FOCUS ISSUE: CARDIAC REGENERATION
Outcomes and Risks of Granulocyte Colony-Stimulating Factor in Patients With Coronary Artery Disease
Jonathan M. Hill, MD*,||,*,
Mushabbar A. Syed, MD ,¶,
Andrew E. Arai, MD,
Tiffany M. Powell, MD, MPH*,#,
Jonathan D. Paul, MD*,**,
Gloria Zalos, RN*,
Elizabeth J. Read, MD,
Hanh M. Khuu, MD,
Susan F. Leitman, MD,
McDonald Horne, MD ,
Gyorgy Csako, MD,
Cynthia E. Dunbar, MD,
Myron A. Waclawiw, PhD and
Richard O. Cannon, III, MD*,*
* Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
|| Department of Cardiology, King’s College, London, United Kingdom
¶ Cardiology Division, Emory University, Atlanta, Georgia
# Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
** University of Chicago Hospitals, Chicago, Illinois
Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland
Manuscript received October 25, 2004;
revised manuscript received January 24, 2005,
accepted January 25, 2005.
* Reprint requests and correspondence: Dr. Richard O. Cannon III, National Institutes of Health, Building 10, Room 7B15, 10 Center Drive, MSC 1650, Bethesda, Maryland 20892-1650. (Email: Jonathan.Hill{at}kcl.ac.uk; cannonr{at}nih.gov). * Dr. Jonathan M. Hill, King’s College London, Department of Cardiology, Bessemer Road, London SE5 9PJ, United Kingdom. (Email: Jonathan.Hill{at}kcl.ac.uk; cannonr{at}nih.gov).
OBJECTIVES: Cytokine mobilization of progenitor cells from bone marrow may promote myocardial neovascularization with relief of ischemia.
BACKGROUND: Patients with coronary artery disease (CAD) have low numbers of endothelial progenitor cells compared with healthy subjects.
METHODS: Granulocyte colony-stimulating factor (G-CSF), 10 µg/kg/day for five days, was administered to 16 CAD patients. Progenitor cells were measured by flow cytometry; ischemia was assessed by exercise stress testing and by dobutamine stress cardiac magnetic resonance imaging.
RESULTS: Granulocyte colony-stimulating factor increased CD34+/CD133+ cells in the circulation from 1.5 ± 0.2 µl to 52.4 ± 10.4 µl (p < 0.001), similar to the response observed in 15 healthy subjects (75.1 ± 12.6 µl, p = 0.173). Indices of platelet and coagulation activation were not changed by treatment, but C-reactive protein increased from 4.5 ± 1.3 mg/l to 8.6 ± 1.3 mg/l (p = 0.017). Two patients experienced serious adverse events: 1) non–ST-segment elevation myocardial infarction (MI) 8 h after the fifth G-CSF dose, and 2) MI and death 17 days after treatment. At 1 month after treatment, there was no improvement from baseline values (i.e., reduction) in wall motion score (from 25.7 ± 2.1 to 28.3 ± 1.9, p = 0.196) or segments with abnormal perfusion (7.6 ± 1.1 to 7.7 ± 1.1, p = 0.916) and a trend towards a greater number of ischemic segments (from 4.5 ± 0.6 to 6.1 ± 1.0, p = 0.068). There was no improvement in exercise duration at 1 month (p = 0.37) or at 3 months (p = 0.98) versus baseline.
CONCLUSIONS: Granulocyte colony-stimulating factor administration to CAD patients mobilizes cells with endothelial progenitor potential from bone marrow, but without objective evidence of cardiac benefit and with the potential for adverse outcomes in some patients.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | CCS = Canadian Cardiovascular Society | | CRP = high-sensitivity C-reactive protein | | EPC = endothelial progenitor cell | | FGRE = fast gradient echo | | G-CSF = granulocyte colony-stimulating factor | | MRI = magnetic resonance imaging | | TE = echo time | | TR = repetition time | | SSFP = steady-state free precession | | VEGF = vascular endothelial growth factor |
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