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REVIEW PAPER |
Department of Cardiovascular Surgery, European Hospital Georges Pompidou, Paris, France
For reprint information contact: Juan C Chachques, MD, Tel: 33 1 4395 9359, Fax: 33 1 4072 8608, Email: j.chachques{at}brs.ap-hop-paris.fr, Department of Cardiovascular Surgery, Pompidou Hospital, 20 rue Leblanc, Paris 75015, France.
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ABSTRACT |
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 TOP ABSTRACT IMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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IMPACT OF HEART FAILURE |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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Cardiac transplantation remains the only curative treatment for CHF, but has remained limited in its application due to a shortage of donated organs, age of recipients, and other strict selection criteria. Non-beating heart donors represent a new alternative to palliate the reduced number of transplantation procedures. Implantable cardiac assist devices are still evolving, and xenotransplantation is in the early research phase with no clinical applications to date.
The epidemiology of CHF is well known due to its dramatic economic impact on health care systems. In France, approximately 600,000 patients have CHF with 150,000 new cases diagnosed annually. Mean age at onset is 73.5 years, and 2/3 of the patients are aged 70 years and older. Annually, about 3,500,000 outpatient visits and 150,000 hospitalizations are related to congestive heart failure. CHF is responsible for more than 32,000 annual deaths. CHF costs represent more than 1% of the total annual medical costs and represent a major and growing public health burden. This should encourage us to optimize the medical treatment and prevention of CHF.
In the US, congestive heart failure affects almost 5 million people, mostly elderly. Significant therapeutic advances in CHF management have resulted in striking declines in mortality rates, but hospitalization is ever increasing, now at more than 1 million hospitalizations annually with a cost greater than $15 billion. One of the most important and challenging factors facing case managers who work with the CHF population is how to minimize treatment costs while enhancing clinical outcomes.
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VENTRICULAR REMODELING |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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In chronic ischemic disease, surgical ventricular reconstruction involves resection of postinfarct scar, septal exclusion, cavity reduction by endoventricular patch, and complete coronary grafting. The overall intent is to convert the spherical heart into an elliptical configuration. The published results of the RESTORE Group study confirms that relieving the abnormal tension by excluding the scar and reducing the LV volume allows surgical ventricular reconstruction to improve overall mechanical performance by increasing mechanical efficiency.2
Surgical procedures without ventriculotomy can be indicated in heart failure patients who are refractory to medical therapy. Among these techniques, dynamic cardiomyoplasty, aortomyoplasty counterpulsation, ventricular containment (e.g. Acorn wrap), and the myosplint (Myocor LV shape-change) approaches have been proposed.1 The goal of these procedures is to rebuild a more physiological ventricular shape before irreversible myocardial collagen and fibrosis develop. The many proposed mechanisms of action of latissimus dorsi dynamic cardiomyoplasty are: (1) systolic assist; (2) limitation of ventricular dilation; (3) reduction of ventricular wall stress (sparing effect); and (4) reverse ventricular remodeling due to the active girdling effect. In the literature, long-term survival is equivalent for cardiomyoplasty and heart transplanted patients.1,3
Cell transplantation, growth factors, and gene therapy represent emerging biological treatments in ischemic heart failure conceived to improve myocardial viability.4–5 Alternatively, non-biological surgical approaches have been proposed such as transmyocardial laser, radiofrequency heating of dyskinetic myocardium, and prosthetic (Marlex and Dacron) patches. These techniques induce myocardial fibrosis with uncertain functional results. A biologic regenerative approach to patients at risk of congestive heart failure seems to be a more effective and physiological approach in preventing infarct expansion, ventricular dilatation, and postischemic remodelling.6–8
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CELL THERAPY |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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RATIONALE OF CELLULAR CARDIOMYOPLASTY
Cellular cardiomyoplasty (CMP) is a combination of cellular biology with cardiac surgery or with interventional cardiology. It aims to regenerate the myocardium by the transplantation of living cells in order to reduce the fibrosis and the size of the myocardial infarct scar. Cellular CMP consists of intramyocardial cell implantation intended to induce the growth of new muscle fibers (myogenesis) and the development of angiogenesis and vasculogenesis in the damaged myocardium. Cultured autologous cells do not raise immunological, ethical, tumorogenesis, or donor availability problems.10–11
CHOICE OF CELLS
Different cell types have been proposed for myocardial regeneration:
The most investigated cells for clinical myocardial repair are skeletal myoblasts and bone marrow cells.
Skeletal Muscle Cells are able to regenerate after injury because of the presence of satellite cells. In postnatal muscle, skeletal muscle precursors (myoblasts) can be derived from satellite cells (reserve cells located on the surface of mature myofibers). When activated by appropriate stimuli, satellite cells proliferate and differentiate into new skeletal muscle fibers. This cell type’s major advantage is that skeletal myoblasts are highly resistant to ischemia and multiply after injury, presenting a high power for multiple mitoses. Differentiated myotubes derived from transplanted skeletal myoblasts have been detected following implantation in a post-infarction lesion.12
The major drawback of using myoblasts is the lack of gap junctions and electromechanical connections between the implanted cells and the host myocardium. Thus, it is uncertain whether an improvement in LV performance could be mediated by increased systolic function caused by synchronous contraction of the graft since skeletal myoblasts are known to not contract spontaneously. Moreover, denervated skeletal myoblasts could progressively become atrophic.13
Gap junctions between grafted myoblasts and host myocardium were not demonstrated. The explanation is the downregulation amongst the myoblasts themselves. When they differentiate into myotubes, they downregulate the mechanical coupling protein (N-cadherine) and the electrical coupling protein (connexine 43); therefore, the transplanted cells remain isolated within the cardiac tissue. However, it is possible that the myotubes might be indirectly connected with the surrounding cardiomyocytes via the extracellular matrix. Analogous to the evolution of the latissimus dorsi muscle in dynamic cardiomyoplasty, when electrostimulation is associated with cell transplantation, grafted myotubes can differentiate into slow muscular fibers resisting fatigue and contracting synchronically with the cardiomyocytes.13
Clinical protocols using myoblasts follow three precise steps: 1) muscular biopsy (10–15 grams) from the thigh vastus lateralis; 2) cell isolation and primary culture over 2 to 3 weeks with a minimum of 300 million cells with at least 70% of myoblasts; 3) re-implantation of the cells in the infarcted area using a surgical or catheter-based approach. Instead of fetal bovine serum, autologous human serum is strongly recommended during the process of cell expansion or eventually in final steps of culturing to avoid surface antigens and subsequent rejection. During cell culture procedures, pre-plating techniques are used to separate non-myogenic cells (e.g. fibroblasts) at the beginning of cell processing. Non-myogenic cells attach to dishes before myoblasts.
Bone Marrow Stem Cells are principally used for the induction of angiogenesis in ischemic diseases. These cells can be obtained from bone marrow aspiration or from peripheral blood. In most cellular CMP protocols, after aspiration of the ilium bone, mononuclear bone marrow cells are selected by Ficoll density separation. This simple cell selection procedure avoids 3 weeks "in vitro" cultures and multiple passage procedures which can attenuate the viability of cells.14–15 The major drawback in using these cells is that bone marrow cells can undergo milieu-dependent differentiation. When transplanted in normal myocardium, they may differentiate into cardiocytes. However, when these cells are implanted in a myocardial scar, they may differentiate into fibroblasts, increasing the fibrosis of the postischemic scar.
Experimentally, bone marrow stromal cells can be induced to differentiate into myocytes prior to transplant using a co-culture system with cardiomyocytes or by including 5-azacytidine in the cultures.16 These approaches may be effective in driving myocardial remodeling; however, clinical trials can be compromised in terms of potential cell mutations by azacytidine. In vitro electrostimulation of stem cell cultures is used experimentally by our group for predifferentiation of cells in a myogenic lineage.
There are 4 cell lineages that can be isolated from bone marrow: hematopoietic stem cells (HSC), mesenchymal stem cells (MSC), multipotent adult progenitor cells (MAPC), and progenitor endothelial cells (PEC). The mesenchymal stem cells (also called bone marrow stromal cells) are capable of giving rise to multiple cell lines. There is a new tendency towards the utilization of a given sub-population of bone marrow cells, in particular, the CD 133+ progenitors (cells expressing surface antigen AC133) having a tendency to differentiate into true angioblasts and muscle cells. These cells are rich in hemangioblast progenitors and can be isolated from bone marrow biopsies or from G-CSF (granulocyte-colony stimulating factor) mobilized peripheral blood, using a cell isolation kit including a magnetic separation column (Clinimacs® Cell Selection System, Miltenyi Biotec, Bergisch Gladbach, Germany). This approach avoids in vitro cell culture procedures17 (Table 1
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Nuclear transfer techniques have been proposed as a strategy of generating an unlimited supply of rejuvenated and histocompatible stem cells for the treatment of cardiac diseases. For this purpose, c-kit-positive fetal liver stem cells obtained from cloned embryos were injected into the border zone of infarcted mice myocardium to induce tissue reconstitution. Experimentally, these stem cells derived by nuclear transfer cloning restored infarcted myocardium.19 The magnitude of myocardial regeneration obtained in this study was significantly superior to that achieved with adult bone marrow cells. Although problems currently plague nuclear transplantation, including the potential for epigenetic and imprinting abnormalities, stem cells derived from cloned embryos are sufficiently normal to repair damaged tissue in vivo.
Fetal Cells: The clinical use of fetal cells raises ethical, immunological, and availability problems. Fetal and neonatal cardiomyocytes have been experimentally grafted into the myocardium after in vitro expansion. The presence of intercalated disks and connexin 43, a marker of gap junctions required for cell-to-cell electrical coupling, has been observed within grafted cardiomyocytes and between grafted cells and host myocytes.
Vascular Endothelial Cells can be harvested from the intima of autologous arteries (e.g. segments of the radial artery) or peripheral veins. After ex vivo expansion, these cells are transplanted into ischemic myocardium.5 This approach illustrates the advantage of inducing and moderating angiogenesis without the limitations of the release of a single protein (VEGF, bFGF). Endothelial cells induce an extensive capillary network, but they might not induce the formation of sufficient conduit vessels to regenerate the ischemic myocardium.
Mesothelial Cells are accessible in human patients by excision and digestion of epiploon or from peritoneal fluid or lavage. They are also easy to culture to obtain large quantities in vitro and they can be genetically modified. This cell type is probably the precursor of coronary arteries during embryogenesis, they secrete a broad spectrum of angiogenic cytokines including SDF-1
, growth factors and extracellular matrix molecules. Indeed mesothelial cells are transitional mesodermal-derived cells, but share similar morphological and functional properties with endothelial cells and conserve properties of transdifferentiation. These cells have been used experimentally to create neoangiogenesis in an experimental model of myocardial infarction.20
Smooth Muscle Cells can be obtained from a segment of artery, the vermiform appendix, or the uterus during laparoscopy. After implantation in pathologic myocardium, smooth muscle cells proliferate and hypertrophy in response to the stress of cardiac contractions.8 Due to the difficulties in obtaining these cells from patients’ tissues (in comparison to simple skeletal muscle biopsies) and considering that their effects are similar to those of skeletal myoblasts, smooth muscle cells seem to be destined exclusively to experimentation for the moment.
Adipose Tissue Stroma Cells: White adipose tissue has long attracted attention because of its great and reversible capacity for expansion, which appears to be permanent throughout adult life. Adipose tissue enlargement is the result of adipocyte hypertrophy and the recruitment and differentiation of regenerative precursors located in the stromal-vascular fraction (SVF). However, development of the capillary network is also required to ensure adipose tissue remodeling. Indeed, a crucial link exists between adipose cells and the capillary network.21
SVF represents a heterogeneous cell population surrounding adipocytes in fat tissue, including mature microvascular endothelial cells. This fraction was also reported to be a convenient and nonrestrictive source of pluripotent cells such as hematopoietic progenitors and spare mesodermal stem cells able to differentiate into osteogenic, chondrogenic, and myogenic lineages. The understanding of adipose tissue development and plasticity opens a new perspective for angiogenic therapy based on the administration of adipose tissue-derived stem cells in the treatment of cardiovascular disease. Interestingly, spontaneous cardiomyocyte differentiation from adipose tissue stroma cells has been observed.22
Dental Stem Cells: Teeth develop from reciprocal interactions between mesenchymal cells and epithelium, where the epithelium provides the instructive information for initiation. Embryonic stem cells, neural stem cells, and adult bone marrow-derived cells all respond by expressing odontogenic genes. The dental pulp seems to be a viable source of easily attainable cells with possible potential for development of autologous cell transplantation therapies. Glial cell line-derived neurotrophic factor (GDNF) mRNA is highly expressed by dental pulp cells prior to the initiation of dental pulp innervation. A recent study showed that a population of neural crest-derived dental pulp cells acquire clear neuronal morphology and protein expression profile in vitro, indicating the presence of a cell population in the dental pulp with neuronal differentiation capacity that might provide additional benefits when grafted into the central nervous system (e.g. in patients with Parkinson’s disease).23
Other studies suggest that the periodontal ligament (PDL) contains stem cells that have the potential to generate cementum/PDL-like tissue in vivo. Transplantation of these cells, which can be obtained from an easily accessible tissue resource and expanded ex vivo, might hold promise as a therapeutic approach for reconstruction of tissues destroyed by periodontal diseases. Dental epithelial and mesenchymal stem cells can be maintained and expanded in vitro and may be proposed for regenerative medicine and biology.
G-CSF Cytokine Therapy: Stem cell mobilization with granulocyte colony-stimulating factor cytokine (G-CSF) can be used as a single therapy for myocardial regeneration. Mobilized stem cells have been used to repair cardiac tissue following acute myocardial infarction. Cell mobilization is achieved by systemic administration of G-CSF. Experimental and clinical studies suggest that cell mobilization by hematopoietic growth factors can promote angiogenesis in the infarcted myocardium.24 This therapeutic approach should be evaluated carefully since risks related to the occlusion of microcoronary circulation exist,25 as well as the possibility to increase the number of inflammatory cells which may destabilize atherosclerotic plaques.
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INDICATIONS AND INCLUSION CRITERIA |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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MECHANISMS OF ACTION
Current research on the mechanisms by which cell transplantation brings a functional benefit is based on the following hypotheses. The implanted cells seem to provide a supporting "band-aid"-scaffolding effect, which can limit the spread of the infarcted area, preventing excessive remodeling of the ventricle. This hypothesis is strongly suggested by experimental and clinical observations showing a reduction in the telediastolic volumes of the cell transplanted hearts. Therapeutic strategies that limit adverse matrix remodeling in heart failure may prevent ventricular dilatation and maintain the structural support necessary for effective cardiomyocyte contraction. Many studies are investigating the effects of cell transplantation on the fibrillar collagen network.
In the case of skeletal myoblasts, the mechanism may involve mechanical stimulation exerted by the surrounding cardiomyocytes via extracellular matrixes through which mechanical impulses would be transferred via a "coupling effect". The modalities and condition of the connection of the myoblasts to this matrix have to be precisely specified. The hypothesis that the transplanted cells may be a source of releasing growth hormones and angiogenic factors, which may increase their survival and even restore the contractile function of a dormant myocardium, is not confirmed. Our group has done experimental studies with myoblasts in association with vascular endothelial growth factor (VEGF). The angiogenesis induced by myoblast transplantation was not superior to that observed in the case of a cellular culture medium injection.28
In the case of bone marrow cell transplantation, principally when specific progenitors are grafted, the intrinsic contractile characteristics of the differentiated cells will be implicated, and the functional benefit will be related to the improvement of the systolic function. The presence of cell type gap-junctions would allow the electrical influx to be propagated between the host cells and the graft cells, which would contract in a synchronous fashion. In addition, the angiogenic effects of bone marrow cells should contribute to the recovery of stunned and hibernating myocardium.
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TECHNIQUES FOR CELL INJECTION |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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Percutaneous selective coronary artery cannulation for cell injection can be used for myocardial regeneration.30–31 This intravascular delivery is based on the potential migratory properties of some cells which retain their ability to cross the basal lamina. This approach should be reserved for mononuclear bone marrow cells, since intracoronary delivery of skeletal myoblasts and bone marrow mesenchymal cells could provoke microemboli.32 In fact, the myoblasts size (length 25–30 µm) and shape (stellar and spindle-shaped) are more prone to embolizations than bone marrow mononuclear cells (spherical and disc-shaped, diameter 8–18 µm).
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CLINICAL TRIALS |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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The experimental results in the field of cell transplantation for myocardial regeneration led our team to perform multicenter clinical trials.26 In our experience, the best clinical results of cellular CMP seem to be obtained in patients presenting a heterogeneous infarct area (patchy appearance), i.e. a mixture of viable myocardial tissue and multiple small scars. So a "vascularized fibrosis" might be a more appropriate lesion to be treated by cells than a "non-vascularized" postinfarction scar.
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NEW DEVELOPMENTS |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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1. ELECTROSTIMULATED "DYNAMIC" CELLULAR CMP
Ex vivo Pre-implant Cell Electrostimulation
Electrostimulation was investigated by our group for driving the conditioning process of bone marrow stem cells towards cardiac-type myogenic cells. Electrostimulation of human bone marrow cell cultures for myogenic preconditioning have been performed in our laboratory, the protocol consists of "in vitro" bipolar electrostimulation of cell cultures using an external pacemaker and specific electrodes. After 3 weeks, we observed an increase in cell multiplication, cell reorganization, and myogenic differentiation. Since stem cells can differentiate into fibroblasts after implantation in myocardial scars, this method might be used to precondition stem cells before implantation.43
In vivo Post-implant Cell Electrostimulation
Atrial synchronized biventricular pacing is indicated in many heart failure patients to correct conduction disorders associated with chronic systolic and diastolic dysfunction. Electrostimulation associated with cellular cardiomyoplasty was performed experimentally by our group to transform passive cell therapy into "dynamic cellular support". Thus, the principles of electrophysiological conditioning of muscle fibers (e.g., dynamic cardiomyoplasty) were applied in our laboratory in cellular cardiomyoplasty. Electrostimulation of both ventricles following skeletal myoblast implantation induced the contraction of the transplanted cells and a higher expression of slow myosin, better adapted for chronic ventricular assistance.44
2. AUTOLOGOUS-HUMAN-SERUM FOR CELL CULTURE
Traditional cell culture techniques involve the use of fetal bovine serum for cell growth. Contact of human cells with fetal bovine serum results in, after a 3-week fixation, animal proteins on the cell surface, representing an antigenic substrate for immunological and inflammatory adverse events. After cell implantation into the heart, an inflammatory reaction can occur with subsequent fibrosis, representing a risk for micro re-entry circuits that can generate ectopic ventricular arrhythmias. Thus, directly injecting skeletal myoblast-derived cells cultivated with bovine serum into ischemic myocardium seems to provide the substrate for electrical instability leading to malignant arrhythmias. In fact, current clinical experience with cellular cardiomyoplasty using serum bovine-cultivated myoblasts has demonstrated significant malignant ventricular arrhythmias and sudden death in patients; therefore, in several ongoing clinical trials, implantation of cardioverter-defibrillators becomes mandatory.35–36
To reduce the risk of arrhythmias, a total autologous cell culture procedure was used by our group in 20 patients treated with skeletal myoblasts.45 Cells were cultivated without cytokines in a complete human medium over 3 weeks, using the patient’s own serum obtained from plasmapheresis or from blood samples. This approach obviated the need for the implantation of defibrillators. An additional benefit of human-autologous-serum cell expansion is that it can be performed without risk of prions, viral, or zoonoses contamination. Since patients treated with non-cultivated bone marrow cells are free of arrhythmias, we can extrapolate that the bovine-culture medium used for myoblast expansion could be responsible for this complication.
3. NEW "CELL-FIX" CATHETER FOR INFARCT DETECTION AND CELL DELIVERY
New technologies for cell implantation derived from interventional cardiology procedures are emerging. Intracoronary and endoventricular catheter-based cell delivery procedures for therapeutic angiogenesis and myogenesis have been performed. Nevertheless, the quantity of the cells injected in the target infarcted area is unknown, despite the use of myocardial mapping to identify the pathologic myocardium. The success is largely dependent on many technical considerations, namely, the risk of cell loss at the moment of injection and the precise localization of the post-ischemic scar and the peri-infarct areas.
A new diagnostic-therapeutic electrode catheter for local myocardial treatment has been created by our group, called "CELL-FIX" catheter. This second generation system includes a method and apparatus to identify by electrophysiology the infarcted area and simultaneously to deliver the cells, stabilizing the scar by vacuum at the moment of injection.46
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CONCLUSION |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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New therapeutic approaches to myocardial regeneration aim to augment the effects of the loss of cardiomyocytes, which is generally considered irreversible, and the cause of the cardiac insufficiency. Although terminal differentiation of cardiomyocytes is disputed, it appears as a permanent turnover of contractile cells, which also occurs in cases of cardiac insufficiency. This might not be enough to compensate the cell death due to a pathological process. In particular, myocardial infarction leaves an akinetic fibrotic scar, which with remodeling leads to ventricular dilation and an overall loss of the mechanical function of the heart.
It is accepted that cardiomyocytes are differentiated cells without the capacity to proliferate and, therefore, to regenerate. However, recently published studies suggest that in patients who suffered an acute myocardial infarction, there is a small percentage of cardiomyocytes able to enter actively into the cell cycle. The low proportion of proliferating cells in relation to the damaged muscle makes the clinical impact, in the best of cases, limited.47–48 From fetal cardiac tissues or from cell lines grown "in vitro", it has been demonstrated that it is possible to obtain stable cardiac grafts in experimental models. However, the long-term functionality of these grafts and the need to use immunosuppression due to the fact that they are allogenic tissues, together with the ethical aspects derived from the use of embryonic tissues in human, limits its clinical application.
Cellular CMP for ischemic and non-ischemic cardiomyopathies27,49 is a rapidly burgeoning field, in view of the number of randomized controlled trials of this treatment modality currently in progress or being initiated. The idea of transplanting single cells has a number of attractive attributes and is dependent on an ever-expanding understanding of the molecular basis of angiogenesis and myogenesis. Cellular therapy’s primary objective is to ensure the recolonization and restoration of postinfarction myocardial tissue, thus improving viability and function. Left and/or right ventricular infarction and ischemic mitral regurgitation constitute valid indications for cell therapy.26
Cellular CMP appears to be a promising technique capable of restoring ventricular function and limiting or reversing remodeling in patients following myocardial infarction. It can be considered that cellular angiogenic therapy (using bone marrow or other cells) may be performed in myocardial infarction, before myogenic cell transplantation (using skeletal myoblasts), to improve local conditions for cell survival (preconditioning).50–51 The development of new catheters for percutaneous cell delivery should facilitate this combined approach. In summary, cell transplantation already offers the promise to induce angiogenesis, restore myocardial viability and regional ventricular function, therefore limiting remodeling for patients who have had a non-massive myocardial infarction and probably for patients presenting with non-ischemic dilated cardiomyopathy.
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FUTURE PROSPECTS |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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One hypothesis is that staged procedures of cell delivery could be necessary to regenerate large postischemic scars. In these cases, catheter-based procedures should play an essential role. The different cell sources, principally skeletal myoblast and bone marrow cells, should provide complementary beneficial effects. The association of cell-based angiogenic and myogenic therapy showed important benefits in experimental models of myocardial regeneration.54–55
The effects of cell therapy on cardiac function need to be further investigated, analyzing the contribution of transplanted cells to myocardial contractility, since until now the effects of this therapy seem principally limited to stabilization or reduction of ventricular dilatation and reverse remodeling. It appears that cell therapy can be beneficial either following acute myocardial infarction or several months after the ischemic complication. Preliminary clinical reports show promising data in this respect.
Most of these questions will probably be answered in ongoing clinical investigations. It is also likely that cell therapy, the biology of its development, growth factors, and genetic manipulations might mutually benefit from their respective advances. Tissue engineering will probably contribute to the healing process, incorporating exogenous pro-angiogenic matrix onto dyskinetic thin infarct scars (e.g. dyskinetic scars with less than 4 mm of ventricular wall thickness).56 These fields must be considered as complementary with combined strategies of revolutionizing the treatment of myocardial injury.
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REFERENCES |
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TOPABSTRACTIMPACT OF HEART FAILUREVENTRICULAR REMODELINGCELL THERAPYINDICATIONS AND INCLUSION...TECHNIQUES FOR CELL INJECTIONCLINICAL TRIALSNEW DEVELOPMENTSCONCLUSIONFUTURE PROSPECTSREFERENCES |
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This article has been cited by other articles:
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  J. C Chachques, O. Jegaden, T. Mesana, Y. Glock, P. A Grandjean, and A. F Carpentier Cardiac Bioassist: Results of the French Multicenter Cardiomyoplasty Study Asian Cardiovasc Thorac Ann, December 1, 2009; 17(6): 573 - 580. [Abstract] [Full Text] [PDF]
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S. Guhathakurta, U. R Subramanyan, R. Balasundari, C. K Das, N. Madhusankar, and K. M. Cherian Stem Cell Experiments and Initial Clinical Trial of Cellular Cardiomyoplasty Asian Cardiovasc Thorac Ann, December 1, 2009; 17(6): 581 - 586. [Abstract] [Full Text] [PDF]
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 A. Shafy, T. Lavergne, C. Latremouille, M. Cortes-Morichetti, A. Carpentier, and J. C. Chachques Association of electrostimulation with cell transplantation in ischemic heart disease J. Thorac. Cardiovasc. Surg., October 1, 2009; 138(4): 994 - 1001. [Abstract] [Full Text] [PDF]
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 J. C. Chachques Cardiomyoplasty: is it still a viable option in patients with end-stage heart failure? Eur. J. Cardiothorac. Surg., February 1, 2009; 35(2): 201 - 203. [Full Text] [PDF]
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 J. C. Chachques, J. C. Trainini, N. Lago, M. Cortes-Morichetti, O. Schussler, and A. Carpentier Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Trial): Clinical Feasibility Study Ann. Thorac. Surg., March 1, 2008; 85(3): 901 - 908. [Abstract] [Full Text] [PDF]
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 R. P. Gallegos and R. M. Bolman III Stem Cell Induced Regeneration of Myocardium Card. Surg. Adult, January 1, 2008; 3(2008): 1657 - 1668. [Full Text]
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