Response to Exercise and Nitric Oxide in PAD: the RESIST PAD Trial

PAD 对运动和一氧化氮的反应：RESIST PAD 试验

基本信息

批准号：
10656845
负责人：
Mary McGrae McDermott
金额：
$ 74.92万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10656845
关键词：
4 hydroxynonenal Biological Biological Availability Biopsy Blood capillaries Cardiovascular Diseases Cardiovascular system Clinical Trials Control Groups Cyclic GMP Data Disabled Persons Disease Exercise Exercise Test Future Gastrocnemius Muscle Half-Life Impairment Intervention Juice Leg Lower Extremity Measures Mediating Mediator Medical Mitochondria Muscle Muscle Mitochondria Nitrates Nitric Oxide Nitric Oxide Synthase Nitrites Outcome Oxidative Stress Participant Pathway interactions Patients Performance Perfusion Peripheral arterial disease Persons Placebos Plasma Production Randomized Reporting Research Personnel Skeletal Muscle Spirometry Testing Time Walking brachial artery comparison control consumption measures density exercise intervention follow-up improved randomized trial response satellite cell shear stress tetrahydrobiopterin therapeutic target treadmill

项目摘要

Walking exercise is the only highly effective medical therapy that improves walking impairment in people with lower extremity peripheral artery disease (PAD). However, approximately 45% of people with PAD do not meaningfully improve in response to exercise. Biologic pathways that mediate the beneficial effects of exercise and biologic explanations for non-response to exercise in PAD are unknown. Based on our preliminary data, we hypothesize that exercise-induced shear stress stimulates nitric oxide synthase to increase nitric oxide (NO) bioavailability during exercise, thereby improving leg perfusion, skeletal muscle mitochondrial activity, and walking ability in PAD. We further people without cardiovascular disease between the beginning Maximal exercise test start Maximal exercise test end and end of a maximal exercise test, but declined by 44.2% Figure. Δ nitrite: Change in plasma nitrite during a between the beginning and end of a maximal exercise test in maximal exercise test 29 untrained people with PAD (Figure). In this trial, change in plasma nitrite between beginning and end of a maximal exercise test is defined as “Δ nitrite”. In preliminary study, we reported that a 12 week exercise intervention significantly increased Δ nitrite at 12 week follow-up in people with PAD (Figure). Greater Δ nitrite increases were associated with greater walking improvement (r squared =0.59, <0.01). We now propose a mechanistic randomized trial of supervised exercise in 200 people Plasma Nitrite hypothesize that exercise increases plasma NO during exercise in “responders”, but that exercise does not meaningfully increase NO during exercise in “non- Improvement responders”. NO has a short half-life and is oxidized to nitrite, with exercise a more stable measure of NO abundance. We previously demonstrated that plasma nitrite increased by 39.3% in 41 with PAD to test these hypotheses: 1) that a 12 week exercise intervention significantly increases Δ nitrite at 12-week f/up, compared to a no-exercise control; 2) that exercise “responders” have greater Δ nitrite increases than “non-responders”; 3) among non-responders to 12 weeks of supervised exercise, that supplementing exercise with nitrate-rich beetroot juice for an additional 12 weeks increases Δ nitrite and improves 6-min. walk at 24-week f/up, compared to placebo; 4) that greater increases in Δ nitrite are associated with greater improvements in calf muscle perfusion and mitochondrial activity, brachial artery FMD, and 6-minute walk. If our hypotheses are correct, this trial will, for the first time, establish Δ nitrite as a critical mediator of the benefits of exercise in PAD. Results will also delineate a key biologic pathway of exercise non- response, thereby identifying an important therapeutic target for future interventions in PAD.

步行锻炼是唯一一种能够改善患有糖尿病的人的步行障碍的高效药物疗法下肢外周动脉疾病 (PAD) 然而，大约 45% 的 PAD 患者没有。有意义地改善对运动的反应的生物途径。根据我们的研究，PAD 对运动无反应的运动和生物学解释尚不清楚。初步数据，我们发现运动引起的剪切应力会刺激一氧化氮合酶增加运动过程中一氧化氮 (NO) 的生物利用度，从而改善腿部灌注、骨骼肌我们进一步研究 PAD 中的线粒体活性和行走能力。没有心血管疾病的人最大运动测试开始最大运动测试结束和最大运动测试结束，但下降了 44.2% 图 Δ 亚硝酸盐：最大运动测试开始和结束期间血浆亚硝酸盐的变化最大运动试验 29 名未经训练的人患有 PAD（图）。最大运动测试开始和结束之间的血浆亚硝酸盐初步定义为“Δ亚硝酸盐”。研究中，我们报告说，12 周的运动干预在 12 周的随访中显着增加了 Δ 亚硝酸盐患有 PAD 的人（图） Δ 亚硝酸盐的增加与步行改善程度的提高相关（r）。平方=0.59，<0.01）我们现在提出一项对 200 人进行监督运动的机械随机试验。血浆亚硝酸盐增加运动量会增加血浆 NO 在“反应者”中进行锻炼，但这种锻炼并没有在“非”运动期间有意义地增加NO NO的半衰期短，会被氧化成亚硝酸盐，通过锻炼，我们可以更稳定地测量一氧化氮丰度。证明 41 名患者的血浆亚硝酸盐增加了 39.3% 使用 PAD 来检验这些假设：1) 12 周的运动干预显着增加了 Δ 亚硝酸盐 12 周 f/up，与不运动对照相比；2) 运动“反应者”的 Δ 亚硝酸盐增加更大； 3）在 12 周监督锻炼的无反应者中，补充使用富含硝酸盐的甜菜根汁进行额外 12 周的锻炼会增加 Δ 亚硝酸盐并改善 6 分钟步行能力。 24 周 f/up 时，与安慰剂相比；4) Δ 亚硝酸盐的增加越大，相关性越大；小腿肌肉灌注和线粒体活性、肱动脉 FMD 和 6 分钟步行的改善。我们的假设是正确的，这项试验将首次确立 Δ 亚硝酸盐作为运动对 PAD 的益处结果还将描绘运动非运动的关键生物学途径。反应，从而确定未来 PAD 干预的重要治疗靶点。