Peripheral artery disease (PAD) affects 5% of the US population over 50 yrs, one third of which suffer from intermittent claudication (IC). The incidence of PAD in subjects with diabetes (DM+PAD) is so greatly increased that screening for PAD in asymptomatic diabetic subjects is recommended. DM+PAD patients are at increased risk for disease progression to critical leg ischemia, lower extremity amputation, and cardiovascular events. Reduced bioavailable vascular NO may be a particularly pertinent issue in diabetes given that endothelial derived NO production has been shown to be decreased by hyperglycemia, and NO is inactivated by advanced glycation end products and reactive oxygen species. We have previously shown PAD-only, but not type 2 diabetic (T2D)+PAD, subjects are able to up-regulate vascular NO bioavailability and related plasma nitrite signaling following exercise training and that these changes mediate a more pronounced functional response. We have also shown an 18% and 17% increase in COT and PWT respectively in PAD-only, following a single dose ingestion of a high-nitrate containing beverage which raises plasma nitrite in comparison to placebo. Additionally, following chronic treatment;A) In a murine model hind limb ischemia of angiogenesis and arteriogenesis were significantly increased only in the ischemic limb;and B) following two days treatment in healthy humans mitochondrial oxygen efficiency was increased causing a reduction in oxygen cost during exercise. The hypothesis of this proposal is that in T2D+PAD subjects with IC, regular consumption of a high nitrate supplement which raises plasma nitrite, in conjunction with 12 weeks of supervised exercise training at the limb ischemic threshold (SET) will produce a greater clinical benefit (increases in COT and PWT) relative to a group with the same exercise training but supplemented with placebo (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 T2D+PAD and IC:
Specific Aim 1 : To determine group differences in the change in COT, PWT and VO2peak during a maximal graded exercise test, following 12 weeks of supervised exercise training.
Specific Aim 2 : To determine group differences in the change in (a) tissue oxygenation (by NIRS) and (b) NO-derived species (plasma and RBC nitrite, nitrate, nitrosothiols, plasma nitrotyrosine), cGMP during a maximal graded exercise test, and (c) vascular function at rest (endothelial function), calf blood flow (plethysmography).
Specific Aim 3 a: To determine group differences in the change in gastrocnemius muscle for (a) angiogenesis (capillaries per unit area and per muscle fiber, endothelial cells with surrounding pericytes, relative fraction of type I, versus type II fibers). If differences exist we will look for changes in cell proliferation (PCNA) nd apoptosis (TUNEL);(b) oxidative capacity (citrate synthase activity);(c) mitochondrial volume and density;(d) mitochondrial oxygen efficiency (respiratory control ratio, the ratio of ATP phosphorylation rate per oxygen consumption rate (P/O ratio), and maximal rate of ATP production).
Peripheral artery disease (PAD) affects 5% of the US population over 50 yrs, one third of which suffer from intermittent claudication (IC). The incidence and progression of PAD in subjects with diabetes (DM+PAD) is so greatly increased that screening for PAD in asymptomatic diabetic subjects is recommended. 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.
|Woessner, Mary; VanBruggen, Mitch D; Pieper, Carl F et al. (2018) Beet the Best? Circ Res 123:654-659|