Carnosine for Peripheral Arterial Disease
Condition: Peripheral Arterial Disease
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      The hypothesis is that oral supplementation of L-carnosine will inhibit PHDs, increase
      HIF1-translocation and angiogenesis and thus improve the functioning of lower extremities in
      PAD patients.

      Primary Aim:

      1. Compare the effect of carnosine and placebo supplementation on the 6MWT in PAD patients
      with and without claudication.

      Secondary Aim:

        1. Determine whether carnosine supplementation improves the pain-free treadmill walking
           ability of the subjects supplemented with carnosine compared to placebo.

        2. Compare the levels of carnosine, VEGF, HIF-1α, and PHDs activity in the skeletal muscle
           before and after placebo and carnosine supplementation.

        3. Compare the levels of EPCs (CD34+/CD133+), inflammatory markers (serum amyloid A, hsCRP)
           and thrombotic markers (fibrinogen, homocysteine) as cardiovascular risk markers in
           these subjects.

        4. Explore the effects of race and gender on VEG, carnosine, and HIF-1α levels in both
           groups.
    

Detailed description: 
      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 PAD. 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. Pre-clinical studies
      have shown that supplementation of carnosine (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. Similarly supplementation of carnosine (2g/day) for 12 weeks has
      been shown to normalize glucose intolerance and reduce insulin levels in obese individuals.
      No side effects were reported at these doses. Carnosine (β-alanine-histidine) 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 synthetase6 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 pH. Numerous studies have shown that the
      supplementation of -alanine 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) shows that both the pretreatment and the supplementation of
      carnosine after femoral artery ligation increases blood flow in the ischemic limb compared
      with the non-treated mice. Mechanistic studies show that the supplementation of carnosine
      increases 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, is increased in the hypoxic C2C12 cells (murine
      myoblasts).

      Based on these pre-clinical studies and our initial observations the Investigator will
      examine whether supplementation of carnosine (1 g/day) to PAD patients for 6 months will
      improve walking performance compared with the placebo-treated patients. Further, the
      Investigator will examine whether the supplementation of carnosine increases the capacity of
      pain-free treadmill walking time and levels of VEGF, HIF-1α, and carnosine in the skeletal
      muscle of PAD patients.
    

Intervention name(s): Carnosine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment