Peripheral arterial disease (PAD) impairs arterial blood flow to the legs & is a major indicator of systemic atherosclerosis. PAD affects 5% of the US population over 50. Approx 1/3 of patients with PAD have typical claudication, defined as pain in one or both legs on walking that is relieved by rest. Patients with claudication have a marked impairment in exercise performance similar to patients with NYHA class III heart failure. Goals of treatment for PAD patients include risk-factor modification & antiplatelet drug therapy to address increased cardiovascular mortality risk. Supervised exercise training is the most efficacious treatment to improve walking capacity, demonstrated in many (small) randomized trials. Neither the pathophysiology of claudication nor the mechanism(s) by which exercise training improves walking times in persons with IC are completely understood. It is unknown how long-term exercise training affects skeletal muscle or to what extent skeletal muscle abnormalities in PAD are reversible. Women have been largely underrepresented in mechanistic studies of IC and exercise training. There is an urgent need for clinical research directed towards defining the basis of the exercise training changes induced in PAD patients in order to: 1) provide insights into the general pathophysiology of the exercise impairment in PAD; 2) permit scientifically plausible & testable modifications to currently prescribed exercise regimens to better employ this critical therapeutic modality &, 3) identify novel targets from pharmacotherapy that are capable of inducing the repertoire of molecular responses induced by exercise training. In this RFA (HL-03-003) (AMNESTI in PAD), men & women (n=160), over 40 years, with IC & an ankle/brachial systolic blood pressure ratio (ABI) <0.8 at rest, will be recruited from Duke University Medical Center and the University of Colorado Health Science Center. Patients will be randomized to a supervised or home-based exercise program. Evaluations will be at baseline, 3-weeks (supervised exercise) and 3-months. Age-gender matched healthy controls (n=66) will be tested at base line. The central hypothesis is that the beneficial effects of exercise training are primarily mediated through an angiogenic effect.
Sp Aim 1 will establish the baseline vascular abnormalities present in patients.
Sp Aim 2 will establish the ability of the selected vascular abnormalities in Sp Aim I to predict peak oxygen consumption in PAD using a prediction model.
Sp Aim 3 will establish the ability of exercise training to modify the vascular abnormalities in PAD.
Sp Aim 4 will examine the gender specificity of the results obtained in Sp Aim 1-3.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075752-05
Application #
7279172
Study Section
Special Emphasis Panel (ZHL1-CSR-I (S1))
Program Officer
Ershow, Abby
Project Start
2003-09-25
Project End
2008-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$344,271
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Heuslein, Joshua L; Li, Xuanyue; Murrell, Kelsey P et al. (2015) Computational Network Model Prediction of Hemodynamic Alterations Due to Arteriolar Rarefaction and Estimation of Skeletal Muscle Perfusion in Peripheral Arterial Disease. Microcirculation 22:360-9
Allen, Jason D; Stabler, Thomas; Kenjale, Aarti A et al. (2014) Diabetes status differentiates endothelial function and plasma nitrite response to exercise stress in peripheral arterial disease following supervised training. J Diabetes Complications 28:219-25
Jones, W Schuyler; Duscha, Brian D; Robbins, Jennifer L et al. (2012) Alteration in angiogenic and anti-angiogenic forms of vascular endothelial growth factor-A in skeletal muscle of patients with intermittent claudication following exercise training. Vasc Med 17:94-100
Allen, Jason D; Giordano, Tony; Kevil, Christopher G (2012) Nitrite and nitric oxide metabolism in peripheral artery disease. Nitric Oxide 26:217-22
Duscha, Brian D; Robbins, Jennifer L; Jones, William S et al. (2011) Angiogenesis in skeletal muscle precede improvements in peak oxygen uptake in peripheral artery disease patients. Arterioscler Thromb Vasc Biol 31:2742-8
Allen, Jason D; Stabler, Thomas; Kenjale, Aarti et al. (2010) Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training. Free Radic Biol Med 49:1138-44
Allen, Jason D; Miller, Elizabeth M; Schwark, Earl et al. (2009) Plasma nitrite response and arterial reactivity differentiate vascular health and performance. Nitric Oxide 20:231-7
Findley, Clarence M; Mitchell, Robert G; Duscha, Brian D et al. (2008) Plasma levels of soluble Tie2 and vascular endothelial growth factor distinguish critical limb ischemia from intermittent claudication in patients with peripheral arterial disease. J Am Coll Cardiol 52:387-93
Mitchell, Robert G; Duscha, Brian D; Robbins, Jennifer L et al. (2007) Increased levels of apoptosis in gastrocnemius skeletal muscle in patients with peripheral arterial disease. Vasc Med 12:285-90
Annex, Brian H (2007) Is a simple biomarker for peripheral arterial disease on the horizon? Circulation 116:1346-8

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