Protocol Number: 04-H-0268

Title:

Effect of Nitric Oxide Donor on Endothelial Progenitor Cells in Patients with Coronary Artery Disease

Number:

04-H-0268

Summary:

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.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

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.

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.

Special Instructions: Currently Not Provided

Keywords:

Atherosclerosis

Bone Marrow

Exercise

Endothelium

Nitroglycerin

Recruitment Keywords:

Coronary Artery Disease

CAD

Conditions:

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Ades PA.

Cardiac rehabilitation and secondary prevention of coronary heart disease.

N Engl J Med. 2001 Sep 20;345(12):892-902. Review. No abstract available.

Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze TH.

Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ Res. 1994 Feb;74(2):349-53.

Noris M, Morigi M, Donadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A.

Nitric oxide synthesis by cultured endothelial cells is modulated by flow conditions.

Circ Res. 1995 Apr;76(4):536-43.

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