Far Red Light to Improve Functioning in PAD: the LIGHT PAD Trial

远红光改善PAD的功能：LIGHTER PAD试验 65岁及以上人群中有10%-15%的人患有下肢外周动脉疾病，15%-20%的人患有此病。 年龄在75岁及以上的人。患有PAD的老年人有更大的功能障碍，功能更快 下降，与没有PAD的人相比，行动不便的比率更高。在PAD中，减少了 腓肠肌与腓肠肌氧化应激增加，线粒体损伤， 和肌肉纤维损伤。然而，很少有非侵入性疗法改善PAD患者的功能。 一氧化氮(NO)是一种信号分子，具有改善血液灌流和逆转血管紧张素转换酶的治疗作用。 PAD的骨骼肌病理改变。在临床前研究中，一氧化氮增加血管生成和灌流，保护 抗缺血损伤，增强骨骼肌线粒体活性，激活卫星细胞，从而 恢复和修复骨骼肌。增加NO生物利用度的干预措施具有重大的治疗作用 对于患有PAD的人来说是有潜力的。 亚硝硫醇是NO和NO生物活性的主要来源。临床前研究和我们的初步人类 有证据表明，远红光(波长为670 nm)会释放亚硝硫醇、亚硝酸盐和其他血管活性物质 物种。为准备这项提案而完成的四项试点研究表明，单次剂量的远红光 治疗可提高血浆亚硫醇水平，改善下肢血流量，并有意义地改善 PAD患者的功能表现。 因此，我们提出了一项II期随机临床试验，以收集初步数据来测试是否有四个 几个月的日常远红光治疗改善了行走能力，改善了腿部 PAD患者与假PAD患者的血流灌注和缺血相关的腓肠肌损伤 控制力。32名PAD患者将被随机分配到每天10分钟的家庭治疗中， 红灯或假灯四个月。我们的主要结果是6分钟步行距离在4- 一个月的随访。在次要和探索性目标中，我们将区分急性和慢性影响 6分钟步行时的远红灯，测量远红灯对跑步机步行性能的影响 患者报告的结果，并描绘了远红光改善行走的生物途径 通过测量血浆亚硝酸盐和亚硝硫醇、腓肠肌灌注量的变化来评估PAD的表现 (磁共振动脉自旋标记)与腓肠肌健康和线粒体活动(以肌肉衡量) 活组织检查)。如果我们的假设得到第二阶段试验的支持，结果将被用来设计一个最终的 远红光对PAD患者的随机试验。如果远红光改善了PAD中的功能性能， 这种简单、易用、耐受性好的疗法将对预防行动不便和 改善因PAD致残的大量且数量不断增加的老年人的生活质量。

Far Red Light to Improve Functioning in PAD: the LIGHT PAD Trial Lower extremity peripheral artery disease (PAD) affects 10-15% of people age 65 and older and 15 to 20% of those age 75 and older. Older people with PAD have greater functional impairment, faster functional decline, and higher rates of mobility loss than people without PAD. In PAD, reduced perfusion of gastrocnemius muscle is associated with increased gastrocnemius oxidative stress, mitochondrial impairment, and muscle fiber damage. Yet few non-invasive therapies improve functioning in people with PAD. Nitric oxide (NO) is a signaling molecule with therapeutic properties that improve perfusion and reverse the skeletal muscle pathology in PAD. In preclinical studies, NO increases angiogenesis and perfusion, protects against ischemic injury, enhances skeletal muscle mitochondrial activity, and activates satellite cells, which restore and repair skeletal muscle. Interventions that increase NO bioavailability have major therapeutic potential for people with PAD. Nitrosothiols are a major source of NO and NO bioactivity. Preclinical studies and our preliminary human evidence show that far red light (at wavelength of 670 nm) releases nitrosothiols, nitrite, and other vasoactive species. Four pilot studies completed in preparation for this proposal showed that a single dose of far red light therapy increased plasma nitrosothiols, improved lower extremity blood flow, and meaningfully improved functional performance in people with PAD. Therefore, we propose a Phase II randomized clinical trial to collect preliminary data to test whether four months of daily far red light treatment of the lower extremities improves walking performance, lower extremity perfusion, and ischemia-related gastrocnemius muscle damage in people with PAD, compared to a sham control. Thirty- two people with PAD will be randomized to 10 minutes of daily home treatment with either far red light or a sham light for four months. Our primary outcome is change in six-minute walk distance at 4- month follow-up. In secondary and exploratory aims, we will distinguish between acute and chronic effects of far red light on six-minute walk, measure the effects of far red light on treadmill walking performance and patient-reported outcomes, and delineate biologic pathways by which far red light improves walking performance in PAD, by measuring change in plasma nitrite and nitrosothiols, gastrocnemius muscle perfusion (MRI arterial spin labeling) and gastrocnemius muscle health and mitochondrial activity (measured by muscle biopsy). If our hypotheses are supported by this Phase II trial, results will be used to design a definitive randomized trial of far red light for people with PAD. If far red light improves functional performance in PAD, this simple, accessible, 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 older people disabled by PAD.