Non-Invasive Assessment of Atherosclerosis in Patients With CGD and Other Disorders of the Immune System

Heart disease kills more than half a million people in the U.S. each year. Atherosclerosis,
the major cause of heart disease, is thought to relate to dysregulated inflammation in the
cardiovascular system and possibly results from over production of reactive oxygen species
(ROS). The rate of atherosclerosis in patients with disorders of the immune system has not
been well characterized but is likely to be dramatically different than that seen in the
general population. Specifically, patients with Chronic Granulomatous Disease (CGD) may be
protected from developing atherosclerosis due to reduced superoxide and other ROS production
by phagocytic cells. We hypothesize that patients with CGD are at decreased risk of
developing atherosclerosis. The primary objective of this study is to determine the
prevalence of atherosclerosis and it s inflammatory characteristics in these and other
patients with in-born disorders of immune function. The primary objective will be assessed
using carotid studies and other imaging techniques to measure coronary artery calcium scores
and the presence or absence of soft plaque. Secondary endpoints include physiologic
characteristics such as blood pressure as well as circulating biomarkers associated with
heart disease such as C-reactive protein and lipid profile. This study may lead to improved
understanding of the pathophysiology of atherosclerosis, specifically the role of free
radical stress, and could lead to novel therapies for atherosclerosis that may benefit
patients with immune disorders and the general population.

- INCLUSION CRITERIA:

Patients will be identified for this protocol who are enrolled on existing protocols
studying patients with disorders of the immune system who volunteer for participation and
who do not have any of the listed exclusion criteria. Patients will remain enrolled on
their existing protocol. Normal volunteers will be enrolled as controls on this protocol.
They will be recruited through the normal volunteer office which will provide a list of
volunteers including their age to allow for inclusion of controls that approximate the
study population.

All patients enrolled on this protocol will be over the age of 18 and may be male or female
and will be accrued without regard to religion, race or sexual orientation. They must be
able to understand and sign informed consent documents and comply with study procedures
that include undergoing a CT scan and an MRI scan. Patients who are unable or unwilling to
complete one or more of the studies will not be excluded. The available data will be
included in the appropriate analysis.

EXCLUSION CRITERIA:

For Participation in MRI-Based Studies Only:

1. Subjects with contraindication to MRI scanning. These contraindications include but
are not limited to the following devices or conditions:

1. Implanted cardiac pacemaker or defibrillator

2. Cochlear Implants

3. Ocular foreign body (i.e., metal shavings)

4. Embedded shrapnel fragments

5. Central nervous system aneurysm clips

6. Implanted neural stimulator

7. Medical infusion pumps

8. Any implanted device that is incompatible with MRI

2. Patients whose medical condition is such that in the referring physicians estimation,
they could not tolerate an MRI scan. Examples of medical conditions that would not be
accepted would include unstable angina and dyspnea at rest.

3. Subjects with a condition precluding entry into the scanner (e.g. morbid obesity,
claustrophobia, etc.) or who require more than oral sedation (i.e. IV sedation) for
anxiety associate with MRI studies.

4. Pregnant or lactating women are excluded from this study because excessive exposure of
the developing human fetus and child to radiation and/or intravenous contrast agents
can be detrimental.

5. Subjects with severe back-pain or motion disorders who will be unable to tolerate
supine positioning within the MRI scanner and hold still for the duration of the
examination.

For Gadolinium-Based MRI Studies Only:

6. History of severe allergic reaction to gadolinium contrast agents despite the use of
premedication with an anti-histaminic and/or corticosteroid.

7. eGFR less than 60mL/min

8. Serum creatinine greater than 3.0 mg/dl

For Iodine-Based Contrast CT Studies Only:

9. Contraindication to the use of iodine based CT contrast agents:

1. Serum creatinine greater than 1.4 mg/dl

2. History of multiple myeloma

3. Use of metformin-containing products less than 24 hours prior to contrast
administration

4. History of significant allergic reaction to CT contrast agents despite the use of
premedication with an anti-histaminic and cortisone.

For Coronary CT Angiography Only:

10. Contraindication to the use of CT contrast agents:

1. Creatinine value greater than1.4 mg/dl

2. History of multiple myeloma

3. Use of metformin-containing products less than 24 hours prior to contrast
administration

4. History of significant allergic reaction to CT contrast agents despite the use of
premedication with an anti-histaminic and cortisone.

11. Subjects with contraindication precluding the use of beta blockers necessary to
perform the coronary CT angiography. These include:

1. Severe, uncontrolled asthma

2. Active bronchospasm

3. Moderate or severe COPD

4. 2nd or 3rd degree AV block

5. Decompensated cardiac failure

6. Allergy to beta blockers

7. Systolic blood pressure less than100 mm Hg

8. Pregnancy or nursing

Participation of Minors: Atherosclerosis is a disease that does not generally
affect young children. This protocol involves exposure to a low dose of
radiation. As radiation exposure may increase the risk of malignancy, it is
prudent to avoid this in children. Therefore, patients under the age of 18 will
not be considered for enrollment under this protocol.

Participation of Women: Excessive radiation exposure of the developing human
fetus can be detrimental. For this reason, women of childbearing-age will have a
pregnancy test prior to undergoing study procedures. Should a woman become
pregnant or suspect that she is pregnant while participating in this study, she
should immediately inform study staff and her primary care physician.

Pregnancy: Pregnant women are excluded from this study because excessive exposure
of the developing human fetus to radiation can be detrimental.

Co-enrollment Guidelines: Co-enrollment in other trials is not restricted.

Medical Exclusions: Patients with current atrial fibrillation will not be
considered for enrollment under this protocol. Patients who are medically
unstable (e.g. severe sepsis, acute myocardial infarction) and/or would require
active, acute medical management in order to be medically stable enough to
participate in this protocol will not be enrolled.

X-linked CGD Cohort: Patients in this cohort must have X-linked CGD as
demonstrated by DHR or genetic screening. Patients who have undergone bone marrow
transplant may not be enrolled in this cohort for analysis. Carriers of X-linked
CGD must be evaluated by DHR to determine the extent of X-inactivation
(lyonization) in their neutrophils.

AutosomalRecessive CGD Cohort: Patients in this cohort must have autosomal
recessive CGD (p47phox, p67phox, or p22phox deficiency) as demonstrated by DHR or
genetic screening. Patients who have undergone bone marrow transplant may not be
enrolled in this cohort for analysis.

Inflammatory Bowel Disease Cohort: Patients enrolled into this cohort may not
have been diagnosed with CGD.

Normal Volunteer Cohort: Patients in this cohort may not have been diagnosed with
CGD, Inflammatory Bowel Disease, or another primary disease of the immune system.