Peripheral artery disease (PAD) and its associated declines in physical function and glucose metabolism affect nearly 20% of older adults and result in substantial health care costs. The current standard of care for PAD patients includes only medical management or surgical revascularization, but this does not sufficiently address functional and metabolic impairments related to impaired angiogenesis and capillary rarefaction. Aerobic exercise training (AEX) results in modest functional improvements in PAD patients, but does not restore functional status to that of healthy older adults. This may be attributable, in part, to a limited angiogenic response to AEX in PAD patients. Adjunct therapies such as neuromuscular electrical stimulation (NMES) may enhance skeletal muscle angiogenesis to improve function and metabolism in these patients. This study will test the hypothesis that AEX+NMES improves angiogenic growth factor expression, endothelial progenitor cell (EPC) mobilization, skeletal muscle capillary density, and muscle perfusion more than AEX or NMES alone, and that improvements in these mechanisms will translate to greater increases in ambulatory capacity and glucose metabolism in older PAD patients with impaired glucose tolerance (IGT). This will be tested through two aims.
Aim 1 : Determine the effects of AEX+NMES, AEX-only, and NMES-only compared to Control on skeletal muscle capillary density and associated angiogenic mechanisms.
Aim 2 : Determine whether the effects of the interventions on angiogenesis translate to improvements in muscle perfusion, ambulatory capacity, and glucose metabolism. We will study 48 older men and women with PAD and IGT (60- 75yrs, Fontaine Stage I-II PAD) randomized, with stratification by sex and race, to one of four groups (AEX+NMES, AEX-only, NMES-only, or Control; n=12/group). Before and after the 3-month interventions, participants will complete research testing consisting of: a) A standardized treadmill test to assess ambulatory capacity and calf muscle perfusion by contrast-enhanced ultrasound; b) Assessment of mobility function by modified physical performance test and 6-minute walk; c) Oral glucose tolerance test; d) Gastrocnemius muscle sampling to measure capillary density and angiogenic growth factor expression; and e) An acute bout of AEX or NMES to assess effects on circulating angiogenic growth factor levels and EPC mobilization. Repeated measures ANCOVA will be used to determine the effects of EX+NMES, NMES-only, and AEX-only compared to Control. This would be the first study to use NMES as an adjunct to AEX with the goal of improving muscle perfusion, physical function, and metabolism in older PAD patients with IGT. Moreover, this study design will assess the independent and combined effects of AEX and NMES on angiogenic mechanisms associated with any improvements in function and metabolism. This could lead to larger trials intended to improve the treatment of older PAD patients in order to reduce the loss of functional independence, rates of surgical intervention, morbidity and mortality.
The research in this R21 Exploratory/Developmental Research Grant application is designed to determine the effects of a novel neuromuscular and exercise rehabilitation program on angiogenesis, physical function, and glucose metabolism in older patients with peripheral artery disease (PAD) who are at high risk for frailty and loss of functional independence. Further, it will determine skeletal muscle mechanisms by which these interventions may improve blood flow and muscle perfusion to enhance function and metabolism in these older patients. This is especially relevant to the aging population as the identification of efficacious rehabilitation programs could significantly alter the clinical management of the 20% of older adults with PAD, with the ultimate goal of reducing the rates of surgical intervention, morbidity and mortality in older veterans.
