COCOA flavanols to improve walking performance in PAD: the COCOA-PAD II Trial

摘要 在美国，10-15%的≥65岁的人会受到下肢外周动脉疾病(PAD)的影响， 随着美国人患有慢性病而活得更长，这种情况越来越常见。患有PAD的人有更多 与无PAD组相比，步行障碍和功能下降更快。然而，很少有治疗方法是 已确定可改善PAD患者的行走障碍或防止功能下降。 在PAD患者中，步行活动过程中小腿肌肉的缺血再灌注会引起病理生理变化 小腿骨骼肌的变化，包括氧化应激增加，肌纤维损伤，以及 线粒体活性。这些小腿肌肉异常与功能损害和 PAD功能减退。可可黄烷醇来自可可树Theobroma Cacao的种子，具有 可改善小腿肌肉血流灌注和逆转小腿肌肉异常的治疗特性 垫子。临床前证据表明，可可黄烷醇增加一氧化氮(NO)、毛细血管密度和肢体 而且还可以减少骨骼肌中的氧化应激和改善线粒体的活性。一致 有了这一临床前证据，在我们由NIA资助的44名PAD参与者的试点临床试验中，可可黄烷醇 与安慰剂组相比，在6个月的随访中，6分钟步行距离显著增加了42.6米 (P=0.005)。因此，我们现在提出一项第三阶段的双盲、多中心随机试验。 参与者使用PAD，以确定6个月的可可黄烷醇是否显著改善6- 与安慰剂组比较，6个月随访时的分钟步行距离。在此修订后的申请中(原始分数： 36，百分位数：17)，我们还将评估可可黄烷醇对一氧化氮测量的影响(通过 肱动脉血流介导的扩张、小腿肌肉内皮型一氧化氮合酶和小腿肌肉 磷酸化eNOS)，小腿肌肉灌注量，全身耗氧量，体力活动，最大 在6个月的随访中，跑步机步行距离和额外的小腿肌肉活检措施。作为对.的回应 审查者评论，提出了新的分析来描绘机制并评估 可可黄烷醇对改善PAD步行能力的影响。如果我们对可可的初步研究的结果 黄烷醇在最终的第三阶段随机试验中得到证实，这种廉价、安全、可获得和良好的 耐受性治疗有可能显著改善数量庞大且数量不断增加的老年人的活动能力 被PAD致残的人。

ABSTRACT Lower extremity peripheral artery disease (PAD) affects 10-15% of people age ≥65 in the U.S. and will be increasingly common as the U.S. population lives longer with chronic disease. People with PAD have greater walking impairment and faster functional decline than those without PAD. Yet few therapies have been identified that improve walking impairment or prevent functional decline in people with PAD. In people with PAD, ischemia-reperfusion of calf muscle during walking activity causes pathophysiologic changes in calf skeletal muscle, including increased oxidative stress, myofiber injury, and reduced mitochondrial activity. These calf muscle abnormalities are associated with functional impairment and functional decline in PAD. Cocoa flavanols, from the seeds of theobroma cacao, the “cocoa” tree, have therapeutic properties that may improve calf muscle perfusion and reverse the calf muscle abnormalities in PAD. Pre-clinical evidence shows that cocoa flavanols increase nitric oxide (NO), capillary density, and limb perfusion and also reduce oxidative stress and improve mitochondrial activity in skeletal muscle. Consistent with this pre-clinical evidence, in our NIA-funded pilot clinical trial of 44 participants with PAD, cocoa flavanols significantly improved 6-minute walk distance by 42.6 meters at six-month follow-up, compared to placebo (P=0.005). Therefore, we now propose a Phase III double-blinded, multi-centered randomized trial in 190 participants with PAD, to definitively determine whether 6-months of cocoa flavanols significantly improves 6- minute walk distance at six-month follow-up, compared to placebo. In this revised application (original score: 36, percentile: 17), we will also assess the effects of cocoa flavanols on measures of nitric oxide (measured by brachial artery flow-mediated dilation, calf muscle endothelial nitric oxide synthase (eNOS) and calf muscle phosphorylated eNOS), calf muscle perfusion, whole body oxygen consumption, physical activity, maximal treadmill walking distance, and additional calf muscle biopsy measures at six-month follow-up. In response to reviewer comments, new analyses are proposed to delineate mechanisms and assess persistence of the cocoa flavanols effect on improved walking performance in PAD. If results from our pilot study of cocoa flavanols are confirmed in a definitive Phase III randomized trial, this inexpensive, safe, accessible, and well- tolerated therapy has the potential to meaningfully improve mobility in the large and growing number of older people disabled by PAD.