PROgenitor Cell Release Plus Exercise To Improve Functional Performance In PAD

描述（由申请人提供）：我们和其他人的研究表明，与没有PAD的人相比，患有下肢外周动脉疾病（PAD）的男性和女性有更大的功能损害和更快的功能衰退。PAD患者记录的功能障碍与活动能力丧失、死亡率增加和生活质量差有关。初步证据表明，增加循环CD34+细胞水平的干预措施可能改善PAD患者的功能表现。然而，三个测试粒细胞单核细胞集落刺激因子（GM-CSF）是否能改善PAD患者行走性能的小型临床试验得出了不同的结果。GM-CSF与PAD患者行走能力改善的关系尚未明确确立。初步数据还表明，步行运动引起的下肢缺血可能会增加循环CD34+细胞水平，增强CD34+细胞向缺血部位的归家，并增强GM-CSF改善PAD患者步行表现的能力。我们提出了一项随机对照临床试验（2 × 2因子设计），240名PAD患者将被随机分为四组：a) GM-CSF +监督运动治疗；b) GM-CSF治疗+注意对照组；C)安慰剂+监督运动疗法；d)安慰剂+注意力控制组。在我们的主要具体目标中，我们将确定在12周的随访中，与GM-CSF单独和监督运动相比，GM-CSF联合监督跑步机运动是否能显著提高6分钟的步行表现。我们还将确定在12周的随访中，与安慰剂相比，GM-CSF是否能显著改善6分钟步行表现。我们将证实，在12周的随访中，与注意力控制组相比，有监督的跑步机运动疗法显著提高了6分钟步行的表现。在我们的第二个特定目标中，我们将确定与GM-CSF单独和监督运动相比，GM-CSF联合监督跑步机运动是否与12周随访时肱动脉血流介导扩张（FMD）和最大跑步机步行时间的增加有关。在我们的探索目标中，我们将建立6分钟步行表现、最大跑步机步行时间和肱动脉FMD对GM-CSF的响应的时间变化轨迹。我们还将建立响应监督跑步机运动的祖细胞增加的时间轨迹。除了确定我们的干预措施的治疗益处外，本研究还有望确定与PAD患者功能表现改善相关的生物学途径。

DESCRIPTION (provided by applicant): Our work and that of others demonstrates that men and women with lower extremity peripheral arterial disease (PAD) have greater functional impairment and more rapid functional decline compared to those without PAD. The functional impairments documented in patients with PAD are associated with mobility loss, increased mortality, and poor quality of life. Preliminary evidence suggests that interventions to increase circulating levels of CD34+ cells may improve functional performance in PAD. However, three small clinical trials testing whether granulocyte monocyte colony stimulating factor (GM-CSF) improves walking performance in PAD yielded mixed results. The association of GM-CSF with improved walking performance in PAD is not definitively established. Preliminary data also suggest that lower extremity ischemia, induced during walking exercise, may increase circulating CD34+ cell levels, enhance homing of CD34+ cells to ischemic sites, and augment the ability of GM-CSF to improve walking performance in PAD. We propose a randomized controlled clinical trial (2 x 2 factorial design) of 240 participants with PAD who will be randomized to one of four arms: a) GM-CSF + supervised exercise therapy; b) GM-CSF therapy + an attention control group; c) placebo + supervised exercise therapy; and d) placebo + attention control group. In our primary specific aim, we will determine whether GM-CSF combined with supervised treadmill exercise significantly improves six-minute walk performance at 12-week follow-up, compared to GM-CSF alone and supervised exercise alone, respectively. We will also determine whether GM-CSF alone significantly improves six-minute walk performance at 12-week follow-up, compared to placebo. We will confirm that supervised treadmill exercise therapy significantly increases six-minute walk performance at 12-week follow- up, compared to an attention control group. In our secondary specific aim, we will determine whether GM-CSF combined with supervised treadmill exercise is associated with greater increases in brachial artery flow- mediated dilation (FMD) and maximal treadmill walking time at 12-week follow-up, compared to GM-CSF alone and supervised exercise alone, respectively. In our exploratory aim, we will establish the temporal trajectory of changes in six-minute walk performance, maximal treadmill walking time, and brachial artery FMD in response to GM-CSF. We will also establish the temporal trajectory of increases in progenitor cells in response to supervised treadmill exercise. In addition to establishing the therapeutic benefit of our interventions, this study is expected to identify biological pathways associated with improved functional performance in participants with PAD.