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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

G-CSF in the setting of acute myocardial infarction

Hüseyin Ince*, Tim C. Rehders, Stephan Kische, Stephan Drawert, Esther Adolf, Tilo Kleinfeldt, Michael Petzsch and Christoph A. Nienaber

Department of Medicine, Division of Cardiology, University Hospital Rostock, Rostock School of Medicine, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany

* Corresponding author. Tel: +49 381 494 7701; fax: +49 381 494 7702.E-mail address: hueseyin.ince{at}med.uni-rostock.de


   Abstract
Top
 Abstract
Introduction
 Cardioprotective effects of G...
 Clinical results
 Safety issues
 References
 
Experimental data suggest that stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) may have potential as a novel regenerative strategy in the setting of acute myocardial infarction (AMI). Potentially beneficial effects of G-CSF may be attributed mainly to direct action of the cytokine G-CSF on injured myocardium by inhibition of apoptosis, rather than to differentiation of mobilized bone marrow stem cells into cardiac myocytes. This article reviews potential cardioprotective effects of G-CSF and discusses experimental and clinical findings with G-CSF in the setting of AMI.

Key Words: G-CSF • Acute myocardial infarction • Cytokines • Stem cells


   Introduction
Top
 Abstract
 Introduction
Cardioprotective effects of G...
 Clinical results
 Safety issues
 References
 
Important advances in the management of patients with acute myocardial infarction (AMI) have led to improved survival. As outcome after AMI depends on the extent of damaged myocardium, the concept of myocardial salvage in evolving necrosis by coronary thrombolysis or by percutaneous transluminal coronary revascularization (PCI) is of paramount and primary importance. Although modern therapeutic strategies have reduced early AMI mortality, they conversely have led to an increase in the number of patients suffering from chronic heart failure.1,2

Recently, increasing interest in myocardial regeneration has grown with focus on gene- and cell-based experimental therapies. Moreover, several haematopoietic cytokines including interleukin-3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor, stem cell factor (SCF), and erythropoietin have been shown to regulate both growth and differentiation of haematopoietic progenitor cells. As a side effect, such cytokines have potential to mobilize bone marrow stem cells (BMSCs).3 Although BMSCs may eventually differentiate into cardiac myocytes, endothelial cells (ECs), and vascular smooth muscle cells, at least in a mouse model of AMI,4 cytokine-mediated recruitment of BMSCs has also been reported to improve cardiac dysfunction and reduce mortality after AMI in mice.5 According to experimental findings, G-CSF prevents left ventricular (LV) remodelling and dysfunction after AMI in various animal models6–12; the mechanism of beneficial effects of G-CSF, however, is likely to be the result of its direct action on injured myocardium, rather than related to differentiation of BMSCs into cardiac myocytes. This article reviews potential cardioprotective effects of G-CSF and discusses experimental and clinical findings with G-CSF in the setting of AMI.


   Cardioprotective effects of G-CSF
Top
 Abstract
 Introduction
 Cardioprotective effects of G...
Clinical results
 Safety issues
 References
 
Orlic et al.5 have reported that the combined application of G-CSF and SCF has the potential to improve cardiac function and reduce mortality after AMI in mice. In this model, however, cytokine treatment was started prior to experimental infarction, which, of course, is far from a clinically relevant setting with post-MI administration of G-CSF. In a recent experimental setting, mice with acute AMI were produced by ligation of left coronary artery and divided into the following four groups: (i) administration of a vehicle only (control group), (ii) administration of G-CSF (100 µg/kg/day) and SCF (200 µg/kg/day) from 5 days before AMI through 3 days after (pre-GS group), (iii) administration of G-CSF (100 µg/kg/day) and SCF (200 µg/kg/day) for 5 days after MI (post-GS group), and (iv) administration of G-CSF (100 µg/kg/day) alone for 5 days after MI (post-G group). In post-GS and post-G groups, first injection of vehicle, G-CSF, or SCF was subcutaneously given at 2 h after MI. All three groups that received G-CSF showed less LV remodelling and improved cardiac function and survival rate after AMI,6 and the number of apoptotic cells was decreased in the infarct border zone of all groups subjected to G-CSF application. Even with G-CSF given early after AMI, LV remodelling and dysfunction were at least, in part, prevented through an increase in neovascularization and a decrease in apoptosis in the border zone.

The same group examined the effect of G-CSF on prevention of post-infarction remodelling in large animals,9 such as swine in which AMI produced by ligation of left anterior descending coronary artery. G-CSF (10 µg/kg/day) was injected subcutaneously from 24 h after coronary ligation for the duration of 7 days. Echocardiographic examination revealed that G-CSF improved cardiac function and reduced LV remodelling, as measured at 4 weeks after MI.9 In the post-ischaemic region, the number of apoptotic ECs was lower with more extensive capillarization in the G-CSF group than that in the control group. Moreover, vascular endothelial growth factor (VEGF) was more abundantly expressed and the protein Akt more strongly activated in the ischaemic region exposed to G-CSF treatment. As Akt has been reported to play an important role in cell survival and angiogenesis, this protein seems to be responsible for the cardioprotective action of G-CSF.9

Furthermore, and in a similar way, direct myocardial effects of G-CSF after ischaemia–reperfusion injury were also demonstrated in a Langendorff-perfused heart model.10 Isolated rat hearts underwent 30 min of ischaemia followed by 120 min reperfusion using a perfusate containing G-CSF (300 ng/mL) or just a vehicle. Only G-CSF reduced the infarct size significantly measured by triphenyltetrazolium chloride staining.10 LV-developed pressure was significantly higher after G-CSF at 120 min of reperfusion than that without G-CSF.10 Western blot analysis has demonstrated that G-CSF significantly increased phosphorylation of Akt, Jak2, STAT3, and extracellular signal-regulated kinase in those hearts subjected to ischaemia followed by 7 min of reperfusion, and conversely that infarct reduction afforded by G-CSF administration was abolished in the presence of Akt inhibitor LY294002 or Jak2 inhibitor AG490, but not with MEK inhibitor PD98059.13

Similarly, Minatoguchi et al.7 demonstrated in a rabbit model that G-CSF prevented cardiac remodelling and dysfunction at 3 months after ischaemia and reperfusion; G-CSF increased both, the number of macrophages in the infarcted area at 2 days after MI and the expression of MMP-1 and MMP-9 in the ischaemic region at 7 days after MI, suggesting that G-CSF had beneficial effects on infarcted tissue through acceleration of healing processes and myocardial regeneration. In contrast, however, some reports failed to recognize any beneficial effects of G-CSF or stem cells in the setting of acute experimental infarction.14,15 This discrepancy in results of baboons and mice is not yet fully understood.


   Clinical results
Top
 Abstract
 Introduction
 Cardioprotective effects of G...
 Clinical results
Safety issues
 References
 
Recent clinical studies have failed to generate clear evidence of transdifferentiation of BMSC into cardiomyocyte,16 although intracoronary injection of autologous progenitor cells was claimed to ameliorate post-infarction remodelling and perfusion.17–20 Similarly, mobilization of autologous bone marrow mononuclear CD34+ cells (MNCCD34+) by G-CSF has recently attracted attention because of the atraumatic nature by subcutaneous injections with no need for bone marrow aspiration, manipulation of stem cells in culture, or any repeat invasive procedures.21

Moreover, an increase of circulating MNCCD34+ after AMI is a well-documented phenomenon,22,23 potentially influencing LV function in the post-infarction setting24 and in congestive heart failure.25 Moreover, there is recent evidence for a significant correlation between spontaneous mobilization of MNCCD34+ and endogenous G-CSF in patients with AMI.26 Furthermore, G-CSF is synthesized and released from the heart in the early phase of AMI, probably as an archaic natural defence mechanism.27

On aggregate, the therapeutic use of a potential physiological concept may even enhance exposure of post-ischaemic injured myocardium to higher concentration of circulating primitive cells during the first week after myocardial necrosis.

In the FIRSTLINE-AMI study, for instance, both safety and functional impact of G-CSF in the setting of human myocardial infarction in conjunction with primary percutaneous coronary intervention (PCI) and abciximab were tested in a randomized protocol with serial assessment of LV function after 1 and 4 months and coronary morphology at 6 months.28 FIRSTLINE-AMI was set up to recruit 50 consecutive patients with acute ST-elevation myocardial infarction (STEMI) subjected to primary PCI with stenting and abciximab administration according to recent guidelines; after successful reperfusion, patients were randomized (closed-envelope method) in 1:1 allocation (with 25 subjects per group) to 10 µg/kg G-CSF over a period of 6 days in addition to standard care or to standard post-interventional care alone.

Demographics, clinical characteristics, and comorbidity profiles were homogeneous and revealed a typical distribution of risk factors and evidence-based medication. Angiographic and infarction-related characteristics showed a balanced distribution, including enzyme release and baseline myocardial function. Moreover, time from the onset of symptoms to PCI with stent placement was similar, at 299±101 min in the G-CSF group and 304±111 min in the control subjects (P=0.86). No complications were associated with acute PCI, and all occluded infarct-related arteries were recanalized and stented with adjunctive abciximab infusion and subsequent clopidogrel loading; TIMI III flow was documented in all patients after PCI. Most importantly, subcutaneous G-CSF injection began 89±35 min after reperfusion.

At baseline, all parameters of LV function were similar in both the G-CSF-treated and the control groups. Interestingly, with G-CSF, LV end-diastolic diameter (LVEDD) showed no enlargement over a period of 4 months, whereas LVEDD increased to 58±4 mm in control subjects and was worse than with G-CSF (P=0.002). Moreover, with G-CSF, mean wall thickness in the infarct territory revealed enhancement by 0.7 mm at day 35 (P<0.01), a finding sustained after 4 months (P<0.01). Recovery of LV ejection fraction (EF) with G-CSF was documented at 35 days and over 4 months (P<0.01) and eventually measured 54±8% (P<0.001 vs. control), whereas no longitudinal improvement was present in control subjects.

Similar to LVEF, resting wall motion score index revealed partial recovery with G-CSF, from 1.71±0.22 at baseline to 1.41±0.25 after 4 months (P<0.001), but no change in control subjects.28

In a recent study by Valgimigli et al.,29 20 patients with STEMI (mean age 61±10 years), of whom 14 were subjected to primary PCI, were randomized to G-CSF (5 mg/kg/day subcutaneously for 4 consecutive days) or placebo. In this series, G-CSF was given 37±66 h after symptoms onset. At entry and then at months 3 and 6, 99mTc-Sestamibi gated-single-photon emission computed tomography (SPECT) was performed to estimate the extension of perfusion defect (PD) and LV function. G-CSF was well tolerated and induced a significant increase in CD34 cells co-expressing AC133 and VEGFR-2. At follow-up, both the G-CSF and placebo groups did not differ in angiographic coronary late loss and showed a similar pattern of PD recovery, whereas in the former, at 6 months, LVEF tended to be relatively higher (P=0.068), whereas LVEDV was lower (P=0.05).29

Moreover, in a recent prospective, non-randomized, open-label study by Kuethe et al.,30 14 patients were enrolled in the G-CSF group. Forty-eight hours after successful recanalization and stent implantation, the patients of the treatment group received 10 µg/kg body weight per day G-CSF subcutaneously for 7 days. Nine patients fulfilled the entry criteria; however, refused participation and served as control group. In both groups, regional wall motion and perfusion were evaluated with ECG-gated Sestamibi-SPECT imaging and EF before discharge and after 3 months. No severe side effects of G-CSF treatment were observed, whereas significant improvement of the regional wall motion and perfusion was seen with G-CSF. Moreover, EF in the treatment group increased from 0.40±0.11 to 0.48±0.13 (P<0.01), whereas in the control group, EF changed only from 0.40±0.13 to 0.43±0.13 (P=0.049). A control angiography of the treatment group after 12.4±6.6 months showed one in-stent restenosis in one patient.30

In a similar study by Suarez de Lezo et al.,31 13 patients (53±8 years) with anterior wall AMI were initially treated with intravenous thrombolytics. The first cardiac catheterization was performed between days 0 and 5 after AMI, when the left anterior descending artery was stented. A 10-day course of 10 µg/kg/day G-CSF was started 5 days after AMI. At 3-month follow-up, the gain in EF varied among patients from –22 to +18% (mean difference, 6.2±12%) and correlated directly with the total number of circulating CD34+CD38 cells/µL on the fifth day of G-CSF treatment (r=0.78; P<.003). Furthermore, no restenosis was observed in the patients after 3 months. All patients did well initially, but one had spontaneous spleen rupture on day 8 of G-CSF administration, which required emergency splenectomy.31

Nakayama et al.32 presented results in 35 patients with AMI randomized to G-CSF (2.5 µg/kg/day s.c. for 5 days, n=16) or control group (saline, n=19). G-CSF treatment was started within 24 h after PCI. 99mTc-tetrofosmin imaging using SPECT was performed at 4 days and 6 months after AMI. At follow-up, defect scores in the G-CSF group were significantly decreased (P=0,005), compared with controls. LVEF was significantly increased in the G-CSF group (P=0.0005), but not changed in the control group. Although no significant difference was observed for the EDV between the two groups, end-systolic volume tended to be decreased only in the G-CSF group (P=0,135). Moreover, the restenosis rate at 6 months after AMI was not different between the two groups.32 Results of all the published G-CSF studies are summarized in Table 1.


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  		Table 1 Studies in humans with G-CSF after acute myocardial infarction

 

   Safety issues
Top
 Abstract
 Introduction
 Cardioprotective effects of G...
 Clinical results
 Safety issues
References
 
Concerns were raised about safety of G-CSF treatment, considering an unexpectedly high restenosis rate after PCI in AMI.33 The controversial impact of G-CSF alone (n=3) or with adjunct stem cell infusion (n=7) on progression of coronary disease was deduced, however, from only 10 patients with angiographic follow-up in MAGIC,33 a finding that failed to reproduce in a individual patient–data meta-analysis on 106 patients28–31 with no evidence of an increased risk of in-stent restenosis after G-CSF treatment (H. Ince et al., unpublished results). A potential explanation for the observation in MAGIC may relate to G-CSF given over 4 successive days before reperfusion was established; in such unrealistic scenario, circulating cells of the haematopoietic cell lineage may, in fact, stimulate the inflammatory reaction of a given vulnerable lesion and accelerate proliferatory processes prior to reperfusion and stent implantation.34,35

Conversely, there is growing experimental evidence that G-CSF pre-treatment may enhance re-endothelialization with less neointimal thickening via mobilization of MNC.(CD34+)36,37

On aggregate, G-CSF after reperfusion of infarcted myocardium seems to be safe, feasible, and promising and is not associated with aggravated post-PCI restenosis rate. Potential beneficial effects of G-CSF after AMI, however, have been recently challenged by REVIVAL-2, a randomized, double-blind, placebo-controlled trial in post-MI patients.38 Patients diagnosed with STEMI and successful reperfusion by PCI within 12 h after onset of infarction were randomly assigned to receive subcutaneously either a daily dose of 10 µg/kg of G-CSF or placebo for 5 days. The primary endpoint was reduction of LV infarct size according to technetium Tc-99m Sestamibi scintigraphy between baseline assessment and 4–6 months after randomization. Secondary endpoints included improvement of LVEF measured by magnetic resonance imaging and the incidence of angiographic restenosis. Of the 114 patients, 56 were assigned to receive treatment with G-CSF and 58 to receive placebo. G-CSF produced significant mobilization of stem cells in REVIVAL-2, a finding in line with FIRSTLINE-AMI. Between baseline and follow-up, LV infarct size was reduced by 6.2±9.1% in the G-CSF group and 4.9±8.9% in the placebo group (P=0.56) and LVEF was improved by 0.5±3.8% in the G-CSF group and 2.0±4.9% in the placebo group (P=0.14). Angiographic restenosis occurred in 19 (35.2%) of 54 patients in the G-CSF group and in 17 (30.9%) of 55 patients in the placebo group (P=0.79).38

The authors concluded that stem cell mobilization by G-CSF therapy in patients with AMI and successful mechanical reperfusion has no influence on infarct size, LV function, or coronary restenosis.38

With respect to coronary restenosis, the finding of REVIVAL-2 corroborates results of an individual patient–data meta-analysis on 106 patients, which fails to justify an elevated risk for coronary restenosis after PCI in the setting of AMI when used after state-of-the-art treatment in carefully conducted clinical protocols (H. Ince et al., unpublished results). The more intriguing conclusion, however, that stem cell mobilization by G-CSF therapy in patients with AMI and successful mechanical reperfusion has no influence on infarct size and LV function deserves commentary and must be tempered down, because important pathophysiological consideration in the use of G-CSF has not been met. Thus, the only conclusion justified from REVIVAL-2 is that late application of G-CSF (5 days after reperfusion) has no influence on infarct size and LV function even after successful PCI within 12 h of STEMI. In contrast to the late application in REVIVAL-2, subcutaneous G-CSF was given as early as 89±35 min after reperfusion in FIRSTLINE-AMI.22 This important aspect could explain conflicting differences between these two studies and the recent negative STEMMI trial39 (a randomized, double-blind, placebo-controlled trial), because there is growing experimental evidence of a time sensitive direct cardioprotective effect of G-CSF, rather than a cell-mediated effect. As recently shown, beneficial effects of G-CSF on cardiac function were significantly reduced by delayed start (after 3 days) of the treatment.10 Furthermore, patients in FIRSTLINE-AMI were 10 years younger and one may speculate that this could have had an influence on the different results, because of experimental evidence for an age-associated cardioprotective effect of G-CSF. Hare et al. could demonstrate in a mice-reperfusion model that G-CSF led to significant beneficial effects on cardiac function only in younger, but not in older animals (J. Hare, personal communication).

With the above-mentioned important differences in the design of these studies and the attractive inherent advantage of the non-invasive nature of G-CSF treatment, a logical consequence would be to conduct an adequately powered double-blinded, randomized multicentre endpoint study with, most importantly, no time delay between PCI and G-CSF application. Only after such a study, we will be able to draw firm prognostic conclusions about G-CSF after PCI for STEMI.

Conflict of interest: No author had any conflict of interest.


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 Introduction
 Cardioprotective effects of G...
 Clinical results
 Safety issues
 References
 

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