Granulocyte colony stimulating factor in myocardial infarction with low ejection fraction

Division of Cardiology, Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0103, USA.
Cytokine (Impact Factor: 2.66). 09/2010; 51(3):278-85. DOI: 10.1016/j.cyto.2010.06.003
Source: PubMed


We investigated the safety and efficacy of GCSF therapy in a porcine model of ischemia-reperfusion with left ventricle ejection fraction of <45% using a clinically relevant dosing and timing regimen.
MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either GCSF (IV bolus of 10 microg/kg at time of reperfusion, followed by SC injections of 5 microg/kg days 5-9 post-MI) or saline (control group). Inflammatory markers, bone marrow cell mobilization and LV function (echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI.
GCSF therapy was associated with a significant increase in white blood cell counts. At week 6, GCSF therapy resulted in less deterioration of LVEF compared to control (38+/-2% vs. 33+/-2%, p<0.02) and improved wall motion score index (p<0.05). Histopathology revealed increased vascular density (p<0.05) and a trend toward increased areas of viable myocardium compared to control (p=0.058).
GCSF therapy prevents further deterioration of LV function in a porcine model of MI with lower EF (<45%). These results support future clinical trials with GCSF in selected patients with larger MI.

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    • "Animals were assigned to one of two treatment groups using the same protocol previously published by our group testing EPO and GCSF monotherapy [8, 15]: 1) Long-acting EPO analog (Aranesp, Amgen, Thousand Oaks, CA) was given as IV bolus at the time of reperfusion (0.9 ug/Kg), then as weekly SC injections for 4 weeks (0.4 ug/Kg), and GCSF (Neupogen, Amgen, Thousand Oaks, CA) was given as IV bolus at time of reperfusion and then daily SC injections from day 5 to 9 post MI; and 2) control group (normal saline in equivalent volume given IV and SC to match the administration of the EPO therapy group). EPO dosages were selected following clinical data showing safety and feasibility with a single bolus of a fixed dose of darbepoetin [20], clinical studies addressing safety of chronic use of darbepoetin in patients with chronic renal failure [21], and pre-clinical data showing improvement in cardiac function and neovascularization using prolonged EPO therapy in a dose that did not increase the hematocrit [14]. "
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    ABSTRACT: Erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF) have generated interest as novel therapies after myocardial infarction (MI), but the effect of combination therapy has not been studied in the large animal model. We investigated the impact of prolonged combination therapy with EPO and GCSF on cardiac function, infarct size, and vascular density after MI in a porcine model. MI was induced in pigs by a 90 min balloon occlusion of the left anterior descending coronary artery. 16 animals were treated with EPO+GCSF, or saline (control group). Cardiac function was assessed by echocardiography and pressure-volume measurements at baseline, 1 and 6 weeks post-MI. Histopathology was performed 6 weeks post-MI. At week 6, EPO+GCSF therapy stabilized left ventricular ejection fraction, (41 ± 1% vs. 33 ± 1%, p < 0.01) and improved diastolic function compared to the control group. Histopathology revealed increased areas of viable myocardium and vascular density in the EPO+GCSF therapy, compared to the control. Despite these encouraging results, in a historical analysis comparing combination therapy with monotherapy with EPO or GCSF, there were no significant additive benefits in the LVEF and volumes overtime using the combination therapy. Our findings indicate that EPO+GCSF combination therapy promotes stabilization of cardiac function after acute MI. However, combination therapy does not seem to be superior to monotherapy with either EPO or GCSF.
    Full-text · Article · Dec 2010 · Cardiovascular Drugs and Therapy
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