PROgenitor Cell Release Plus Exercise To Improve Functional Performance In PAD

描述(申请人提供)：我们的工作和其他人的工作表明，与没有PAD的人相比，患有下肢周围动脉疾病(PAD)的男性和女性有更大的功能损害和更快的功能下降。PAD患者记录的功能损害与行动能力丧失、死亡率增加和生活质量低下有关。初步证据表明，提高CD34+细胞循环水平的干预措施可能会改善PAD的功能表现。然而，三项小型临床试验测试了粒细胞单核细胞集落刺激因子(GM-CSF)是否改善了PAD的行走能力，结果喜忧参半。GM-CSF与改善PAD步行能力之间的联系尚不明确。初步数据还表明，步行运动诱发的下肢缺血可能会增加循环中CD34+细胞的水平，增强CD34+细胞对缺血部位的归巢，并增强GM-CSF改善PAD步行能力的能力。我们提出了一项随机对照临床试验(2×2析因设计)，将240名PAD患者随机分为四组：a)GM-CSF+监督运动疗法；b)GM-CSF疗法+注意对照组；c)安慰剂+监督运动疗法；以及d)安慰剂+注意对照组。在我们的主要具体目标中，我们将确定在12周的随访中，GM-CSF与有监督的跑步机运动相结合是否分别比单独的GM-CSF和有监督的运动显著改善6分钟的步行能力。我们还将确定，与安慰剂相比，在12周的随访中，单用GM-CSF是否显著改善了6分钟的步行能力。我们将证实，与注意力控制组相比，在12周的随访中，有监督的跑步机运动疗法显著提高了6分钟步行能力。在我们的第二个特定目标中，我们将确定GM-CSF联合监督跑步机锻炼是否与12周随访时与单独GM-CSF和监督锻炼相比，臂动脉血流介导的扩张(FMD)和最大跑步机行走时间的增加更大相关。在我们的探索目标中，我们将建立6分钟步行能力、最大跑步机步行时间和对GM-CSF反应的臂动脉FMD变化的时间轨迹。我们还将建立祖细胞增加的时间轨迹，以响应有监督的跑步机运动。除了确定我们的干预措施的治疗益处外，这项研究还有望确定与改善PAD参与者的功能表现相关的生物学途径。

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.