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

BEET根汁逆转PAD的功能障碍：BEET PAD试验 我们和其他人的工作表明，下肢外周动脉疾病（PAD）患者 有更大的功能障碍，更快的功能下降，更快的移动性损失比那些没有 垫.在PAD中，步行活动期间下肢缺血增加腓肠肌（小腿）肌肉氧化 应激，损伤肌纤维，并诱导小腿肌肉线粒体功能障碍。然而，很少有医学疗法 改善PAD功能障碍或预防PAD活动性丧失。 甜菜根汁中富含的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，恢复和修复骨骼肌。在三个小型的临床试验中， 包括我们的合作研究者Jason艾伦博士的两项研究，口服硝酸盐或甜菜根汁显著改善了 PAD患者的步行能力，与安慰剂相比。我们提出了一个明确的多中心双盲 甜菜根汁与安慰剂在210名PAD患者中的随机试验。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的行走性能。我们的主要目标是确定，与安慰剂相比， 甜菜根汁在4个月的随访中显著改善了6分钟步行。在次要目标中，我们将 区分甜菜根汁对6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 损伤问卷和短期物理性能电池（SPPB）。 甜菜根汁中的硝酸盐代谢为亚硝酸盐，随后代谢为NO，达到峰值亚硝酸盐水平2.5 几小时后就死了个体间的变异性存在于硝酸盐到亚硝酸盐的代谢转化的程度。 因此，在次要目标中，在随机分配到甜菜根汁的PAD参与者中，我们将确定 无论是那些在甜菜根汁后2.5小时血浆亚硝酸盐达到更高峰值或更大增加的人， 在4个月的随访中，与那些达到 血浆亚硝酸盐的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， 在最后一次服用甜菜根汁或安慰剂后的第7天和第14天，重复6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。 如果甜菜根汁能改善PAD的功能表现并防止其功能下降， 可用且耐受性良好的治疗将对预防活动性丧失和改善 由于PAD而致残的人数越来越多的人的生活质量。

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.