Increased Plasma Nitrite, Tissue Oxygenation and Functional Changes in PAD

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DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is caused by atherosclerotic occlusions in the legs. It affects 5% of the US population over 50 yrs, one third of which suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. An intervention that could (A) acutely improve oxygenation to areas of ischemia and (B) chronically increase vessel growth to these ischemic areas would allow for greater exercise tolerance and compliance and facilitate greater improvements in function and quality of life. Plasma nitrite was once considered a biologically inert byproduct and marker of endothelial NO production. Recently, several studies have demonstrated an endocrine role for NO equivalents, including nitrite. These equivalents may be transported in the blood to peripheral tissue beds, where under hypoxic conditions they can be converted to NO and increase blood flow and O2 delivery. This may be pertinent in an arterial occlusive disease (PAD), especially during exercise when tissue ischemia is the limiting factor. The hypothesis of this proposal is that in subjects with PAD and IC, regular consumption of a high nitrate supplement which raises plasma nitrite, in conjunction with 8 weeks of supervised exercise training at the limb ischemic threshold (SET) will produce a greater clinical benefit (increases in COT and PWT) than placebo plus supervised exercise at the limb ischemic threshold (PET). In order to adequately develop, power and execute a larger study, the following specific aims will explore our hypothesis using 24 individuals (12 per group) with PAD and IC: Specific Aim 1a: To determine the segment of PAD patients that can achieve the desired level of plasma nitrite (>500nM at 180min post beverage consumption) at a tolerable volume for an 8 week study. Specific Aim 1b: In these subjects, determine differences in COT, PWT and VO2peak during a graded exercise test, between randomization to 8 weeks of SET or PET. Specific Aim 2: To determine differences in (a) tissue oxygenation (by NIRS) and (b) NO-derived species (plasma and RBC nitrite, nitrate, nitrosothiol), cGMP, oxidative and nitrosative stress (plasma nitrotyrosine and F2-isoprostane) during treadmill testing following SET or PET Specific Aim 3: To determine differences in gastrocenemius muscle (via biopsy) (a) angiogenesis and arteriogenesis (capillary density with surrounding pericytes, proliferating cell nuclear antigen, and apoptosis) and oxidative capacity (fiber type composition, citrate synthase activity), and (b) endothelial function (brachial artery FMD) after SET or PET. PUBLIC HEALTH RELEVANCE: Peripheral artery disease (PAD) is a form of cardiovascular disease (CVD) caused by atherosclerotic occlusions in the legs. It affects approximately 5% of the US population over 50 yrs of age, one third of which suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest. We propose by supplementing plasma nitrite via a beverage we can (A) acutely improve oxygenation to areas of ischemia and (B) chronically increase vessel growth to these ischemic areas, would allow for greater acute exercise tolerance, ease the burden of exercise compliance and facilitate greater improvements in function and quality of life