Peripheral artery disease (PAD) and its associated declines in physical function impair quality of life (QOL) in nearly 20% of older veterans and result in substantial VA health care costs. Revascularization addresses the anatomical pathology, but does not restore mobility function and QOL. Optimal therapy may require post- revascularization rehabilitation to address lingering defects in skeletal muscle, such as reduced capillary density, that limit function; however, the current standard of care after revascularization does not include rehabilitation. Exercise training improves ambulatory capacity and QOL in early stage PAD, and neuromuscular electrical stimulation (NMES) increases blood flow and angiogenesis in muscle which may enhance function by increasing muscle perfusion. Together, these two therapies may work in a complementary manner to improve outcomes in older veterans with PAD after revascularization. This study tests the hypothesis that the combination of supervised exercise training and NMES (Exercise+NMES) will improve mobility function, ambulatory capacity, and QOL more than standard care, and these improvements occur through mechanisms including increases in angiogenesis, capillary density, and muscle perfusion in veterans with PAD after revascularization. This will be tested through two aims.
Aim 1 : Determine the effects of exercise training and NMES on mobility function and QOL in middle-aged to older patients who have undergone endovascular revascularization for PAD. Mobility function and ambulatory capacity will be assessed using the modified physical performance test (MPPT), 6-minute walk test, and a standardized treadmill test. QOL will be assessed using general (SF-36) and disease-specific (VascuQoL) questionnaires.
Aim 2 : Determine the effects of the exercise and NMES interventions on muscle perfusion and underlying angiogenic mechanisms in skeletal muscle by measuring calf muscle perfusion (contrast-enhanced ultrasound) and oxygen saturation (StO2, by near-infrared spectroscopy), as well as gastrocnemius muscle capillary density and expression of angiogenic growth factors (VEGF and bFGF). We will enroll veterans (50-80 years of age) with PAD (Fontaine Stage IIb-III) who are planned for percutaneous revascularization. Participants will complete research testing consisting of: a) Assessment of mobility function (MPPT and 6-minute walk) and QOL (SF-36 and VascuQoL questionnaires); b) Treadmill tests to assess ambulatory capacity (claudication onset time and peak walking time), calf muscle perfusion and StO2; and c) A gastrocnemius needle biopsy to measure capillary density and angiogenic growth factor expression. Participants will undergo baseline testing prior to revascularization (with the exception of the muscle biopsy) and will repeat research testing 2-3 weeks after revascularization to determine the effect of only revascularization on functional outcomes. After post-revascularization testing, 52 patients will be randomized to one of four groups (Exercise-only, NMES-only, Exercise+NMES, or Standard Care; n=13/group) in a 2x2 study design with matching for age ( 5 yrs) and sex. After completion of the 3-month intervention, participants will repeat all tests to determine the effects of the interventions compared to standard care. This patient-oriented research uses the novel application of standardized rehabilitation programs to veterans with PAD after endovascular revascularization, and the novel application of NMES therapy as an alternative or adjuvant to exercise rehabilitation in these patients. This study has the potential to provide the first evidence that combined Exercise+NMES improves, physical function and QOL in PAD patients after revascularization through muscle mechanisms including increases in angiogenesis and muscle perfusion. This could lead to larger trials intended to alter the management of PAD in order to ultimately reduce the rates of re- intervention, morbidity and mortality in older veterans. Such interventions could be easily disseminated across medical centers and potentially reduce disability and health care costs related to the consequences of PAD.

Public Health Relevance

The research in this VA SPiRE Award application is designed to determine the effects of supervised rehabilitation on physical function and quality of life in veterans undergoing endovascular revascularization to treat peripheral artery disease (PAD). Further, it will determine mechanisms by which exercise rehabilitation and neuromuscular electrical stimulation (NMES) therapy may increase angiogenesis and vascular function to improve physical function in these older veterans. This is especially relevant to veterans' health, as nearly 20% of older veterans have PAD, and the associated comorbidities reduce quality of life and result in substantial VA health care costs. The identification of efficacious rehabilitation programs could significantly alter the management of veterans with PAD as these interventions could be easily disseminated across medical centers. This would potentially reduce disability and health care costs related to the consequences of PAD by ultimately reducing the rates of re-intervention, morbidity and mortality in older veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Rehabilitation Research and Development SPiRE Program (RRDS)
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Baltimore VA Medical Center
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Addison, Odessa; Prior, Steven J; Kundi, Rishi et al. (2018) Sarcopenia in Peripheral Arterial Disease: Prevalence and Effect on Functional Status. Arch Phys Med Rehabil 99:623-628
Addison, Odessa; Kundi, Rishi; Ryan, Alice S et al. (2018) Clinical relevance of the modified physical performance test versus the short physical performance battery for detecting mobility impairments in older men with peripheral arterial disease. Disabil Rehabil 40:3081-3085
Kundi, Rishi; Prior, Steven J; Addison, Odessa et al. (2017) Contrast-Enhanced Ultrasound Reveals Exercise-Induced Perfusion Deficits in Claudicants. J Vasc Endovasc Surg 2: