Detection of Hypoxia in Human Thoracic Aorta Using Pimonidazole Hydrochloride

The proposed study is designed to identify the level of tissue hypoxia in patients presenting
with ascending aortic aneurysm. Ascending aortic aneurysms affect approximately 15,000 people
in the United States each year, and represent a serious clinical problem because there is a
known, but unspecified risk of aortic rupture or dissection. Despite progress made in the
surgical management of ascending aortic aneurysms, the molecular and cellular mechanisms
involved remain elusive. However, indirect evidence of tissue hypoxia have recently been
described in the literature.

This pilot study will use pimonidazole-HCl, a compound that is retained by hypoxic cells and
that has been used for detection of tissue hypoxia in human since the early 2000s. This pilot
study will involve twenty patients who are candidates for aortic replacement due to aneurysm
and twenty non-aneurysmal patients undergoing coronary artery bypass graft (controls).
Patients will be administered pimonidazole-HCl orally in a single dose (0.5g/m2) 24 hours
prior to scheduled surgical time. During surgery, the resected aneurysmal aortic specimens
(for patients undergoing aortic replacement) or aortic punch (for patients undergoing
coronary artery bypass graft) will be harvested. Tissue hypoxia will be qualitatively and
quantitatively assessed in the investigator's research laboratory. Based on previous
toxicological animal studies and previous use in human studies, the anticipated risk of
severe or serious side effect will be relatively minimal.

Inclusion Criteria:

1. Adults ≥ 18 years of age who require one of the following open surgery:

- Ascending thoracic aorta repair due to aneurysm;

- Aortic valve replacement due to aortic valve insufficiency;

- Coronary artery bypass graft procedure due to coronary heart disease. Imaging CT
scans and echography defining the presence of ascending aortic aneurysm will be
centrally reviewed prospectively to ensure adherence to subject inclusion
criteria.

2. Adequate hematologic functions:

- White blood cells > 2500/µ;

- Platelets > 100,000/µL;

- Hemoglobin > 8 g/dl.

3. Adequate renal functions: serum creatinine < 2.0 mg/dl.

4. Adequate hepatic function: serum alkaline phosphatase, bilirubin, and serum glutamate
oxaloacetate transaminase twice normal levels.

5. If the subject or partner is of childbearing potential, he or she must be willing to
use adequate contraception (hormonal or barrier method or abstinence) from the time of
screening and for a period of at least 16 weeks after procedure.

6. Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form, release of medical
information, and Health Insurance Portability and Accountability Act (HIPAA)
documentation.

7. Female subjects of childbearing potential must have a negative serum pregnancy test at
screening. human chorionic gonadotropin levels will be assessed for all women of
childbearing years prior to the procedure.

Exclusion Criteria:

1. Severe septicemia or severe infection in the 4 weeks prior to study entry;

2. The subject has a baseline NIHSS > 1 or modified Rankin Scale > 1.

3. Active participation in other research therapy for cardiovascular repair/regeneration;

4. Pregnant or breastfeeding at time of screening;

5. Cardiothoracic surgery within 30 days prior to screening;

6. The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).