APelin, EXercise, and mobility in Peripheral Artery Disease, the APEX-PAD Study

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APelin, EXercise, and mobility in Peripheral Artery Disease, the APEX-PAD Study People with lower extremity peripheral artery disease (PAD) have faster functional decline than those without PAD. Ischemia-reperfusion of calf muscle during walking activity in people with PAD increases oxidative stress and is associated with calf mitochondrial dysfunction and myofiber loss. Walking exercise substantially improves walking impairment in PAD but it does not reduce lower extremity atherosclerotic obstruction. Biologic pathways by which exercise improves walking impairment without altering arterial obstruction in PAD are unknown. Furthermore, patients with PAD vary in their responsiveness to an exercise intervention. Biologic reasons for this variable response to exercise remain unclear. We hypothesize that exercise-induced increases in plasma and calf muscle apelin abundance contribute to improved walking performance following an exercise intervention in PAD. Apelin is an endogenous peptide and ligand of the G protein-coupled receptor APJ. Preclinical evidence suggests that apelin stimulates nitric oxide release, enhances Iimb perfusion, and stimulates muscle regeneration and mitochondrial activity. Based on preliminary evidence of favorable effects of apelin on both vasculature and skeletal muscle, we propose the APEX-PAD Study. We hypothesize that lower extremity ischemia induced by walking exercise stimulates apelin release from lower extremity arterial endothelial cells, thereby increasing nitric oxide (NO), stimulating angiogenesis, promoting favorable changes in calf muscle, and improving walking performance in PAD. We hypothesize that variability in baseline plasma apelin abundance and in changes in apelin abundance in response to exercise contribute to variability in response to an exercise intervention in people with PAD. The APEX-PAD Study will measure apelin in our unique biobank of plasma and calf muscle biopsy specimens collected at baseline and at 6-month follow-up from 248 well characterized people with PAD (N=35 with muscle biopsy) randomized into one of two completed NHLBI-funded clinical trials of supervised treadmill exercise. In each trial, the 6-month exercise intervention meaningfully improved six-minute walk distance, compared to control, but did not alter the ankle brachial index, a measure of lower extremity atherosclerosis severity. We will determine whether the exercise intervention increased plasma and calf muscle apelin abundance, compared to control. Among participants randomized to exercise, we will determine whether those with higher plasma apelin at baseline and whether those with greater increases in plasma apelin after the intervention had greater improvement in study outcomes (six-minute walk distance, brachial artery flow- mediated dilation, and calf biopsy measures). Our results will determine whether interventions that increase apelin may improve walking performance in the large and growing number of people who are disabled by PAD.