Oxygen-guided Supervised Exercise Therapy for Peripheral Artery Disease
This study is testing a new way to do supervised exercise therapy for people with peripheral artery disease (PAD). PAD is a condition where narrowed arteries reduce blood flow to your limbs, often causing leg pain when walking. The study will compare a modified supervised exercise therapy that uses muscle oxygen levels to guide exercise with the standard supervised exercise therapy. The goal is to see if the modified approach can better improve walking distance and energy levels. You may be able to join if you have documented lower extremity arterial disease, experience chronic leg pain when walking (claudication), and have stable blood pressure, lipid, and diabetes treatments. The study will measure how far you can walk and your energy use before and after a 12-week exercise program. The current recruitment status is unclear.
- Study design
- This interventional study plans to enroll 12 participants. It compares two types of supervised exercise therapy.
- What's involved
- You would participate in a 12-week exercise program with 3 sessions per week. Each session lasts 50 minutes, plus warm-up and cool-down.
- Compensation
- Not stated in the trial record.
- Follow-up
- Your walking distance and energy expenditure will be measured before and after the 12-week exercise program. Reactive oxygen species will be measured before, immediately after, 30 minutes after, and 1 hour after exercise.
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Oxygen-guided Supervised Exercise Therapy
At a glance
Conditions
Where it's being run
1 sites across 1 statesStudy leadership
- Iraklis I Pipinos, MD · PRINCIPAL_INVESTIGATOR · Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
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Do you actually qualify for this trial?
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Inclusion
Exclusion
What this trial measures
- Distance walkedBefore and after 12 week exercise program
Total distance walked during the exercise session (standard or M-SET) will be determined using the total time of walking multiplied by the walking speed.
- Energy expenditureBefore and after 12 weeks after the exercise program
Energy expenditure57 will be assessed via oxygen consumption as measured by a metabolic cart (K5, Cosmed USA, Inc., Chicago, IL). Subjects will stand quietly for five minutes to collect resting energy expenditure. Standing steady state energy expenditure will be calculated for each subject by plotting VO2 and assigning a sliding best fit line over a two-minute window. Steady-state oxygen consumption in ml/kg/min will be calculated during the exercise session. Energy cost of transport will be calculated by subtracting the energy consumption values at standing from walking to achieve net metabolic cost for each bout of exercise.
- Reactive oxygen speciesBefore exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise
Quantification of reactive oxygen species (ROS) related markers and free radicals: Electron paramagnetic resonance (EPR), which has been known as a gold standard for free radical assessment, will be used to quantify free radicals such as superoxide as we have previously performed (1-3). Plasma samples will be used for measuring ROS-related markers such as TAC, SOD, GSH:GSSG, ONOO- and MDA with commercially available and previously validated ELISA Assay Kits (CAT#s ab65329, ab65354, ab138881, ab233469, and ab233471 Abcam, UK) according to the manufacturer's instructions60. The average intra-assay variability measured as the coefficient of variation for each sample was 2.9%, 3.8%, and 3.3% for SOD, TAC, and MDA, respectively.
- Protein expression of ROS-related enzymesBefore exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise
Protein expression of ROS-related enzymes: Enzymes related to ROS will be quantified with western blots of isolated PBMCs analyzed for catalase, 4 hydroxynonenal (4HNE), and glutathione peroxidase 1 (GPX) (4). All samples will be homogenized in RIPA buffer (Boston Bioproducts) and 100X protease inhibitor (Sigma Aldrich). A 150-volt electrical potential will be applied to the gel for 1 hr to separate proteins based on mass. A 250-volt electrical potential will then be applied to the gel for 7 min to transfer protein bands to transfer paper with TurboTransfer (Biorad). Primary antibodies for catalase, 4HNE, and GPX will be recombinant anti-catalase antibody (ab209211), anti-4 hyroxynonenal antibody (ab243070), and recombinant anti-glutathione peroxidase 1 antibody (ab108429), respectively.
- Markers of systemic inflammationBefore exercise, immediately after exercise, 30 minutes after exercise, and 1 hour after exercise
Markers of systemic inflammation: Standard ELISA kits will be used to test blood samples for interleukin 6, tumor necrosis factor-a, vascular cell adhesion protein 1, and vascular endothelial growth factor-a (Cat#s, ab178013, ab285312, ab223591, ab119566). Oxidized low density lipoproteins (LDL) will be measured with an oxidized LDL assay kit (ab242302). All measurements will be made per validated manufacturer specifications.
- Initial and absolute walking distancesBefore and after 12 week supervised exercise program
Initial and absolute walking distances will be determined from the progressive-load treadmill test. Subjects will walk on a treadmill that starts at 0% grade and 2.0 mph. Every two minutes, the grade will be increased by 2% up to a maximum of 15% grade, and the speed held constant throughout the test. Initial claudication distance is the distance walked prior to claudication pain onset. Absolute claudication distance is the total distance walked before subjects had to stop walking due to claudication pain.
- Comprehensive mitochondrial respiratory complex functionBefore and after 12 week supervised exercise program
Comprehensive mitochondrial respiratory complex function (complex I, II, III, IV, and V) will be completed with previously validated high resolution respirometry with complex agonists/antagonists. Skeletal muscle tissue will be manually teased and permeabilized with 15 l of digitonin for 30 min. Samples will then be rinsed twice in 2 ml of MIRO5 for 10-min. 3-5 mg (dry weight) of tissue will then be isolated and placed in the high-resolution respirometer with 2 ml of MIRO5 solution. The order and quantity of each agonist and antagonist will be applied as follows: 5 l malate and 10 l glutamate (complex I agonist), 20 l adenosine diphosphate (complex V agonist), 20 l succinate (complex II agonist), 1 l rotenone (complex I antagonist), 1 l oligomycin (complex V antagonist), 1 l antimycin A (complex III antagonist), and 5 l ascorbate + 5 l TMPD (complex IV agonist).
- Mitochondrial dynamicsBefore and after 12 week supervised exercise program
Specific proteins we will assess are Fis-1 and DRP-1 (fission), Mfn-1, Mfn-2 and OPA-1 (fusion), and UPC-1 and UCP-2 (dynamics). We will perform the same Western Blot technique mentioned in Aim #262. Primary antibodies for Fis-1, DRP-1, Mfn-1, Mfn-2, OPA-1, UPC-1, and UCP-2 will be recombinant anti- TTC11/FIS1 (ab156865), recombinant anti-DRP1 (ab184247), anti-mitofusin 1 antibody-N-terminal (ab191853), recombinant anti-mitofusin 2 (ab205236), recombinant anti-OPA1 (ab157457), anti-UCP1 (ab155117), and anti-UCP2 (ab247184), respectively.
- Mitochondrial reactive oxygen species productionBefore and after 12 week supervised exercise program
Mitochondrial reactive oxygen species production will be assessed with fluorescent imaging of skeletal muscle biopsy samples treated with H2DCFDA (D399, ThermoFisher), which is validated to detect ROS within cells. The validated mitochondrial targeted antioxidant MitoTempo (SML0737, Sigma-Aldrich) will be used to confirm the presence of mitochondrial ROS. EPR will be used to quantify free radicals such as superoxide.