Peripheral arterial disease (PAD) is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. PAD is largely thought to be a macrovascular disease manifested by atherosclerosis. The contribution of microvascular dysfunction in the end-organ, muscle, to the incidence of symptoms and progression of PAD is uncertain. Similar to vascular disease in the coronary arteries, it is likely that a combination of macrovascular and microvascular dysfunction is involved in the pathophysiology of PAD progression. A more thorough understanding of the pathophysiology of PAD progression and symptom origin is required to provide the basis for new methods of evaluation and novel therapeutic strategies.
Aims :
Aim -1)To determine in a group of patients with moderate PAD, the relationship between claudication limited exercise tolerance (Peak Walking Time-PWT) and microvascular blood flow.
Aim -2)To determine if changes in PWT with exercise rehabilitation correlate with changes in microvascular blood flow.
Aim -3) To determine if the vascular health profile, as measured with circulating Endothelial Progenitor Cells (EPCs) and endothelially-derived microparticles (MPs), biomarkers of endothelial health, improves following exercise rehabilitation and correlate with microvascular blood flow. Design &Methods: Subjects with moderate PAD will undergo measurement of treadmill PWT. Continuous Arterial Spin Labeling-Perfusion MRI will be used to measure skeletal muscle calf microvascular blood flow and flow cytometry will be used to characterize the endothelial vascular health profile described above. We anticipate that a supervised exercise rehabilitation program will improve PWT, microvascular blood flow, and the endothelial vascular health profile.

Public Health Relevance

Peripheral arterial disease is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. Early disability derives from claudication or ischemic muscle pain, inhibiting ambulation. The pathophysiology of this disorder is thought to be of macrovascular origin, however the contribution of the microvasculatrue to this disorder is not well understood and may be important. Improved knowledge of the contribution of the microvasculature to this disorder, and improvement in our ability to monitor, via relatively nonivasive imaging and circulating cellular biomarker assays, the impact of rehabilitation or other therpaeutic interventions, may assist in the treatment of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL075649-06A2
Application #
8042007
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Reid, Diane M
Project Start
2003-09-22
Project End
2014-11-30
Budget Start
2011-04-01
Budget End
2011-11-30
Support Year
6
Fiscal Year
2011
Total Cost
$791,531
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Englund, Erin K; Rodgers, Zachary B; Langham, Michael C et al. (2018) Simultaneous measurement of macro- and microvascular blood flow and oxygen saturation for quantification of muscle oxygen consumption. Magn Reson Med 79:846-855
Magland, Jeremy F; Li, Cheng; Langham, Michael C et al. (2016) Pulse sequence programming in a dynamic visual environment: SequenceTree. Magn Reson Med 75:257-65
Englund, Erin K; Rodgers, Zachary B; Langham, Michael C et al. (2016) Measurement of skeletal muscle perfusion dynamics with pseudo-continuous arterial spin labeling (pCASL): Assessment of relative labeling efficiency at rest and during hyperemia, and comparison to pulsed arterial spin labeling (PASL). J Magn Reson Imaging 44:929-39
Langham, Michael C; Desjardins, Benoit; Englund, Erin K et al. (2016) Rapid High-resolution, Self-registered, Dual Lumen-contrast MRI Method for Vessel-wall Assessment in Peripheral Artery Disease:: A Preliminary Investigation. Acad Radiol 23:457-67
Englund, Erin K; Langham, Michael C; Ratcliffe, Sarah J et al. (2015) Multiparametric assessment of vascular function in peripheral artery disease: dynamic measurement of skeletal muscle perfusion, blood-oxygen-level dependent signal, and venous oxygen saturation. Circ Cardiovasc Imaging 8:
Langham, Michael C; Li, Cheng; Englund, Erin K et al. (2013) Vessel-wall imaging and quantification of flow-mediated dilation using water-selective 3D SSFP-echo. J Cardiovasc Magn Reson 15:100
Englund, Erin K; Langham, Michael C; Li, Cheng et al. (2013) Combined measurement of perfusion, venous oxygen saturation, and skeletal muscle T2* during reactive hyperemia in the leg. J Cardiovasc Magn Reson 15:70
Langham, Michael C; Floyd, Thomas F; Mohler 3rd, Emile R et al. (2010) Evaluation of cuff-induced ischemia in the lower extremity by magnetic resonance oximetry. J Am Coll Cardiol 55:598-606
Langham, Michael C; Magland, Jeremy F; Epstein, Charles L et al. (2009) Accuracy and precision of MR blood oximetry based on the long paramagnetic cylinder approximation of large vessels. Magn Reson Med 62:333-40
Langham, Michael C; Magland, Jeremy F; Floyd, Tom F et al. (2009) Retrospective correction for induced magnetic field inhomogeneity in measurements of large-vessel hemoglobin oxygen saturation by MR susceptometry. Magn Reson Med 61:626-33

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