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

甜菜根汁逆转PAD功能损害：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 功能障碍更严重，功能衰退更快，行动不便更快 垫子。在PAD中，步行活动中的下肢缺血增加了腓肠肌(小腿)的氧化 应激，损伤肌纤维，并诱导小腿肌肉线粒体功能障碍。然而，很少有药物治疗。 改善PAD中的功能损害或防止行动不便。 甜菜根汁中含有大量的无机硝酸盐，是一氧化氮(NO)的主要来源。在临床前研究中， NO增加血管生成和灌流，保护缺血损伤，增强线粒体活性， 并激活卫星细胞，恢复和修复骨骼肌。在三个小型试点临床试验中， 包括我们的合作研究员杰森·艾伦博士的两项研究，口服硝酸盐或甜菜根汁显著改善 与安慰剂相比，PAD患者的行走能力。我们提出了一种确定性的多中心双盲 210例PAD患者甜菜根汁与安慰剂的随机对照试验。我们假设通过增加 腿部血流、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中的行走能力。我们的主要目标将决定，与安慰剂相比， 在4个月的随访中，甜菜根汁显著改善了6分钟的步行能力。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，并测量甜菜根汁的影响 果汁对小腿肌肉的灌流、肱动脉血流介导的扩张、体力活动(活动图)、步行 损伤问卷和短时物理性能电池(SPPB)。 甜菜根汁中的硝酸盐被代谢成亚硝酸盐，然后代谢成一氧化氮，达到亚硝酸盐水平的峰值2.5 摄取后数小时。硝酸盐向亚硝酸盐的代谢转化程度存在个体间的差异。 因此，在第二个目标中，在随机服用甜菜根汁的PAD参与者中，我们将确定 无论是甜菜根汁2.5小时后血浆亚硝酸盐达到较高峰值或升高较大者 与那些在4个月后达到6分钟步行的人相比，在4个月的随访中，6分钟步行的消耗量有更大的增长 血浆亚硝酸盐峰值较低或升高幅度较小。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分钟的步行距离。我们会 进行小腿肌肉活组织检查，研究甜菜根汁对肌肉的影响 线粒体的生物发生和活性、有丝分裂、毛细血管特征和肌纤维健康。 如果甜菜根汁改善功能表现并防止PAD功能下降，这一广泛的 现有的和耐受性良好的治疗将对预防行动能力丧失和改善产生重大影响。 因PAD而致残的人数越来越多，生活质量越来越高。

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.