Response to Exercise and Nitric Oxide in PAD: the RESIST PAD Trial

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Walking exercise is the only highly effective medical therapy that improves walking impairment in people with lower extremity peripheral artery disease (PAD). However, approximately 45% of people with PAD do not meaningfully improve in response to exercise. Biologic pathways that mediate the beneficial effects of exercise and biologic explanations for non-response to exercise in PAD are unknown. Based on our preliminary data, we hypothesize that exercise-induced shear stress stimulates nitric oxide synthase to increase nitric oxide (NO) bioavailability during exercise, thereby improving leg perfusion, skeletal muscle mitochondrial activity, and walking ability in PAD. We further people without cardiovascular disease between the beginning Maximal exercise test start Maximal exercise test end and end of a maximal exercise test, but declined by 44.2% Figure. Δ nitrite: Change in plasma nitrite during a between the beginning and end of a maximal exercise test in maximal exercise test 29 untrained people with PAD (Figure). In this trial, change in plasma nitrite between beginning and end of a maximal exercise test is defined as “Δ nitrite”. In preliminary study, we reported that a 12 week exercise intervention significantly increased Δ nitrite at 12 week follow-up in people with PAD (Figure). Greater Δ nitrite increases were associated with greater walking improvement (r squared =0.59, <0.01). We now propose a mechanistic randomized trial of supervised exercise in 200 people Plasma Nitrite hypothesize that exercise increases plasma NO during exercise in “responders”, but that exercise does not meaningfully increase NO during exercise in “non- Improvement responders”. NO has a short half-life and is oxidized to nitrite, with exercise a more stable measure of NO abundance. We previously demonstrated that plasma nitrite increased by 39.3% in 41 with PAD to test these hypotheses: 1) that a 12 week exercise intervention significantly increases Δ nitrite at 12-week f/up, compared to a no-exercise control; 2) that exercise “responders” have greater Δ nitrite increases than “non-responders”; 3) among non-responders to 12 weeks of supervised exercise, that supplementing exercise with nitrate-rich beetroot juice for an additional 12 weeks increases Δ nitrite and improves 6-min. walk at 24-week f/up, compared to placebo; 4) that greater increases in Δ nitrite are associated with greater improvements in calf muscle perfusion and mitochondrial activity, brachial artery FMD, and 6-minute walk. If our hypotheses are correct, this trial will, for the first time, establish Δ nitrite as a critical mediator of the benefits of exercise in PAD. Results will also delineate a key biologic pathway of exercise non- response, thereby identifying an important therapeutic target for future interventions in PAD.