West Los Angeles,
The purposes of this pilot project are to (a) determine changes in calf muscle blood flow
and energy supply resulting from calf muscle exercise, and (b) to determine changes in these
variables resulting from exercise training (walking and calf muscle exercise). This is a
pilot study to prepare for a larger project in the future. Exercise and exercise training
should increase blood flow and energy supply to the calf muscles.
Specific Objectives: 1.Develop an appropriate graded calf exercise test protocol for
evaluating perfusion and metabolism during exercise in subjects with peripheral arterial
disease (PAD), 2.compare perfusion in gastroc-soleus and tibialis anterior muscles during
exercise and recovery from exercise, and to compare metabolism in those muscles during
exercise, 3.compare the perfusion during exercise and recovery between groups with and
without PAD, and to compare metabolism during exercise between groups with and without PAD,
4.estimate sample sizes and effect sizes for a future clinical trial to determine the
efficacy of walking and calf muscle exercise training for improving calf muscle perfusion
and metabolism. 5.determine the sensitivity and specificity of the PET exercise test in
classifying subjects into groups with or without PAD, and 6. determine the test-retest
reliability coefficients of perfusion and metabolic measures.
Two groups of subjects will participate in this study. Group I (n=25 subjects with PAD)
will undergo two sets of assessments. Each assessment will consist of completing three
questionnaires, two exercise tests, and one PET scan session. Additionally, they will
receive one MRI of the legs. Then they will participate in a three-month exercise training
intervention consisting of treadmill walking and calf muscle exercise. Finally, they will
repeat one set of assessments (listed above with MRI). Group II (n=25 healthy control
subjects) will undergo two sets of assessments. Each assessment will consist of three
questionnaires, two submaximal exercise tests, one MRI, and one PET scan session (no
exercise tests). Additionally they will receive only one MRI. They will not participate in
an exercise training intervention.
Experimental Design The project is a pilot study that is both cross-sectional and
longitudinal in nature. The initial baseline measurement sessions will allow comparisons of
acute perfusion and metabolic physiologic responses between two groups of subjects (with and
without PAD). Duplicate testing for each subject will allow assessment of the test-retest
reliability of the measurements. The PAD subjects' perfusion and metabolic responses will
be assessed again after three months of exercise training (walking and calf muscle
exercise). While not a definitive clinical trial of the exercise training intervention, the
results should provide estimates of sample and effect sizes to design a more definitive
future clinical trial.
Subjects Recruitment and Sampling: Fifty different subjects (N=50) will participate in the
project, reflecting the available veteran patient population. The sample will include
primarily men, of any age and ethnicity. Twenty-five subjects will have PAD and will be
identified and recruited via convenience sampling primarily from the Physical Medicine and
Rehabilitation (PM&R) Outpatient Clinic, Diabetes Clinic, and Peripheral Vascular Clinic at
the VA West Los Angeles Healthcare Center (VAWLAHC). Other participants may be recruited
from other VA Greater Los Angeles Healthcare System locations, specifically the Los Angeles
Ambulatory Care Center and the Sepulveda Ambulatory Care Center. Twenty-five "normal"
healthy control subjects will be recruited via convenience sampling from well veterans and
the general community; the two groups will be matched on gender and age. We plan to enroll
25 subjects with PAD for the three-month exercise training intervention.
Screening and Consent: Research staff will recruit and interview prospective subjects.
Prospective subjects who meet all initial inclusion and exclusion criteria will be requested
to review and sign the IRB-approved informed consent form and will be enrolled in the
project. A physician will physically examine prospective subjects and provide medical
clearance prior to participation.
Assessments and Measurements
After screening and consent, the assessment process will progress in four phases:
1. Questionnaires to evaluate walking impairment, physical activity, and general health.
The information will be used to better characterize the study groups.
2. Exercise tolerance testing to demonstrate claudication symptoms in PAD subjects during
both treadmill walking and calf muscle exercise and to assess functional changes
resulting from training. The control subjects will also perform the exercise tests, but
these tests will be submaximal and without pain. The data will be used for comparison
to the data from PAD subjects.
3. Magnetic Resonance Imaging (MRI) of the legs to measure popliteal artery diameter and
document locations of individual muscles and muscle groups.
4. PET-exercise testing to measure muscle perfusion and glucose metabolism during calf
muscle exercise and recovery.
Group I (n=25 PAD patients). This sample will represent the population of veterans with
PAD with mild mobility impairment secondary to intermittent claudication in the
Inclusion Criteria for PAD Subjects:
- diagnosis of PAD (acute or chronic occlusive arterial disease), with or without
- positive Edinburgh Claudication Questionnaire
- Fontaine stage IIa only (mild claudication, walking distance > 200 feet (one-half
- ambulatory, without assistive devices
- calf muscle claudication within 10 minutes of treadmill walking and calf muscle
Group II (n=25 normal control/reference subjects). This reference sample will represent
the population of adults without PAD and related problems. They will undergo the
PET-exercise testing for perfusion and glucose metabolism measurements, but will not
perform the exercise training intervention.
Inclusion Criteria for Controls:
- healthy adults, matched by age and sex to PAD subjects
Exclusion Criteria for PAD and Control Subjects
- PAD secondary to Buerger's disease, autoimmune arteritis, fibromuscular dysplasia,
chronic and repetitive occupational trauma, venous stasis, hypercoagulability
disorder, or arterial embolic disease.
- inability to perform ankle dorsi and plantar flexion exercise
- cigarette smoking within last 6 months
- severe claudication, leg rest pain, skin ulceration, necrosis or gangrene (Fontaine
stage >= IIa)
- poorly controlled diabetes mellitus (bA1c >= 9%)
- poorly controlled hypertension (resting BP > 140/90 mmHg)
- Raynaud's syndrome
- changes in prescribed cardiovascular medications within the past 6 months
- exertional angina, dyspnea, fatigue, or dizziness
- severe coronary artery disease
- congestive heart failure
- severe COPD
- exercise intolerance limited by leg pain of nonvascular origin (e.g., arthritis,
- transmetatarsal or more proximal lower-extremity amputation
- nonambulatory in the last 6 months
- severe leg weakness preventing leg exercise
- surgery related to PAD during preceding 3 months
- myocardial infarction within preceding 3 months
- unstable claudication symptoms during preceding 3 months
- terminal disease with < 6 months prognosis
- dementia (Minimental score < 24) (Folstein et al., 1975)
- pregnancy (Females of childbearing potential will be given a pregnancy test prior to
acceptance into the study.)