Carnosine for Peripheral Arterial Disease Patients

Study Overview
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Brief Summary
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Oral supplementation of L-carnosine will increase muscle carnosine, stabilize HIF1-alpha promote angiogenesis, and thus improve the functioning of lower extremities in PAD patients.

Detailed Description
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Peripheral arterial disease (PAD) is caused by atherosclerotic occlusion of the lower extremities that reduces blood flow and leads to intermittent claudication and critical limb ischemia. PAD is diagnosed by calculating the ratio of blood pressure at the ankle to that of the arm (the ankle-brachial index [ABI]). An ABI of <0.90 is indicative of atherosclerosis in the leg. Recent data from developed and developing countries have estimated that >200 million people worldwide and approximately 12 million people in United States have PAD3. Both symptomatic and asymptomatic PAD patients have an increased risk of mortality, morbidity, and a lower quality of life. With the increasing incidence of type 2 diabetes (T2D) and a rising aging population, the number of PAD patients is likely to increase. Because PAD is an under-recognized disease, currently few medications are available to improve the functional performance of these patients. Although surgical revascularization is an available treatment, grafts can fail and the stenosis can reoccur in these patients. To adequately compensate the loss of tissue due to occlusion, the current emphasis is to increase the therapeutic angiogenesis and arteriogenesis in the ischemic limb that could improve the walking ability and the quality of life in PAD patients. In a recent pre-clinical study it was shown that supplementation of carnosine(β-alanine-histidine) (500 mg/day) in heart failure patients for 6 months improves their performance on the 6-minute walking test (6MWT) compared with placebo-treated patients. Carnosine is a histidyl dipeptide present in high concentration in the skeletal muscle, brain, and heart. It is a food constituent that is present in red meat, chicken, and turkey. This dipeptide is synthesized by the ATP grasp enzyme carnosine synthetase and hydrolyzed to β-alanine and histidine by the serum and kidney carnosinase. Carnosine has the abilities to quench reactive aldehydes, bind metals, and buffer intracellular pH7. Numerous studies have shown that the supplementation of beta-alanine or carnosine increases the levels of carnosine in the skeletal muscle and improves the exercise performance in humans. Our preliminary studies with the mice model of hind limb ischemia (HLI) showed that both the pretreatment and supplementation of carnosine after femoral artery ligation increased blood flow in the ischemic limb compared with the non-treated mice. Mechanistic studies showed that the metal quenching ability of carnosine increased the expression of angiogenic factor VEGF and endothelial progenitor cells mobilization in the carnosine treated HLI mice. Similarly, the stabilization of HIF-1α, the master regulator of angiogenesis and angiogenic factor VEGF, was increased in the hypoxic C2C12 cells (murine myoblasts). Based on these pre-clinical studies, in this study PAD subjects will be recruited and supplemented with carnosine (2 g/day) for 3 months to examine if its supplementation improves walking performance compared with the baseline. Further, we will examine whether the supplementation of carnosine increases the capacity of pain-free treadmill walking time, extrusion of oxidative stress markers and mobilizes the endothelial progenitor cells in the blood.

Official Title
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Carnosine for Peripheral Arterial Disease Patients (Car-PAD)

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Biological: Carnosine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects more than >50 to <80 years of age. White or African American race. English Speaking. ABI 0.4-< 0.60 Willing to comply with protocol requirements. Able to provide informed consent. - Exclusion Criteria: Subjects with HIV, hepatitis, significant liver disease, active infection, anemia, organ transplant, renal disease requiring dialysis, lung disease requiring oxygen, significant congenital heart disease, cancer of any type, and untreated thyroid disease. Diagnosis of carnosinemia. Known allergy to L-carnosine or meat. Presence of a pacemaker. Obesity from a known genetic defect. Dementia. Critical limb ischemia with below or above knee amputations. Foot ulcers. Major amputations. Participating in other clinical trials. End stage renal disease. Presence of significant injury within 30 days before enrollment. Prisoners. Any metallic implants. Poorly controlled diabetes (HbA1C >9%) -

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: In a single arm open labelled safety trial, we will supplement carnosine for 3 months to subjects with non-claudication and claudication peripheral arterial disease (PAD), and determine if it improves walking ability. In our pilot study, we will enroll 20 male subjects measure the distance covered on the 6-minute walk test and the pain free walking capacity on the treadmill before, at baseline, and three months after carnosine supplementation.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carnosine intervention for patients with PAD<br>This is a single arm open labelled safety trial, where we will supplement carnosine for 3 months to subjects with non-claudication and claudication peripheral arterial disease (PAD), and determine if it improves walking ability. | Biological: Carnosine<br>* Determine whether carnosine supplementation (2 g/day) for 3 months in peripheral arterial disease patients improves 6MWT ability.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carnosine for Peripheral Arterial Disease patients | Compare the effects of carnosine supplementation on the 6-minute walk test (6MWT) at the baseline and after three months of carnosine supplementation. Measure the total walking distance and compare the walking distance covered by the subjects at the start and completion of carnosine supplementation | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graded treadmill test | Measure the onset of claudication onset time and peak walk time | one year |