1/2 + PROmote weight loss in obese PAD patients to preVEnt mobility loss: the PROVE Trial

PROVE试验的项目总结 超过65%的下肢外周动脉疾病（PAD）患者超重或肥胖。 超重或肥胖的PAD患者功能障碍更大，功能下降更快 体重正常的PAD患者。步行锻炼是改善功能表现的一线疗法 在PAD中。然而，我们的纵向观察数据显示，超重和肥胖的PAD参与者， 与那些为了锻炼而步行的人相比，减肥与步行锻炼相结合的人的功能下降较少， 没有减肥。因此，我们假设在超重或肥胖的PAD患者中， 减肥干预结合运动（WL+EX）将比单独的EX更能改善步行能力。 然而，在患有PAD的超重/肥胖人群中，故意减肥的效果尚不清楚， 如果体重减轻加重了PAD相关的肌肉减少症，则没有益处。实现持续的行为改变 WL在患有慢性疾病的老年肥胖患者中具有挑战性。因此，在PAD和BMI>28的人群中， kg/m2，我们将检验WL+EX在功能性能方面比 EX单独我们创新的减肥干预使用了一个群体介导的认知行为框架， 连接的移动的技术，教练的远程监控，以及卡路里限制的DASH衍生 OMNI心脏饮食。在一项为期七周的试点研究中，我们的干预措施平均减轻了5.6磅， 在8名BMI> 28 kg/m2的PAD参与者中，6分钟步行改善了64.1米。 临床前证据表明，肥胖与肢体灌注受损有关。人类证据 显示肥胖与骨骼肌线粒体生物发生和活性降低有关。这些 肥胖相关的变化加剧了PAD的病理生理学。因此，我们假设减肥 将通过改善小腿灌注和增加小腿线粒体活性来部分改善行走能力。 我们将212名PAD和BMI > 28 kg/m2的参与者随机分为两组，为期12个月： WL+ EX与单独EX。参与者将从西北大学、杜兰大学和 联合明尼苏达州。我们的主要结果是12个月随访时6分钟步行距离的变化。 次要结局是6个月随访时6分钟步行距离的变化和运动的变化 依从性、体力活动、患者报告的步行能力（通过步行障碍测量） 调查问卷）和生活质量（通过SF 12身体成分评分测量）。 三级结局包括MRI测量的小腿灌注、MRI测量的小腿肌肉量和脂肪 丰富度和饮食质量。我们将对50名参与者进行小腿肌肉活检， 生物发生和活性、毛细血管密度、炎症和衰老细胞丰度。如果我们的假设 正确，PROVE试验将通过预防功能衰退和活动性产生重大的公共卫生影响 大量和越来越多的PAD超重或肥胖患者的损失。

PROJECT SUMMARY for the PROVE Trial More than 65% of people with lower extremity peripheral artery disease (PAD) are overweight or obese. People with PAD who are overweight or obese have greater functional impairment and faster functional decline than normal weight people with PAD. Walking exercise is first line therapy to improve functional performance in PAD. However, our observational longitudinal data show that overweight and obese PAD participants who combined weight loss with walking exercise had less functional decline than those who walked for exercise but did not lose weight. Therefore, we hypothesize that among people with PAD who are overweight or obese, a weight loss intervention combined with exercise (WL+EX) will improve walking ability more than EX alone. However, effects of intentional weight loss in overweight/obese people with PAD are unknown and may not be beneficial if weight loss exacerbates PAD-related sarcopenia. Behavior change that achieves sustained WL is challenging in older obese people with chronic disease. Therefore, among people with PAD and BMI>28 kg/m2, we will test the hypothesis that WL+EX achieves greater improvement in functional performance than EX alone. Our innovative weight loss intervention uses a group mediated cognitive behavioral framework, connective mobile technology, remote monitoring by a coach, and a calorie restricted DASH-derived OMNIHeart diet. In a seven week pilot study, our intervention achieved mean weight loss of 5.6 pounds and improved the 6-minute walk by 64.1 meters in eight PAD participants with BMI> 28 kg/m2. Preclinical evidence shows that obesity is associated with impaired limb perfusion. Human evidence shows that obesity is associated with reduced skeletal muscle mitochondrial biogenesis and activity. These obesity related changes exacerbate the pathophysiology of PAD. Therefore, we hypothesize that weight loss will improve walking ability in part by improving calf perfusion, and increasing calf mitochondrial activity. We will randomize 212 participants with PAD and BMI > 28 kg/m2 to one of two groups for 12 months: WL+ EX vs. EX alone. Participants will be randomized from Northwestern University, Tulane University, and the U. of Minnesota. Our primary outcome is change in six-minute walk distance at 12-month follow-up. Secondary outcomes are change in 6-minute walk distance at 6-month follow-up and change in exercise adherence, physical activity, patient-reported walking ability (measured by the Walking Impairment Questionnaire), and quality of life (measured by the SF12 Physical Component Score) at 12-month follow-up. Tertiary outcomes include MRI measured calf perfusion, MRI-measured calf muscle quantity and fat abundance, and diet quality. We will perform calf muscle biopsies in 50 participants to measure mitochondrial biogenesis and activity, capillary density, inflammation, and senescent cell abundance. If our hypotheses are correct, the PROVE Trial will have a major public health impact by preventing functional decline and mobility loss in the large and growing number of people with PAD who are overweight or obese.