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

APEX-PAD研究表明，APEX-PAD研究表明，Apelin、运动与外周动脉疾病的流动性 下肢外周动脉疾病(PAD)患者的功能下降速度比那些 不带垫子。PAD患者步行活动时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丢失有关。步行锻炼 显著改善PAD的行走障碍，但不能减少下肢动脉粥样硬化 障碍物。运动在不改变动脉的情况下改善步行障碍的生物途径 PAD中的梗阻原因不明。此外，PAD患者对运动的反应各不相同。 干预。这种对运动的不同反应的生物学原因尚不清楚。 我们假设运动导致血浆和小腿肌肉中apelin含量的增加 在PAD中进行运动干预后，有助于改善步行能力。阿佩林是一种 G蛋白偶联受体APJ的内源性多肽和配体。临床前证据表明 Apelin刺激一氧化氮释放，增强IIMB灌流，刺激肌肉再生和 线粒体活性。根据初步证据，阿佩林对血管系统和 骨骼肌，我们建议APEX-PAD研究。我们推测，大鼠局灶性脑缺血 步行运动刺激下肢动脉内皮细胞释放apelin，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，并改善步行 在PAD中的性能。我们假设基线血浆apelin丰度的变异性和 运动反应中的apelin丰度对运动干预反应的变异性有贡献 有PAD的人。 APEX-PAD研究将测量我们独特的血浆和小腿肌肉活检生物库中的apelin 在基线和6个月随访时收集的样本来自248名特征良好的PAD患者(N=35 肌肉活检)随机进入NHLBI资助的两个已完成的监督跑步机临床试验之一 锻炼身体。在每个试验中，为期6个月的运动干预显著提高了6分钟的步行距离， 与对照组相比，但没有改变踝臂指数，该指数是衡量下肢动脉粥样硬化的指标 严肃性。我们将确定运动干预是否增加了血浆和小腿肌肉APEIN 丰度，与对照相比。在随机接受锻炼的参与者中，我们将确定 基线时血浆apelin升高的患者，以及治疗后血浆apelin升高幅度更大的患者 干预在研究结果方面有更大的改善(6分钟步行距离，臂动脉血流- 中介扩张和小腿活组织检查措施)。我们的结果将决定干预措施是否会增加 阿佩林可能会改善大量且不断增加的PAD致残患者的行走能力。

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.