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

长期COVID的患病率在退伍军人中激增，患有这种疾病的退伍军人通常会 功能逐渐下降，生活质量下降，残疾增加。骨骼肌 病理生理学被认为是长期COVID病理生理学和临床的重要决定因素。 下降。Forman博士是一名心脏病学家和老年病学家，目前正在研究 研究性新药（IND）亚硝酸盐胶囊补充剂在老年人中的应用 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， 骨骼肌线粒体呼吸其次，他正在探索线粒体呼吸是否会改变 与身体功能的变化有关。特别是，他正在研究如果增加血清和骨骼肌 亚硝酸盐升高与心肺适应性的改善相关（即，峰值氧利用率[VO 2]），以及 降低疲劳性（即，在稳态次最大[1.5英里/ 小时]步行）。在这个SPiRE应用程序中，Forman博士建议将他在亚硝酸盐治疗方面的专业知识重新定向到 退伍军人与长期COVID。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施用。 安慰剂当甜菜根汁被摄入时，硝酸盐被代谢为亚硝酸盐。与IND亚硝酸盐胶囊相比， 甜菜根汁相对更容易给药，更便宜，并且在血液动力学上更安全。而血清 与亚硝酸盐相比，在甜菜根汁干预的研究中，亚硝酸盐水平并不一直高 胶囊，该建议旨在优化亚硝酸盐水平，每天使用210毫升的甜菜硝酸盐饮料（詹姆斯 白色饮料有限公司，Ipswich，UK）提供16 mmol硝酸盐/天，持续14天，而210 ml硝酸盐- 耗尽的安慰剂。所有参与者还将接受物理治疗。本SPiRE研究的终点为 主要用于生理功能。终点（2周干预前后测量）包括 疲劳性以及稳态步行期间的步行效率（VO 2/kg）。此外，传统 功能指标包括峰值VO 2、无氧阈下VO 2、6分钟步行距离、短体力 还将评估性能电池和肺功能测试。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 变化此外，骨骼肌的分析将阐明亚硝酸盐介导的身体功能变化 与骨骼肌呼吸的变化相关。总的来说，这项提议符合退伍军人事务部的要求。 研究与发展办公室致力于研究，帮助受COVID-19影响的退伍军人， 它也符合康复研究与发展的使命，以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 应用这一引人注目的基于SPiRE的分析的数据和动力来追求随后的MERIT 这项试验更明确地强化了亚硝酸盐疗法对长期COVID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.