Improving exercise rehabilitation efficacy and outcomes in Veterans with peripheral artery disease: Targeting oxidative stress and inflammation

提高患有外周动脉疾病的退伍军人的运动康复效果和结果：针对氧化应激和炎症

• 批准号: 10638943
• 负责人: Jesse Charles Craig
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638943
• 关键词: Abate; Acceleration; Activities of Daily Living; Address; Adherence; Antioxidants; Arteries; Atherosclerosis; Behavioral; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular system; Clinical; Clinical Trials; Development; Diabetes Mellitus; Diagnosis; Disease; Effectiveness; Event; Exercise; Exercise Tolerance; Functional disorder; Future; General Population; Goals; Health; Healthcare Systems; Hypertension; Impairment; Inflammation; Inflammatory; Insurance Coverage; Knowledge; Lower Extremity; Medicine; Metabolic; Metabolic dysfunction; Mitochondria; Morbidity - disease rate; Motivation; Muscle; Obesity; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygen; Pain; Pathology; Pathway interactions; Patients; Peripheral; Peripheral arterial disease; Phase; Physical activity; Placebos; Play; Population; Prevalence; Quality of life; Randomized; Regulation; Rehabilitation therapy; Research; Respiration; Risk; Risk Factors; Role; Safety; Site; Skeletal Muscle; Smoking; Supplementation; Symptoms; Testing; Therapeutic; Treatment Effectiveness; Vascular Diseases; Veterans; antioxidant enzyme; cardiovascular risk factor; clinical practice; cognitive function; cost effective treatment; evidence base; exercise capacity; exercise intolerance; exercise rehabilitation; functional decline; functional improvement; hemodynamics; improved; in vivo; insight; mitochondrial dysfunction; mortality; novel strategies; novel therapeutics; nuclear factor-erythroid 2; pain reduction; pharmacologic; physical inactivity; psychosocial; readmission rates; response; therapeutic target

Peripheral artery disease (PAD) is a debilitating atherosclerotic disease caused by plaque development in the arteries leading to diminished skeletal muscle blood flow, oxygen delivery, and metabolic dysfunction during ambulation causing marked exercise intolerance. Veterans have a disproportionate risk of developing PAD compared to the general population because of higher levels of smoking, hypertension, diabetes, and obesity. Worryingly, the mortality rate for PAD in Veterans (~30%) is nearly double that of the general population. Currently, the best treatment of PAD is exercise rehabilitation, however, issues with patient motivation and pain reduce the effectiveness of this treatment. There is a pressing, and unmet need to identify the sites and underlying mechanisms of the systemic dysfunction leading to exercise intolerance induced by PAD. Oxidative stress and inflammation play important roles in the development and progression of PAD. Critically, the peripheral vasculature (diminished blood flow) and mitochondria (diminished respiration) are primary determinants/mechanisms responsible for exercise intolerance in health and disease that are particularly vulnerable to elevations in oxidative stress and inflammation, making these likely sites of systemic dysfunction leading to exercise intolerance in Veterans with PAD. Any vascular or mitochondrial dysfunction would further augment oxidative stress and inflammation initiating a vicious cycle. It is our central hypothesis that increased endogenous antioxidant capacity and diminished inflammation will improve oxygen delivery and utilization during exercise, thus, increasing the efficacy of exercise rehabilitation due to increased adherence and exercise capacity. To test this hypothesis, we will utilize the naturally-derived Nuclear Factor Erythroid-2-like 2 (Nrf2; the “master regulator of antioxidant enzymes”) activator, PB125, to stimulate induction of endogenous antioxidants and decrease the activity of inflammatory pathways. Veterans with PAD will be randomly assigned to receive either PB125 or Placebo supplementation. Each Veteran will undergo three phases of testing: 1) baseline, 2) post 1 month of supplement loading, and 3) post 12 weeks of exercise rehabilitation with continued supplementation. Functional capacity and cognitive function (Aim 1), Vascular function and exercising hemodynamics (Aim 2), and in vivo and ex vivo mitochondrial respiration (Aim 3) will be assessed each phase. Monthly assessments of functional capacity, behavioral regulation, quality of life, and physical activity will track improvements across the trial. At the conclusion of these studies, we will have expanded our knowledge of the mechanisms underlying exercise intolerance in Veterans suffering from PAD, and, more importantly from a clinical perspective, provided insight into a potential novel therapeutic treatment to improve exercise rehabilitation efficacy for this population. It is anticipated this advancement will contribute to advancing clinical practice in rehabilitative medicine, and ultimately, improving the quality of life for Veterans living with PAD.

外围动脉疾病（PAD）是一种令人衰弱的动脉粥样硬化疾病，由斑块发育引起 导致骨骼肌血流减少，氧气输送和代谢功能障碍的动脉 行动引起了明显的运动肠道。退伍军人有开发垫的风险不成比例 与普通人群相比，由于吸烟，高血压，糖尿病和肥胖水平较高。 令人担忧的是，退伍军人PAD的死亡率（约30％）几乎是普通人群的两倍。 目前，PAD的最佳治疗方法是运动康复，但是，患者动机和疼痛的问题 降低这种治疗的有效性。有一个紧迫的，未满足的需要识别站点和 全身功能障碍的基本机制导致PAD引起的运动耐药性。氧化 压力和炎症在PAD的发展和发展中起着重要作用。至关重要的是 周围脉管系统（血流减少）和线粒体（呼吸减少）是主要的 确定负责健康和疾病运动的运动的机制，特别是 容易受到氧化应激和注射的升高的影响，使这些可能的全身功能障碍部位 通过垫子在退伍军人中进行运动。任何血管或线粒体功能障碍都将进一步 增强氧化应激和炎症会引发恶性循环。我们的中心假设增加了 内源性抗氧化能力和注射降低将改善氧气的递送和利用率 因此，由于依从性和锻炼的增加而提高了运动康复效率 容量。为了检验这一假设，我们将利用天然衍生的核因子红细胞-2样2（NRF2； “抗氧化剂的主调节剂”）激​​活剂PB125，以刺激内源性抗氧化剂的诱导 并降低炎症途径的活性。带有垫子的退伍军人将被随机分配给接收 PB125或安慰剂补充。每位退伍军人将进行三个测试阶段：1）基线，2） 邮政1个月的补充装加载，3）续12周，继续进行锻炼康复 补充。功能能力和认知功能（AIM 1），血管功能和运动 血液动力学（AIM 2）以及体内和体内线粒体呼吸（AIM 3）将在每个阶段进行评估。 每月对功能能力，行为调节，生活质量和体育锻炼的评估将跟踪 整个试验的改进。在这些研究结束时，我们将扩大我们对 在患有PAD的退伍军人中进行运动的机制，更重要的是 临床视角，提供了一种潜在的新型治疗治疗的见解，以改善运动 该人群的康复效率。预计这一进步将有助于提高临床 练习康复医学，并最终改善了与PAD一起生活的退伍军人的生活质量。