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.

Condition	Intervention	Phase
Diabetes Mellitus, Type 2 Intermittent Claudication	Behavior: Physical exercise  Behavior: Physical walking and calf muscle exercise	Phase I Phase II

Further Study Details: 

Primary Outcomes: Muscle perfusion via H2(15)O PET scan and glucose metabolism via (18)FDG PET scans.
Secondary Outcomes: Initial and absolute claudication distance on the treadmill; Number of calf muscle contractions at maximal claudication; Percentage saturation of calf muscle hemoglobin and myoglobin with oxygen (%StO2).
Expected Total Enrollment:  50

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.

1. Questionnaires:

a. Walking Impairment Questionnaire (WIQ): The WIQ measures self-reported walking speed and distance among subjects on a 0-100% scale.

b. International Physical Activity Scale (IPAQ): The IPAQ is a brief self-report of frequency, duration and intensity of a person’s physical activity within the past seven days. It provides an absolute total physical activity score in MET.min/day and/or categorization as insufficiently, sufficiently, or highly active. It has been recently validated in 2450 male and female adults in 14 countries. Test-retest reliability coefficients averaged 0.80. Initial criterion validity against portable accelerometry indicates acceptable measurement properties, at least as good as other established self-report instruments.

c. SF-36v2TM Health Survey: The SF-36 Health Survey is a self-reported summary of the participant’s perceived physical and mental health. It has been validated in numerous studies with older adults, including populations with serious disabilities including congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, and back pain/sciatica). The various subscales of the SF-36 include five physical health components (physical functioning, role-physical, bodily pain, general health, and vitality) and three mental health components (social functioning, role-emotional, and mental health).

2. Exercise Testing:

a. Treadmill Test: All subjects will perform treadmill exercise tests. PAD subjects will perform this test twice within a two-week period of time before exercise training and once after five months of exercise training. This test will measure walking distances at onset and at maximal claudication according to the protocol of Gardner and co-workers. The protocol involves a symptom-limited treadmill exercise test with a constant speed of 2 mph and an increase in grade of 2% every two minutes beginning at 0% grade (1-2 METs/stage). Initial claudication distance (meters) is defined as the total distance walked at the onset of claudication. Absolute claudication distance (meters) is defined as the distance at which claudication becomes intolerable, as judged by the subject. 12-lead ECG will be used to monitor heart rate, rhythm and waveforms. We will use a validated 0-4 pain scale to assist patients in identifying progression of claudication pain during the test: 0 = absent, 1 = onset of pain, 2 = moderate pain, 3 = intense pain, 4 = maximal pain (Gardner, 1997). Heart rate, ECG waveforms and rhythm will be monitored and recorded every two minutes with 12-lead ECG, along with other symptoms of exercise intolerance. Brachial systolic and diastolic blood pressure during the last minute of each 2-minute exercise stage will be recorded. All standard precautions used in cardiac exercise testing will be observed. Claudication distances will be used as secondary outcome measures in the exercise training intervention. Control subjects will perform the treadmill test to rule out serious coronary artery disease and provide data for comparison with PAD subjects. They are not expected to experience claudication. They should experience only normal symptoms associated with mild-to-moderate exercise such as increased heart rate, blood pressure, and increased body temperature and breathing. 12-lead ECG will be used to monitor heart rate and rhythm, ECG waveforms, and any symptoms of exercise intolerance.

b. Calf Muscle Exercise Test: After a five-minute rest period, PAD subjects will perform a test of isolated calf muscle exercise with their most affected gastroc-soleus muscles using a pulley-weight ankle exercise device. The subject will assume the semi-recumbent position on a treatment table and the ankle exerciser will be mounted at the foot of the bed. The subject’s foot will be positioned on the exerciser pedal. After a five-minute baseline rest period, the subject will exercise for up to 10 minutes or until claudication becomes intolerable as judged by the subject. The number of contractions at the onset of claudication and at maximal claudication will be counted and recorded. Isolation of this muscle group is justified because PAD patients report it to be the most symptomatic muscle group during walking-induced intermittent claudication. The ankle exercise device provides standardized reproducible resistance to ankle plantar flexion at a specified cadence (60 contractions per minute, 40° ankle range of motion) paced by a metronome and counted electronically. The exercise consists of alternating up and down movements of the foot against a pedal that resists with 4-8-kg of force, producing a power output of 4-8 W. The test will be followed by 5 additional minutes of rest/recovery. During each test, the calf tissue oxygenation (%StO2) will be measured non-invasively with an Hutchinson InSpectra Tissue Spectrometer Model 325. A researcher will stick a plastic patch (about 2.5 by 3.5 inches in size) that holds the light probe onto the skin of the most symptomatic calf. The probe is connected to the tissue spectrometer that shines near-infrared laser light into the skin and measures the calf muscle oxygen to a depth of 25-35 mm. During these tests, the researcher will also measure the subject’s blood pressure and heart rate with an arm cuff and stethoscope. Control subjects will perform the same calf muscle exercise test with the same measurements, except that they should not experience claudication. They will perform the test twice within a two-week period of time.

3. MRI and PET Scans:

a. MRI: Before all subjects begin the first trial of PET-exercise protocol, an MRI of the legs will be performed. The coordinates of the artery in MRI images will be co-registered with the PET images to allow identification of individual muscles/muscle groups and measurement of popliteal artery diameter required to correct PET-detected activity of H2[15]O in arterial blood to permit blood flow calculation .

b. PET Scans: PAD subjects will undergo two positron emission tomography (PET) scan sessions within a two-week period before exercise training begins and one PET scan session after the five months of exercise training. Control subjects will undergo two PET scan sessions within two weeks of each other.

(1) Measurement Protocol: The PET scanner is located in the trailer outside of Bldg. 507 at our medical center. During a PET-exercise testing session, subjects will lie supine on the padded PET testing table. Both lower limbs will be positioned in the scanner, with one leg marked for scanning the proximal calf (1.0-15.4 cm from the lateral knee joint line). In PAD subjects, the most affected leg will be scanned; in control subjects, a randomly chosen leg will be scanned. Figure 2 illustrates the exercise testing protocol with three test stages. Stage 1 will consist of a H2[15]O injection and 3.5-min PET scan during 4-W calf exercise with the ankle ergometer. At minute 3 of the 5-min exercise bout, a bolus of 25 mCi of H2[15]O will be injected intravenously and the scanner will be started simultaneously. Exercise will continue for another two minutes after tracer injection or until claudication becomes intolerable, as judged by the subject. 10 minutes after cessation of exercise, Stage 2 will involve another H2[15]O injection and 3.5-minute PET scan with no exercise. Again a bolus of 25 mCi of H2[15]O will be injected intravenously and the scanner will be started simultaneously. After a 25-minute rest from the previous exercise bout, Stage 3 will consist of a second 4-W, 5-minute calf exercise bout, with [18]FDG i.v. injection at minute 3. At Stage 4, a 15-minute PET scan will be performed. The 25-minute rest period between stages 1 and 3 is necessary to allow the exercised muscles to recover fully and to generate and deliver the next dose ([18]FDG) tracer. PET scans for both perfusion and metabolism cannot be performed simultaneously during Stages 1 and 2 due to interaction of two different radioactive tracers. Due to its short half-life (123 s), the first two stages scans can be performed in rapid succession (separated by 10 min). The [18]FDG PET scan must be performed 45 minutes after [18]FDG injection to allow the wash-out of nonphosphorylated [18]FDG from muscles. Subjects with PAD will be instructed to report changes in claudication intensity continuously during the test with the 0-4 scale used during exercise.

(2) Perfusion calculation via H2[15]O PET. Measurements will be obtained using an adaptation of the autoradiographic method in which the arterial input function will be derived from the time-activity curve of the popliteal artery PET image instead of on line radioactivity measurements from blood obtained by arterial cannulation as described originally. This technique uses water labeled with [15]O as a blood flow tracer. Due to the short half-life of [15]O (123 sec), scans can be repeated at short intervals. Thus, several scans can be typically performed without removing the subject from the scanner. H2[15]O will be produced in the on-site cyclotron by the bombardment of natural water with protons of 25-30 MeV. After purification, approximately 100 mCi will be transported to the PET suite by pneumatic tube. At the time of injection, approximately 25 mCi remaining in the sample will be administered as an intravenous bolus in 8-10 ml of saline. The scanner will be started at the moment of injection. Data will be stored in 16 frames, the first twelve will be 10-s and the last four 30-s frames. Muscle blood flow will be quantified using the equation of Iida et al. (1986). Thirty-six planes will be generated and average perfusion (ml/100ml/min) will be calculated for anterior compartment, posterior compartment, individual muscles and the entire limb cross-sectional area in every level defined by the anatomical templates.

(3) Glucose metabolism calculation via [18]FDG PET. A bolus of 10 mCi of [18]FDG will be injected 45 minutes after the second 4-W calf exercise bout and [18]FDG injection as described above. The volume tool will be used to view transaxial, coronal and sagittal slices of the leg. Transaxial planes will be serially arranged and co-registered with a similar set of images from H2[15]O scans of the same leg, and with the MRI images obtained as described above to calculate pixel-by-pixel ratios of [18]FDG to H2[15]O levels. The location of individual muscles will be verified by comparing their tomographic images. The index of glucose metabolism will be the [18]FDG activity (Standardized Uptake Ratio, SUR, in counts/s, cps). It reflects the extent of [18]FDG uptake in the muscle tissue and is calculated by the equation: SUR = (aROI . m) / d, where aROI = mean activity of the ROI in mCi /ml), m = body mass in g, and d = injected dose in mCi. All data will be corrected for dead time, decay, and the measured photon attenuation. For Stage 3 involving 4-W calf exercise, the ratio of SUR values of PAD subjects to control subjects (i.e., SURPAD / SURcontrol) will also be computed and compared between the gastroc-soleus and tibialis anterior muscle groups.

(4) Retesting: All subjects will be tested at the same time of day on two occasions within a two-week period to assess between-day reliability of PET and treadmill/exercise measures.

Exercise Training Intervention

After the completion of two pretraining PET exercise protocols and two treadmill and ankle ergometer evaluations, subjects with PAD will progress to the three-month exercise training intervention, followed by one final post-training PET exercise protocol and treadmill and ankle ergometer evaluations. Subjects will enter and exit from the training intervention in a staggered fashion over a two-year period. Subjects with PAD will participate in a structured exercise training program conducted at our medical center three sessions/week and at home two sessions/week. During the training intervention, subjects will be asked to continue their normal daily activities and not to initiate any new exercise programs that might confound the training effects of this project. The clinic-based program will consist of supervised treadmill walking and calf muscle exercise training, three days/week for three months (39 training sessions) at either the Wellness Center (Bldg. 508), Cardiac Rehab (Bldg. 500), or the PM&R Outpatient Clinic (Bldg. 500) at the VA West Los Angeles Healthcare Center. It will be supervised by a rehabilitation therapist who will record detailed training data will be recorded in an exercise log. The specific training exercises will be intervals of treadmill walking and calf muscle exercise interspersed with rest/recovery periods. The walking activity will be based on that of Gardner et al. (2002)---3 sessions/week, 40 min/session, 40-80% max workload. Walking will be performed on a motor-driven treadmill at a speed of two mph. Walking duration will begin at 16 minutes for the first month of the program, and will progressively increase by 8 minutes per month until a total of 40 minutes of walking can be accomplished by the third month. Walking intensity will begin at 50% of the maximal workload achieved during the treadmill exercise test, and progressively increase on an individual basis throughout the program to 80% by the third month. Five minutes of cycling on a stationary cycle ergometer will serve as warm-up and cool-down during each session. Each walking training session will be followed by a progressive calf muscle training session, according to the following protocol: Each session will consist of three bouts of exercise on the ankle ergometer. Each bout will be up to five minutes long (or until maximal claudication), separated by recovery periods long enough for the claudication to disappear for five minutes. The exerciser device’s resistance will be constant at 8 kg of force and the workload (power output) will be incremented by increasing the rate of contractions (paced by a metronome), as follows: Set 1 = 45 contractions/min (cpm) (6 W), Set 2 = 60 cpm (8 W), and Set 3 = 75 cpm (10 W). If Sets 1 and 2 do not produce claudication, then Set 1 work rate will be increased to 60 cpm, Set 2 = 75 cpm, and Set 3 = 90 cpm (12 W). All work performed will be recorded to chart progress. The home-based portion of the exercise program will be twice per week (total of 26 sessions). It will consist of over-ground walking inside/outside of the home (wherever it is most feasible) and calf muscle exercise (standing and seated calf raises). Bouts of these exercises will have the same symptom-limited end-points as during training at WLA. When claudication becomes unbearable, they will rest until the pain goes away; this will be repeated for a total of three bouts of walking and three bouts of calf muscle exercises. Subjects will keep a detailed written log of their exercises that will be turned into the investigators when they attend the next training session at WLA. The log provided by investigators will allow entries for session date, times, location, weather, exercise mode (walking or calf exercise), workloads, durations of bouts and rest periods, and symptoms. Additionally, we will use commercially available pedometers (Lifestyle Tracer) to estimate distances walked during home training. Subjects will wear this small device on their belt or waistband during walking and record the times and distances of each walking bout in their exercise log.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

Inclusion Criteria:

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 gastroc-soleus muscles.

Inclusion Criteria for PAD Subjects:

• diagnosis of PAD (acute or chronic occlusive arterial disease), with or without diabetes mellitus
• positive Edinburgh Claudication Questionnaire
• Fontaine stage IIa only (mild claudication, walking distance > 200 feet (one-half block)
• ambulatory, without assistive devices
• calf muscle claudication within 10 minutes of treadmill walking and calf muscle exercise

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:

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, orthopedic pain)
• 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.)

Please refer to this study by ClinicalTrials.gov identifier  NCT00118560

Mark Hori      310-268-3045    Mark.Hori@med.va.gov

Study chairs or principal investigators

Stephen F Figoni, PhD,  Principal Investigator,  VA West los Angeles Healthcare Center   

Study ID Numbers:  B3644P
Record last reviewed:  June 2005
Last Updated:  July 18, 2005
Record first received:  July 8, 2005
ClinicalTrials.gov Identifier:  NCT00118560
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-07-26