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.
Resveratrol to Improve Outcomes in older people with PAD (the RESTORE Trial) Public Health Statement Lower extremity peripheral artery disease (PAD) is associated with significantly impaired walking ability, which leads to mobility loss, increased mortality, and poor quality of life. This randomized controlled double-blind pilot study will test ur hypotheses that resveratrol significantly improves calf skeletal muscle oxidative metabolism, increases calf skeletal muscle mitochondrial biogenesis, and improves systemic endothelial function, thereby improving walking ability in older people with PAD.
|White, Sarah H; McDermott, Mary M; Sufit, Robert L et al. (2016) Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study. J Transl Med 14:284|
|McDermott, Mary McGrae (2015) Erasing Disability in Peripheral Artery Disease: The Role of Endovascular Procedures and Supervised Exercise. JAMA 314:1921-3|
|McDermott, Mary McGrae (2015) Lower extremity manifestations of peripheral artery disease: the pathophysiologic and functional implications of leg ischemia. Circ Res 116:1540-50|