Chronic heart failure remains a leading cause of mortality. Although granulocyte 
colony-stimulating factor (G-CSF) is reported to have a beneficial affect on 
postinfarction cardiac remodeling and dysfunction when administered before the 
onset of or at the acute stage of myocardial infarction (MI), its effect on 
established heart failure is unknown. We show here that subcutaneous 
administration of G-CSF greatly improves the function of murine hearts failing 
due to a large, healed MI. G-CSF changed the geometry of the infarct scar from 
elongated and thin to short and thick, induced hypertrophy among surviving 
cardiomyocytes, and reduced myocardial fibrosis. Expression of G-CSF receptor 
was confirmed in failing hearts and was upregulated by G-CSF treatment. G-CSF 
treatment also led to activation of signal transducer and activator of 
transcription-3 and induction of GATA-4 and various sarcomeric proteins such as 
myosin heavy chain, troponin I and desmin. Expression of metalloproteinase-2 and 
-9 was also increased in G-CSF-treated hearts, while that of tumor necrosis 
factor-alpha, angiotensin II type 1 receptor (AT1) and transforming growth 
factor-beta1 was reduced. Although activation of Akt was noted in G-CSF-treated 
hearts, vessel density was unchanged, and apoptosis was too rare to exert a 
meaningful effect. No bone marrow-derived cardiomyocytes or vascular cells were 
detected in the failing hearts of green fluorescent protein chimeric mice. 
Finally, beneficial effects of G-CSF on cardiac function were found persisting 
long after discontinuing the treatment (2 weeks). Collectively, these findings 
suggest G-CSF administration could be an effective approach to treating chronic 
heart failure following a large MI.