Cellular transplantation for the treatment of non-ischaemic dilated cardiomyopathies
Center for Health and Biological Sciences, Pontificia Universidade Catolica do Paraná
* Corresponding author. E-mail address: guaritasouzalc{at}hotmail.com
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Abstract |
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Cellular transplantation is emerging as a promising strategy for the treatment of postinfarction ventricular dysfunction. Whether its beneficial effects can be extended to other cardiomyopathies remains an unexplored question. We discuss the use of various cells types in the non-ischaemic dilated cardiomyopathies.
Key Words: Transplantation • Bone marrow stromal cell • Skeletal myoblast cell • Cardiomyopathies
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Introduction |
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Congestive heart failure is the common final pathway for patients with ischaemic and non-ischaemic cardiomyopathies. Therapeutical options mainly target on the consequences of heart failure, like fluid overload and neurohumoral activation, which are known to be long-term deleterious.1 However, improvement of ventricular contractility by restoration of cardiomyocyte contractile capacity has not been an issue until recently.2
Although some authors have shown evidence of mitotic division of cardiomyocytes, scar formation following myocardial injury leads to remodelling and permanent loss of ventricular contractility.3 Not surprisingly, attempts to restore ventricular contraction in ischaemic cardiomyopathy by cell transplantation have emerged as a feasible therapeutic option.
The beneficial effect of cellular transplantation in the full range of cardiomyopathies remains to be investigated. The most appropriate cell type to be used for each dilated cardiomyopathy will probably vary, since mechanisms of myocardial damage are different. In this article, we will first review the characteristics of some of the cells that have been studied as appropriate for transplantation either in ischaemic or in non-ischaemic cardiomyopathies. Lately, we will review some experimental and human studies in different types of non-ischaemic dilated cardiomyopathies.
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Characteristics of different cells |
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Myoblast
Skeletal myoblasts transplantation has been shown effective in many experimental4–7 and clinical8 studies. These cells differentiate into viable muscle fibres within the scared tissue and they seem to be less prone to ischaemia compared with cardiomyocytes.9
In a phase I clinical trial, Menasche et al. evaluated 10 patients with severe post-infarct ventricular dysfunction who received autologous myoblasts cultured for 16 days after taken from thigh. The authors demonstrated a recovery of function in areas previously akinetic and non-viable, but the mechanism of improvement was not completely understood. They hypothesized that it could happen either by a change in cell phenotype, since they expressed slow myosin instead of fast myosin, or simply by colonizing the infarcted area with new contractile cells and avoiding further dysfunction.8 However, the high incidence of ventricular arrhythmias in patients who received myoblasts was a reason of major concern.
Paradoxically, in the phase II randomized, placebo-controlled trial Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) by the same investigators, there were no statistically significant differences between the treatment and the placebo groups in terms of ventricular arrhythmias (all the patients have received an ICD). However, the study was early ended after an analysis by an independent data-monitoring board indicating that the trial was unlikely to show that treatment was superior to placebo on functional improvements in heart regional wall motion or global ventricular function. (Data presented at the Scientific session of the American Heart Association, Chicago, 2006.)10
In conclusion, there is still controversy whether myoblast is a good option, at least to be used solely. Potential pitfalls of this strategy are the lack of morphological differentiation into cardiomyocytes and also the absence of intercalar discs between transplanted cells and the native adult cardiomyocytes, suggesting there is no synchronicity in contraction between these tissues.
Bone-marrow stem cells
Adult stem cells are pluripotent.11 They have the ability to differentiate into specific cells depending on surrounding tissue and factors. The differentiation capacity of bone marrow cells is not completely understood. Some studies have shown that these cells are able to differentiate into cardiomyocyte,12 but in another study, only neoangiogenesis was seen.13 In fact, different results have been observed according to the studied model.
In a model of myocardial infarction, Orlic et al.14 have demonstrated the beneficial effect of bone marrow cells injection in the border of infracted myocardium shortly after coronary ligation. In this tissue, proliferating myocytes and vascular structures were noted. Bone marrow cells were transplanted in an area with viable myocardium, and not scar tissue, and this may justify why they differentiated into cardiomyocytes. In a clinical trial, Wollert et al.15 evaluated patients with acute myocardial infarction who, after acute treatment with PTCA, were randomized to standard clinical treatment alone or associated with bone marrow cell transplantation. Ventricular function significantly improved in patients who received cells, in comparison with those who did not.
In patients with established fibrosis, results are conflicting. Perin et al.16 showed that transendocardial injection of autologous mononuclear bone marrow cells in patients with end-stage ischaemic heart disease improves perfusion and mechanical function of the injected segments. However, different results were demonstrated by Marzullo,17 who has demonstrated by scintigraphy that bone marrow cells can improve perfusion but not contraction. The author evaluated patients submitted to CABG with cell injection in fibrosis area. In areas where reperfusion was achieved with graft, improvement was seen in perfusion and contraction. On the other hand, in areas where only cell injection was performed, only perfusion improvement was seen.
Combined transplantation
The idea of using a combination of skeletal myoblasts and cells derived from the bone marrow is based on the concept of providing angiomuscular regeneration and not only an isolated muscular or angiogenic regeneration. Our group has evaluated transplantation of co-cultured myoblasts and mesenchymal stem cells (MSC) in a rat model of myocardial infarction, and it was effective in the improvement of ventricular function, with development of new skeletal muscular fibres and new blood vessels in the region of myocardial fibrosis.18 Our results with co-culture in chagasic cardiomyopathy are described in the next section.19
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Cell transplantation in non-ischaemic dilated cardiomyopathy |
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Experimental studies
Although animal models of ischaemia and myocardial infarction can be easily reproduced, models of non-ischaemic dilated cardiomyopathy are lacking. In an interesting myocarditis model, where rats are immunized with porcine cardiac myosin resulting in severe heart failure, Nagaya et al.20 evaluated the effect of MSC on induction of myogenesis and angiogenesis. They isolated MSC from bone marrow aspirates, cultured for 5 weeks, and injected cells or vehicle into myocardium. Some engrafted MSCs were positive for the cardiac markers desmin, cardiac troponin T, and connexin-43, whereas others formed vascular structures and were positive for von Willebrand factor or smooth muscle actin. Compared with the control group, MSCs transplantation significantly increased capillary density and ventricular maximum dp/dt and decreased the collagen volume of myocardium and left ventricular end-diastolic pressure. Authors suggested that MSC transplantation improved cardiac function not only by induction of myogenesis and angiogenesis, but also by inhibition of myocardial fibrosis.
In a similar model of dilated cardiomyopathy, Werner et al.21 investigated the effect of spleen-derived endothelial progenitor cells transferred by femoral vein. These cells reduced the myocardial damage induced by experimental myocarditis and resulted in improvement of cardiac performance as shown by echocardiography. This late finding was consistent with thicker left ventricular wall compared with the control group as demonstrated by histopathology. Another interesting finding was that EPC from rats with dilated cardiomyopathy were compromised in their ability to bind immobilized fibronectin, cultured endothelial cells and cardiomyocytes when compared with progenitor cells from healthy rats, suggesting a whole dysfunctional state.
Working with CHF147 Syrian hamsters, a strain characterized by a 
-sarcoglycan deficiency that phenotypically features the human setting of primary dilated cardiomyopathy, Pouly et al.22 transplanted autologus tibial myoblasts and found an increment of 26% in fractional area change of transplanted hamsters compared with a reduction of 6% in control animals. (Fractional area change is an echo parameter commonly applied to evaluate ventricular function in murine models of heart failure.) Engrafted myotubes were detected by immunohistochemistry in all myoblast transplanted hearts, suggesting that the functional benefits of myobast transplantation seen in ischaemic cardiomyopathies might also extend to non-ischaemic cardiomyopathies.
As Chagasic cardiomyopathy caused by the haemoflagellate protozoa Trypanosoma cruzi infection has been one of the leading causes of heart disease in Latin America for decades, animal models of this disease have been developed to better evaluate new therapeutical options. Nevertheless, studies of cell transplantation in these experimental models are still lacking. In a mouse model, Soares et al.23 demonstrated that bone marrow cells injected intravenously migrated to the heart and caused a significant reduction in the inflammatory infiltrates and in the interstitial fibrosis. Cell therapy induced massive apoptosis of myocardial inflammatory cells. The effect was the same when injected bone marrow cells were obtained from normal or infected mice. Because ventricular function was not assessed, it remains to be proved whether these beneficial histological effects with mononuclear cells transplantation is translated into ventricular function improvement in models of Chagas disease.
Also in a rat model of Chagas disease, our group has evaluated the transplantation of co-cultured skeletal myoblasts and mesenchymal cells derived from bone marrow. As previously described, we had successfully tested this approach in a rat model of myocardial infarction. Because physiopathology in Chagas disease resembles the findings in chronic ischaemic cardiomyopathy, with fibrosis and ischaemia, we hypothesized that simultaneous transplantation of co-cultured MSC and skeletal myoblasts could be an effective approach in this disease.
To develop the rat model, we infected Wistar rats with trypomastigotes (infective form of Trypanosoma cruz) and after 8 months the animals which developed dilated cardiomyopathy (LVEF < 37%) were included in the study. Autologous skeletal myoblasts were isolated from muscle biopsy and MSC from bone marrow aspirates were co-cultured in vitro for 14 days. Rats were randomly assigned to receive subepicardic injection of co-culture of skeletal myoblast and MSC or culture medium as control. Cells were injected in anterior and lateral left ventricle wall. One month after procedure, ejection fraction remained unchanged in the control group (36.7 ± 3.6% to 37.4 ± 6.7%; P = 0.7684) but was enhanced in the treated group (30.1 ± 5.7% to 51.8 ± 6.6%; P < 0.0001). We also found reduced LV end-diastolic and systolic volumes in those rats that received cells. No change was observed in the control group. Histological analysis of the control group demonstrated a high degree of fibrosis, a feature of Chagas disease. In the treated group, skeletal muscles cells, with myotubular characteristics, endothelial cells, and new vessels in formation were identified in the epicardium where cells were transplanted. Musculoskeletal origin was confirmed by positive fast myosin immunostaining in the treated group. In conclusion, the combined cellular transplantation with myoblasts and MSC is functionally effective in the Chagas disease ventricular dysfunction.
Cellular transplantation has also been evaluated in a model of doxorubicin-induced cardiomyopathy. Ishida et al.24 performed the study in rats that randomly received bone marrow mononuclear cells, saline or no injection but sham operation. After 4 weeks of cells delivery through thoracotomy, ventricular function and diameters were evaluated by echocardiography. Systolic left ventricular diameter was smaller and fractional shortening was larger in the transplant group. Beneficial effects of cellular transplantation were confirmed by Langendorf apparatus that revealed greater peak systolic pressure and lower end-diastolic pressure in this group.
Human studies
Experience with cellular transplantation in non-ischaemic cardiomyopathies is still in a very preliminary phase, and bone marrow cells have been widely used for this aim. Lago et al.25 performed the transplantation of bone marrow stem cells in eight patients with non-ischaemic cardiomyopathy, deploying cells directly into coronaries. The ejection fraction significantly increased from 18.3 ± 7 to 26.4 ± 10% (P < 0.005) and left ventricular diastolic diameter showed a non-significant decrease. Symptoms were significantly improved, as demonstrated by a reduction on functional class (NYHA) from 2.5 ± 0.8 to 1.4 ± 0.5 (P < 0.001). Another important issue addressed in this study was safety of the procedure: no mortality or major complications were observed.
Other studies have evaluated different routes for cell transplantation. Ghodsizad et al.26 reported the case of a 58-year-old man with end stage non-ischaemic cardiomyopathy who received bone marrow cells by transepimyocardial route through a minimally invasive surgery approach. Six months after procedure, echocardiography and cardiac magnetic resonance showed improvement of left ventricular contractility. By a similar approach, mini anterior-left thoracotomy, Kalil et al.27 transplanted mononuclear cells into the myocardium of eight patients with dilated idiopathic cardiomyopathy. Evaluation of cardiac performance was performed by magnetic resonance before 4, 6, and 8 months after transplantation. Despite an improvement in the first 4 months, ejection fraction returned to basal values after 8 months, suggesting only transient beneficial effects.
Cellular transplantation has also been tested in patients with Chagas disease. This may be an interesting option for those patients with more advanced stages, particularly when heart transplantation seems to be the only option. It is worth recalling that heart transplantation has some peculiar implications in Chagas disease. At first, most patients affected by the disease inhabit poor areas in developing countries, where high costs of heart transplantation may be unaffordable. Secondly, immunosuppression treatment may reactivate Chagas infection compromising short-term and long-term prognosis.28
Vilas-Boas et al.29 studied 28 class III and IV patients with Chagas disease, all receiving optimized clinical treatment. Mononuclear bone marrow cells were delivered by intracoronary injection. After 60 days of transplantation, there was an increase in ejection fraction (20.1 ± 6.8% to 23 ± 9% P = 0.02), NYHA class (3.1 ± 0.3 to 1.8 ± 0.5 P < 0.0001), and distance walked in 6 min, with no augmentation in the incidence of ventricular tachycardia. Their data demonstrated that injection of bone marrow mononuclear cells is feasible and may be effective in patients with heart failure due to Chagas disease.
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Future directions |
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Despite recent efforts shown in this review, the real benefit of cellular transplantation in heart failure, specially caused by non-ischaemic cardiomyopathies, is still far from being disclosed. Considering the experience of the last few years, we believe that different cardiomyopathies will benefit from different cell types. As myocardial perfusion is preserved in most non-ischaemic cardiomyopathies, we believe that in this group, myoblast transplantation, in order to provide new and effective muscle fibres, may be an interesting and physiological approach. However, this is just a hypothesis waiting to be tested.
Conflict of interest: none declared.
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