Cardiac Autonomic Function in Women With Microvascular Coronary Dysfunction

There are three groups in this study: 40 MCD subjects with abnormal coronary reactivity
testing (CRT), 20 CSX subjects with symptoms and nomral stress testing, and 40 normal
controls. Normal controls will complete two study visits while MCD subjects may have up to
three study visits.

Recruiting participants from Protocol 14906:

To date, no participants from Protocol 14906 have completed the study yet. All the
participants who are currently enrolled in 14906 will be approached by the investigator at
their next study visits. Prospectively new participants will be approached while they are
consented for 14906.

Recruiting participants from Protocol 11753:

Participants who are currently enrolled in Protocol 11753 will be approached at their next
study visits. Prospectively new participants will be approached while they are consented for
11753. Research staff may also identify past patients who have completed 11753 and fulfill
the requirements for healthy individuals.

All participants will be asked to undergo research procedures including mental stress tasks,
heart rate variability, cold pressor testing, and peripheral arterial tonometry. These
procedures are described below by visit:

VISIT ONE:

MENTAL STRESS TESTING Mental Stress Testing will be used to study what happens to heart rate,
blood pressure, heart rhythm, and blood vessels in arms and hands when participants are in a
stressful situation. It will take up to 3 hours to complete all the procedures in the mental
stress testing including the following specific procedures: In Mental Stress Tasks, different
types of stress testing, including a speech task over a situation that made participants
upset or angry, and/or a math test involving adding or subtracting numbers under a specific
constraint, and/or a memory test, will be administered to study the effect of stress on
heart; In Heart Rate Variability (HRV), participants will be asked to wear a Holter monitor
that measures heart rate and rhythm for approximately 24 hours; In Cold Pressor Testing,
participants' heart rate, blood pressure, heart rhythm, and blood vessels will be monitored;
In Peripheral Arterial Tonometry (PAT), a blood pressure cuff will be placed on one arm and
probes will be placed on participants' fingers. The probes and cuff are attached to a
monitoring device that transfers a waveform graph of participants' pulse. Then the blood
pressure cuff will be inflated for 5 minutes. At the end of the 5-minute period, the blood
pressure cuff will be deflated to get the final tracings.

RESPERATE BREATHING TRIAL In subjects who have MCD, to know whether a controlled breathing
relaxation technique using an FDA-approved paced breathing device, RESPeRATE, helps with
chest pain and shortness of breath and to test to see if this form of biofeedback or
relaxation technique helps with heart rate variability during mental stress, MCD subjects
will be randomized to completing a RESPeRATE breathing trial or performing their own choice
of relaxation technique for 8 weeks.

VISIT TWO:

SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) CARDIAC SCAN WITH 123I-MIBG AND MYOVIEW
Single Photon Emission Computed Tomography (SPECT) cardiac scan with 123I-mIBG and Myoview
will be used to measure cardiac sympathetic activity. The test will take approximately 5
hours with approximately 3.5 hours of break in the middle.

VISIT THREE:

REPEATED MENTAL STRESS TESTING Only subjects with MCD will have the visit that will take
about 3 hours to complete. During this visit, MCD subjects will be asked to complete repeated
Mental Stress Testing, including Mental Stress Tasks, Holter Heart Rate Variability, and PAT
testing as outlined above

All the procedures are research-related. Participants may consent to some but not all of the
procedures due to our current limited funding.

There are no collaborations with other sites.

Inclusion Criteria:

Inclusion criteria for Protocol 14906:

- Women with symptomatic angina or angina equivalent;

- Age > 18 yrs old;

- No obstructive CAD at coronary angiography (performed within the previous 24 months);

- Competent to give informed consent.

Inclusion criteria for Protocol 11753:

- Women without signs and symptoms of myocardial ischemia (chest pain, abnormal stress
testing, abnormal noninvasive testing);

- No cardiac risk factors by Framingham/NCEP criteria;

- Age (35-65) matched to the WISE MCD population;

- A normal maximal exercise stress test.

Exclusion Criteria:

Exclusion criteria for Protocol 14906:

- Obstructive CAD greater than or equal to 50% luminal diameter stenosis in greater than
or equal to 1 epicardial coronary artery;

- Acute coronary syndrome (defined by the ACC/AHA criteria, Braunwald 2000);

- Primary valvular heart disease clearly indicating the need for valve repair or
replacement;

- Patients with concurrent cardiogenic shock or requiring inotropic or intra-aortic
balloon support;

- Prior or planned percutaneous coronary intervention or CABG;

- Acute MI;

- Prior non-cardiac illness with an estimated life expectancy < 4 years;

- Unable to give informed consent;

- Chest pain with a non-ischemic etiology (e.g.,pericarditis, pneumonia, esophageal
spasm);

- Contraindications to CMRI (e.g., AICD, pacemaker, untreatable claustrophobia or known
angio-edema);

- Women with intermediate coronary stenoses (> 20% but < 50% luminal diameter stenosis
assessed visually at the time of angiography) will undergo clinically indicated IVUS
testing based on the judgement of the operator; Those determined to have
flow-obstructing stenosis will be excluded from the overall study;

- Participation in a research study that conflicts with the current WISE study.

- Women with coronary stenosis ≥50% in any epicardial coronary artery, assessed visually
at the time of angiography, will not be included in the CRT subgroup.

- Women who are pregnant.

- Males

Exclusion criteria for Protocol 11753:

- Contraindications to CMR testing (metal devices in chest, claustrophobia, known
angioedema);

- Contraindication to Adenosine including asthma, heart block (second and third degree)
and sinus node disease, significant COPD/asthma, or systemic hypotension (<90mmHg);

- Contraindication to Dobutamine including severe systemic hypertension (≥ 220/120
mmHg), unstable angina, significant aortic valve stenosis, complex cardiac arrhythmia
including uncontrolled atrial fibrillation, hypertrophic obstructive cardiomyopathy,
myocarditis, endocarditis, pericarditis, or uncontrolled congestive heart failure;

- Contraindication to Gadolinium (renal impairment);

- Any renal disease;

- Pregnant and lactating women;

- Inability to perform exercise, e.g. orthopedic limitations.