PROJECT SUMMARY Lower-extremity peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis that affects more than 236 million individuals worldwide. Patients with PAD have a worse quality of life (QOL) than their healthy counterparts, due in part to the marked decline in physical functioning. Few non-invasive therapies currently exist to improve functional performance and restore QOL in people with PAD. The goal of the proposed experiments is to determine the benefits of home-based leg heat therapy (HT) on lower-extremity functioning and QOL in patients with PAD. This novel approach consists of custom engineered trousers and a portable water pump. Hot water is circulated through the trousers, evenly heating the buttocks, thighs and calf. This system is safe and convenient for application in the home setting without supervision. We demonstrated that repeated exposure to leg HT using these customized water-circulating trousers enhanced muscle strength and capillarization and accelerated recovery following muscle damage in young, sedentary individuals. In a preclinical model of PAD, we reported that HT via repeated lower-body immersion in a water bath enhanced skeletal muscle mass and strength. Our first randomized sham-controlled trial in 32 patients with symptomatic PAD revealed that supervised leg HT elicited a clinically meaningful improvement in perceived physical functioning. Our recent R21-sponsored pilot study revealed that home-based, unsupervised leg HT is safe and well-tolerated by symptomatic PAD patients. Building upon these extensive preliminary data, we propose to conduct a randomized, double-blind, sham-controlled clinical trial in 110 patients with PAD to establish the effect of daily home-based leg HT for 12 weeks on functional capacity and QOL. Patients randomized to the leg HT group (n=55) will be asked to apply the treatment daily for 90 min using water-circulating trousers perfused with water heated to 42ºC. In the sham group (n=55), water at 33ºC will be circulated through the trousers. The primary study outcome is the change in 6-minute walk distance between baseline and the 12- week follow up. Secondary outcomes include changes in leg strength and fatigability, changes in the short physical performance battery score and changes in perceived QOL. In Aim #2, we will determine the tissue- level mechanisms by which HT affects muscle strength and walking performance. We will assess skeletal muscle morphology and blood flow using magnetic resonance imaging (MRI) and biopsies from the calf muscle. If the conclusions based on our preliminary data are substantiated, the proposed experiments will provide an evidence-based framework of feasibility and efficacy of a novel, straightforward approach to improve functional performance and QOL in patients with PAD. Given its accessibility, tolerability and ease of use, HT has the potential for rapid translation and application in the clinical setting, thereby opening new ...