Regular exercise reduces the risk of heart problems, in part because it improves the work of
the endothelium (the cells that line blood vessels). Exercise appears to release precursor
cells from the bone marrow that will later become endothelial cells. A molecule called
nitric oxide (NO) appears to be involved in this release. However, some heart patients do
not improve their endothelial function despite regular exercise. The researchers believe
that the heart disease in these patients may interfere with the normal relationship between
exercise and endothelial function. This study is designed to test whether giving a patient
nitroglycerin (which is converted to NO in the bloodstream) will increase the release of
endothelial precursor cells from the bone marrow. If the study succeeds, it may lead to
improved healing of arteries in heart disease patients.
Adults may be eligible for this study if they have coronary artery disease and do not take
nitroglycerin or nitroglycerin-like medication on a daily basis.
Volunteers will be admitted to the Clinical Center on 2 separate nights at least 1 week
apart. On the morning after each admission, volunteers will have blood drawn from an arm
vein for laboratory tests, and then walk on a treadmill until fatigue or discomfort prevents
further exercise, or until asked to stop. On one of their admissions, volunteers will
receive 1 tablet of nitroglycerin under the tongue shortly before the treadmill test.
Volunteers will be monitored by EKGs and blood pressure tests during the treadmill tests,
and will have more blood drawn at about 15 minutes and 24 hours after each treadmill test.
Researchers will examine the levels of endothelial precursor cells and nitric oxide in the
blood samples taken before and after exercise.
Exercise training has long been recommended as a means of improving cardiac function and
reducing morbidity and mortality in patients with coronary artery disease (CAD). One
mechanism of benefit may be through improved endothelial function and enhanced nitric oxide
(NO) bioactivity, which may improve blood flow to exercising skeletal muscle and to the
myocardium. We have recently determined in a collaborative study with the Suburban Hospital,
however, that many CAD patients do not show improved endothelial function despite compliant
participation in a three month cardiac rehabilitation program with exercise three times
weekly. The initial data from this study suggest that improvement in endothelial function
may be dependent on the release of endothelial progenitor cells (EPCs) from the bone marrow
into the circulation in response to the stimulus of repetitive exercise, with the potential
of repairing damaged endothelium and improving endothelial function and NO release. Thus,
patients who have poor EPC mobilization responses to exercise may have limited capacity to
improve endothelial function over time and, conversely, patients with higher EPC
mobilization responses to exercise may show improved endothelial function as a result of
vascular repair. Animal models indicate that NO is necessary for EPC mobilization during
exercise, likely through nitrosation reactions with key signaling proteins within bone
marrow. In many CAD patients, NO release from endothelium and transport in blood to bone
marrow may be compromised because of atherosclerotic vascular disease, and thus limit EPC
mobilization and vascular repair. We hypothesize that the exogenous administration of NO to
CAD patients may enhance EPC mobilization from bone marrow in response to exercise. If
successful, administration of an NO donor (such as nitroglycerin) prior to exercise may
extend the benefit of exercise to endothelial function-and thus cardiovascular risk-in a
larger segment of CAD patients participating in cardiac rehabilitation programs.
PATIENT INCLUSION CRITERIA
1. Adults older than 21 years.
2. Coronary artery disease established by angiography.
3. No myocardial infarction within 1 month.
4. Left ventricular ejection fraction greater than 30%.
5. No congestive heart failure symptoms within 2 months.
6. No associated medical, neurological or orthopedic condition that might prohibit safe
performance of exercise.
7. Subject understands protocol and provides written, informed consent in addition to
willingness to comply with specified follow-up evaluations.
PATIENT EXCLUSION CRITERIA
1. Significant structural heart disease (e.g. hypertrophic or dilated cardiomyopathy,
valvular heart disease) as determined by echocardiography.
2. History of recent (within 2 months) rest or nocturnal angina
3. Organic nitrate (e.g., nitroglycerin) use other than study medication within 24 hours
of exercise testing
4. Hypersensitivity to organic nitrates.
5. Women of childbearing age unless recent pregnancy test is negative.
6. Lactating women.
ELIGIBILITY CRITERIA - HEALTHY SUBJECTS
Healthy subjects must be older than 50 years of age (to approximate the anticipated age of
CAD patients), without known CAD, and be free of the following risk factors: blood
pressure greater than 140/90 mmHg, fasting glucose greater than 110 mg/dL, smoking, total
cholesterol greater than 250 mg/dL. Healthy subjects taking chronic prescription
medications will be excluded.