Our work and that of others has established that people with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and increased mobility loss compared to people without PAD. Ischemia-reperfusion injury of calf skeletal muscle in PAD is associated with increased calf muscle oxidative stress, myofiber damage, and impaired mitochondrial activity. No medical therapies have been identified that target these calf skeletal muscle abnormalities in PAD. Few medical therapies improve functioning or prevent functional decline in people with PAD.Nicotinamide riboside (NR) is a B vitamin and pre-cursor of nicotinamide adenine dinucleotide (NAD+). NAD+ is essential for mitochondrial respiration and for sirtuin1 (SIRT1) activity. SIRT1 stimulates mitochondrial activity, activates endothelial nitric oxide synthase (eNOS) and reduces oxidative stress. In animal models, orally administered NR increases skeletal muscle NAD+ abundance and SIRT1 activity and also increases mitochondrial activity, skeletal muscle regeneration, and running endurance. We hypothesize that in people with PAD, NR will increase calf muscle mitochondrial activity and promote calf muscle regeneration, thereby achieving better walking performance in PAD. Resveratrol is a natural polyphenol found in grape skin with pharmacological properties that also enhances mitochondrial activity through SIRT1. Resveratrol increases SIRT1 affinity for NAD+. We hypothesize that combining resveratrol (a SIRT1 activator) with NR (which increases NAD+, an essential SIRT1 cofactor) will have a particularly potent stimulatory effect on calf muscle mitochondrial activity and will improve walking performance in PAD. We propose a placebo controlled randomized clinical trial to assess whether NR alone and NR with resveratrol, respectively, improve walking performance in PAD. Ninety participants with PAD will be randomized to NR alone, NR and resveratrol, or placebo for six months. Our primary outcome is change in six-minute walk at 6-month follow-up. In an exploratory aim, we will determine whether NR combined with resveratrol increases the six-minute more than NR alone. If NR alone and/or NR with resveratrol improve functional performance or prevent functional decline in PAD, these well tolerated therapies will have a major impact on preventing mobility loss and improving quality of life in the large and growing number of people with PAD.
|Program type||Strategically Focused Research Network|
|Effective start/end date||04/01/2018 → 03/31/2022|