BEET root juice to reverse functional impairment in PAD: The BEET PAD Trial

甜菜根汁逆转 PAD 功能损伤：甜菜 PAD 试验

• 批准号: 10649671
• 负责人: Mary McGrae McDermott
• 金额: $ 65.7万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649671
• 关键词: Acute; Arteries; Biogenesis; Biological; Biopsy; Blood capillaries; Cell Nucleus; Characteristics; Chronic; Clinical Trials; Consumption; Disabled Persons; Dose; Double-Blind Method; Elderly; Environment; Fiber; Gastrocnemius Muscle; Health; Hour; Hypoxia; Impairment; Ingestion; Ischemia; Juice; Lower Extremity; Magnetic Resonance Imaging; Measures; Mediating; Medical; Metabolic; Mitochondria; Muscle; Muscle Mitochondria; NOS3 gene; Natural regeneration; Nitrates; Nitric Oxide; Nitrites; Oral; Outcome; Oxidative Stress; Oxygen Consumption; Participant; Pathway interactions; Performance; Perfusion; Peripheral arterial disease; Persons; Physical Performance; Physical activity; Placebos; Plasma; Quality of life; Questionnaires; Randomized; Reperfusion Injury; Research Personnel; Skeletal Muscle; Source; Spirometry; Walking; Work; actigraphy; angiogenesis; arterial spin labeling; brachial artery; density; disability; follow-up; functional decline; functional disability; improved; inter-individual variation; ischemic injury; mitochondrial dysfunction; preclinical study; prevent; primary outcome; randomized trial; randomized, clinical trials; repaired; satellite cell

BEETroot juice to reverse functional impairment in PAD: The BEET PAD Trial Our work and that of others demonstrate that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, more rapid functional decline, and faster mobility loss than those without PAD. In PAD, lower extremity ischemia during walking activity increases gastrocnemius (calf) muscle oxidative stress, damages myofibers, and induces calf muscle mitochondrial dysfunction. Yet few medical therapies improve functional impairment or prevent mobility loss in PAD. Inorganic nitrate, abundant in beetroot juice, is a major source of nitric oxide (NO). In preclinical studies, NO increases angiogenesis and perfusion, protects against ischemic injury, enhances mitochondrial activity, and activates satellite cells, which restore and repair skeletal muscle. In three small pilot clinical trials, including two by our co-investigator Dr. Jason Allen, oral nitrate or beetroot juice meaningfully improved walking ability in people with PAD, compared to placebo. We propose a definitive multi-centered double-blind randomized trial of beetroot juice vs. placebo in 210 people with PAD. We hypothesize that by increasing lower extremity perfusion, calf muscle mitochondrial activity, and myofiber health and regeneration, beetroot juice will improve walking performance in PAD. Our primary aim will determine whether, compared to placebo, beetroot juice significantly improves six-minute walk at 4-month follow-up. In secondary aims, we will distinguish acute from chronic effects of beetroot juice on six-minute walk and measure the effects of beetroot juice on calf muscle perfusion, brachial artery flow-mediated dilation, physical activity (ActiGraph), the Walking Impairment Questionnaire, and the short physical performance battery (SPPB). Nitrate in beetroot juice is metabolized to nitrite and subsequently to NO, attaining peak nitrite levels 2.5 hours after ingestion. Inter-individual variability exists in the extent of metabolic conversion of nitrate to nitrite. Therefore, in a secondary aim, among PAD participants randomized to beetroot juice, we will determine whether those who attain a higher peak or a greater increase in plasma nitrite 2.5 hours after beetroot juice consumption have greater increases in six-minute walk at 4-month follow-up, compared to those who attain a lower peak or a smaller increase in plasma nitrite. We will also measure the durability of beetroot juice effects, by repeating six-minute walk distance 7 and 14 days after the final dose of beetroot juice or placebo. We will perform calf muscle biopsy at baseline and follow-up to study the effects of beetroot juice on muscle mitochondrial biogenesis and activity, mitophagy, capillary characteristics, and myofiber health. If beetroot juice improves functional performance and prevents functional decline in PAD, this widely available and well tolerated therapy will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people disabled by PAD.

甜菜根汁以逆转PAD中的功能障碍：甜菜垫试验 我们的工作和其他工作表明，下肢外围动脉疾病（PAD）的人 比没有的功能障碍更大，功能下降和更快的移动性损失比没有 软垫。在PAD中，步行活动期间的下肢缺血会增加胃g骨（小牛）肌肉氧化 压力，损坏肌纤维并诱导小腿肌肉线粒体功能障碍。但很少有医疗疗法 改善功能障碍或防止PAD中的活动损失。 无机硝酸盐，含有甜菜根汁的无机硝酸盐是一氧化氮的主要来源（NO）。在临床前研究中 没有增加血管生成和灌注，防止缺血性损伤，增强线粒体活性， 并激活卫星细胞，该卫星细胞恢复和修复骨骼肌。在三个小型试验临床试验中， 包括我们的共同入选者Jason Allen博士，口服硝酸盐或甜菜根汁有意义地改进 与安慰剂相比，患有垫子的人的步行能力。我们提出了一个确定的多中心双盲 甜菜根果汁与安慰剂的随机试验，有210人的垫子。我们通过增加来假设 下肢灌注，小腿肌肉线粒体活动以及肌纤维健康与再生，甜菜根 果汁将改善垫子中的步行性能。我们的主要目的将确定与安慰剂相比是否 在4个月的随访中，甜菜根汁可显着改善六分钟的步行路程。在次要目标中，我们将 区分急性与甜菜根汁对六分钟步行的慢性作用，并测量甜菜根的影响 小腿肌肉灌注，臂动脉流介导的扩张，体育锻炼（Actigraph），步行，步行 损伤问卷和短体性能电池（SPPB）。 甜菜根汁中的硝酸盐被代谢为亚硝酸盐，随后是NO，达到亚硝酸盐水平2.5 摄入后数小时。个体间的可变性存在于硝酸盐代谢转化为亚硝酸盐的程度。 因此，在次要目标中，在随机将甜菜根汁的参与者中，我们将确定 那些达到较高峰的人还是在甜菜根汁后2.5小时的血浆亚硝酸盐增加 与达到A的人相比 较低的峰或血浆亚硝酸盐的增加。我们还将测量甜菜根汁效应的耐用性， 通过在最终剂量的甜菜根汁或安慰剂剂量后，重复六分钟的步行距离7和14天。我们将 在基线和随访中进行小腿肌肉活检以研究甜菜根汁对肌肉的影响 线粒体生物发生和活性，线粒体，毛细血管特征和肌纤维健康。 如果甜菜根汁可以提高功能性能并防止PAD的功能下降，则可以广泛 可用且容忍良好的疗法将对预防移动损失和改善产生重大影响 大量和越来越多的人的生活质量被PAD残疾。