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Cell based therapy for ischemic heart disease has the potential to reduce post infarct heart failure and chronic ischemia. Treatment with granulocyte-colony stimulating factor (G-CSF) mobilizes cells from the bone marrow to the peripheral blood. Some of these cells are putative stem or progenitor cells. G-CSF is injected subcutaneously. This therapy is intuitively attractive compared to other cell based techniques since repeated catheterizations and ex vivo cell purification and expansion are avoided. Previous preclinical and early clinical trials have indicated that treatment with G-CSF leads to improved myocardial perfusion and function in acute or chronic ischemic heart disease. The hypothesis of this thesis is that patient with ischemic heart disease will benefit from G-CSF therapy. We examined this hypothesis in two clinical trials with G-CSF treatment to patients with either acute myocardial infarction or severe chronic ischemic heart disease. In addition, we assed a number of factors that could potentially affect the effect of cell based therapy. Finally, we intended to develop a method for in vivo cell tracking in the heart. Our research showed that subcutaneous G-CSF along with gene therapy do not improve myocardial function in patients with chronic ischemia despite a large increase in circulation bone marrow-derived cells. Also, neither angina pectoris nor exercise capacity was improved compared to placebo treatment. We could not identify differences in angiogenic factors or bone marrow-derived cells in the blood that could explain the neutral effect of G-CSF. Next, we examined G-CSF as adjunctive therapy following ST segment elevation myocardial infarction. We did not find any effect of G-CSF neither on the primary endpoint--regional myocardial function--nor on left ventricular ejection fraction (secondary endpoint) compared to placebo treatment. In subsequent analyses, we found significant differences in the types of cells mobilized from the bone marrow by G-CSF. This could explain why intracoronary injections of unfractionated bone marrow-derived cells have more effect that mobilization with G-CSF. A number of other factors could explain the neutral effect of G-CSF in our trial compared to previous studies. These factors include timing of the treatment, G-CSF dose, and study population. It is however, remarkable that the changes in our G-CSF group are comparable to the results of previous non-blinded studies, whereas the major differences are in the control/placebo groups. We found that ejection fraction, wall motion, edema, perfusion, and infarct size all improve significantly in the first month following ST-segment myocardial infarction with standard guideline treatment (including acute mechanical revascularization), but without cell therapy. This is an important factor to take into account when assessing the results of non-controlled trials. Finally, we found that ex vivo labeling of cells with indium-111 for in vivo cell tracking after intramyocardial injection is problematic. In our hand, a significant amount of indium-111 remained in the myocardium despite cell death. It is difficult to determine viability of the cells after injection in human trials, and it is thus complicated to determine if the activity in the myocardium tracks viable cells. Cell based therapy is still in the explorative phase, but based on the intense research within this field it is our hope that the clinical relevance of the therapy can be determined in the foreseeable future. Ultimately, this will require large randomized, double-blind and placebo-controlled trials with "hard" clinical endpoints like mortality and morbidity.

Background: Granulocyte-colony stimulating factor (G-CSF) therapy after ST-elevation myocardial infarction (STEMI) have not demonstrated impact on systolic recovery compared to placebo. However, recent studies suggest that timing of G-CSF therapy is crucial., Methods: Timing of G-CSF treatment was analyzed in the STEMMI MRI subpopulation including 54 patients with STEMI treated with primary percutaneous coronary intervention (PCI) <12 h after symptom onset. Patients were randomized to double blind treatment with G-CSF (10 microg/kg/day) or placebo. Treatment was initiated from 17 to 65 h (mean 30) after PCI. Left ventricular ejection fraction (LVEF) was evaluated with MRI., Results: Recovery of LVEF from baseline to 6 months was not associated with time from PCI to G-CSF. An identical improvement in LVEF was found in the placebo group and the G-CSF group (p=0.8). There was no correlation between time from PCI to G-CSF and maximum plasma concentration of CD34+ cells (r=-0.3, p=0.1). Similar results were found from data on recovery of the infarction size and change in the systolic wall thickening., Conclusions: In the time window from 17 to 65 h after STEMI treated with PCI, the timing of G-CSF treatment does not seem to affect the recovery of LVEF. It remains to be determined if very early, or very late G-CSF treatment might be effective., (Copyright (c) 2008 Elsevier Ireland Ltd. All rights reserved.)

This review of adjunctive therapy with subcutaneous granulocyte-colony stimulating factor (G-CSF) to patients with acute myocardial infarction (AMI) focus on the cardioprotective effects and potential mechanisms of G-CSF and discuss the therapeutic potential of G-CSF. All clinical trials published in peer-reviewed journals identified through PubMed are discussed. G-CSF treatment seems to be safe, and initial unblinded trials in patients with AMI were encouraging. However, larger double-blind placebo-controlled trials have not been able to demonstrate improved myocardial recovery after G-CSF treatment. Current controversies in interpretation of the results include 1) importance of direct cardiac effect of G-CSF vs indirect through bone marrow stem and progenitor cell mobilization, 2) importance of timing of G-CSF therapy, 3) importance of G-CSF dose, and 4) importance of cell types mobilized from the bone-marrow. Cell-based therapies to improve cardiac function remain promising and further experimental and clinical studies are warranted to determine the future role of G-CSF.

Objectives: The objective of this meta-analysis was to evaluate the effect of stem cell mobilization by granulocyte colony-stimulating factor (G-CSF) on myocardial regeneration on the basis of a synthesis of the data generated by randomized, controlled clinical trials of G-CSF after acute myocardial infarction (AMI)., Background: Experimental studies and early-phase clinical trials suggest that stem cell mobilization by G-CSF may have a positive impact on cardiac regeneration after AMI. The role of G-CSF in patients with AMI remains unclear considering the inconsistent results of several clinical trials., Methods: For our analysis, PubMed, the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to August 2007 served as sources. Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest. Eligible studies were randomized trials with stem cell mobilization by G-CSF after reperfused AMI that reported data regarding the change in left ventricular ejection fraction (LVEF) at follow-up., Results: Ten trials using stem cell mobilization by G-CSF, including 445 patients, met the inclusion criteria. Significant improvement in LVEF at follow-up was observed in both the G-CSF and placebo groups. Compared with placebo, stem cell mobilization by G-CSF did not enhance the improvement of LVEF at follow-up (mean difference 1.32% [95% confidence interval -1.52 to 4.16; p = 0.36]). Moreover, the mean difference of reduction of infarct size between the treatment and placebo groups was -0.15 (95% confidence interval -0.38 to 0.07, p = 0.17)., Conclusions: Cumulatively, available evidence does not support a beneficial effect of G-CSF in patients with AMI after reperfusion.

Background: Granulocyte-colony stimulating factor (G-CSF) after myocardial infarction does not affect systolic function when compared with placebo. In contrast, intracoronary infusion of bone marrow cells appears to improve ejection fraction. We aimed to evaluate the G-CSF mobilization of subsets of stem cells., Methods and Results: We included 78 patients (62 men; 56+/-8 years) with ST-elevation myocardial infarction treated with primary percutaneous intervention <12 hours after symptom onset. Patients were randomized to double-blind G-CSF (10 microg/kg/d) or placebo. Over 7 days, the myocardium was exposed to 25x10(9) G-CSF mobilized CD34+ cells, compared with 3x10(9) cells in placebo patients (P<0.001); and to 4.9x10(11) mesenchymal stem cells, compared with 2.0x10(11) in the placebo group (P<0.001). The fraction of CD34+ cells/leukocyte increased during G-CSF treatment (from 0.3+/-0.2 to 1.1+/-0.9 x10(-3), P<0.001 when compared with placebo), whereas the fraction of putative mesenchymal stem cells/leukocyte decreased (from 22+/-17 to 14+/-11 x10(-3), P=0.01 when compared with placebo). An inverse association between number of circulating mesenchymal stem cells and change in ejection fraction was found (regression coefficient -6.8, P=0.004), however none of the mesenchymal cell subtypes analyzed, were independent predictors of systolic recovery., Conclusions: The dissociated pattern for circulating CD34+ and mesenchymal stem cells could be attributable to reduced mesenchymal stem cell mobilization from the bone marrow by G-CSF, or increased homing of mesenchymal stem cells to the infarcted myocardium. The inverse association between circulating mesenchymal stem cells and systolic recovery may be of clinical importance and should be explored further.

Mobilization of stem cells into the peripheral circulation for myocardial regeneration using subcutaneous injections of granulocyte-colony-stimulating factor (G-CSF) has been tested in both patients with acute myocardial infarction (AMI) and patients with chronic myocardial ischaemia. G-CSF treatment seems to be safe and unblinded trials in patients with AMI were encouraging. However, larger double-blind placebo-controlled trials have not been able to demonstrate effect of G-CSF treatment. In patients with chronic myocardial ischaemia, small-unblinded G-CSF trials did not show effect on myocardial perfusion and function. In both patient populations, G-CSF did mobilize stem cells of known importance to myocardial regeneration, but there seemed to be a general lack of homing of the stem cells into the ischaemic myocardium. In AMI, factors of importance to homing of stem cells, stem cell derived factor-1, are maximally elevated in plasma 3 weeks after infarction, suggesting that this time point could be the optimal time for stem cell mobilization treatment. The known complex interaction of stem cells and cytokines for induction of vasculogenesis should be implemented in future clinical trials, to elucidate whether G-CSF mobilization of stem cells might be useful as a new regenerative treatment in patients with ischaemic heart disease.

Aims: To assess the safety and effects of combined treatment with vascular endothelial growth factor-A(165) plasmid (VEGF-A(165)) and granulocyte- colony stimulating factor (G-CSF) mobilization of bone marrow stem cells in patients with severe chronic ischaemic heart disease (IHD)., Methods and Results: Sixteen patients with severe chronic IHD were treated with intramyocardial injections of VEGF-A(165) plasmid followed 1 week later by G-CSF (10 microg/kg/day for 6 days). Two control groups included (i) sixteen patients treated with intramyocardial injections of VEGF-A(165) plasmid and (ii) sixteen patients treated with intramyocardial injections of placebo. In the G-CSF group, circulating CD34+ stem cells increased almost 10-fold compared with the control groups (P<0.0001). After 3 months, there was no improvement in myocardial perfusion at single photon emission computerized tomography in the VEGF-A(165) and G-CSF treated group, and clinical symptoms were unchanged. There were no side effects to the gene and G-CSF therapy., Conclusion: Intramyocardial VEGF-A(165) gene transfer followed by bone marrow stem cell mobilization with G-CSF seemed safe. However, a significant increase in circulating stem cells did not lead to improved myocardial perfusion or clinical effects suggesting a neutral effect of the treatment. To improve homing of stem cells, higher doses of VEGF-A(165) and/or use of SDF-1 transfer might be considered.

Background: Phase 1 clinical trials of granulocyte-colony stimulating factor (G-CSF) treatment after myocardial infarction have indicated that G-CSF treatment is safe and may improve left ventricular function. This randomized, double-blind, placebo-controlled trial aimed to assess the efficacy of subcutaneous G-CSF injections on left ventricular function in patients with ST-elevation myocardial infarction., Methods and Results: Seventy-eight patients (62 men; average age, 56 years) with ST-elevation myocardial infarction were included after successful primary percutaneous coronary stent intervention <12 hours after symptom onset. Patients were randomized to double-blind treatment with G-CSF (10 microg/kg of body weight) or placebo for 6 days. The primary end point was change in systolic wall thickening from baseline to 6 months determined by cardiac magnetic resonance imaging (MRI). An independent core laboratory analyzed all MRI examinations. Systolic wall thickening improved 17% in the infarct area in the G-CSF group and 17% in the placebo group (P=1.0). Comparable results were found in infarct border and noninfarcted myocardium. Left ventricular ejection fraction improved similarly in the 2 groups measured by both MRI (8.5 versus 8.0; P=0.9) and echocardiography (5.7 versus 3.7; P=0.7). The risk of severe clinical adverse events was not increased by G-CSF. In addition, in-stent late lumen loss and target vessel revascularization rate in the follow-up period were similar in the 2 groups., Conclusions: Bone marrow stem cell mobilization with subcutaneous G-CSF is safe but did not lead to further improvement in ventricular function after acute myocardial infarction compared with the recovery observed in the placebo group.