Clinical view on experimental stem cell and cytokine research in cardiac disease
Department of Medicine, Division of Cardiology at the University Hospital Rostock, Rostock School of Medicine, Ernst-Heydemann-Str. 6, 18057 Rostock, Germany
* Corresponding author. Tel: +49 381 494 77 03; fax: +49 381 494 77 02, E-mail address: hueseyin.ince{at}med.uni-rostock.de
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Abstract |
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 Top Abstract Stem cells in non-ischaemic...Cytokines and acute myocardial...Skeletal myoblasts and heart...ConclusionReferences |
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Recent translational research in the emerging field of cardiac cell therapy has paved the way for novel experimental and clinical treatment strategies. However, neither the ideal source and type of cell nor the critical quantity and mode of application have yet been defined. This article summarizes the pre-clinical session of the fourth international symposium on stem cell therapy and applied cardiovascular biology (Madrid, Spain, 26th–27th April 2007), with the focus on application in the clinical arena.
Key Words: Heart failure • Myocardial infarction • Cytokines • Stem cells
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Stem cells in non-ischaemic cardiomyopathy |
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TopAbstractStem cells in non-ischaemic...Cytokines and acute myocardial...Skeletal myoblasts and heart...ConclusionReferences |
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Bayes-Genis1 pointed out that ultrastructural findings of idiopathic dilated cardiomyopathy (IDCM) include myocyte atrophy and myofilament loss, but little is known about the vascular abnormalities present in IDCM. He could show in his study that main epicardial coronary arteries are shorter and smaller, and microvascular density is reduced in the epicardium in IDCM, despite abundant circulating VEGF-A and endothelial progenitor cells (21-fold increase of the CD133+/VEGF-R2+ cell fraction).1 Moreover, this defective vascularization is associated with reduced myocardial expression of vascular catenin, an important angiogenic regulator. Collectively, this study shows that both vasculogenesis, the de novo vascular organization of mobilized endothelial progenitors, and angiogenesis, by which new blood vessels are formed from pre-existing mature endothelial cells, are altered in IDCM.
Guarita-Souza2 presented results of a very interesting experimental approach of cell transplantation in heart failure caused by Chagas disease (non-ischaemic dilated cardiomyopathy), which is characterized by diffuse fibrosis and impairment of microcirculation. His group evaluated the effects of simultaneous autologous transplantation of co-cultured stem cells (SC) and skeletal myoblasts (SM). Eighty Wistar rats weighing 200 g were infected intraperitoneally with 15 x 104 trypomastigotes. After 8 months, a 2D echocardiographic study was performed for baseline assessment of left ventricle (LV) ejection fraction (EF), end-diastolic volume (LVEDV), and end-systolic volume (LVESV). Seventeen animals (21%) developed LV dysfunction (EF < 37%) and were selected for the study. Skeletal myoblasts isolated from muscle biopsy and mesenchymal SC from bone marrow aspirates were co-cultured in vitro for 14 days. Seven animals received autologous transplant of 5.4 x 106 and 8.0 x 106 cells into the LV wall. The control group (n = 8) received culture medium. Cells were marked with vimentin and fast myosin. After 4 weeks, ventricular function was reassessed by echo and the animals were euthanized. For histological analysis, heart tissue was stained with haematoxilin and eosin and immunostained for fast myosin, bromodeoxyuridine (BrdU), and factor VIII. After 4 weeks, cell transplantation significantly improved EF and reduced LVEDV and LVESV. No change has been observed in the control group. Moreover, skeletal fibres and neoangiogenesis were identified within the myocardium of the transplanted group.2 On the basis of these results, co-transplantation of SC and SM could be effective in experimental Chagas disease.
Clinical aspect
The latter presentation led to some interesting clinical aspects. End-stage heart failure usually requires more aggressive treatment such as heart transplantation, a rather limited therapeutic option because of donor shortage and high medical costs. In this scenario, new therapies are clearly needed and cell-based therapies emerge as a potential alternative. Interestingly, there is a large ongoing trial on this topic, the Multicenter Randomized Cell Therapy Trial in Cardiopathies (MiHeart), composed of four independent clinical trials, each one dealing with a specific cardiopathy (Chagasic cardiomyopathy, dilated non-ischaemic cardiomyopathy, acute myocardial infarction (MI), and chronic ischaemic heart disease).3 All trials are multicentre, randomized, double-blind, and placebo controlled. In each trial, 300 patients will be enrolled and receive optimized therapy. In addition, half of the patients will receive the autologous bone marrow cells, whereas the other half will receive placebo (saline with 5% autologous serum). The method for cell delivery is intramyocardial for the chronic ischaemic heart disease and intracoronary for all others. Primary endpoint for all studies will be the difference in EF 6 and 12 months after intervention in relation to the basal EF. The main hypothesis of this study is that the patients who receive the autologous bone marrow stem cell implant will have after a 6 month follow-up a mean increase of 5% in absolute LVEF in comparison with the control group.3 The results of this study will give us important new clinical insights into cell-based therapies.
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Cytokines and acute myocardial infarction |
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TopAbstractStem cells in non-ischaemic...Cytokines and acute myocardial...Skeletal myoblasts and heart...ConclusionReferences |
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Multiple clinical trials showed that bone marrow mononuclear cells or even selected subpopulations of cells may have beneficial effects when infused to the coronary artery after acute MI.4–6 Trafficking of SC involves the mobilization into peripheral blood, homing, adhesion and transmigration across the endothelium, and engraftment into the target tissue. This process being part of inflammatory response and tissue repair requires signalling mediated primarily by chemokines, which are the most important regulators of cell trafficking, survival, and function.7
Wojakowski8 showed that stromal-derived factor-1 (SDF-1), which is an exclusive ligand of CXCR4 receptor, is a crucial factor involved in the progenitor cell mobilization and homing. As shown in animal as well as human models of AMI, there is an increase of SDF-1 production and release from ischaemic myocardium generating the SDF-1 gradient towards the heart. In addition, in patients with acute MI, the absolute number of CD34+CXCR4+, CD34+c-kit+, and c-met+ cells was significantly higher in comparison with patients with stable angina and healthy subjects.8 The adult bone marrow harbours a heterogenous population of cells positive for CXCR4, which express genes specific, for example, for early muscle, myocardial, and endothelial progenitor cells. The homing of tissue-committed SC is also dependent on other chemokines and their receptors such as leukaemia inhibitory factor (LIF) receptor and hepatocyte growth factor (c-met axis). Wojakowski pointed out that all the mentioned mechanisms regulate the mobilization and homing of primarily non-haematopoietic cells of the following immonophenotype: CXCR4+/Sca-1+/lin-/CD45– in mice and CXCR4+/CD34+/AC133+/CD45– in humans expressing early cardiac and endothelial markers to the site of myocardial injury. In addition, he presented that progenitor cells mobilization is correlated with clinically important parameters of LV function, such as LVEF and LV remodelling.8
Clinical aspect
At present, no therapeutic approach has convincingly shown efficacy and success in replacing myocardial scar with functioning contractile tissue after MI in man. Recent studies have failed to generate clear evidence of transdifferentiation of BMSC into cardiomyocyte,9 although intracoronary injection of autologous progenitor cells was claimed to ameliorate post-infarction remodelling and perfusion.4–6 Conversely, the mobilization of autologous bone marrow mononuclear CD34+ cells (MNCCD34+) by granulocyte colony-stimulating factor (G-CSF) has recently attracted attention because of the atraumatic nature by subcutaneous injections with no need for bone marrow aspiration, manipulation of SC in culture, and repeat invasive procedures.10
Moreover, an increase of circulating MNCCD34+ after AMI is a well-documented phenomenon11,12 potentially influencing LV function in the post-infarction setting13 and in congestive heart failure.14 Moreover, there is recent evidence for a significant correlation between spontaneous mobilization of MNCCD34+ and endogenous G-CSF in patients with AMI.15
But the clinical results are conflicting. In FIRSTLINE-AMI, both safety and functional impact of G-CSF in the setting of human MI in conjunction with primary percutaneous coronary intervention (PCI) and abciximab was tested in a randomized study with the serial assessment of LV function after 1 and 4 months and coronary morphology at 6 months.16 G-CSF after reperfusion of infarcted myocardium seems to be safe, feasible, and effective and was not associated with aggravated post-PCI restenosis rate at 6 months.16
On the other side, REVIVAL-2 could demonstrate 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.17
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.16 This important aspect could explain conflicting differences between both studies, since there is growing experimental evidence of a time-sensitive direct cardioprotective effect of G-CSF, rather than a cell-mediated effect. As shown recently, beneficial effects of G-CSF on cardiac function were significantly reduced by delayed start of the treatment.18,19
Furthermore, there is another important difference between FIRSTLINE-AMI and REVIVAL-2. Patients in FIRSTLINE-AMI were 10 years younger and one may speculate that this could have had an influence on the different results, because there is experimental evidence for an age-associated cardioprotective effect of G-CSF. Lehrke et al.20 could demonstrate this in a mice reperfusion model, where G-CSF led to significant beneficial effects on cardiac function in younger compared with older animals.
With earlier-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 of an adequately powered double-blind, randomized, multicentre endpoint study with sophisticated imaging modalities and, 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.
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Skeletal myoblasts and heart failure |
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TopAbstractStem cells in non-ischaemic...Cytokines and acute myocardial...Skeletal myoblasts and heart...ConclusionReferences |
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Small-scale clinical trials suggested the feasibility and the efficacy of autologous myoblast transplantation to improve ventricular function after MI.21–23 However, these trials were hampered by unexpected episodes of life-threatening ventricular tachyarrhythmias.21–23 Lemarchand24 investigated the cardiac electrical stability after myoblast transplantation. Her group demonstrated in an infarcted rat model that myoblast transplantation but not bone marrow mononuclear cells or myocardial injection per se induced electrical ventricular instability.
Prosper25 compared the efficacy of surgical vs. percutaneous administration of skeletal myoblasts (SM) in a swine model of chronic MI. Two months after the induction of MI, Goettingen miniature pigs underwent autologous SM transplant either by direct surgical injection (n = 6) or by percutaneous access and intramyocardial delivery under fluoroscopic and echocardiographic guidance (n = 6). Control animals received media alone (n = 4). Animals received a median of 407.55 ± 115 x 106 BrdU-labelled autologous SM. Functional analysis was performed by 2D echocardiography. Myoblast engraftment, in vivo cell differentiation, vessel formation, fibrosis, and the ratio between collagen type I/III deposition were analysed in the infarct (IA) and non-infarct area (NIA). Prosper25 demonstrated that myoblast transplantation was associated with a statistically significant increase in LVEF (P < 0.01), increased vasculogenesis and decreased fibrosis (P < 0.05), and reduced collagen-type I/III ratio in the IA and NIA areas compared with control animals. Interestingly, no differences were found between groups receiving SM by percutaneous or surgical access.25
Clinical aspect
The equivalent benefit observed from surgical and percutaneous delivery has important clinical implications. Two small percutaneuos studies26,27 have demonstrated significant improvement on LV function by the stand-alone procedure. Moreover, results of the ongoing SEISMIC trial could give us further information about the less invasive percutaneous approach. The ongoing SEISMIC trial is a phase II, open-label, randomized, multicentre study designed to assess the cardiovascular effects and safety of myoblast implantation by catheter delivery system in patients who experienced MI.28 A minimum of 46 patients will be enrolled in the study at more than 10 European centres. Two-thirds will be allocated to receive the treatment arm and the other third allocated to the control arm. The primary endpoint of the study was to assess the efficacy and safety of autologous myoblasts on myocardial function in post-MI heart failure patients. The efficacy endpoint will be evaluated by the mean change in the LVEF at 3 and 6 months by MUGA compared with baseline.28
The results of the MAGIC trial presented by the principal investigator (Menache) at this symposium are very interesting in this context.29 The MAGIC trial is a multicentre, randomized, placebo-controlled, double-blind three-arm trial including patients with LV dysfunction (EF <35%) and indication for coronary artery bypass surgery. Each patient received either cells (400 or 800 million) grown from a skeletal muscle biopsy for 3 weeks or a placebo solution injected into 30 sites in and around the scar. An internal cardioverter–defibrillator was implanted in all patients before hospital discharge. The 6 month safety endpoints comprised a composite index of major cardiac adverse events (MACE) and ventricular arrhythmias.29 The co-primary efficacy endpoints were changes in global and regional LV functions assessed by echocardiography. Ninety patients received injections of myoblasts (400 million; n = 33; 800 million; n = 34) or placebo (n = 30). The time-to-first MACE and the time-to-first arrhythmia did not differ significantly between the three groups. Myoblast transfer did not improve regional or global LV function beyond that seen in control patients. Interestingly, however, the high-dose cell group demonstrated a significant decrease in LV end-diastolic and end-systolic volumes compared with the placebo group.29 In a subgroup of 48 patients who underwent an additional functional assessment by nuclear angiography, EF was significantly increased in those injected with the high cell dose of cells compared with the placebo group. Myoblast injections as an adjunct to coronary surgery in patients with ischaemic cardiomyopathy and depressed LV function look safe but failed to further improve echocardiographic heart function at 6 month follow-up. However, the significant reversal of LV remodelling following high-dose myoblast injections provides additional proof of concept for cardiac cell therapy.29 The results of this landmark trial give us important clinical insights but raise the question of critical quantity of autologous myoblasts.
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Conclusion |
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TopAbstractStem cells in non-ischaemic...Cytokines and acute myocardial...Skeletal myoblasts and heart...ConclusionReferences |
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The enormous clinical potential of SC and cytokines has generated great expectations in both clinicians and patients. The realization of cardiac cell therapy depends on the outcome of basic research and its application to the clinic. Careful clinical trials using the various stem cell sources may significantly advance this field but should be performed in tandem with further intensive investigation of the basic mechanisms at play. In our view, future investigation should include four important points.
- Find the best stem cell types or cytokines for the repair of cardiovascular disease.
- Identify cardiovascular SC among circulating SC; adipose tissue; epithelial cells; bone marrow-derived SC and compare their capabilities in cardiovascular repair in relevant experimental animal models.
- Identify optimal cell numbers and methods of administration of SC in cardiovascular repair.
- Identify clinical problems most susceptible to stem cell or cytokine treatments.
Taken together, it is too early to consider cell therapy for heart disease to be effective. Future setbacks are likely, but both clinicians and basic scientists will eventually introduce more potent cell-based strategies into the clinical arena.
Conflict of interest: none declared.
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References |
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TopAbstractStem cells in non-ischaemic...Cytokines and acute myocardial...Skeletal myoblasts and heart...ConclusionReferences |
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- Guarita-Souza LC. Cellular transplantation for the treatment of non-ischemic dilated cardiomyopathies. 4th international symposium on stem cell therapy and applied cardiovascular biology, 26th–27th April 2007: Madrid, Spain.
- Tura BR, Martino HF, Gowdak LH, Dos Santos RR, Dohmann HF, Krieger JE, Feitosa G, Vilas-Boas F, Oliveira SA, Silva SA, Bozza AZ, Borojevic R, de Carvalho AC. Multicenter randomized trial of cell therapy in cardiopathies—MiHeart Study. Trials (2007) 8:2.[CrossRef][Medline]
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