Supplement to RESveratrol To Improve Outcomes in oldeR pEople with PAD (the RESTORE-S Trial)

描述(申请人提供)：我们的工作和其他人的工作表明，患有下肢外周动脉疾病(PAD)的老年男性和女性比没有PAD的老年人有更大的功能损害和更快的功能下降。老年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。然而，只有两种药物被FDA批准用于改善与PAD相关的行走限制。新出现的证据，包括我们自己的试点数据，表明小腿骨骼肌线粒体功能受损导致老年PAD患者的功能损害。白藜芦醇是一种多酚和天然补充剂，具有针对PAD患者存在的特定线粒体损伤的药理学特性。此外，动物模型和初步的人类证据表明，白藜芦醇对缺血再灌注损伤具有保护作用，促进血管生成，改善内皮功能。缺血再灌注损伤、血管生成受损和内皮功能障碍都是PAD患者行动能力受损的原因。因此，白藜芦醇专门针对PAD中常见的几种与活动能力受损有关的病理生理损伤。然而，白藜芦醇从未在患有PAD的老年人中进行过研究。我们现在提议对40名65岁及以上的PAD参与者进行试点研究：一项双盲、随机对照的试点临床试验，以提供初步数据来验证我们的假设，即白藜芦醇通过改善小腿骨骼肌氧化代谢、增加小腿骨骼肌线粒体生物生成以及改善老年PAD患者的系统内皮功能，显著改善PAD患者的下肢功能。在我们的主要具体目标中，我们将确定与随机服用安慰剂的PAD参与者相比，与随机服用白藜芦醇1000 mg的PAD参与者相比，在6个月的随访中，PAD参与者的6分钟步行能力是否有更大的提高或更少的下降。在我们的次要目标中，我们将确定与随机服用白藜芦醇的患者相比，随机服用白藜芦醇的PAD参与者在6个月的随访中是否会改善跑步机行走能力，增加小腿肌肉活检测量的线粒体功能，增加小腿肌肉活检测量的线粒体生物生成，以及改善肱动脉血流介导的扩张。如果我们的假设是正确的，结果将被用于设计一项大规模的、决定性的白藜芦醇治疗随机对照试验，以改善因PAD而致残的大量且越来越多的老年人的下肢功能，并防止行动不便。

DESCRIPTION (provided by applicant): Our work and that of others demonstrate that older men and women with lower extremity peripheral artery disease (PAD) have greater functional impairment and more rapid functional decline than older people without PAD. The functional impairments documented in older people with PAD are associated with mobility loss, increased mortality, and poor quality of life. Yet only two medications are FDA approved for improving the walking limitations associated with PAD. Emerging evidence, including our own pilot data, demonstrates that impaired calf skeletal muscle mitochondrial function contributes to functional impairment in older people with PAD. Resveratrol, a polyphenol and natural supplement, has pharmacological properties that target the specific mitochondrial impairments that are present in people with PAD. In addition, animal models and preliminary human evidence show that resveratrol protects against ischemia-reperfusion injury, promotes angiogenesis, and improves endothelial function. Ischemia-reperfusion injury, impaired angiogenesis, and endothelial dysfunction all contribute to impaired mobility in people with PAD. Thus, resveratrol specifically targets several pathophysiologic impairments that are common in PAD and that are associated with impaired mobility. However, resveratrol has never been studied in older people with PAD. We now propose a pilot study of 40 PAD participants age 65 and older: a double-blind, randomized controlled pilot clinical trial to provide preliminary data to address our hypothesis that resveratrol significantly improves lower extremity functioning in people with PAD by improving calf skeletal muscle oxidative metabolism, increasing calf skeletal muscle mitochondrial biogenesis, and improving systemic endothelial function in older people with PAD. In our primary specific aim, we will determine whether PAD participants randomized to resveratrol 1000 mgs daily achieve greater increases or have less decline in six-minute walk performance at 6-month follow-up, compared to those randomized to placebo. In our secondary aims, we will determine whether PAD participants randomized to resveratrol will have improved treadmill walking performance, increased calf muscle biopsy- measured mitochondrial function, increased calf muscle biopsy-measured mitochondrial biogenesis, and improved brachial artery flow-mediated dilation at six-month follow-up, compared to those randomized to control. If our hypotheses are correct, results will be used to design a large, definitive randomized controlled trial of resveratrol therapy to improve lower extremity functioning and prevent mobility loss in th large and growing number of older people who are disabled by PAD.