Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating factor after myocardial infarction
1 Institute of Cardiology, University of Ferrara and Cardiovascular Research Centre, Salvatore Maugeri Foundation, IRCCS, GS, Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara, Italy
2 Interventional Cardiology, Division of Cardiology, University of Turin, Turin, Italy
3 Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
4 VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA
* Corresponding author. Tel: +39 0532 202143; fax: +39 0532 241885. E-mail address: vlgmrc{at}unife.it
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Abstract |
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 Top Abstract IntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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Nine randomized controlled studies have so far evaluated the safety and efficacy profile Granulocyte-colony stimulating factor (G-CSF) in the setting of the acute/subacute phase of myocardial infarction (MI) in humans on a total of 409 patients. The drug, administered at various regimen, ranging from 2.5 to 10 mg/kg for a minimum of 4 to a maximum of 6 days, has been well tolerated. In one single prematurely stopped study (MAGIC), safety concerns were raised by an unexpected high restenosis rate in stented vessel. This was not confirmed in all subsequent studies. A clear improvement in the treated vs. control group at follow-up in left ventricular (LV) function/remodelling indexes has been reported in two studies (FIRST-LINE and RIGENERA). In a third investigation, LV ejection fraction improved in the treated but not in the control group with respect to baseline, but no significant difference emerged between G-CAF and placebo group at follow-up (Takano et al.). In all other six studies, no clear effect of treatment was noted. Future properly powered randomized controlled studies ideally targeting patients with large anterior MI with poor response to early reperfusion are warranted to further clarify the role of G-CSF in this setting.
Key Words: Granulocyte-colony stimulating factor • Myocardial infarction • Bone-marrow • CD34 antigen
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Introduction |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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There is increasing evidence that stem cell (SC) mobilization to the heart and their differentiation into myocytes and endothelial cells is a naturally occurring process.1,2 During acute myocardial infarction (MI), an increase of endothelial progenitor cells (EPC) and a selective homing of SC to the damaged heart have been described.3,4 Although the exact role of this potential self-repair mechanism is currently unknown, it has been hypothesized that manipulating its magnitude by cytokines administration soon after necrotic injury would prime and enhance left ventricular (LV) recovery thereafter. This hypothesis is currently being supported by studies showing that (i) ‘poor-mobilizer’ during acute MI undergo a more significant LV remodelling over time compared to patients who spontaneously show a greater mobilization of bone marrow (BM) SC soon after MI5,6 and (ii) patients with more advance heart failure have lower circulating levels of CD34+ cells and EPC.7
Contrasting evidence from animal studies has been so far provided regarding the efficacy of cytokine-based SC mobilization in the setting of acute MI. In mouse, cytokine-mediated BM cell recruitment was beneficial in terms of improving heart function and survival during MI.8 However, in a primate model of acute MI, the combined use of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) failed to improve myocardial function9 and in rats, the granulocyte-macrophage colony-stimulating factor (GM-CSF) induction by romurtide indeed facilitated infarct expansion and adverse LV remodelling.10 Therefore, the consequences of drug-induced EPC mobilization during MI are still unclear and possibly confounded by the effect of the pharmacological compound(s) employed for such an aim.11
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The magic study |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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The first clinical study to address the use of G-CSF in patients in the setting of MI was the MAGIC study, in which 30 patients were scheduled to undergo conventional medical treatment (control group), treatment with intracoronary G-CSF alone (G-CSF group), or use of G-CSF followed by intracoronary re-infusion of G-CSF-mobilized SC (cell group). No improvements in LV function or volumes were observed in the G-CSF group, whereas the study was prematurely stopped due to safety concerns in both treated groups in terms of an unexpected high restenosis rate in stented vessels.12 However, only three patients in the G-CSF group received angiographic follow-up, thus no clear conclusion about the incidence of restenosis should have reasonably be drawn from this study.12 The recently reported 2 year follow-up of the MAGIC study confirmed previous findings.13
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Early post-magic randomized controlled studies |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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In the attempt to redefine its clinical-angiographic safety profile in this setting, Valgimigli et al.14 investigated the effect of G-CSF when given in humans soon after necrotic injury to improve LV recovery after the first MI. Forty-seven patients, consecutively admitted for ST segment elevation MI, were screened for possible inclusion. Sixteen of them were not eligible according to exclusion criteria, while 11 refused to give informed consent. Therefore, 20 patients (16 men, 60 ± 11 years) were randomized to either G-CSF (Filgrastim®, Amgen) (5 µg/kg/day s.c.) or placebo on a single-blind basis for four consecutive days.
Cumulatively, time from symptoms onset to study drug administration was 37 ± 66 h (range: 3–265), which was reduced to 16 ± 19 (range 3–61) in those patients presenting within 12 h from symptoms. G-CSF induced a marked elevation of WBC, CD34+ cells (Figure 1), and EPC and overall the drug was well tolerated.
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P < 0.05 vs. placebo. From reference.No effect of study drug was recorded on erythrocytes and platelets count or on tested inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein, whereas a mild, transient increase of alkaline phosphatase, and gamma glutamyl transpeptidase, was noted in the treated group.14 One patient in the placebo and none in the active group presented binary restenosis. The late loss (mm), expressed as median (interquartile range), was 0.3 (0.1–0.65) and 0.35 (0.05–0.55) in the treated and placebo group, respectively (P = 0.2). No difference between treated and placebo group was observed in terms of infarct size, LV systolic or diastolic volumes, or ejection fraction at follow-up.
The FIRSTLINE-AMI study was set up to recruit 50 consecutive patients aged between 18 and 65 years who had had a first acute ST-segment elevation myocardial infarction (STEMI) with ST-elevation in at least three of 12 electrocardiogram leads.15,16 Patients underwent primary PCI, with stenting and abciximab. After successful reperfusion, randomization took place in a 1:1 allocation until 25 patients were assigned to each group. Patients either received 10 µg/kg body weight G-CSF subcutaneously daily for 6 days in addition to standard care or received standard post-interventional care alone. Demographics, clinical characteristics, and co-morbidity profiles were similar in the two groups, with a typical distribution of risk factors and evidence-based medication. The time from the onset of symptoms to PCI with stent placement was similar, with a mean of 299 min (SD 101 min) in the G-CSF-treated group and 304 min (SD 111 min) among controls (P = 0.86). G-CSF administration was started a mean of 89 min (SD 35 min) after reperfusion. At baseline, all parameters of LV function were similar in the G-CSF-treated and control groups. After G-CSF treatment, no enlargement in LV end-diastolic diameter was seen over a period of 4 months, whereas in controls the diameter increased to a mean of 58 mm (SD 4 mm), which was significantly larger than the mean measurement for G-CSF recipients [55 mm (SD 5 mm); P = 0.002]. Moreover, after G-CSF treatment, the mean wall thickness in the infarct territory had increased by 0.7 mm at day 35 (P < 0.01) and remained at this thickness at 4 months (P < 0.01). Significant recovery of left-ventricular ejection fraction in the G-CSF treated group was documented at 35 days and 4 months (both P < 0.01); at 4 months, the final mean measurement was 54% (SD 8%), whereas no longitudinal improvement was present for controls (P < 0.001).15,16 Similar to the LV ejection fraction, the resting wall-motion score index revealed a partial recovery after G-CSF treatment. Again, no association with aggravated restenosis after PCI was recorded at 6 months. Thus, initial studies14–16 helped reassure about safety concerns regarding in-stent late loss after treatment14–16 and suggested that G-CSF-based treatment soon after MI could be beneficial in terms of LV recovery.15,16
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A dose of reality after FIRSTLINE-AMI study |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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Three randomized placebo controlled trials did not confirm the promising results from the small uncontrolled clinical trials and the FIRSTLINE-AMI study despite comparable numbers of circulating SCs were available for regeneration of the necrotic myocardium with the G-CSF dose used.17–19 A total of 78 patients were treated with primary PCI and G-CSF in the STEM cells in Myocardial Infarction (STEMMI) trial.17 The results showed no additional effect of G-CSF BM SC mobilization on LV myocardial function or infarct size after primary PCI treatment of acute STEMI. The improvements in the STEMMI G-CSF group were comparable to the results of the G-CSF-treated patients in the previous non-blinded phase 1 studies and in the first two randomized studies. However, in all but FIRSTLINE-AMI study, a similar improvement in control group has also been reported, in keeping with the notion that myocardial stunning occurs early after ischaemic injury which will recover over time regardless of treatment. The double-blind, placebo-controlled REVIVAL-218 G-CSF trial was designed almost identical to the STEMMI trial, except that baseline studies were performed later and that G-CSF treatment was initiated later 5 days after the primary PCI. In the REVIVAL-2 study, there was no improvement in ejection fraction in the G-CSF group when compared with placebo group. The primary endpoint of the REVIVAL-2 trial was changed in infarct size from baseline to follow-up. This was, according to nuclear angiography, reduced identically in the G-CSF group and the placebo group. In agreement, the STEMMI trial did not demonstrate any effect of G-CSF treatment on change in infarct size. The effect of mobilization of SCs in patients with subacute STEMI and late revascularization between 6 h and 7 days after onset of angina were investigated in the double-blind, placebo-controlled G-CSF-STEMI trial.19 At 3 months follow-up, improvement in ejection fraction was identical in G-CSF and placebo group (Table 1).
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More recently, three additional randomized studies of G-CSF vs. placebo in the setting of acute MI were reported.20,21 While their results are again inconclusive due to small sample size or short-term follow-up after treatment, they failed to show clear benefit from G-CSF administration at the employed regimen.
Takano et al.20 included 40 patients with first MI due to occlusion of the left anterior descending coronary artery, who underwent successful percutaneous coronary intervention (PCI). They were randomized into G-CSF group (n = 18) given at 2.5 µg/kg body weight/day for 5 days or control group (n = 22). G-CSF treatment was started within 24 h after PCI. 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) was performed at 4 days and 6 months after MI. LVEF at 6 months was significantly better than that at 4 days in G-CSF group (P = 0.013), but not changed in control group (P = 0.245). Although no significant difference was observed for LVEDV between the two groups, LVESV tended to be decreased only in GCSF group. Infarct size evaluated through the defect score decreased similarly from 4 days to 6 months after MI in both study arms. Restenosis rate at 6 months after MI was not significantly different between the two groups.20
Ellis et al.21 reported 18 patients with large MI who were randomized in a 2:1 double-blind fashion to G-CSF (at 5 escalating to 10 µg/kg per day subcutaneously for 5 days) or matching placebo. Principal safety and efficacy endpoints were rupture-free survival and recovery of LV function, respectively. Mobilization into the systemic circulation of precursor CD34+ and CD117+ SCs at 30 days was also assessed. Precursor cell mobilization increased by a factor of 5 to 7 in the G-CSF-treated patients. There were no deaths or myocardial ruptures leading to tamponade through 30 days. Baseline and 30-day LV ejection fraction in the placebo, 5 µg, and 10 µg dose groups were 33.7% (1.6) and 41.7% (8.2), 36.8% (7.5) and 41.3% (10.3), and 33.5% (4.8) and 38.7% (7.3), respectively (P = NS for all between-group comparisons). No differences between the G-CSF and placebo groups were noted in any other measure of LV systolic or diastolic function 30 days after infarction.21
The RIGENERA study has analysed the effect of Lenograstim (r-hu G-CSF) at a dose of 10 mcg/Kg/day for 5 days starting at least 5 days after anterior AMI and/or a complete coronary stenting in 41 patients (in whom LVEF was <50% at transthoracic echo) randomized 1:2 to G-CSF therapy or to conventional therapy.22 In the treated group, LVEF improved at 6 month with both respect to baseline or control group.22 Similarly, no increase in LVEDV was noted in the G-CSF, whereas control patients showed progression towards adverse LV remodelling at follow-up.22 Eighty-six patients with anterior MI, treated with primary PCI, and LVEF less than 45% at echocardiogram treated with G-CSF for 4 days or placebo, are currently being evaluated at the University of Ottawa (NCT00394498 [ClinicalTrials.gov] ). The primary endpoint of the study is change in LVEF at 6 months. Recruitment finished in October 2006 and results for the primary endpoint are likely soon to be reported.
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Mechanisms of action |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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The interest in G-CSF lays in its current clinical use for SC mobilization prior to high-dose chemotherapy or transplant. At doses studied in experimental and clinical settings, G-CSF is capable of a significant and reproducible five- to seven-fold increase in WBC count, and CD34+ cell count. The number of circulating CD34+ cells has indeed been used as a surrogate endpoint for G-CSF activity, and a significant association between lower CD34+ cell count and poor prognosis after MI has been documented.5,6 Nevertheless, animal studies suggest that G-CSF may prevent adverse cardiac remodelling by mechanisms other than BM cell mobilization, by promoting neoangiogenesis and inhibiting apoptosis and inflammation (Figure 2).23 Apoptosis, or programmed cell death, in particular, characterizes the progression toward adverse cardiac remodelling and heart failure, therefore, the attempts to counteract cell loss by promoting myocardial regeneration.24
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Safety of granulocyte-colony stimulating factor in clinical studies |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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The only study raising safety concerns regarding the use of G-CSF in the setting of acute MI is the MAGIC trial, which was prematurely stopped for unexpected high restenosis rate in stented vessels.12 This was observed in both G-CSF alone and G-CSF followed by cell re-infusion arms, suggesting a potential link between the use of G-CSF itself and intimal hyperplasia after bare metal stent implantation. Based on this concern, the use of drug-eluting stents in patients submitted to treatment with G-CSF has, therefore, been suggested to overcome this putative safety issue. However, it should be noted that no stopping rule was pre-specified in the MAGIC study;12 thus, it is unclear whether a formal statistical analysis has been applied for stopping the study. This is a relevant point for interpreting available data as only three and seven patients in the G-CSF and cell infusion group received angiographic follow-up, respectively. Thus, no clear conclusion about the incidence of restenosis should have reasonably been drawn from this study. Importantly, no other study has subsequently reported an increased incidence of binary restenosis nor late lumen loss after treatment with G-CSF. Moreover, no similar finding was noted by a meta-analysis of individual data from 106 patients (H. Ince et al., personal communication). Thus, when taken together, currently available data from randomized controlled data fail to support the hypothesis that G-CSF in the setting of acute MI may increase the risk of in-stent restenosis after bare metal stent implantation. Similarly, the drug appeared to be well tolerated with a dose dependent but rapidly reversible increase in total white blood cell count which was not associated to any clinical event in the studies so far conducted. Of note, against common knowledge that G-CSF administration may be associated with a pro-thrombotic state due to platelet activation and modification of circulating coagulation factors, no excess of thrombotic events has been observed in acute MI patients, which may be partly related to antiplatelet and anticoagulant pharmacological compounds which are routinely administered in this setting. Finally, G-CSF was not shown to affect the inflammatory status of acute MI patients, based on C-reactive protein monitoring in several of the conducted randomized controlled trials.
While current data appear re-assuring in terms of overall safety of G-CSF administration, it should be kept in mind the possibility of a type II error due to limited sample size in all so far conducted randomized controlled trials cannot be dismissed. Thus, a cautionary note is currently warranted as it is still not possible to exclude the possibility that this pharmacological regimen in the setting of acute MI is associated with a higher incidence of relatively infrequent adverse events.
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Efficacy of granulocyte-colony stimulating factor in clinical trials |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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The results in terms of efficacy of G-CSF administration in the setting of acute MI are highly controversial. This pharmacological regimen was associated with a clear and statistical significant improvement in LV function over placebo in one single study.16 No clear signal of beneficial effect from treatment has emerged out of other randomized controlled studies.
The reasons why benefits observed in the animal studies failed to fully translate in clinical benefits are still unclear. The controlled experimental scenario may have served for optimization of the G-CSF efficacy, while, on the other hand, the lack of optimal heart failure therapy (i.e. angiotensin-converting enzyme inhibitors, beta-blockers, and aldosterone antagonist) in the animal control group may have increased the potential gain from G-CSF effects.
When interpreting current evidence in terms of efficacy of this pharmacological approach, the following considerations should be kept in mind:
Administration timing, schedule, and dose
The delay to start G-CSF administration after symptom onset has been highly variable among trials, ranging from 6.5 h in the FIRSTLINE-AMI to >1000 h in the MAGIC. Homing signals are upregulated immediately following injury and then downregulated over the following 7 days.25 Thus, it is possible that homing of G-CSF mobilized SCs from BM is impaired if treatment is started too late, which may justify a neutral effect of G-CSF on LV function in studies where this has been administered too late after symptom onset. Interestingly, a recent experimental study in animals has shown that early treatment with G-CSF after MI decreases ventricular dilatation, while delayed treatment has a deleterious effect on LV remodelling.26 If we plot the delay from symptom onset to treatment vs. delta of ejection fraction at 4–6 months in the G-CSF arm of all randomized controlled trials, a significant negative correlation comes out (r = –0.85; P < 0.01, Figure 3A). However, it should be noted that this is mainly driven by one single outlier, again the MAGIC study, in which a very late administration of treatment was associated to a negative delta of EF at follow-up. Accordingly, removing the MAGIC study as a sensitivity analysis leads to a flat and non-significant relationship between the two variables (Figure 3B). Doses used varied from 2.5 to 10 µ g/Kg/day with most studies using the higher dose. No clear relation, however, between dose and effects could be identified. Duration of treatment also varied, although minimally, ranging from 4 to 6 days with most studies treating for 5 days.
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Selection of the patients
In most studies, patients had not been selected based on the extension of myocardial injury. This is in keeping with the average ejection fraction early after index MI being in the range of 50% or even more in many studies. Many of the included patients in all these studies are known to have excellent prognosis with spontaneous LV function recovery due to recovery from stunning after revascularization. Clearly, these patients are not ideal candidates for testing new treatment. Thus, it remains possible that G-CSF administration in patients where poor LV function recovery is expected over time (i.e. those experiencing no reflow after mechanical intervention or those with suboptimal ST segment recovery after treatment) may be particularly beneficial. In keeping with this hypothesis, the RIGENERA study,22 which randomized patients with STEMI and documented LV dysfunction at least 5 days after reperfusion, was one of the few studies showing a significant 5% increase in mean LVEF (40–45%).
It is known that spontaneous BM SC mobilization during acute MI is occurring in many patients.3,5,6 Interestingly, this has been associated to a favourable remodelling pattern over time.5,6 Thus, it may be argued that trials on G-CSF in this setting should rather focus on those patients known to be ‘poor mobiliser’, where a specific effect of treatment may be expected.
Finally, the possibility of a type I error in interpreting current inconclusive data on G-CSF efficacy in patients with acute MI cannot be dismissed. Even when pooled together, the number of patients so far considered in randomized controlled trials is very limited, and the patient population extremely heterogeneous, with patients submitted to early revascularization mixed together to those managed conservatively or to patients submitted to mechanical intervention in a subacute phase.
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Conclusions |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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The effect of G-CSF administration in the setting of acute MI patients to enhance spontaneous SC mobilization from the BM to the circulation remains controversial after 10 placebo-controlled randomized controlled trials. While establishing the safety profile of the treatment, these studies also cast a shadow of doubt on its real efficacy profile in the setting of acute MI. While G-CSF administration in all comer MI patients properly treated with mechanical and pharmacological treatment may not result in clear improvement in parameters of LV function, it remains possible that targeting patients with poor prognosis (i.e. LV dysfunction, large amount of ischaemic myocardium, and/or suboptimal response to reperfusion treatment) may lead to clear advantage over placebo. Future properly powered randomized controlled studies are necessary to assess whether time to study drug administration and targeting treatment to specific subsets of MI patients may affect the effectiveness of mobilized BM precursors to restore LV function and minimize consequences of necrotic injury. New treatment protocols combining G-CSF with other pharmacologic interventions, such as erythropoietin which may also reduce infarct size and inhibit apoptosis, may also warrant investigation.
Conflict of interests: none declared.
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References |
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TopAbstractIntroductionThe magic studyEarly post-magic randomized...A dose of reality...Mechanisms of actionSafety of granulocyte-colony...Efficacy of granulocyte-colony...ConclusionsReferences |
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  A. M. Leone, M. Valgimigli, M. B. Giannico, V. Zaccone, M. Perfetti, D. D'Amario, A. G. Rebuzzi, and F. Crea From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells Eur. Heart J., April 2, 2009; 30(8): 890 - 899. [Abstract] [Full Text] [PDF]
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