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.

外周动脉疾病（PAD）是一种使人衰弱的动脉粥样硬化性疾病， 动脉导致骨骼肌血流减少，氧气输送和代谢功能障碍， 导致明显的运动不耐症的运动。退伍军人患PAD的风险不成比例 与普通人群相比，这是因为吸烟、高血压、糖尿病和肥胖的水平更高。 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，但患者动力和疼痛问题 降低治疗的有效性。有一个紧迫的，未得到满足的需要，以确定网站和 PAD导致运动不耐受的系统功能障碍的潜在机制。氧化 应激和炎症在PAD的发生和发展中起重要作用。关键是， 外周血管系统（血流减少）和线粒体（呼吸减少）是主要的 决定因素/机制负责运动不耐受的健康和疾病，特别是 易受氧化应激和炎症的影响，使这些可能的系统功能障碍部位 导致患有PAD的退伍军人运动不耐受。任何血管或线粒体功能障碍 增加氧化应激和炎症引发恶性循环。我们的核心假设是 内源性抗氧化能力和减少的炎症将改善氧的输送和利用， 锻炼，因此，由于增加的坚持和锻炼， 容量为了检验这一假设，我们将利用天然来源的核因子红细胞样蛋白-2-样2（Nrf 2; “抗氧化酶的主要调节剂”）激活剂，PB 125，以刺激内源性抗氧化剂的诱导 并降低炎症通路的活性。患有PAD的退伍军人将被随机分配接受 PB 125或安慰剂补充。每个退伍军人将接受三个阶段的测试：1）基线，2） 补充负荷1个月后，和3）运动康复12周后， 补充。功能能力和认知功能（目标1），血管功能和运动 将在每个阶段评估血液动力学（目标2）以及体内和离体线粒体呼吸（目标3）。 每月对功能能力、行为调节、生活质量和身体活动进行评估， 在整个试验过程中的改进。在这些研究结束时，我们将扩大我们对 运动不耐受的机制，在退伍军人患有PAD，更重要的是，从一个 临床观点，提供了一个潜在的新的治疗方法，以改善运动的洞察力 对这一人群的康复效果。预计这一进展将有助于推进临床 在康复医学的实践，并最终提高生活与PAD退伍军人的生活质量。