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

基本信息

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
项目类别：
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

项目摘要

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.

甜菜根汁逆转 PAD 功能障碍：甜菜 PAD 试验我们和其他人的工作表明，患有下肢外周动脉疾病 (PAD) 的人与没有症状的人相比，有更严重的功能障碍、更快的功能衰退和更快的行动能力丧失软垫。在 PAD 中，步行活动期间下肢缺血会增加腓肠肌（小腿）肌肉的氧化压力，损害肌纤维，并诱发小腿肌肉线粒体功能障碍。但医学疗法却很少改善 PAD 的功能障碍或预防活动能力丧失。甜菜根汁中富含无机硝酸盐，是一氧化氮 (NO) 的主要来源。在临床前研究中， NO 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，从而恢复和修复骨骼肌。在三项小型试点临床试验中，其中包括我们的联合研究员 Jason Allen 博士的两项研究，口服硝酸盐或甜菜根汁显着改善与安慰剂相比，PAD 患者的步行能力。我们提出了一个明确的多中心双盲在 210 名 PAD 患者中进行甜菜根汁与安慰剂的随机试验。我们假设通过增加下肢灌注、小腿肌肉线粒体活性、肌纤维健康和再生，甜菜根果汁将改善 PAD 的步行表现。我们的主要目标将确定与安慰剂相比，在 4 个月的随访中，甜菜根汁显着改善了六分钟步行能力。在次要目标中，我们将区分甜菜根汁对六分钟步行的急性和慢性影响并测量甜菜根的影响果汁对小腿肌肉灌注、肱动脉血流介导的扩张、体力活动 (ActiGraph)、步行损伤问卷和短期体能表现测试 (SPPB)。甜菜根汁中的硝酸盐代谢为亚硝酸盐，随后代谢为一氧化氮，达到峰值亚硝酸盐水平 2.5 摄入后数小时。硝酸盐代谢转化为亚硝酸盐的程度存在个体差异。因此，在次要目标中，在随机饮用甜菜根汁的 PAD 参与者中，我们将确定饮用甜菜根汁 2.5 小时后，血浆亚硝酸盐是否达到更高峰值或增加更多在 4 个月的随访中，与那些达到 6 分钟步行的人相比，消耗量有更大的增加血浆亚硝酸盐峰值较低或增幅较小。我们还将测量甜菜根汁效果的持久性，在最后一剂甜菜根汁或安慰剂后 7 天和 14 天重复六分钟步行距离。我们将在基线和随访时进行小腿肌肉活检，以研究甜菜根汁对肌肉的影响线粒体生物发生和活性、线粒体自噬、毛细血管特征和肌纤维健康。如果甜菜根汁可以改善 PAD 的功能表现并防止功能下降，那么这将广泛可用且耐受性良好的治疗将对预防活动能力丧失和改善大量且不断增加的 PAD 致残者的生活质量。