- Email: [email protected]
Granulocyte colony-stimulating factor in patients with ST segment elevation myocardial infarction: A disappointment-stimulating factor?
138
Letters to the Editor
surroundings; a number of scholarships and awards have been issued for junior scientists to reward outstanding results and promising projects proposals. In the future, the CNHF is expecting fundamental changes, mostly in terms of financial support. The third funding period of the network is due to expire in 2011; therefore it is currently one major aim of the network management to recruit new sources of funding and partnerships and to establish a valuable business plan. A first step in this direction was the formation of an independent legal entity enabling the network to act as an autonomous business partner. The broad network connections will be utilised to attract private financial sources; the resources of the biomaterial bank as well as the clinical database should also enable the network to attract the pharmaceutical industry, physicians, clinics and research organisations for cooperative projects. Furthermore, the evolution of new diagnostic and therapeutic concepts is targeted in national and international projects. The ambitions of various European cardiac associations in developing a large registry for patients with chronic HF are currently taken into account in a German pilot project. These and other examples and efforts in the development of investigator-initiated research in Germany and Europe will carry forward the original idea of the CNHF —
• area of HF; • care; and •• to patients and public developments in research and therapy and tokeep keep patients andinformed publicof new informed of new developments in • to and and boost boost the efficiency of research of in research the area of in HF;the tocoordinate coordinate the efficiency
• to the the quality of patient care; and toincrease increase quality of patient
thereby playand a keytherapy role in implementing effective strategies. research and thereby playprevention a key role in implementing
effective prevention strategies. We thank all patients, physicians and health care personnel that have been involved in the work of the CNHF. The German Federal Ministry of Research and Education (BMBF) supports the CNHF (funding no. 01GI0205). The authors of this manuscript have certified
that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12]. References [1] Posch M, Gelbrich G, Pieske B, et al. The biomaterial bank of the German Competence Network of Heart Failure (CNHF) is a valuable resource for biomaterial and genetic research. Int J Cardiol 2009;136:108–11. [2] Müller-Tasch T, Peters-Klimm F, Schellberg D, et al. Depression is a major determinant of quality of life in patients with chronic systolic heart failure in general practice. J Card Fail 2007;10:818–24. [3] Göhler A, Conrads-Frank A, Worrell SS, et al. Decision-analytic evaluation of the clinical effectiveness and cost-effectiveness of management programmes in chronic heart failure. Eur J Heart Fail 2008;10:1026–32. [4] Markus MR, Stritzke J, Lieb W, et al. Implications for persistent prehypertension for ageing related changes in left ventricular geometry and function: the MONICA/ KORA Augsburg study. J Hypertens 2008;26(10):2040–9. [5] Jahns R, Boivin V, Lohse MJ. Beta 1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 2006;112:7–14. [6] Neumann T, Esser S, Potthoff A, et al. Prevalence and natural history of heart failure in outpatient HIV-infected subjects: rationale and design of the HIV–HEART study. Eur J Med Res 2007;12:243–8. [7] Düngen HD, Apostolovic S, Inkrot S, et al. Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial. Clin Res Cardiol 2008;97:578–86. [8] Störk S, Hense HW, Zentgraf C, et al. Pharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of patients with chronic heart failure: a prospective cohort study. Eur J Heart Fail 2008;10:1236–45. [9] Köhler F, Schieber M, Lücke S, et al. “Partnership for the Heart”—development and testing of a new remote patient monitoring system. Dtsch Med Wochenschr Mar. 2, 2007;132:458–60. [10] Angermann CE, Gelbrich G, Störk S, et al. Rationale and design of a randomised, controlled, multicenter trial investigating the effects of selective serotonin reuptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD-HF). Eur J Heart Fail 2007;9:1212–22. [11] Pullicino P, Thompson JL, Barton B, Levin B, Graham S, Freudenberger RS. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail Feb. 2006;12:39–46. [12] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.061
Granulocyte colony-stimulating factor in patients with ST segment elevation myocardial infarction: A disappointment-stimulating factor? Turgay Celik a,⁎, Atila Iyisoy a, Ejder Kardesoglu b, Murat Celik a a b
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, 06018 Etlik-Ankara, Turkey Gulhane Military Medical Academy, Haydarpasa Training Hospital, Department of Cardiology, Turkey
a r t i c l e
i n f o
Article history: Received 22 June 2009 Accepted 26 June 2009 Available online 3 August 2009 Keywords: G-CSF ST segment elevation myocardial infarction Stem cell mobilization
⁎ Corresponding author. Tel.: +90 312 3044268; fax: +90 312 3044250. E-mail address: [email protected] (T. Celik).
In their recently published very well-designed article, Engelmann et al. investigated the effect of granulocyte colony-stimulating factor (G-CSF) on left-ventricular ejection fraction (LVEF) and event-free survival in patients suffering from sub-acute ST segment elevation myocardial infarction (STEMI) [1]. In that study, 44 patients suffering from sub-acute STEMI with late revascularization achieved by percutaneous coronary intervention (PCI) were randomized to receive either G-CSF (Filgrastim) at a dose of 10 µg/kg body weight/day subcutaneously or placebo. Changes of global and regional cardiac function from baseline over 1 and 3 months to 12 months of follow-up were analyzed by magnetic resonance imaging. The authors found that G-CSF administration after sub-acute STEMI is feasible and safe but does not improve myocardial function or survival when used as a single substance. The feature of G-CSF to mobilize stem cells from bone marrow (CD34+ mononuclear blood stem cells) and increase their circulating levels has
Letters to the Editor
been used for stem cell mobilization in patients with STEMI and for harvesting stem cells for intracoronary delivery. Research with G-CSF has demonstrated conflicting results. In the MAGIC trial the potential value of G-CSF in comparison to or in combination with stem cell infusion was assessed [2]. Twenty-seven patients with an acute myocardial infarction MI undergoing PCI were randomly assigned to stem cell mobilization with G-CSF followed by stem cell apheresis and intracoronary reinfusion, to GCSF alone, or to a control group. Six-month follow-up data in 10 of the study patients demonstrated an improvement in LVEF with stem cell infusion (from 48.7% to 55.1%) but not with G-CSF alone. Stem cell infusion also increased treadmill exercise time and reduced the size of the myocardial perfusion defect. However, administration of G-CSF was associated with an unexpectedly high rate of in-stent restenosis of the culprit lesion. Although this finding needs to be confirmed, it would suggest that cells capable of differentiation into smooth muscle cells are mobilized in response to G-CSF [3]. This finding is in contrast to animal studies that suggest that endothelial progenitor cell mobilization with GCSF leads to rapid reendothelialization and decreased neointimal formation at sites of arterial injury [4]. The lack of benefit and possible adverse outcomes with G-CSF alone in the MAGIC trial [2] are consistent with other studies of G-CSF or GM-CSF alone that showed no long-term efficacy [5–7] and a possible increase in the risk of coronary ischemia and acute coronary syndrome [7,8]. In contrast to MAGIC trial, the The Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Use of Granulocyte Colony-Stimulating Factor (FIRSTLINE AMI) AMI found a significantly higher LVEF at rest at 4 months with G-CSF therapy (54% versus 43%) and other benefits, including a greater increase in viable myocardium in the infarct territory (11% versus 0%) [9]. But, this trial was unblinded and was a small study. The largest experience comes from the Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells-2 (REVIVAL-2) trial in which 114 patients with STEMI involving at least 5% of the left ventricle underwent successful reperfusion by primary PCI and 5 days later were randomly assigned to G-CSF (10 µg/kg) or placebo daily for 5 days [5]. Despite a marked increase in circulating stem cells, there was no difference between the groups in the primary end point—a reduction in infarct size at 4 to 6 months, as assessed by myocardial perfusion imaging (6.2% versus 4.9% with placebo)—or in the secondary end points of improvement in LVEF (+0.5% versus +2.0%) and angiographic restenosis (35% versus 31%). A similar lack of benefit was noted in the Stem cell mobilization induced by subcutaneous granulocyte colony-stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction (STEMMI) trial in which 78 patients with STEMI undergoing successful primary PCI were randomly assigned to G-CSF (10 µg/kg) or placebo daily for 6 days [6]. At 6 months, there was no difference between the two groups in the primary end point of change in systolic wall thickening on cardiac magnetic resonance imaging (17% improvement), LVEF, or target vessel revascularization. The limited clinical data available do not permit a full assessment of the potential risks of cellular cardiomyoplasty as a therapeutic modality. Two concerns are ventricular tachyarrhythmia and a possible increase in
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.053
139
in-stent restenosis. Episodes of ventricular tachycardia occur in many patients after myoblast injection [10,11]. As a result, an implantable cardioverter-defibrillator is now routinely required for myoblast studies. The pathogenesis of these arrhythmias is not well understood. There are conflicting data as to whether stem cell therapy is [2] or is not [9] associated with an increase in in-stent restenosis and whether there is [7,8] or is not [9] an increase in the risk of coronary ischemia and acute coronary syndrome [7,8]. In conclusion, cellular cardiomyoplasty is an investigational technique that may have the potential to reduce myocardial infarct size and improve cardiac function in patients with ischemic heart disease. However, experience with this approach is still limited to a few small trials, some which were not blinded or had other design problems. Although there is no sufficient evidence to believe that G-CSF may be a useful treatment in patients with STEMI who undergo primary PCI, further large-scale clinical studies are needed to examine the exact role of G-CSF in the management of those patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12].
References [1] Engelmann MG, Theiss HD, Theiss C, et al. G-CSF in patients suffering from late revascularised ST elevation myocardial infarction: final 1-year-results of the G-CSF-STEMI Trial. Int J Cardiol 2010;144:399–404. [2] Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004;363:751–6. [3] Tanaka K, Sata M, Hirata Y, et al. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res 2003;93:783–90. [4] Cho HJ, Kim HS, Lee MM, et al. Mobilized endothelial progenitor cells by granulocyte– macrophage colony-stimulating factor accelerate reendothelialization and reduce vascular inflammation after intravascular radiation. Circulation 2003;108:2918–25. [5] Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colonystimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006;295:1003–10. [6] Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 2006;113:1983–92. [7] Hill JM, Syed MA, Arai AE, et al. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol 2005;46:1643–8. [8] Zbinden S, Zbinden R, Meier P, Windecker S, Seiler C. Safety and efficacy of subcutaneous-only granulocyte–macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol 2005;46:1636–42. [9] Ince H, Petzsch M, Kleine HD, et al. Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI). Circulation 2005;112(9 Suppl):I73–80. [10] Dib N, Michler RE, Pagani FD, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation 2005;112:1748–55. [11] Makkar RR, Lill M, Chen PS. Stem cell therapy for myocardial repair: is it arrhythmogenic? J Am Coll Cardiol 2003;42:2070–2. [12] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
Letters to the Editor
surroundings; a number of scholarships and awards have been issued for junior scientists to reward outstanding results and promising projects proposals. In the future, the CNHF is expecting fundamental changes, mostly in terms of financial support. The third funding period of the network is due to expire in 2011; therefore it is currently one major aim of the network management to recruit new sources of funding and partnerships and to establish a valuable business plan. A first step in this direction was the formation of an independent legal entity enabling the network to act as an autonomous business partner. The broad network connections will be utilised to attract private financial sources; the resources of the biomaterial bank as well as the clinical database should also enable the network to attract the pharmaceutical industry, physicians, clinics and research organisations for cooperative projects. Furthermore, the evolution of new diagnostic and therapeutic concepts is targeted in national and international projects. The ambitions of various European cardiac associations in developing a large registry for patients with chronic HF are currently taken into account in a German pilot project. These and other examples and efforts in the development of investigator-initiated research in Germany and Europe will carry forward the original idea of the CNHF —
• area of HF; • care; and •• to patients and public developments in research and therapy and tokeep keep patients andinformed publicof new informed of new developments in • to and and boost boost the efficiency of research of in research the area of in HF;the tocoordinate coordinate the efficiency
• to the the quality of patient care; and toincrease increase quality of patient
thereby playand a keytherapy role in implementing effective strategies. research and thereby playprevention a key role in implementing
effective prevention strategies. We thank all patients, physicians and health care personnel that have been involved in the work of the CNHF. The German Federal Ministry of Research and Education (BMBF) supports the CNHF (funding no. 01GI0205). The authors of this manuscript have certified
that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12]. References [1] Posch M, Gelbrich G, Pieske B, et al. The biomaterial bank of the German Competence Network of Heart Failure (CNHF) is a valuable resource for biomaterial and genetic research. Int J Cardiol 2009;136:108–11. [2] Müller-Tasch T, Peters-Klimm F, Schellberg D, et al. Depression is a major determinant of quality of life in patients with chronic systolic heart failure in general practice. J Card Fail 2007;10:818–24. [3] Göhler A, Conrads-Frank A, Worrell SS, et al. Decision-analytic evaluation of the clinical effectiveness and cost-effectiveness of management programmes in chronic heart failure. Eur J Heart Fail 2008;10:1026–32. [4] Markus MR, Stritzke J, Lieb W, et al. Implications for persistent prehypertension for ageing related changes in left ventricular geometry and function: the MONICA/ KORA Augsburg study. J Hypertens 2008;26(10):2040–9. [5] Jahns R, Boivin V, Lohse MJ. Beta 1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int J Cardiol 2006;112:7–14. [6] Neumann T, Esser S, Potthoff A, et al. Prevalence and natural history of heart failure in outpatient HIV-infected subjects: rationale and design of the HIV–HEART study. Eur J Med Res 2007;12:243–8. [7] Düngen HD, Apostolovic S, Inkrot S, et al. Bisoprolol vs. carvedilol in elderly patients with heart failure: rationale and design of the CIBIS-ELD trial. Clin Res Cardiol 2008;97:578–86. [8] Störk S, Hense HW, Zentgraf C, et al. Pharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of patients with chronic heart failure: a prospective cohort study. Eur J Heart Fail 2008;10:1236–45. [9] Köhler F, Schieber M, Lücke S, et al. “Partnership for the Heart”—development and testing of a new remote patient monitoring system. Dtsch Med Wochenschr Mar. 2, 2007;132:458–60. [10] Angermann CE, Gelbrich G, Störk S, et al. Rationale and design of a randomised, controlled, multicenter trial investigating the effects of selective serotonin reuptake inhibition on morbidity, mortality and mood in depressed heart failure patients (MOOD-HF). Eur J Heart Fail 2007;9:1212–22. [11] Pullicino P, Thompson JL, Barton B, Levin B, Graham S, Freudenberger RS. Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail Feb. 2006;12:39–46. [12] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.061
Granulocyte colony-stimulating factor in patients with ST segment elevation myocardial infarction: A disappointment-stimulating factor? Turgay Celik a,⁎, Atila Iyisoy a, Ejder Kardesoglu b, Murat Celik a a b
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, 06018 Etlik-Ankara, Turkey Gulhane Military Medical Academy, Haydarpasa Training Hospital, Department of Cardiology, Turkey
a r t i c l e
i n f o
Article history: Received 22 June 2009 Accepted 26 June 2009 Available online 3 August 2009 Keywords: G-CSF ST segment elevation myocardial infarction Stem cell mobilization
⁎ Corresponding author. Tel.: +90 312 3044268; fax: +90 312 3044250. E-mail address: [email protected] (T. Celik).
In their recently published very well-designed article, Engelmann et al. investigated the effect of granulocyte colony-stimulating factor (G-CSF) on left-ventricular ejection fraction (LVEF) and event-free survival in patients suffering from sub-acute ST segment elevation myocardial infarction (STEMI) [1]. In that study, 44 patients suffering from sub-acute STEMI with late revascularization achieved by percutaneous coronary intervention (PCI) were randomized to receive either G-CSF (Filgrastim) at a dose of 10 µg/kg body weight/day subcutaneously or placebo. Changes of global and regional cardiac function from baseline over 1 and 3 months to 12 months of follow-up were analyzed by magnetic resonance imaging. The authors found that G-CSF administration after sub-acute STEMI is feasible and safe but does not improve myocardial function or survival when used as a single substance. The feature of G-CSF to mobilize stem cells from bone marrow (CD34+ mononuclear blood stem cells) and increase their circulating levels has
Letters to the Editor
been used for stem cell mobilization in patients with STEMI and for harvesting stem cells for intracoronary delivery. Research with G-CSF has demonstrated conflicting results. In the MAGIC trial the potential value of G-CSF in comparison to or in combination with stem cell infusion was assessed [2]. Twenty-seven patients with an acute myocardial infarction MI undergoing PCI were randomly assigned to stem cell mobilization with G-CSF followed by stem cell apheresis and intracoronary reinfusion, to GCSF alone, or to a control group. Six-month follow-up data in 10 of the study patients demonstrated an improvement in LVEF with stem cell infusion (from 48.7% to 55.1%) but not with G-CSF alone. Stem cell infusion also increased treadmill exercise time and reduced the size of the myocardial perfusion defect. However, administration of G-CSF was associated with an unexpectedly high rate of in-stent restenosis of the culprit lesion. Although this finding needs to be confirmed, it would suggest that cells capable of differentiation into smooth muscle cells are mobilized in response to G-CSF [3]. This finding is in contrast to animal studies that suggest that endothelial progenitor cell mobilization with GCSF leads to rapid reendothelialization and decreased neointimal formation at sites of arterial injury [4]. The lack of benefit and possible adverse outcomes with G-CSF alone in the MAGIC trial [2] are consistent with other studies of G-CSF or GM-CSF alone that showed no long-term efficacy [5–7] and a possible increase in the risk of coronary ischemia and acute coronary syndrome [7,8]. In contrast to MAGIC trial, the The Front-Integrated Revascularization and Stem Cell Liberation in Evolving Acute Myocardial Infarction by Use of Granulocyte Colony-Stimulating Factor (FIRSTLINE AMI) AMI found a significantly higher LVEF at rest at 4 months with G-CSF therapy (54% versus 43%) and other benefits, including a greater increase in viable myocardium in the infarct territory (11% versus 0%) [9]. But, this trial was unblinded and was a small study. The largest experience comes from the Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells-2 (REVIVAL-2) trial in which 114 patients with STEMI involving at least 5% of the left ventricle underwent successful reperfusion by primary PCI and 5 days later were randomly assigned to G-CSF (10 µg/kg) or placebo daily for 5 days [5]. Despite a marked increase in circulating stem cells, there was no difference between the groups in the primary end point—a reduction in infarct size at 4 to 6 months, as assessed by myocardial perfusion imaging (6.2% versus 4.9% with placebo)—or in the secondary end points of improvement in LVEF (+0.5% versus +2.0%) and angiographic restenosis (35% versus 31%). A similar lack of benefit was noted in the Stem cell mobilization induced by subcutaneous granulocyte colony-stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction (STEMMI) trial in which 78 patients with STEMI undergoing successful primary PCI were randomly assigned to G-CSF (10 µg/kg) or placebo daily for 6 days [6]. At 6 months, there was no difference between the two groups in the primary end point of change in systolic wall thickening on cardiac magnetic resonance imaging (17% improvement), LVEF, or target vessel revascularization. The limited clinical data available do not permit a full assessment of the potential risks of cellular cardiomyoplasty as a therapeutic modality. Two concerns are ventricular tachyarrhythmia and a possible increase in
0167-5273/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.06.053
139
in-stent restenosis. Episodes of ventricular tachycardia occur in many patients after myoblast injection [10,11]. As a result, an implantable cardioverter-defibrillator is now routinely required for myoblast studies. The pathogenesis of these arrhythmias is not well understood. There are conflicting data as to whether stem cell therapy is [2] or is not [9] associated with an increase in in-stent restenosis and whether there is [7,8] or is not [9] an increase in the risk of coronary ischemia and acute coronary syndrome [7,8]. In conclusion, cellular cardiomyoplasty is an investigational technique that may have the potential to reduce myocardial infarct size and improve cardiac function in patients with ischemic heart disease. However, experience with this approach is still limited to a few small trials, some which were not blinded or had other design problems. Although there is no sufficient evidence to believe that G-CSF may be a useful treatment in patients with STEMI who undergo primary PCI, further large-scale clinical studies are needed to examine the exact role of G-CSF in the management of those patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [12].
References [1] Engelmann MG, Theiss HD, Theiss C, et al. G-CSF in patients suffering from late revascularised ST elevation myocardial infarction: final 1-year-results of the G-CSF-STEMI Trial. Int J Cardiol 2010;144:399–404. [2] Kang HJ, Kim HS, Zhang SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004;363:751–6. [3] Tanaka K, Sata M, Hirata Y, et al. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res 2003;93:783–90. [4] Cho HJ, Kim HS, Lee MM, et al. Mobilized endothelial progenitor cells by granulocyte– macrophage colony-stimulating factor accelerate reendothelialization and reduce vascular inflammation after intravascular radiation. Circulation 2003;108:2918–25. [5] Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colonystimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006;295:1003–10. [6] Ripa RS, Jorgensen E, Wang Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 2006;113:1983–92. [7] Hill JM, Syed MA, Arai AE, et al. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol 2005;46:1643–8. [8] Zbinden S, Zbinden R, Meier P, Windecker S, Seiler C. Safety and efficacy of subcutaneous-only granulocyte–macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol 2005;46:1636–42. [9] Ince H, Petzsch M, Kleine HD, et al. Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI). Circulation 2005;112(9 Suppl):I73–80. [10] Dib N, Michler RE, Pagani FD, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation 2005;112:1748–55. [11] Makkar RR, Lill M, Chen PS. Stem cell therapy for myocardial repair: is it arrhythmogenic? J Am Coll Cardiol 2003;42:2070–2. [12] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.