Outcomes and Risks of Granulocyte Colony-Stimulating Factor in Patients With Coronary Artery Disease

Harvard University, Cambridge, Massachusetts, United States
Journal of the American College of Cardiology (Impact Factor: 16.5). 12/2005; 46(9):1643-8. DOI: 10.1016/j.jacc.2005.01.067
Source: PubMed


Cytokine mobilization of progenitor cells from bone marrow may promote myocardial neovascularization with relief of ischemia.
Patients with coronary artery disease (CAD) have low numbers of endothelial progenitor cells compared with healthy subjects.
Granulocyte colony-stimulating factor (G-CSF), 10 microg/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.
Granulocyte colony-stimulating factor increased CD34+/CD133+ cells in the circulation from 1.5 +/- 0.2 microl to 52.4 +/- 10.4 microl (p < 0.001), similar to the response observed in 15 healthy subjects (75.1 +/- 12.6 microl, 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.
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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Available from: Jonathan Michael Hill, Mar 09, 2014
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    • "G-CSF-mobilized hematopoietic cell grafts are currently the preferred source for hematopoietic cell transplantation (Gratwohl et al., 2005; To et al., 2011, and references within) and stem cell gene therapy applications (Ott et al., 2006; Cartier et al., 2009; Boztug et al., 2010; Sadelain et al., 2010). G- CSF mobilization, however, is associated with certain morbidities (Falzetti et al., 1999; Hill et al., 2005); furthermore, a number of patients fail to mobilize effectively or certain normal donors need to undergo extended aphereses (Anderlini et al., 1997; Stiff et al., 2000; Miller et al., 2008). In addition, certain limitations have been raised with the use of G-CSF in autologous transplantation settings, including gene therapy. "
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    ABSTRACT: Successful stem cellgene therapy requires high numbers of genetically-engineered hematopoietic stem cells collected using optimal mobilization strategies. Here we focus on stem cell mobilization strategies for thalassemia and present the results of a plerixafor-based mobilization trial with emphasis on the remobilization with G-CSF+plerixafor in those patients who have previously failed mobilization. Plerixafor rapidly mobilized CD34+cells without inducing hyperleukocytosis, however, 35% of patients failed to reach the target cell dose of ≥6X106CD34+cells/kg. Four subjects who failed either on plerixafor or G-CSF were remobilized with G-CSF+plerixafor. The combination proved highly synergistic; the target cell dose was readily reached and the per apheresis yield was significantly increased over initial mobilization, ultimately resulting in single-apheresis collections, despite a more than50% reduction of the dose of G-CSF in splenectomized patients to avoid hyperleukocytosis. The total stem and progenitor cells mobilized in G-CSF+plerixafor patients were higher than in patients treated by plerixafor-alone. Importantly, the G-CSF+plerixafor-mobilized cells displayed a primitive stem cell phenotype and higher clonogenic capacity over plerixafor-mobilized cells. G-CSF+plerixafor represents the optimal strategy when very high yields of stem cells or a single apheresis is required. The high yields and the favorable transplantation features, render the G-CSF+plerixafor-mobilized cells the optimal CD34+cell source for stem cell gene therapy applications.
    Full-text · Article · Sep 2013 · Human gene therapy
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    • "Recently, G-CSF has been used to treat acute myocardial infarction (AMI) patients with intention to mobilize autologous stem cells and thus to replace infarct cardiac muscle cells. Although G-CSF treatment improved cardiac function in both clinical studies and in animal models of AMI [3-5], this treatment remains controversial since equivocal benefits [6-8] and some AMI patients developed re-stenosis and worsened condition post G-CSF delivery [9,10]. In addition, three cases of late stent thrombosis were reported in a cohort study of 24 patients who had undergone intra-coronary infusion of G-CSF after primary stenting for AMI [11]. "
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    ABSTRACT: Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, was recently used to treat patients of acute myocardial infarction with beneficial effect. However, controversy exists as some patients developed re-stenosis and worsened condition post G-CSF delivery. This study presents a new disease model to study G-CSF induced cardiac thrombosis and delineate its possible mechanism. We used iron loading to mimic condition of chronic cardiac dysfunction and apply G-CSF to mice to test our hypothesis. Eleven out of fifteen iron and G-CSF treated mice (I+G) showed thrombi formation in the left ventricular chamber with impaired cardiac function. Histological analysis revealed endothelial fibrosis, increased macrophage infiltration and tissue factor expression in the I+G mice hearts. Simvastatin treatment to I+G mice attenuated their cardiac apoptosis, iron deposition, and abrogated thrombus formation by attenuating systemic inflammation and leukocytosis, which was likely due to the activation of pAKT activation. However, thrombosis in I+G mice could not be suppressed by platelet receptor inhibitor, tirofiban. Our disease model demonstrated that G-CSF induces cardiac thrombosis through an inflammation-thrombosis interaction and this can be attenuated via statin therapy. Present study provides a mechanism and potential therapy for G-CSF induced cardiac thrombosis.
    Full-text · Article · Apr 2011 · Journal of Biomedical Science
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    • "The G-CSF treatment protocol used here has been evaluated to promote cardiac regeneration in patients with MI (Orlic et al., 2001; Kocker et al., 2001; Zohlnhö fer et al., 2006; Ince et al., 2005; Ripa et al., 2006; Ellis et al., 2006; Hill et al., 2005). These trials have been disappointing, with only 1 out of 5 trials showing any significant clinical benefit (Zohlnhö fer et al., 2006; Ince et al., 2005; Ripa et al., 2006; Ellis et al., 2006; Hill et al., 2005). As we reveal here, such limited clinical success might be because G-CSF administration is not a particularly efficacious regimen for mobilizing EPCs or SPCs, which may be important for cardiac regeneration. "
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    ABSTRACT: G-CSF stimulates mobilization of hematopoietic progenitor cells (HPCs) from bone marrow by disrupting the CXCR4/SDF-1alpha retention axis. We show here that distinct factors and mechanisms regulate the mobilization of endothelial (EPCs) and stromal progenitor cells (SPCs). Pretreatment of mice with VEGF did not disrupt the CXCR4/SDF-1alpha chemokine axis but stimulated entry of HPCs into the cell cycle via VEGFR1, reducing their migratory capacity in vitro and suppressing their mobilization in vivo. In contrast, VEGF pretreatment enhanced EPC mobilization via VEGFR2 in response to CXCR4 antagonism. Furthermore, SPC mobilization was detected when the CXCR4 antagonist was administered to mice pretreated with VEGF, but not G-CSF. Thus, differential mobilization of progenitor cell subsets is dependent upon the cytokine milieu that regulates cell retention and proliferation. These findings may inform studies investigating mechanisms that regulate progenitor cell recruitment in disease and can be exploited to provide efficacious stem cell therapy for tissue regeneration.
    Preview · Article · Feb 2009 · Cell stem cell
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