Improving exercise rehabilitation efficacy and outcomes in Veterans with peripheral artery disease: Targeting oxidative stress and inflammation

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Peripheral artery disease (PAD) is a debilitating atherosclerotic disease caused by plaque development in the arteries leading to diminished skeletal muscle blood flow, oxygen delivery, and metabolic dysfunction during ambulation causing marked exercise intolerance. Veterans have a disproportionate risk of developing PAD compared to the general population because of higher levels of smoking, hypertension, diabetes, and obesity. Worryingly, the mortality rate for PAD in Veterans (~30%) is nearly double that of the general population. Currently, the best treatment of PAD is exercise rehabilitation, however, issues with patient motivation and pain reduce the effectiveness of this treatment. There is a pressing, and unmet need to identify the sites and underlying mechanisms of the systemic dysfunction leading to exercise intolerance induced by PAD. Oxidative stress and inflammation play important roles in the development and progression of PAD. Critically, the peripheral vasculature (diminished blood flow) and mitochondria (diminished respiration) are primary determinants/mechanisms responsible for exercise intolerance in health and disease that are particularly vulnerable to elevations in oxidative stress and inflammation, making these likely sites of systemic dysfunction leading to exercise intolerance in Veterans with PAD. Any vascular or mitochondrial dysfunction would further augment oxidative stress and inflammation initiating a vicious cycle. It is our central hypothesis that increased endogenous antioxidant capacity and diminished inflammation will improve oxygen delivery and utilization during exercise, thus, increasing the efficacy of exercise rehabilitation due to increased adherence and exercise capacity. To test this hypothesis, we will utilize the naturally-derived Nuclear Factor Erythroid-2-like 2 (Nrf2; the “master regulator of antioxidant enzymes”) activator, PB125, to stimulate induction of endogenous antioxidants and decrease the activity of inflammatory pathways. Veterans with PAD will be randomly assigned to receive either PB125 or Placebo supplementation. Each Veteran will undergo three phases of testing: 1) baseline, 2) post 1 month of supplement loading, and 3) post 12 weeks of exercise rehabilitation with continued supplementation. Functional capacity and cognitive function (Aim 1), Vascular function and exercising hemodynamics (Aim 2), and in vivo and ex vivo mitochondrial respiration (Aim 3) will be assessed each phase. Monthly assessments of functional capacity, behavioral regulation, quality of life, and physical activity will track improvements across the trial. At the conclusion of these studies, we will have expanded our knowledge of the mechanisms underlying exercise intolerance in Veterans suffering from PAD, and, more importantly from a clinical perspective, provided insight into a potential novel therapeutic treatment to improve exercise rehabilitation efficacy for this population. It is anticipated this advancement will contribute to advancing clinical practice in rehabilitative medicine, and ultimately, improving the quality of life for Veterans living with PAD.