To the Editor: We would like to raise possible reasons for the treatment failure of granulocyte colony-stimulating factor (G-CSF) in the Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL-2) trial by Dr Zohlnhöfer and colleagues1 based on what we believe to be the mechanism of action of G-CSF in both the myocardium and the brain.
Protective effects of G-CSF in experimental acute myocardial infarction (AMI) or stroke have been shown,2 - 4 but the probable mechanism of action has remained uncertain. Most studies have assumed activation and mobilization of bone marrow–derived stem cells by G-CSF that integrate into the infarcted organ and contribute to recovery by transdifferentiation or other unknown mechanisms. Based on this assumption, REVIVAL-2 was designed with a delayed treatment start (5 days after AMI), and with a G-CSF dose sufficient to stimulate bone marrow mobilization (10 μg/kg per day for 5 days).1 However, recent evidence from studies of the heart and brain cast doubt on the concept that mobilization of stem cells is the sole or even most important mechanism.
The idea that bone marrow–derived stem cells can transdifferentiate into cardiomyocytes or neurons may have resulted from experimental artifacts such as cell fusions, and therefore be wrong. Granulocyte colony-stimulating factor directly protects cells at risk.2 - 3 This action may be the cause of its acute effects in AMI or stroke, which would have 2 consequences. First, there would be a brief time window for treatment and efficacy for tissue salvage would decrease with time.2 - 3 Second, dose dependency related to this mechanism would be different from that of bone marrow mobilization.2 - 3
In view of this hypothesis for the mode of action of G-CSF in the acute setting, REVIVAL-2 had a suboptimal design with respect to both time window and dose. Consistent with data from experimental stroke,2 improvement in cardiac function after experimental AMI was reduced when delaying the time window for G-CSF to day 3 after the AMI, and effects were no longer detectable when treatment was delayed to day 7.3 Treatment with G-CSF in REVIVAL-2 was initiated at a time that was not supported by this experimental evidence. Also, a G-CSF dose at least 10 times that used in REVIVAL-2 was required to be effective in improving cardiac function after experimental AMI.3
Financial Disclosure: Drs Schäbitz and Schneider are inventors on a patent application regarding the neuroprotective effect of granulocyte colony-stimulating factor.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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