doi: 10.1161/CIRCULATIONAHA.106.639385
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(Circulation. 2006;114:353-358.)
© 2006 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
Cardiac Stem Cell Therapy
Need for Optimization of Efficacy and Safety Monitoring
From the Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Mass.
Correspondence to Peter Oettgen, MD, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02115. E-mail joettgen{at}bidmc.harvard.edu
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Introduction |
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 Top Introduction Type of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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Cardiovascular disease remains the number one cause of morbidity and mortality in the United States and Europe. In the United States alone,
1 million patients suffer a myocardial infarction every year, with an associated mortality of 25% at 3 years.1 A more sobering statistic is the fact that there are 5 million Americans with congestive heart failure, with an associated 20% mortality per year. This remains the case despite advances in pharmacotherapy, cardiac resynchronization therapies, and the use of implantable cardioverter-defibrillators.2 Some patients with end-stage congestive heart failure are considered for cardiac transplantation, but the demand for this therapeutic approach greatly outweighs the availability of donor hearts. Over the past few years, several animal studies and a few clinical trials have supported the use of stem cells as a potential therapeutic modality to address this unmet clinical need.
Response by Boyle et al p 358
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Type of Cells Used for Cardiac Transplantation |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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Several different types of cells have been used in both animal studies and patients to promote the repair of damaged myocardium. The 2 main sources of stem cells are adult stem and embryonic stem (ES) cells.
ES Cells
ES cells are derived from the inner mass of developing embryos during the blastocyst stage. Characteristic features of ES cells include their proliferative and self-renewing properties and their ability to differentiate into a wide variety of cell types, including cardiac myocytes.3 The major concerns with their use in human trials include the formation of teratomas when ES cells are injected into immunocompromised animals. This is particularly important because the ES cells currently available for use in humans would be of allogeneic origin and therefore would require immunosuppression. As nuclear transfer techniques improve, they will provide a way of generating an unlimited supply of histocompatible ES cells using the nuclei of cells obtained directly from the recipient patients with heart disease.4
Adult Stem Cells
Bone Marrow–Derived Stem Cells
Several different types of stem cells can be isolated from adult bone marrow. Examples of some of these subpopulations of cells include hematopoietic stem cells, endothelial progenitors, and mesenchymal stem cells. Several investigators have chosen to deliver unfractionated bone marrow–derived cells, a technique that has the advantage of minimizing extensive ex vivo manipulation of the cells to isolate and expand a selected population of cells. The potential disadvantage of delivering a mixture of cells is that the percentage of cells that are therapeutically useful may be small. An alternative strategy is to isolate purer populations of cells that express specific antigens. For example, endothelial progenitors express the cell surface marker CD133. These cells have a greater potential to promote angiogenesis but are more technically challenging to isolate in significant quantities.5 Mesenchymal cells represent a rare population of bone marrow–derived cells that do not express CD34 or CD133. Mesenchymal cells can differentiate into bone, cartilage, adipocytes, and, under certain culture conditions, cardiac myocytes.6 One advantage of using mesenchymal cells is that clones of these cells can easily be expanded in vitro, exhibit relatively low immunogenicity, and might be particularly useful when autologous stem cells are not readily available.7
Skeletal Myoblasts
Skeletal myoblasts are a population of progenitor cells that can be isolated from skeletal muscle biopsies and expanded in vitro. These myoblasts can differentiate into myotubes and exhibit skeletal muscle phenotype after transplantation, leading to improvements in left ventricular (LV) systolic and diastolic function.8 However, the transplanted skeletal myocytes are not electrically coupled to surrounding cardiomyocytes and thus may lead to the development of arrhythmias.
Resident Cardiac Stem Cells
Several investigators have recently identified a population of stem cells within the myocardium that are capable of differentiating into cardiac myocytes. It has recently been reported that these cells can be harvested from cardiac biopsies. Injecting these cells in the setting of myocardial infarction can promote cardiomyocyte formation with associated improvements in systolic function.9 At present, these cells are limited in number and require ex vivo separation and expansion over several weeks.
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Methods of Stem Cell Delivery |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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A major goal of cardiac stem cell therapy is to transplant enough cells into the myocardium at the site of injury or infarction to maximize restoration of function. Several different approaches currently are being used to deliver stem cells.
Transvascular Route
A transvascular approach is particularly well suited to treat patients with acutely infarcted and reperfused myocardium. Stem cells can be infused directly into the coronary arteries and have a greater likelihood of remaining in the injured myocardium as a result of the activation of adhesion molecules and chemokines.10 The advantage of an intracoronary infusion is that the cells can be directed to a particular territory. An alternative approach is to inject stem cells intravenously.11 In the setting of myocardial infarction, circulating stem cells have been shown to home to sites of injury, but the number of cells that home to the heart in this way is significantly less than by local injection.
Direct Injection Into the Ventricular Wall
Direct injection of stem cells is used in patients presenting with established cardiac dysfunction in whom a transvascular approach may not be possible because of total occlusion or poor flow within the vessel of the affected territory. There are 3 different approaches to direct injection. A transendocardial approach can be used in which a needle catheter is advanced across the aortic valve and positioned against the endocardial surface.12 Cells can then be injected directly into the left ventricle. Electrophysiological mapping can be used to differentiate sites of viable, ischemic, or scarred myocardium. In a transepicardial approach, cells are injected during open heart surgery. The advantage of this approach is that it allows direct visualization of the myocardium and easier identification of regions of scar and border zones of infarcted tissues. A third approach involves the delivery of cells through one of the cardiac veins directly into the myocardium.13 The limitation of this approach is that positioning the catheter within a particular coronary vein may be considerably more time consuming and technically challenging.
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Safety Concerns |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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Arrhythmias
Over the past few years, some of the early-phase clinical studies have suggested the possibility of a proarrhythmic effect associated with stem cell transplantation. In 1 study, skeletal myoblasts were injected transepicardially at the time of coronary artery bypass surgery. Four patients had documented ventricular tachycardia at 11, 12, 13, and 22 days after stem cell implantation.14 Interestingly, these events occurred early and were not observed in treated patients later after several months of follow-up. A similar proarrhythmic effect was observed when autologous skeletal myoblasts were delivered via a transvascular route.15 Other studies have similarly reported an increased frequency of nonsustained ventricular tachycardia in patients treated with skeletal myoblasts, peaking 11 to 30 days after stem cell transplantation.16,17 A proposed mechanism for the increased incidence of arrhythmias is that the injected stem cells do not communicate electrically with neighboring cardiac myocytes and/or result in slowed conduction, thereby promoting reentrant arrhythmias. It has recently been suggested that skeletal myoblasts that have been genetically engineered to express gap junction protein connexin 43 exhibited decreased arrhythmogenicity.18 Although proarrhythmic effects have been observed predominantly in patients receiving skeletal myoblast transplantation, they also have been observed recently in 2 patients shortly after transplantation of CD133+ cells.19,20
Restenosis, Accelerated Atherosclerosis, and Coronary Obstruction
There have been conflicting reports regarding the potential for increased restenosis after stem cell transplantation. In 1 study, a high rate of restenosis was observed after intracoronary delivery of peripheral blood stem cells mobilized with granulocyte colony-stimulating factor in the setting of myocardial infarction and stent placement.21 In another study, CD133+ cells were delivered via intracoronary injection in the setting of myocardial infarction, with in-stent restenosis rates of 37% and reocclusion rates of 11%.19 Relatively low rates of restenosis were observed in earlier studies using bone marrow–derived stem cells.10,20 In addition to restenosis, it is also possible that stem cell transplantation may promote the formation of de novo lesions or atherosclerotic plaque progression. In 2 recent studies, there was a fairly high proportion of new lesions identified in the nonstented vessels after stem cell transplantation.19,22 It is also possible that if the cells are delivered at a high enough concentration via the coronary circulation, they may adhere to each other, form aggregates, and thereby lead to the occlusion of microvessels. In 1 study in which mesenchymal stem cells were administered by intracoronary injection in pigs, there was associated occlusion of microvessels and macrovessels.23
Abnormal Cellular Differentiation
Fortunately, no clinical trials to date that have used stem cells to promote cardiac tissue regeneration have demonstrated an increased frequency of tumor formation. However, most of the clinical trials have been conducted on small numbers of patients. Furthermore, it is not clear how adequate testing would be conducted to monitor for this potential side effect. Because stem cells are known to migrate to several other organs after delivery to the heart, it is conceivable that aberrant cellular differentiation with the potential of tumor formation could occur in any of these organs.
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Tracking of Stem Cells |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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One of the major concerns regarding the delivery of stem cells is determining which cells remain in the heart and which cells ultimately end up in other organs as a result of a washout effect.24 Within a few hours after transplantation, stem cells injected locally within the heart also are observed within the lungs, spleen, liver, and kidney. One day after transplantation of neonatal cardiac myocytes into rat hearts, only 24% of the originally injected cells remained in the heart.25 Given the small fraction of stem cells that remain within the heart after injection and the multiple organs to which the stem cells migrate, it is imperative that better methods of tracking stem cells be developed to determine the fate of these cells after transplantation. Several potential methods have been developed to label and track stem cells in animal models, including scintigraphy, PET, and MRI.26–28 PET scanning and MRI also have been tested recently in humans to track stem cells.29,30 One hour after injection of 18F-fluorodeoxyglucose–labeled CD34+ cells, only 5.5% of the cells were detectable in the heart by PET scanning. Unfortunately, because of the short half-life of 18F-fluorodeoxyglucose, other isotopes with a longer half-life may need to be evaluated for optimal long-term tracking of stem cells.
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Evidence for Tissue Regeneration |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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The ultimate goal of stem cell therapy is to promote cardiac tissue regeneration so that the regenerated cardiac tissue leads to improvements in cardiac function in a fashion that is synchronized with the rest of the functioning heart in the absence of proarrhythmic or other adverse effects. More recently, however, there is evidence that stem cells may lead to improvements in cardiac function that are independent of tissue regeneration. Although early studies supported the ability of bone marrow–derived mononuclear cells to differentiate into cardiac myocytes, subsequent studies failed to support these initial observations.31–33 It has been suggested that the locally injected cells can act in a paracrine fashion to improve ventricular function through the release of growth factors or other paracrine mediators. These mediators may act to directly augment systolic function, prevent apoptosis of ischemic myocardial cells, or limit injury by promoting angiogenesis.34 The locally injected stem cells would promote the salvage of injured myocardium rather than tissue regeneration. Additional long-term studies are needed to determine whether the improvements observed after weeks to a few months are generally sustained over longer periods of time. These paracrine effects are more likely to be useful in patients with acute myocardial ischemia or with hibernating myocardium and less likely to be beneficial in patients with chronically infarcted myocardium with significant scar formation. Significant challenges remain with regard to cardiac tissue regeneration. Future studies are needed to identify the best stem cell type to use. To promote cardiac tissue regeneration, sufficient numbers of cells will need to be delivered and maintained within the heart at the site of LV dysfunction, and the new tissue needs to be vascularized, electrically and mechanically coupled with the rest of the myocardium. The hope is that the strategies will include ways of replacing scarred or fibrotic tissue in regions of LV dysfunction. Unless autologous cells can be used to generate the cardiac tissue, potential graft rejection needs to be addressed. Real progress toward this goal will require the collaborative interaction of investigators with expertise in tissue engineering, molecular biology, electrophysiology, cardiac physiology, immunology, and vascular biology.
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Recent Clinical Trials |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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Several small clinical studies using a variety of different cell types have shown some initial promise regarding the benefit of stem cell therapy, but these small clinical studies have several limitations. In addition to being small, some of the studies lacked adequate controls or randomization in a blinded fashion. Furthermore, some of the studies failed to assess infarct size or ventricular function before administration of the stem cells, and the follow-up period often was short.
Results of recent randomized clinical trials evaluating the therapeutic effect of administering bone marrow–derived mononuclear cells via intracoronary injection at the time of myocardial infarction have recently been reported (Table). Results of these studies have been mixed. The primary end point of these studies was LV ejection fraction. The administration of stem cells in 2 studies, BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) and Reinfusion of Enriched Progenitor cells And Infarct Remodelling in Acute Myocardial Infarction (REPAIR-AMI), resulted in significant increases in LV ejection fraction.35,36 The differences in ejection fraction of the treated and control groups at 6 months in the BOOST trial were 56.7% and 52.0%; in the REPAIR-AMI treated and control groups, the differences were 54% versus 50%. In contrast, in the study by Janssens et al,37 no difference between control and treated groups was observed, and in the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial, the LV ejection fraction was higher in the control group.36,38 The cause of these differences is unclear but may relate to how the cells were prepared before delivery or to the fact that the baseline ejection fractions at the time of myocardial infarction were only mildly diminished. There are ongoing additional randomized trials. BOOST-II will enroll 200 patients with large myocardial infarctions and depressed ejection fractions to receive bone marrow–derived mononuclear cells or placebo. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial will evaluate the effect of autologous skeletal muscle myoblasts in patients with chronic heart failure who are undergoing coronary bypass and defibrillator implantation.
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One attractive alternative to delivering autologous stem cells via local injection is to identify the mechanisms by which stem cells are recruited to the heart and try to augment mobilization of stem cells, particularly in the setting of acute infarction. Small clinical studies suggested that cytokines such as granulocyte colony-stimulating factor could promote the mobilization of bone marrow–derived stem cells in the setting of myocardial infarction, leading to improvements in myocardial function.39,40 The advantage of this approach is that the cells are autologous and can be mobilized via systemic injections of granulocyte colony-stimulating factor. Two larger randomized trials, consisting of 78 and 114 patients, similarly used granulocyte colony-stimulating factor to mobilize stem cells in the setting of myocardial infarction.41,42 Unfortunately, neither of these studies demonstrated a significant benefit with respect to cardiac function after 6 months. Furthermore, another smaller study in which intracoronary injections of stem cells isolated after stimulation with granulocyte colony-stimulating factor were administered in the setting of myocardial infarction resulted in an increased rate of restenosis.21
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Conclusions |
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TopIntroductionType of Cells Used...Methods of Stem Cell...Safety ConcernsTracking of Stem CellsEvidence for Tissue RegenerationRecent Clinical TrialsConclusionsReferences |
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Stem cells remain a highly promising therapeutic modality that could address the large, unmet clinical need of treating patients throughout the world with significant cardiac dysfunction that cannot be adequately treated with conventional therapeutic approaches or cardiac transplantation because of the limited availability of this resource. On the basis of the mixed results of more recent larger clinical trials, we should err on the side of caution before committing precious resources to conduct additional large clinical trials. Several questions need to be addressed. First, have we identified which stem cell type to use? Second, have we determined the mechanisms by which stem cells promote myocardial function or repair? At present, there is limited evidence to support that stem cells used thus far in patients promote significant cardiac tissue regeneration. Third, can the stem cell be retained efficiently within the heart? Finally, can clinical trials be done in such a way that important safety issues will be adequately addressed? What methods will be used to monitor the development of life-threatening arrhythmias and to track injected stem cells throughout the body? Because the financial resources available for clinical and basic stem cell research are not unlimited and because of the high cost associated with conducting larger clinical trials, it is particularly important that we address the aforementioned questions before proceeding with larger clinical trials. It is clear that additional basic research is needed to optimize ways to promote cardiac tissue regeneration, to improve methods by which delivered stem cells will remain in the heart, and to optimize the way in which stem cells are tracked after delivery.
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Acknowledgments |
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Funding
This work was supported by National Institutes of Health grant PO1-HL-76540.
Disclosures
Dr Oettgen has received a received a research grant from the NIH.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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