Granulocyte Colony Stimulating Factor in the Treatment of Cardiac Ischemic Disease. A Decade has Passed: Is it Time to Give Up?

Abstract

Therapies with stem cells have been proposed as a solution for decreased systolic capacity after cardiomyocyte death and/or to prevent cell death after an ischemic event. New host cell formation, activation of tissue progenitor cells, secretion of angiogenic and/or survival signals are some of the mechanisms that may explain the benefits of cell transplantation. Cell administration has been done by either intramyocardial or intracoronary route, implying that patients or animals are subject to surgery or to invasive hemodynamic procedure. The possibility of using growth factors capable of mobilizing stem cells to the circulation and induce their homing to the infarcted heart has therefore great therapeutic appeal since it would avoid invasive procedures. Granulocyte-colony stimulating factor (G-CSF) appears to be the major potential candidate because it has been used for many decades in patients with hematopoietic disorders without any serious adverse side effects and is known to mobilize hematopoietic [1], endothelial [2] and mesenchymal [3] precursor cells from bone marrow. In the present issue of Cardiovascular Drugs and Therapy Liu et al point out a distinct effect of G-CSF after myocardial infarction (MI): a disassociation between left ventricular mechanical and electrical properties in ischemic rat heart after G-CSF treatment [4]. For this purpose, the authors treated ischemic rats with subcutaneous G-CSF injections (100 μg/kg/d for five consecutive days) 1 h or 24 h after infarction. The main finding was that administration of G-CSF regardless of time of injection had no beneficial effects on cardiac function after cardiac ischemia. Nevertheless, G-CSF treatment was associated with improved electrophysiological properties, decreasing the number of arrhythmic events. G-CSF research in the field of ischemic heart disease is celebrating 10 years of pre-clinical and clinical work attempting to find a new therapeutic approach for this epidemic worldwide disease. In 2001, Orlic and coworkers, following their previous work using bone marrow lin– c-kit + cells for MI treatment [5], tested G-CSF in combination with Stem Cell Factor (SCF) in a model of acute MI in mice [6]. They found a significant decrease in mortality rate, and increased cardiac function. However the approach used could not be translated to the clinic, since the therapy was started 5 days before MI induction, besides including the use of SCF. Many reports followed the original work of Orlic et al. (2001) due its promising results, increasing the number of G-CSF and MI publications exponentially until 2006 (Fig. 1a). In a simple search at the National Library of Medicine of the National Institutes of Health (http://www.ncbi.nlm.nih.gov/pubmed) combining G-CSF and MI key words present in the title and/or the abstract we found 268 papers between 2000, January first, and 2011, May fifth. In a further delimitation, R. A. N. Louzada : J. P. S. Werneck-de-Castro (*) Departamento de Biociencias e Atividade Fisica, CCS, Escola de Educacao Fisica e Desportos, Ilha do Fundao, Universidade Federal do Rio de Janeiro (UFRJ), Carlos Chagas Filho av, 540, 21941–599, Rio de Janeiro, RJ, Brazil e-mail: joaopedrowerneck@yahoo.com.br