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

步行锻炼是唯一一种能改善患者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 有意义地提高对锻炼的反应。介导阿司匹林有益效果的生物途径 运动和PAD对运动无反应的生物学解释尚不清楚。基于我们的 初步数据，我们假设运动诱导的切应力刺激一氧化氮合酶 提高运动中一氧化氮(NO)的生物利用度，从而改善腿部血液灌流，骨骼肌 PAD中线粒体活性和行走能力。我们进一步 没有心血管疾病的人在一开始 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% 体形。Δ亚硝酸盐：在最大运动试验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PAD患者(图)。在本试验中，更改 最大运动试验开始和结束之间的血浆亚硝酸盐被定义为“Δ亚硝酸盐”。在预赛中 研究中，我们报告了12周运动干预显著增加了12周随访的Δ亚硝酸盐。 有PAD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，&lt；0.01)。我们现在建议在200人中进行一项有监督锻炼的机械性随机试验 血浆亚硝酸盐 运动增加血浆一氧化氮的假说 在“响应者”中进行练习，但该练习不会 在运动中有意义地增加NO的含量 改进响应者“。NO的半衰期很短，被氧化成亚硝酸盐， 随着锻炼的进行，没有更稳定的衡量标准。我们之前 显示血浆亚硝酸盐在41年增加了39.3% 用PAD来验证这些假设：1)12周的运动干预显著增加了Δ亚硝酸盐在 12周后，与不锻炼的对照组相比；2)锻炼“响应者”的Δ亚硝酸盐增加幅度更大 3)在无应答者中，在12周的监督锻炼中，补充 用富含硝酸盐的甜菜根汁锻炼12周可以增加Δ亚硝酸盐，并提高6分钟。步行 在24周的F/UP中，与安慰剂相比；4)Δ亚硝酸盐的增加越多，与 改善小腿肌肉的血流灌注和线粒体活性，改善臂动脉FMD，以及6分钟步行。如果 我们的假设是正确的，这项试验将首次确定Δ亚硝酸盐是一种关键的 在PAD中锻炼的好处。研究结果还将描绘出一条关键的非运动生物途径 从而为PAD的未来干预确定一个重要的治疗靶点。

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.