Near-Infrared Spectroscopy-Guided Exercise Training in Peripheral Arterial Disease

Background: In peripheral arterial disease (PAD), supervised exercise programs generally improve claudication but are poorly adhered to since the patient is expected to repeatedly 'walk to the point of pain'. Meanwhile, the mechanism of benefit remains unclear. One hypothesis is that repeated leg muscle hypoxia activates endogenous angiogenic mechanisms that improve local oxygen delivery. A second possible adaptation is that exercise improves abnormal muscle mitochondrial utilization of oxygen. In pilot studies we have characterized calf muscle oxygen delivery and use in patients with claudication with near infrared spectroscopy (NIRS). Using this non-invasive measure, we have devised a strategy of 'exercising to hypoxia' at an intensity below the pain threshold; moreover, we derived a technique for characterizing muscle mitochondrial function. In this proposal, we will explore whether a novel walk-to-hypoxia strategy is as effective as traditional walk-to-pain approaches in subjects with PAD, whether improving mitochondrial function is implicated in clinical improvements, and whether these responses to exercise correspond to changes in cellular and molecular ischemic signaling. Methods: In subjects with symptomatic PAD, we will assess the efficacy of a novel NIRS-based strategy of thrice-weekly exercise training. Subjects will be randomized to NIRS-based training, traditional claudication-based training, or self-directed walking. We will test the hypotheses that 1) NIRS-directed exercise improves claudication to a similar degree as pain-directed exercise training and 2) is superior to self-directed walking. In the pain-based group, physical effort will be dictated by claudication symptoms, whereas in the hypoxia-based training program, physical effort is dictated by NIRS measure of calf oxygen tension. Efficacy in the training programs will be evaluated by total walking time on a standard graded treadmill test after 12 weeks. In addition, using NIRS we will measure oxygen utilization kinetics in calf muscle at baseline and after 12 weeks. We will determine whether NIRS-based training elicits progenitor cell mobilization and ischemic marker signaling as is seen in pain-based training. Conclusions: We will test whether a hypoxia-based training program is as effective as and more tolerable than traditional pain-based training programs in PAD. These findings may transform how we prescribe exercise to patients with claudication. (AHA Program: Grant-in-Aid)