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

步行锻炼是唯一一种高效的医学疗法，可以改善患有 下肢外周动脉疾病（PAD）。然而，大约45%的PAD患者没有 有意义地改善对锻炼的反应。生物途径介导的有益效果 运动和生物学对PAD运动无反应的解释尚不清楚。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， 增加运动期间一氧化氮（NO）生物利用度，从而改善腿部灌注、骨骼肌 线粒体活性和PAD的行走能力。我们进一步 没有心血管疾病的人 最大运动试验开始最大运动试验结束和最大运动试验结束，但下降了44.2% 图.Δ亚硝酸盐：血浆亚硝酸盐在最大运动试验开始和结束之间的变化， 极量运动试验 29名未经培训的PAD患者（图）。在本试验中， 最大运动试验开始和结束之间的血浆亚硝酸盐定义为“Δ亚硝酸盐”。初步 在一项研究中，我们报告说，12周的运动干预在12周的随访中显著增加了Δ亚硝酸盐， PAD患者（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）。我们现在提出了一个机械随机试验的监督运动在200人 血浆亚硝酸盐 假设运动增加血浆NO， 在“反应者”中进行锻炼，但这种锻炼并不 有意义地增加NO在运动期间在“非- 改善应对措施”。NO具有短的半衰期并被氧化成亚硝酸盐， 运动是一种更稳定的NO丰度测量方法。我们之前 结果表明，41例患者血浆亚硝酸盐水平升高39.3%， 用PAD测试这些假设：1）12周的运动干预显著增加Δ亚硝酸盐， 12-与无运动对照组相比，运动“应答者”的Δ亚硝酸盐增加更大 3）在12周监督锻炼的无应答者中， 用富含硝酸盐的甜菜根汁锻炼12周，增加Δ亚硝酸盐，改善6分钟步行 在24周f/up时，与安慰剂相比; 4）Δ亚硝酸盐的增加越大， 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。如果 我们的假设是正确的，这项试验将首次建立Δ亚硝酸盐作为一个关键的调解人， 运动对PAD的好处。结果还将描绘出运动非运动性的关键生物学途径。 反应，从而确定一个重要的治疗目标，为未来的干预PAD。

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.