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

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $160,711

## Abstract

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 ...

## Key facts

- **NIH application ID:** 9875087
- **Project number:** 1R21AG065705-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mary McGrae McDermott
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $160,711
- **Award type:** 1
- **Project period:** 2020-02-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875087

## Citation

> US National Institutes of Health, RePORTER application 9875087, APelin, EXercise, and mobility in Peripheral Artery Disease, the APEX-PAD Study (1R21AG065705-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875087. Licensed CC0.

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