitrate (in beetroot juice) to nitrite.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
VO2 at anaerobic threshold (AT) normalized to weight
VO2 (ml/kg/min) at AT will be assessed using symptom-limited CPET. The VO2 at AT for the general population occurs at approximately 50-60% of the peak VO2.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
Serum Nitrite
5 ml of blood will be collected from participants and spun down using a centrifuge to separate the plasma from the rest of the blood. Serological sampling is completed at baseline and at final visit. Serum nitrite (µmol/L) and nitrate levels (µmol/L) will be measured at baseline and after the study intervention to evaluate the successful metabolism of nitrate (in beetroot juice) to nitrite.
Time frame: Baseline (pre-intervention) to Follow-up (post-intervention); approx. 2 weeks
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