The Impact of Branched-Chain Amino Acid Metabolism on Limb Dysfunction in PAD

Study Overview
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Brief Summary
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Test the theory that abnormalities in the large blood vessels that deliver blood to your leg and the very small blood vessels in your leg's muscles (invisible to the eye) work together to worsen your leg function and walking.

Official Title
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The Impact of Branched-Chain Amino Acid Metabolism on Limb Dysfunction in PAD (MicroPAD)

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Behavioral: Supervised Exercise
* Behavioral: Vascular Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion/exclusion criteria for Healthy Subjects Inclusion criteria Male or female, age ≥ 50 years old Non-smoker Exclusion criteria Presence of peripheral artery disease History of a heart attack or stroke Diabetes Active cancer Severe renal disease (CrCl < 60) Severe liver disease Active rheumatological diseases Inclusion/exclusion criteria for PAD Subjects Inclusion criteria Male or female, age 50 years or older Atherosclerotic PAD, ABI ≤0.85 Willing to comply with protocol, attend follow-up appointments, complete all study assessments, and provide informed consent For Aim 3, subjects will have Rutherford stage 4 or 5 disease For Aim 3, subjects will be undergoing revascularization as standard of care Exclusion criteria Presence of a femoral, popliteal or tibial aneurysm of the index limb Life expectancy less than 2 years A vascular disease prognosis that includes an anticipated above ankle amputation on index limb within 4 weeks of index procedure Renal dysfunction defined as MDRD eGFR ≤ 20ml/min/173 m2 at the time of screening Currently on dialysis or history of a renal transplant Cirrhosis or active hepatitis A documented hypercoagulable state Myocardial infarction within 6 months Stroke within 6 months Nonatherosclerotic occlusive disease of the lower extremity Any prior infrainguinal revascularization on index limb Current immunosuppressive medication, chemotherapy or radiation therapy Inability to have an MRI Exercise limitation aside from that due to PAD (i.e. COPD, degenerative joint disease, etc.) Women who are pregnant Women who are nursing Primary indications for systemic oral anticoagulation for active arterial or venous thromboembolic disease.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy Subjects<br> | Behavioral: Vascular Assessment<br>* Screen: Subjects will undergo a H&P, ankle brachial index, ECG, CBC, CMP, lipid panel, HgA1C, and urinalysis. A urine pregnancy test will be performed on women of childbearing age. Testing Visit 1: MRI, IV in common femoral vein with phlebotomy (60 cc total) before and after sphygmomanometric cuff occlusion of lower limb, 6-minute walk test, 4-meter walk speed test, walking impairment questionnaire, and muscle biopsy. Supervised exercise and leg revascularization patients will return in 12 weeks and have the same study procedures as testing visit 1, plus an ankle brachial index, repeated.<br>|
| Experimental: Peripheral Artery Disease (PAD) with Supervised Exercise<br>Subjects will be referred for supervised exercise therapy. Subjects will have 3 visits per week for 12 weeks. Each visit will include a minimum of 30 to 40 minutes of exercise to improve ambulation with a certified trainer. | Behavioral: Supervised Exercise<br>* Subjects will have 3 visits per week for 12 weeks.<br>Behavioral: Vascular Assessment<br>* Screen: Subjects will undergo a H&P, ankle brachial index, ECG, CBC, CMP, lipid panel, HgA1C, and urinalysis. A urine pregnancy test will be performed on women of childbearing age. Testing Visit 1: MRI, IV in common femoral vein with phlebotomy (60 cc total) before and after sphygmomanometric cuff occlusion of lower limb, 6-minute walk test, 4-meter walk speed test, walking impairment questionnaire, and muscle biopsy. Supervised exercise and leg revascularization patients will return in 12 weeks and have the same study procedures as testing visit 1, plus an ankle brachial index, repeated.<br>|
| Active Comparator: PAD Subjects Who Undergo Revascularization of the Leg<br>This group of subjects are receiving leg revascularization as part of standard of care. | Behavioral: Vascular Assessment<br>* Screen: Subjects will undergo a H&P, ankle brachial index, ECG, CBC, CMP, lipid panel, HgA1C, and urinalysis. A urine pregnancy test will be performed on women of childbearing age. Testing Visit 1: MRI, IV in common femoral vein with phlebotomy (60 cc total) before and after sphygmomanometric cuff occlusion of lower limb, 6-minute walk test, 4-meter walk speed test, walking impairment questionnaire, and muscle biopsy. Supervised exercise and leg revascularization patients will return in 12 weeks and have the same study procedures as testing visit 1, plus an ankle brachial index, repeated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C3/C5acylcarnitine levels in healthy control subjects. |  | baseline | 
| C3/C5acylcarnitine levels in PAD exercise group after 12 weeks |  | Change from baseline to 12 weeks | 
| C3/C5 acylcarnitine levels in PAD surgical bypass group |  | Change from baseline to 12 weeks |