Clinical Utility of Endothelial Dysfunction in PAD

Part 1 of the study will involve only patients with PAD who are undergoing non-cardiac
surgery and is an intervention study. Part 2 will involve patients with PAD who have
participated in Part 1 and patients with PAD who are not undergoing surgery. This part of the
study does not involve an intervention.

The protocol for patients undergoing surgery is as follows: Part 1. Intervention study with
follow-up for 30 days after surgery. Patients with planned surgery will be enrolled. We will
test endothelial function at baseline using ultrasound and tonometry. They will then be
randomzied to one of three groups: Atorvastatin 80 mg/d, Vitamin C 500 mg/d, or placebo.
Subjects already on a statin medication at the time of enrollment will receive 40 mg/d of
atorvastatin. Patients taking high dose statin (>40 mg/day) will be randomized to received
vitamin C or placebo, and will not be eligible to receive any additional statin as part of
the study. In the week immediately prior to surgery, we will test endothelial function a
second time. They will then be followed for 30 days beginning with the day of surgery for
cardiovascular events. Part 1 of the study involves 4 visits as follows: Visit 1 at
enrollment will take place within 7-30 days of non-emergent vascular surgery and will last
approximately 60 minutes Visit 2 will take place within approximately 1 week of surgery and
will last approximately 30-40 minutes Visit 3 will occur on the 1st post-operative day and
will last approximately 10-15 minutes Visit 4 will take place only if the subject is still an
in-patient. It will take approximately 10-15 minutes Telephone contact will occur at 30 days
post surgery and every six months thereafter for two years. The duration of telephone
follow-up is expected to be approximately 5-10 minutes. Part 2 (long term follow-up):
Patients who have completed Part 1 will be continued on in Part 2 of the study. Part 2
involves two year follow-up with no study medication. Telephone contact will be made every 6
months. subjects will make a visit to our research unit one year after the initial visit for
physical examination, and if applicable, an ultrasound study of their bypass grafts.

The protocol for patients with PAD who are not undergoing surgery is as follows. These
patients will participate in Part 2 of the study only (long-term follow-up with no
intervention). Visit 1: will last approximately 60 minutes and involve measurement of
endothelial function by ultrasound and tonometry. We will contact the subject every 6 months
by telephone (5-10 minutes) for two years to determine whether a cardiovascular event has
occurred. Visit 2 will occur at 1 year post enrollment and will last approximately 20-30
minutes. If the subject has had peripheral bypass surgery, we will perform an ultrasound
study to determine graft blood flow.

Inclusion Criteria:

1. Male and female subjects age 21-99 years old.

2. Peripheral Arterial Disease. PAD is defined clinically and by angiography, magnetic
resonance imaging, vascular ultrasound, or ankle brachial index less than 0.9.

3. Able to provide informed consent and complete the study procedure.

4. Patients undergoing non-emergent vascular surgery (peripheral arterial bypass,
abdominal aortic aneurysm repair, carotid endarterectomy, or limb amputation) or other
non-cardiac surgery.

Exclusion Criteria:

1. Emergent or urgent surgery that must be performed sooner than one week after
enrollment

2. Unstable angina, myocardial infarction, stroke, coronary revascularization, or
decompensated heart failure within 1 month of enrollment. Patients who require cardiac
catheterization and surgical or percutaneous coronary revascularization prior to
vascular surgery will be excluded.

3. Clinically evident major illness of other organ systems, including cancer, end-stage
renal disease, hepatic failure, or other conditions that make participation
inappropriate.

4. Women who are lactating, pregnant, or of childbearing potential and not using a
reliable contraceptive method. Pregnancy will be excluded by a urine pregnancy test.

5. Patients with liver function tests or serum creatine kinase >3 times the upper limit
of normal.

6. Patients who have received an investigational drug within 30 days of enrollment.

7. Patients or subjects with a history of a psychological illness or condition such as to
interfere with the subject's ability to understand the requirements of the study.

8. Known occlusive atherosclerosis of the subclavian artery or upper extremity, because
such disease will interfere with induction of reactive hyperemia during the brachial
artery ultrasound studies.

9. Patients will be excluded if they are taking vitamin C in a dose greater than 2 times
the Recommended Daily Allowance (>120 mg/day) within 1 month of enrollment.