Nitrite Supplementation to Mitigate Fatigability and Increase Function in Long COVID Patients

长期冠状病毒感染在退伍军人中的患病率正在激增，患有这种疾病的退伍军人通常会发生 功能进行性下降，生活质量下降，残疾增加。骨骼肌 病理生理学被认为是长冠状病毒病病理生理学和临床的重要决定因素。 下降了。福尔曼博士是一名心脏病专家和老年病学家，目前正在进行研究，研究 研究用新药(IND)亚硝酸盐胶囊补充剂治疗老年糖尿病 久坐和/或心力衰竭。在这项工作中，他主要关注亚硝酸盐的效用，以增加 骨骼肌线粒体呼吸。其次，他正在探索线粒体呼吸是否会发生变化 与身体机能的变化有关。特别是，他正在研究是否增加了血清和骨骼肌 亚硝酸盐水平的升高与心肺健康状况(即最高氧利用率[VO2])的改善相关，以及 疲劳性降低(即，在稳态次极值[1.5英里/秒]期间感觉到的消耗[RPE]的额定值 小时]步行)。在这项SPIRE申请中，福尔曼博士建议将他在亚硝酸盐疗法方面的专业知识重新定向到 患有长期冠状病毒的退伍军人。亚硝酸盐将作为富含硝酸盐的甜菜根汁与缺乏硝酸盐的甜菜根汁进行管理 安慰剂。当甜菜根汁被摄入时，硝酸盐被代谢成亚硝酸盐。与IND亚硝酸盐胶囊相比， 甜菜根汁相对更容易服用，价格更低，血液动力学更安全。鉴于血清 在甜菜根汁干预研究中，与亚硝酸盐相比，亚硝酸盐水平并不是一直很高。 胶囊，这项建议旨在优化亚硝酸盐水平，每天使用210毫升甜菜硝酸盐饮料(詹姆斯 英国伊普斯威奇的白色饮料有限公司)每天提供16毫摩尔的硝酸盐，持续14天，而不是210毫升的硝酸盐- 耗尽的安慰剂。所有参与者还将接受物理治疗。这项SPIRE研究的终点是 主要面向身体功能。终点(在两周干预前和干预后测量)包括 稳态步行时的疲劳性和步行效率(VO2/kg)。此外，传统的 功能指标：峰值VO2、无氧阈值VO2、6分钟步行距离、短程体能 还将评估电池性能和肺功能测试。亚硝酸盐水平(血清学和 在骨骼肌本身)将被测量，以最好地确定亚硝酸盐和假定的临床关系 改变。此外，对骨骼肌的分析将澄清亚硝酸盐是否介导了身体机能的变化。 与骨骼肌呼吸的变化有关。总体而言，这项建议符合退伍军人事务部的要求 研究和发展办公室致力于帮助受新冠病毒影响的退伍军人的研究， 它也符合康复研究和发展组织的使命，即最大限度地提高退伍军人的 功能独立、生活质量和参与生活和社区。福尔曼博士预计 应用来自这一引人注目的基于尖顶的分析的数据和动量来追求后续的优点 这项试验更明确地强化了亚硝酸盐疗法对慢性冠状病毒感染患者的价值。

Prevalence of long COVID is surging among Veterans, and Veterans afflicted with this disease typically incur progressive declines in function, diminished quality of life and increased disability. Skeletal muscle pathophysiology has been implicated as a significant determinant of long COVID pathophysiology and clinical declines. Dr. Forman is a cardiologist and geriatrician who is currently engaged in research studying benefits of nitrite supplementation with investigational new drug (IND) nitrite capsule supplements in older adults with sedentariness and/or heart failure. In that work, he is focusing primarily on the utility of nitrites to increase skeletal muscle mitochondrial respiration. Secondarily, he is exploring if mitochondrial respiration changes correlate to changes in physical function. In particular, he is studying if increased serum and skeletal muscle nitrite elevations correlate to improvements in cardiorespiratory fitness (i.e., peak oxygen utilization [VO2]), and to decreased fatigability (i.e., rating of perceived exertion [RPE] during steady-state submaximal [1.5 miles per hour] walking). In this SPiRE application, Dr. Forman proposes to redirect his expertise in nitrite therapeutics to Veterans with long COVID. Nitrites will be administered as nitrate-rich beetroot juice versus nitrate-poor placebo. When beetroot juice is ingested, nitrates are metabolized to nitrite. Compared to IND nitrite capsules, beetroot juice is relatively easier to administer, less expensive, and hemodynamically safer. Whereas serum nitrite levels have not been consistently high in studies of beetroot juice interventions as compared to nitrite capsules, this proposal aims to optimize nitrite levels using 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) to provide 16 mmol of nitrate/day for 14 days versus a 210 ml of nitrate- depleted placebo. All participants will also undergo physical therapy. Endpoints in this SPiRE study are oriented principally to physical function. Endpoints (measured pre- and post- the 2-week intervention) include fatigability as well as walking efficiency (VO2/kg) during steady-state walking. Furthermore, traditional functional indices of peak VO2, VO2 at anaerobic threshold, 6-minute walk distance, short physical performance battery, and pulmonary function tests will also be assessed. Nitrite levels (both serologically and in the skeletal muscle itself) will be measured to best ascertain the relationship of nitrite and putative clinical changes. In addition, analyses of skeletal muscle will clarify if nitrite-mediated changes in physical function correlate to changes in skeletal muscle respiration. Overall, this proposal aligns with the Veteran’s Affairs Office of Research and Development’s commitment to research that helps Veterans affected by COVID-19, and it also aligns with the Rehabilitation Research and Development’s mission to maximize Veterans’ functional independence, quality of life and participation in their lives and community. Dr. Forman anticipates applying the data and momentum from this compelling SPiRE-based analysis to pursue a subsequent MERIT trial that reinforces the value of nitrite therapeutics more definitively for long COVID patients.