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FOCUS ISSUE: CARDIAC REGENERATION

Granulocyte Colony-Stimulating Factor and Stem Cell Factor Improve Contractile Reserve of the Infarcted Left Ventricle Independent of Restoring Muscle Mass

Casilde Sesti, PhD^_*, Sharon L. Hale, BS^_*, Carolyn Lutzko, PhD and Robert A. Kloner, MD, PhD^_*,_*

^_* Heart Institute, Good Samaritan Hospital, Cardiovascular Division, Keck School of Medicine at the University of Southern California, Los Angeles, California
Children’s Hospital-Los Angeles, Los Angeles, California

Manuscript received November 2, 2004; revised manuscript received February 3, 2005, accepted February 8, 2005.

^_* Reprint requests and correspondence: Dr. Robert A. Kloner, The Heart Institute, Good Samaritan Hospital, University of Southern California, 1225 Wilshire Boulevard, Los Angeles, California 90017-2395. (Email: Rkloner{at}goodsam.org).

OBJECTIVES: We investigated whether granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) could promote myocardial regeneration after coronary artery occlusion and improve left ventricular (LV) function.

BACKGROUND: Cytokine-induced mobilization of bone marrow stem cells in the heart may represent a promising strategy for replacing infarcted myocardium.

METHODS: Sprague-Dawley rats were subjected to permanent coronary occlusion. A treated group (n = 19) received G-CSF (100 µg/kg) and SCF (25 µg/kg) subcutaneously, starting 2 h after surgery and continuing daily for an additional 4 days. Control rats (n = 21) received sterile water. The peripheral blood content in hematopoietic progenitor cells was analyzed.

RESULTS: At eight weeks, LV angiograms (rest and dobutamine stress) and histologic analysis were performed. At rest, LV ejection fraction (LVEF) was 0.45 in controls and 0.52 in treated hearts (p = 0.16). For any infarct size, LVEF was greater in the treated group (p = 0.045). Under dobutamine stress, treated animals had smaller LV end-diastolic and -systolic volumes (0.37 ± 0.04 ml and 0.16 ± 0.03 ml) versus control animals (0.51 ± 0.05 ml and 0.26 ± 0.04 ml; p = 0.026 and 0.048) with a 7% improvement in ejection fraction. Scar thickness was 1.1 ± 0.1 mm in treated hearts and 1.0 ± 0.1 mm in controls (p = 0.36). Scar morphology was similar in both groups without obvious new muscle in the scar.

CONCLUSIONS: Because we did not find evidence of new muscle cells in the infarct area, our conclusion is that G-CSF and SCF enhanced the LV functional reserve of the heart without replacing scar tissue.

Abbreviations and Acronyms   EF = ejection fraction   G-CSF = granulocyte colony-stimulating factor   GM-CSF = granulocyte-macrophage colony-stimulating factor   IL = interleukin   IS = infarct size   LV = left ventricular/ventricle   MAP = mean arterial pressure   MI = myocardial infarction   RMBF = regional myocardial blood flow   SCF = stem cell factor

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