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

• 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
• 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

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.

步行运动是唯一一种高效的医疗疗法，可改善患有患者的步行障碍 下肢外周动脉疾病（PAD）。但是，大约45％的垫子没有 有意义地改善运动。介导的生物学途径介导 在PAD中进行无反应的运动和生物学解释尚不清楚。基于我们 初步数据，我们假设运动诱导的剪切应力刺激一氧化氮合酶 在运动过程中增加一氧化氮（否）生物利用度，从而改善腿部灌注，骨骼肌肉 线粒体活动和垫子中的步行能力。我们进一步 开始之间没有心血管疾病的人 最大运动测试开始最大运动测试的最大运动测试结束和结束，但下降了44.2％ 数字。 δ亚硝酸盐：在最大运动测试的开始和结尾之间的血浆亚硝酸盐的变化 最大运动测试 29名未经训练的人有垫子（图）。在此试验中，更改 在最大运动测试的开始和末端之间的血浆亚硝酸盐定义为“δ亚硝酸盐”。在初步 研究，我们报道了12周的12周运动干预在12周随访中显着增加δ亚硝酸盐 有垫子的人（图）。更大的δ亚硝酸盐增加与更大的步行改善相关（R 平方= 0.59，<0.01）。现在，我们提出了200人的机械随机试验的机械随机试验 血浆亚硝酸盐 假设运动会增加血浆NO 在“响应者”中锻炼，但是练习没有 在运动中有意义地增加“非 改善响应者”。没有半衰期的短期，被氧化为亚硝酸盐， 锻炼更稳定的测量不丰富。我们以前 证明血浆亚硝酸盐在41中增加了39.3％ 使用PAD检验这些假设：1）12周的运动干预显着增加了δ亚硝酸盐 与无运动控制相比，为期12周的F/UP； 2）运动“响应者”具有更大的δ亚硝酸盐增加 而不是“非反应者”； 3）在无反应者到12周的监督运动中， 用富含硝酸盐的甜菜根汁再锻炼12周，增加了δ亚硝酸盐并改善了6分钟。走 与安慰剂相比，在24周f/up； 4）δ亚硝酸盐的增加与更大的相关 小腿肌肉灌注和线粒体活性，臂动脉FMD和步行6分钟的改善。如果 我们的假设是正确的，该试验将首次建立δ亚硝酸盐作为关键介体 运动垫的好处。结果还将描述运动非运动的关键生物学途径 响应，从而确定了未来干预PAD的重要治疗靶标。