• Pain/free and maximal treadmill walking time [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
  

• Insulin resistance [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
  
• Skeletal muscle glucose utilization [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
  
• Systemic inflammatory markers [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
  
• Circulating and local adipocyte markers of PPAR activation [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
  
• In vivo vascular function by ultrasonography [ Time Frame: Measured at 3 months ] [ Designated as safety issue: No ]
  
• Change in ankle/brachial index (ABI) [ Time Frame: Measured pre/post treadmill exercise and at 3 months ] [ Designated as safety issue: No ]
  

BACKGROUND:

Patients with peripheral arterial disease (PAD) frequently have functional limitations and symptoms of claudication that impact adversely on their quality of life. Many patients progress to critical limb ischemia and require revascularization. Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Moreover, both inflammation and insulin resistance cause abnormalities in vascular function, and insulin resistance interferes with skeletal muscle metabolism. Therefore, inflammation and insulin resistance provide attractive targets for therapy that could potentially ameliorate the development of symptomatic PAD or improve the function and clinical outcomes of patients with PAD. This study will determine whether inflammation and insulin resistance contribute to the functional and clinical consequences of PAD.

DESIGN NARRATIVE:

This study will test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with IC by impairing vascular reactivity and skeletal muscle metabolic function. Plasma markers of inflammation and insulin resistance, endothelium-dependent and independent vasodilation (by vascular ultrasonography), and skeletal muscle glucose utilization (by [18F] fluorodeoxyglucose [FDG] positron emission tomography[PET]) will be measured before and after 12 weeks of treatment with rosiglitazone, atorvastatin, or placebo in a 2 times 2 factorial design protocol. Patients with IC will be recruited from the vascular center at Brigham and Women's Hospital and then randomized. Outcome measurements of the study will include insulin resistance, skeletal muscle glucose utilization by PET, systemic inflammatory markers, circulating and local adipocyte markers of peroxisome proliferator-activated receptor (PPAR) activation, in vivo vascular function by ultrasonography, ankle/brachial index (ABI), and treadmill walking time.

Inclusion Criteria:

• IC group inclusion criteria are as follows:

  1. Lower extremity PAD and IC
  2. Stable IC (as defined by the San Diego Claudication Questionnaire) for at least 6 months prior to study entry
  3. Resting ABI of less than or equal to 0.90
  4. Maximal walking time (MWT) between 1 and 20 minutes and post-exercise ABI drop by greater than or equal to 20% (as measured by an exercise treadmill test at the baseline visit, with assessment of pain free walking time [PFWT], MWT, and measurement of the ABI in the index [most symptomatic] leg within 1 minute of concluding exercise)

• Revascularization group inclusion criteria are as follows:

  1. PAD
  2. Scheduled to undergo lower extremity percutaneous revascularization
• Control group participants will have no known medical problems and a normal cardiovascular exam

Exclusion Criteria:

• Myocardial infarction or coronary artery bypass surgery within 6 months prior to study entry
• Transient ischemic attack or ischemic stroke 6 months prior to study entry
• Pregnancy
• Uncontrolled hypertension, defined as a systolic pressure greater than 180 mm Hg and/or diastolic pressure greater than 100 mm Hg
• Serum creatinine greater than 2.5
• Hepatic transaminases greater than 3 times upper limit of normal
• Creatine kinase greater than 5 times upper limit of normal

• IC group exclusion criteria are as follows:

  1. Must discontinue treadmill exercise for reasons other than muscular leg pain (e.g., shortness of breath, chest pain, back pain)
  2. Type 1 or insulin-dependent Type 2 diabetes
  3. Lower extremity revascularization (surgical or percutaneous intervention) within 6 months prior to study entry
  4. Fasting glucose greater than 110mg/dL
  5. Hypersensitivity to HMG-CoA reductase inhibitors
  6. Low-density lipoprotein levels greater than 190mg/dL, after HMG-CoA reductase inhibitors discontinuation (patients treated with HMG-CoA reductase inhibitors [statins] must discontinue therapy for 4 weeks prior to the baseline screening visit, and remain off treatment throughout the study [maximum of 15 weeks])
• Revascularization group will exclude patients with an active infection