APelin, EXercise, and mobility in Peripheral Artery Disease, the APEX-PAD Study

外周动脉疾病中APelin、运动和活动度的APEX-PAD研究 下肢外周动脉疾病（PAD）患者的功能下降速度快于 没有PAD。PAD患者步行活动期间小腿肌肉缺血再灌注增加 氧化应激，并与小牛线粒体功能障碍和肌纤维损失有关。步行锻炼 显著改善PAD患者的行走障碍，但不能减少下肢动脉粥样硬化 梗阻运动改善行走障碍而不改变动脉的生物学途径 PAD中的阻塞未知。此外，PAD患者对运动的反应不同 干预这种对运动的可变反应的生物学原因尚不清楚。 我们假设运动引起的血浆和小腿肌肉爱帕琳素丰度的增加 有助于改善PAD运动干预后的行走性能。Apelin是一种 G蛋白偶联受体APJ的内源性肽和配体。临床前证据表明， 爱帕琳刺激一氧化氮释放，增强肢体灌注，并刺激肌肉再生， 线粒体活性基于爱帕琳肽对血管系统和组织的有利作用的初步证据， 骨骼肌，我们建议APEX-PAD研究。我们假设， 步行运动刺激下肢动脉内皮细胞释放爱帕琳，从而增加 一氧化氮（NO），刺激血管生成，促进小腿肌肉的有利变化，并改善行走 在PAD的表现。我们假设基线血浆爱帕琳蛋白丰度的变化和 响应于运动的爱帕琳肽丰度有助于响应于运动干预的变异性， PAD患者。 APEX-PAD研究将在我们独特的血浆和小腿肌肉活检生物库中测量爱帕琳 在基线和6个月随访时从248名特征良好的PAD患者（N = 35）中采集标本 肌肉活检）随机分配到两个已完成的NHLBI资助的监督跑步机临床试验之一， 锻炼的在每项试验中，6个月的运动干预都有意义地改善了6分钟步行距离， 与对照组相比，但没有改变踝肱指数，下肢动脉粥样硬化的测量 严重性。我们将确定运动干预是否增加了血浆和小腿肌肉apelin 与对照组相比，在随机分配到锻炼的参与者中，我们将确定 基线时血浆爱帕琳素较高的患者， 干预在研究结果（6分钟步行距离，肱动脉血流- 介导的扩张和小牛活检测量）。我们的研究结果将决定是否干预，增加 apelin可以改善大量且不断增长的PAD残疾人的行走能力。

APelin, EXercise, and mobility in Peripheral Artery Disease, the APEX-PAD Study People with lower extremity peripheral artery disease (PAD) have faster functional decline than those without PAD. Ischemia-reperfusion of calf muscle during walking activity in people with PAD increases oxidative stress and is associated with calf mitochondrial dysfunction and myofiber loss. Walking exercise substantially improves walking impairment in PAD but it does not reduce lower extremity atherosclerotic obstruction. Biologic pathways by which exercise improves walking impairment without altering arterial obstruction in PAD are unknown. Furthermore, patients with PAD vary in their responsiveness to an exercise intervention. Biologic reasons for this variable response to exercise remain unclear. We hypothesize that exercise-induced increases in plasma and calf muscle apelin abundance contribute to improved walking performance following an exercise intervention in PAD. Apelin is an endogenous peptide and ligand of the G protein-coupled receptor APJ. Preclinical evidence suggests that apelin stimulates nitric oxide release, enhances Iimb perfusion, and stimulates muscle regeneration and mitochondrial activity. Based on preliminary evidence of favorable effects of apelin on both vasculature and skeletal muscle, we propose the APEX-PAD Study. We hypothesize that lower extremity ischemia induced by walking exercise stimulates apelin release from lower extremity arterial endothelial cells, thereby increasing nitric oxide (NO), stimulating angiogenesis, promoting favorable changes in calf muscle, and improving walking performance in PAD. We hypothesize that variability in baseline plasma apelin abundance and in changes in apelin abundance in response to exercise contribute to variability in response to an exercise intervention in people with PAD. The APEX-PAD Study will measure apelin in our unique biobank of plasma and calf muscle biopsy specimens collected at baseline and at 6-month follow-up from 248 well characterized people with PAD (N=35 with muscle biopsy) randomized into one of two completed NHLBI-funded clinical trials of supervised treadmill exercise. In each trial, the 6-month exercise intervention meaningfully improved six-minute walk distance, compared to control, but did not alter the ankle brachial index, a measure of lower extremity atherosclerosis severity. We will determine whether the exercise intervention increased plasma and calf muscle apelin abundance, compared to control. Among participants randomized to exercise, we will determine whether those with higher plasma apelin at baseline and whether those with greater increases in plasma apelin after the intervention had greater improvement in study outcomes (six-minute walk distance, brachial artery flow- mediated dilation, and calf biopsy measures). Our results will determine whether interventions that increase apelin may improve walking performance in the large and growing number of people who are disabled by PAD.