G-CSF in acute myocardial infarction--experimental and clinical findings/Akut miyokard infarktusunde G-CSF--Deneysel ve klinik bulgular.

ABSTRACT

Early data from clinical studies suggest that intracoronary injection of autologous progenitor cells may beneficially affect postinfarction remodeling and perfusion. Beyond intracoronary infusion of autologous bone marrow mononuclear CD34+ cells (MNCCD34+), mobilization of stem cells by G-CSF has recently attracted attention because of various advantages such as the noninvasive nature of MNCCD34+ mobilization by subcutaneous injections. It is the aim of the present work to give an overview about the current experimental and clinical findings of G-CSF treatment in acute myocardial infarction. (Anadolu Kardiyol Derg 2006, 6: 261-3)

Keywords: G-CSF, myocardial infarction, stem cells OZET

Onceki calismalarda otolog progenitor hucrelerin intrakoroner enjeksiyonun infarktus sonrasi yeniden yapilandirmayi (remodeling) ve perfuzyonu yararli yonde etkilediklerini belirtilmistir. Kemik iliginin otolog mononukleer CD34+ hucrelerin (MNCCD34+) intrakoroner infuzyonun otesinde, kok hucrelerin G-CSF araciligi ile mobilizasyonu son zamanlarda noninvazif subkutan enjeksiyonlu MNCCD34+ mobilizasyonu gibi farkli avantajlar nedeni ile dikkati uzerine gekmistir. Bu galismanor amaci akut infarktusunde G-CSF tedavisinin guncel deneysel ve klinik bulgulari gozden gegirmektir. (Anadolu Kardiyol Derg 2006- 6: 261-3)

Anahtar kelimeler: G-CSF, miyokard infarktusu, kdk hucreler

Currently, no medication or procedure used clinically, except for cardiac transplantation, has shown efficacy in replacing myocardial scar with functioning contractile tissue. Given the major morbidity and mortality associated with myocardial infarction and subsequent heart failure, recently new generative approaches have been introduced to address the issue of cardiac repair, especially since the dogma of the heart as a post-mitotic organ had recently been challenged by the observation that subpopulation of cardiomyocytes may re-enter the cell cycle and undergo nuclear mitotic division in the infarcted human heart (15). Repair of infarcted myocardium has been demonstrated in experimental models of acute myocardial infarction (AMI), with both improved myocardial function and survival, following local administration of bone marrow-derived stem cells (BMSC) (5-8). Recent studies however, failed to find evidence of transdifferentiation of BMSC into cardiomyocyte (9), although intracoronary injection of autologous progenitor cells may beneficially affect postinfarction remodeling and perfusion (10-13).

Beyond intracoronary infusion of autologous bone marrow mononuclear CD34+ cells (MNCCD34+), mobilization of stem cells by granulocyte colony-simulating factor (G-CSF) has recently attracted attention because of advantages such as the noninvasive nature of MNCCD34+ mobilization by subcutaneous injections; moreover, bone marrow aspiration and preparation is not required (potentially difficult in acute patients), and repeat catheterization with intracoronary infusion is avoided. Finally, exposure of post-ischemic injured myocardium to mobilized MNCCD34+ and leukocytes is sustained over the susceptible first week at concentrations markedly exceeding natural cell mobilization, as recently shown in the setting of human studies on myocardial infarction (14).

It is the aim of the present work to summarize the current experimental and clinical findings of G-CSF treatment in acute myocardial infarction.

Experimental findings

In a myocardial infarction model of mice cytokine-induced cardiac repair decreased mortality by 68%, infarct size by 40%, cavity remodeling by 26%, and diastolic stress by 70%, respectively; left ventricular ejection fraction (LVEF) and hemodynamics improved significantly as a consequence of 15 x 106 new myocytes connected with arterioles and capillaries to the circulation of unaffected myocardium (7). Similarly, human MNCCD34+ mobilized by G-CSF led to stem cell population exclusively in injured myocardium two days after intravenous injection in rat, at 15 weeks new blood vessel formation in the infarct bed and proliferation of preexisting vasculature were observed (7). Moreover, apoptotic cells and infarct size were reduced from 36 to 12 percent with corresponding enhancement of cardiac output. Although both studies suggested beneficial impact of G-CSF to prevent remodeling cytokine treatment was either started before infarction (6) or given in a non-reperfusion setting; both studies are unlikely to reflect the reperfusion scenario in humans. However, recent experimental findings in an occlusion-reperfusion experiment (20) with G-CSF after infarction in rabbits increased LVEF and decreased remodeling at long-term. Minatoguchi et al. (15) could demonstrate in this experimental reperfusion setting that beneficial effect may be derived from G-CSF induced mobilization of leukocytes that are known to play an important role for myocardial repair by regulating phagocytosis of necrotic tissue, fibroblast proliferation and angiogenesis. Moreover, there is evidence of a G-CSF dependent protection of cultured cardiomyocytes from apoptotic cell death through upregulation of Bcl 2 and Bcl xL expression via the G-CSF receptor and the Jak Stat pathway. In vivo experiments have shown the G-CSF led to upregulation of G-CSF receptor and activation of the Stat 3 pathway, thereby preventing both cardiomyocytes apoptosis and remodeling after myocardial infarction (16). Similar results could be demonstrated with G-CSF in experimental stroke models (17, 18).

Recent preliminary data from the MAGIC-trial indicated that G-CSF treatment in patients with acute myocardial infarction could aggravate in-stent restenosis rate (19). Moreover, there is no animal model in which coronary arteries have multiple unstable coronary plaques like in patients with acute myocardial infarction. Theoretically, these plaques might be destabilized by an increased number of circulating leukocytes after G-CSF administration. An elevated white cell count has been suspected to predict an adverse prognosis in acute myocardial infarction (20).

Conversely, there is growing evidence that G-CSF pretreatment as a strategy to stimulate the mobilization of MNCCD34+ accelerates the rate of reendothelialization and inhibits neointi mal thickening in balloon-injured carotid arteries in an experimental setting (21). Similarly G-CSF has been shown to enhance endothelialization of small-caliber prosthetic grafts (22, 23). Moreover, in a model of apolipoprotein E deficient mice G-CSF was shown to even reduce atherosclerotic deposits and coronary lesions by lowering LDL cholesterol, and decreasing plaque burden (24).

Clinical findings

Early data from clinical studies suggest that intracoronary injection of autologous progenitor cells may beneficially affect postinfarction remodeling and perfusion (10-13). In contrast to intracoronary infusion of autologous bone marrow mononuclear CD34+ cells (MNCCD34+) mobilization by G-CSF differs in various ways: first, MNCCD34+ mobilization is noninvasive and requires only subcutaneous injections; second, bone marrow aspiration and preparation is not required (potentially difficult in acute patients);third, repeat catheterization with intracoronary infusion is avoided; fourth, exposure to both G-CSF and to mobilized MNCCD34+ begins early after reperfusion in the susceptible phase (25,26); and fifth, exposure of post-ischemic injured myocardium to mobilized MNCCD34+ is sustained over 1 week at concentrations markedly exceeding natural cell mobilization in acute infarction. Whereas intracoronary delivery was enacted as early as 5-9 days (11) or 4.3 [+ or -] 1.5 days after onset of necrosis (10), G-CSF induced liberation of MNCCD34+was initiated within 89 minutes after percutaneous coronary intervention (PCI) in the FIRSTLINE-AMI study trial (15). Yet, Strauer et al delivered only 5.9 x [10.sup.5] CD34+ cells (9, 10), while Schachinger et al infused 7.35 [+ or -] 7.31 x [10.sup.6] CD34/CD45+ cells per patient (11). Assuming an average blood flow of 0.8ml/min/g, 100 grams of injured myocardium were exposed to approximately 2.8 x [10.sup.10] MNCCD34+ with GCSF stimulation over 8 days in FIRSTLINE-AMI (27).

An increase of circulating MNCCD34+ after AMI is a well documented phenomenon (25,26) potentially influencing left ventricular function in the post-infarction setting (28) and in congestive heart failure (29). Moreover, there is recent evidence for significant correlation between spontaneous mobilization of MNCCD34+ and endogenous G-CSF in patients with AMI (30). Furthermore, G-CSF is synthesized and released from the heart in the early phase of acute myocardial infarction (31).

Safety and feasibility of G-CSF in acute myocardial infarction has been established by our group (27) and findings are in line with those of Jorgensen et al. (32), Valgimigli et al. (33), Kuethe et al. (34) and Suarez de Lezo et al. (35). Considering those encouraging findings, the application of G-CSF could be a non-invasive option to ameliorate post-infarction remodeling; major concerns, however, have been raised about the safety of G-CSF-treatment in acute myocardial infarction due to the unexpected high in-stent restenosis rate in MAGIC (19). The controversial impact of G CSF with (n = 7) or without additional cell infusion (n = 3) on in-stent restenosis, however, was deduced from only 10 patients with angiographic follow-up and should be interpreted with caution in the light of recent human studies with no increased risk of in-stent restenosis after G-CSF treatment (27,32-35). The findings of Kang et al could be related to the fact that G-CSF was given for 4 consecutive days prior to PCI. One may speculate that at the time of stent implantation the number of circulating cells of the haematopoietic cell lineage was high, which may in turn be directly related to the degree of neointima formation (36).

Treatment by G-CSF after reperfusion of infarcted myocardium could offer a pragmatic concept of potential myocardial regeneration, which warrants further investigation of developmental potential of stem cells, longer follow-up surveillance and the scrutiny of multicenter, placebo-controlled trials.

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Huseyin Ince, Michael Petzsch, Tim C. Rehders, Simone Dunkelmann *, Christoph A. Nienaber

From the Department of Medicine, Divisions of Cardiology and * Nuclear Medicine at the University Hospital Rostock, Rostock School of Medicine, Rostock, Germany

Address for Correspondence: Huseyin Ince, MD, Division of Cardiology University Hospital Rostock Rostock School of Medicine Ernst-Heydemann-Str. 6 18057 Rostock, Germany Tel.: [phone] Fax: [phone] E-mail: [e-mail]