Cell-based Therapy for Heart Disease: A Clinically Oriented Perspective
Authors: Philippe Menasche
Journal: Molecular Therapy (2009)

Over the past decade, cell therapy has emerged as a potential new treatment of a variety of cardiac diseases, including acute myocardial infarction, refractory angina, and chronic heart failure. A myriad of cell types have been tested experimentally, each of them being usually credited by its advocates of a high "regeneration" potential. This has led to a flurry of clinical trials entailing the use of skeletal myoblasts or bone marrow–derived cells either unfractionated or enriched in progenitor subpopulations. As often in medicine, the hype generated by the early uncontrolled and small-sized studies has been dampened by the marginally successful outcomes of the subsequent, more rigorously conducted randomized trials. Although they may have failed to achieve their primary end points, these trials have been positive in the sense that they have allowed to identify some key issues and it is reasonable to speculate that if these issues can now be addressed by appropriately focused benchwork, the outcomes of the second generation of cell-transplantation studies would likely be upgraded. It, thus, appears that not "one cell fits all" but that the selection of the cell type should be tailored to the primary clinical indication. On the one hand, it does not make sense to develop an "ideal" cell in a culture dish, if we remain unable to deliver it appropriately and to keep it alive, at least for a while, which requires to improve on the delivery techniques and to provide cells along with the vascular and extracellular matrix type of support necessary for their survival and patterning. On the other hand, the persisting mechanistic uncertainties about cell therapy should not preclude continuing clinical trials, which often provide the unique opportunity of identifying issues missed by our suboptimal preclinical models. Finally, regardless of whether cells are expected to act paracrinally or by physically replacing lost cardiomyocytes and, thus, effecting a true myocardial regeneration, safety remains a primary concern. It is, thus, important that clinical development programs be shaped in a way that allows the final cell-therapy product to be manufactured from fully traceable materials, phenotypically well characterized, consistent, scalable, sterile, and genetically stable as these characteristics are those that will be required by the ultimate gatekeeper, i.e., the regulator, and are thus unbypassable prerequisites for an effective and streamlined leap from bench to bedside. Over the past decade, cell therapy has emerged as a potential new treatment of a variety of cardiac diseases, including acute myocardial infarction, refractory angina, and chronic heart failure. A myriad of cell types have been tested experimentally, each of them being usually credited by its advocates of a high "regeneration" potential. This has led to a flurry of clinical trials entailing the use of skeletal myoblasts or bone marrow–derived cells either unfractionated or enriched in progenitor subpopulations. As often in medicine, the hype generated by the early uncontrolled and small-sized studies has been dampened by the marginally successful outcomes of the subsequent, more rigorously conducted randomized trials. Although they may have failed to achieve their primary end points, these trials have been positive in the sense that they have allowed to identify some key issues and it is reasonable to speculate that if these issues can now be addressed by appropriately focused benchwork, the outcomes of the second generation of cell-transplantation studies would likely be upgraded. It, thus, appears that not "one cell fits all" but that the selection of the cell type should be tailored to the primary clinical indication. On the one hand, it does not make sense to develop an "ideal" cell in a culture dish, if we remain unable to deliver it appropriately and to keep it alive, at least for a while, which requires to improve on the delivery techniques and to provide cells along with the vascular and extracellular matrix type of support necessary for their survival and patterning. On the other hand, the persisting mechanistic uncertainties about cell therapy should not preclude continuing clinical trials, which often provide the unique opportunity of identifying issues missed by our suboptimal preclinical models. Finally, regardless of whether cells are expected to act paracrinally or by physically replacing lost cardiomyocytes and, thus, effecting a true myocardial regeneration, safety remains a primary concern. It is, thus, important that clinical development programs be shaped in a way that allows the final cell-therapy product to be manufactured from fully traceable materials, phenotypically well characterized, consistent, scalable, sterile, and genetically stable as these characteristics are those that will be required by the ultimate gatekeeper, i.e., the regulator, and are thus unbypassable prerequisites for an effective and streamlined leap from bench to bedside. Over the past decade, stem cells have been the subject of intense experimental and clinical research in virtually all fields of medicine. In the specific setting of cardiac diseases, this interest has been largely driven by two major considerations: the improved survival rate of patients with acute myocardial infarction due to revascularization therapies has put more of them at risk of developing heart failure1Velagaleti RS Pencina MJ Murabito JM Wang TJ Parikh NI D'Agostino RB et al.Long-term trends in the incidence of heart failure after myocardial infarction.Circulation. 2008; 118: 2057-2062Crossref PubMed Scopus (366) Google Scholar and despite the advances in drug therapy and resynchronization devices, the proportion of cardiovascular deaths in the group of heart failure patients with depressed left ventricular (LV) function has not substantially improved over time.2Henkel DM Redfield MM Weston SA Gerber Y Roger VL Death in heart failure. A community perspective.Circ Heart Fail. 2008; 1: 91-97Crossref PubMed Scopus (219) Google Scholar Put together, these observations account for the continued search for new option treatments among which cell therapy has gained a growing interest. Although the early wave of clinical trials has generated marginally successful results, it has also provided a huge amount of data that can now be used as a building block to move the field forward. This review will thus highlight some of the lessons learned from these initial clinical studies and discuss how these clinical findings, along with the most recent basic data on stem-cell biology, open attractive perspectives for cardiac regenerative therapy. After almost a decade of experimental studies, clinical trials of myoblast transplantation started in June 2000, when we performed the first human transplantation of autologous myoblasts in a patient with severe ischemic heart failure.3Menasche P Hagege AA Scorsin M Pouzet B Desnos M Duboc D et al.Myoblast transplantation for heart failure.Lancet. 2001; 357: 279-280Abstract Full Text Full Text PDF PubMed Scopus (977) Google Scholar This case initiated a series of 10 patients with a severe LV dysfunction (reflected by an ejection fraction ≤35%), a postinfarction nonviable scar and an indication for coronary artery bypass grafting (CABG) in ischemic but viable areas remote from the transplanted ones (which were thus not revascularized). The reassessment of these patients at an average follow-up of 52 months (18–58) has basically shown a symptomatic improvement, a relatively low incidence of hospitalizations for heart failure (0.13/patient-years) and a stabilization of echocardiographically measured LV ejection fraction (LVEF) and volumes.4Hagege AA Carrion C Menasche P Vilquin JT Duboc D Marolleau JP et al.Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.Circulation. 2006; 114: I108-I113PubMed Google Scholar In one patient who died 18 months postoperatively from a stroke, some engrafted myotubes could still be identified embedded in scar tissue. Three other adjunct-to-CABG transplantation studies were then performed.5Gavira JJ Herreros J Perez A Garcia-Velloso MJ Barba J Martin-Herrero F et al.Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up.J Thorac Cardiovasc Surg. 2006; 131: 799-804Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar,6Siminiak T Kalawski R Fiszer D Jerzykowska O Rzezniczak J Rozwadowska N et al.Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up.Am Heart J. 2004; 148: 531-537Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar,7Dib N Michler RE Pagani FD Wright S Kereiakes DJ Lengerich R et al.Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.Circulation. 2005; 112: 1748-1755Crossref PubMed Scopus (282) Google Scholar Whereas the patient profile and technique of open-chest multiple injections were very similar to those used in our study, the number of transplanted myoblasts was highly variable (221 × 106 in the study of Gavira et al.5Gavira JJ Herreros J Perez A Garcia-Velloso MJ Barba J Martin-Herrero F et al.Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up.J Thorac Cardiovasc Surg. 2006; 131: 799-804Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar from 4 × 105 to 5 × 107 in the study of Siminiak et al.6Siminiak T Kalawski R Fiszer D Jerzykowska O Rzezniczak J Rozwadowska N et al.Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up.Am Heart J. 2004; 148: 531-537Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar 1, 3, 10, 30 × 107 and 3 × 108 in the dose-escalating study of Dib et al.7Dib N Michler RE Pagani FD Wright S Kereiakes DJ Lengerich R et al.Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.Circulation. 2005; 112: 1748-1755Crossref PubMed Scopus (282) Google Scholar). Importantly, the protocol of these three studies also differed from ours in that it systematically entailed a concomitant revascularization of the myoblast-injected areas (Table 1).Table 1Summary of phase I adjunct-to-bypass surgical trials of skeletal myoblast transplantationStudyCell doseControlsRevascularization of the transplanted segmentsResultHagège et al4 (N = 10)871 × 106 (86% CD56+)NoneNo Improved symptoms at 52 months of FUStabilization of EF and LV volumes4 early postop VT (nonfatal) before systematic implementation of perioperative amiodarone prophylaxisGavira et al5 (N = 12)221 × 106 (65.6% CD56+)NoneYes Improved EF at 1 year of FUImproved regional contractility of myoblast-implanted segments (echo)Improved viability of myoblast-implanted segments (18F-FDG PET)Siminiak et al6 (N = 10)4 × 105 to 5 × 107(65.4% desmin+)NoneYes Improved EF at 1 year of FUImproved regional contractility of some myoblast-implanted segments (echo)2 early postop VT and 2 VT at 2 weeks (no additional case after systematic implementation of perioperative amiodarone prophylaxis)Dib et al7 1, 3, 10, and 30 × 107(3 patients per group) and 3 × 108 (12 patients) (79% CD56+)NoneYes Improved EF at 2 years of FUImproved viability of some myoblast-implanted segments (18F-FDG PET and MRI)EF, ejection fraction; FDG PET, fluorodeoxyglucose positron emission tomography; FU, follow-up; LV, left ventricle; MRI, magnetic resonance imaging; VT, ventricular tachycardia. Open table in a new tab EF, ejection fraction; FDG PET, fluorodeoxyglucose positron emission tomography; FU, follow-up; LV, left ventricle; MRI, magnetic resonance imaging; VT, ventricular tachycardia. Put together, these studies have primarily demonstrated the feasibility of the procedure as well as the safety of multiple needle punctures in the postinfarction scar and along its borders. Likewise, none of the myoblast-injected patients have developed a cardiac tumor (our longest survivor was operated on in December 2000). Indeed, the only safety concern has been an increased risk of arrhythmias after some of these early-phase trials reported postoperative episodes of sustained ventricular tachycardia.4Hagege AA Carrion C Menasche P Vilquin JT Duboc D Marolleau JP et al.Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.Circulation. 2006; 114: I108-I113PubMed Google Scholar,6Siminiak T Kalawski R Fiszer D Jerzykowska O Rzezniczak J Rozwadowska N et al.Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up.Am Heart J. 2004; 148: 531-537Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar The currently prevailing hypothesis is that differentiated myotubes fail to express gap junction proteins and, as such, feature islet-like clusters electrically isolated from the surrounding cardiomyocytes;8Leobon B Garcin I Menasche P Vilquin JT Audinat E Charpak S Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host.Proc Natl Acad Sci USA. 2003; 100: 7808-7811Crossref PubMed Scopus (433) Google Scholar this, in turn, could slow the conduction velocity of electrical impulses and consequently predispose to reentry circuits.9Abraham MR Henrikson CA Tung L Chang MG Aon M Xue T et al.Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation.Circ Res. 2005; 97: 159-167Crossref PubMed Scopus (242) Google Scholar This hypothesis is largely based on coculture experimental data showing that myoblast transfection with connexin 43 decreases arrhythmogenicity.9Abraham MR Henrikson CA Tung L Chang MG Aon M Xue T et al.Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation.Circ Res. 2005; 97: 159-167Crossref PubMed Scopus (242) Google Scholar In vivo data have been more conflicting10Fernandes S Amirault JC Lande G Nguyen JM Forest V Bignolais O et al.Autologous myoblast transplantation after myocardial infarction increases the inducibility of ventricular arrhythmias.Cardiovasc Res. 2006; 69: 348-358Crossref PubMed Scopus (107) Google Scholar,11Fouts K Fernandes B Mal N Liu J Laurit KR Electrophysiological consequence of skeletal myoblast transplantation in normal and infarcted canine myocardium.Heart Rhythm. 2006; 3: 452-461Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,12Mills WR Mal N Kiedrowski MJ Unger R Forudi F Popovic ZB et al.Stem cell therapy enhances electrical viability in myocardial infarction.J Mol Cell Cardiol. 2007; 42: 304-314Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar but overall they support an increased risk of myoblast-related arrhythmias, possibly worsened by needle-induced disruption of myocardial tissue and the associated inflammatory damage.13Fukushima S Varela-Carver A Coppen SR Yamahara K Felkin LE Lee J et al.Direct intramyocardial but not intracoronary injection of bone marrow cells induces ventricular arrhythmias in a rat chronic ischemic heart failure model.Circulation. 2007; 115: 2254-2261Crossref PubMed Scopus (156) Google Scholar Clinically, however, the assessment of this risk is complicated by the interplay of several factors including concurrent medications, graft size,9Abraham MR Henrikson CA Tung L Chang MG Aon M Xue T et al.Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation.Circ Res. 2005; 97: 159-167Crossref PubMed Scopus (242) Google Scholar the location of myoblast injections (those performed in the core of the scar seem less arrhythmogenic than those lining the border zone)14Soliman AM Krucoff MW Crater S Morimoto Y Taylor DA Cell location may be a primary determinant of safety after myoblast transplantation into the infarcted heart.J Am Coll Cardiol. 2004; 43: 15AAbstract Full Text PDF PubMed Google Scholar and the intrinsically arrhythmogenic nature of the underlying heart failure. Although these initial studies were neither designed nor powered to provide efficacy data, the functional effects of myoblast injections were nevertheless assessed up to 4 years7Dib N Michler RE Pagani FD Wright S Kereiakes DJ Lengerich R et al.Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.Circulation. 2005; 112: 1748-1755Crossref PubMed Scopus (282) Google Scholar and even later (58 months in our trial).4Hagege AA Carrion C Menasche P Vilquin JT Duboc D Marolleau JP et al.Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.Circulation. 2006; 114: I108-I113PubMed Google Scholar Outcomes were found to range from stabilization of LVEF and volumes4Hagege AA Carrion C Menasche P Vilquin JT Duboc D Marolleau JP et al.Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.Circulation. 2006; 114: I108-I113PubMed Google Scholar to improvements in regional and global LV function from baseline values3Menasche P Hagege AA Scorsin M Pouzet B Desnos M Duboc D et al.Myoblast transplantation for heart failure.Lancet. 2001; 357: 279-280Abstract Full Text Full Text PDF PubMed Scopus (977) Google Scholar,4Hagege AA Carrion C Menasche P Vilquin JT Duboc D Marolleau JP et al.Skeletal myoblast transplantation in ischemic heart failure: long-term follow-up of the first phase I cohort of patients.Circulation. 2006; 114: I108-I113PubMed Google Scholar and, occasionally, in metabolic viability of transplanted areas, as assessed by positron emission tomography and magnetic resonance imaging (MRI).5Gavira JJ Herreros J Perez A Garcia-Velloso MJ Barba J Martin-Herrero F et al.Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up.J Thorac Cardiovasc Surg. 2006; 131: 799-804Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar,7Dib N Michler RE Pagani FD Wright S Kereiakes DJ Lengerich R et al.Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up.Circulation. 2005; 112: 1748-1755Crossref PubMed Scopus (282) Google Scholar It is clear, however, that the small size of these series, their open-label type of design and the lack of controls made these data inconclusive. For this reason, we implemented a randomized, double blind, placebo-controlled trial (MAGIC, an acronym for Myoblast Autologous Grafting in Ischemic Cardiomyopathy), which involved 21 centers in Europe and included patients meeting the same inclusion criteria as in the phase I studies (severe LV dysfunction, postinfarction nonviable scar, and indication for CABG). Muscular biopsies were shipped to two core laboratories where they were cultured and 3 weeks later, either cells (at two different doses: 400 and 800 million) or a placebo solution were injected in ∼30 sites encompassing the core and the margins of the infarct area during the bypass surgery. Notably, an internal cardioverter-defibrillator was implanted in every patient before hospital discharge. Out of 120 randomized patients, 97 were effectively treated and the major outcomes, at the 6-month study point, can be summarized as follows: (i) the proportion of patients who experienced arrhythmias was not significantly different between the myoblast-treated and the placebo-injected groups. However, analysis of the time course of events showed that arrhythmias tended to be clustered in the early postoperative period in the myoblast-treated groups, whereas they were more evenly distributed over time in the placebo arm of the trial. Not unexpectedly, these findings make a strong case for the benefits of internal cardioverter-defibrillator implantation in this high-risk patient population irrespective of any cell therapy; (ii) neither regional nor global LV function, as assessed blindly by echocardiography in a core laboratory, were significantly improved by myoblast injections, regardless of the dose, compared with controls, which sharply contrasts with the encouraging results of the above-mentioned phase I trials and once again highlight the importance of randomization, blind assessment, and adequate controls to draw meaningful conclusions; (iii) however, the highest dose of cells resulted in a significant reversal of remodeling, evidenced by a decrease in LV enddiastolic and endsystolic volumes (a prespecified secondary end point) compared with the placebo group.15Menasché Ph Alfieri O Janssens S McKenna W Reichenspurner H Trinquart L et al.The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) Trial. First Randomized Placebo-Controlled Study of Myoblast Transplantation.Circulation. 2008; 117: 1189-1200Crossref PubMed Scopus (765) Google Scholar Although this encouraging signal tended to validate the concept that cells can exert some beneficial effects, it is clear that under the conditions of the trial, these effects were not powerful enough to translate into meaningful improvements in contractile function. In parallel to these surgical trials, three phase I catheter–based studies have been reported. One has entailed administration of myoblasts through the coronary sinus with a dedicated catheter, which allows direct cell injections into the target area under endovascular ultrasound guidance.16Siminiak T Fiszer D Jerzykowska O Grygielska B Rozwadowska N Kalmucki P et al.Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial.Eur Heart J. 2005; 26: 1188-1195Crossref PubMed Scopus (206) Google Scholar Experimentally, this system has resulted in a successful engraftment of myoblasts17Brasselet C Morichetti MC Messas E Carrion C Bissery A Bruneval P et al.Skeletal myoblast transplantation through a catheter-based coronary sinus approach: an effective means of improving function of infarcted myocardium.Eur Heart J. 2005; 26: 1551-1556Crossref PubMed Scopus (44) Google Scholar and the 10-patient clinical study, conducted by Siminiak et al.16Siminiak T Fiszer D Jerzykowska O Grygielska B Rozwadowska N Kalmucki P et al.Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial.Eur Heart J. 2005; 26: 1188-1195Crossref PubMed Scopus (206) Google Scholar has confirmed both the feasibility and safety of this approach. However, this route of cell transfer may be technically challenging, particularly in patients who have previously undergone lead implantation for cardiac-resynchronization therapy. The other two percutaneous trials have entailed endoventricular injections of myoblasts under electromechanical guidance18Biagini E Valgimigli M Smits PC Poldermans D Schinkel AF Rizzello V et al.Stress and tissue Doppler echocardiographic evidence of effectiveness of myoblast transplantation in patients with ischaemic heart failure.Eur J Heart Fail. 2006; 8: 641-648Crossref PubMed Scopus (29) Google Scholar,19Ince H Petzsch M Rehders TC Chatterjee T Nienaber CA Transcatheter transplantation of autologous skeletal myoblasts in postinfarction patients with severe left ventricular dysfunction.J Endovasc Ther. 2004; 11: 695-704Crossref PubMed Scopus (83) Google Scholar and are clearly fraught with the same methodologic limitations as those of the phase I surgical trials. These hurdles have been partly overcome by another percutaneous study, which has randomized 23 patients with LVEF <40% and old (>10 years) infarction to endoventricular myoblast injections or optimal medical management alone.20Dib N Dinsmore J Mozak R White B Moravec S Diethrich EB Safety and feasability of percutaneous autologous skeletal myoblast transplantation for ischemic cardiomyopathy: six-month interim analysis.Circulation. 2006; 114: II88Google Scholar Although the 6-month interim results look encouraging (no major safety concern and a trend toward smaller LV dimensions in the myoblast-treated patients), they are still limited and in contradiction with those of the randomized SEISMIC trial reported by Serruys at the 2008 American College of Cardiology meeting; in this study, which allocated 31 patients to myoblast injections while 16 patients received "optimal medical therapy," there was no added benefit of cell therapy on LV function measured at 6 months after the procedure. An upcoming larger-scale randomized controlled trial will hopefully help in clarifying this issue but one has to admit that currently available data have not provided conclusive evidence for a favorable shift of the risk-to-benefit ratio following skeletal myoblast transplantation. In this setting, mononuclear cells (MNCs) derived from bone marrow or peripheral blood, CD133+ progenitors and mesenchymal stem cells (MSCs) have undergone clinical testing. Most studies have focused on MNC extemporaneously processed from bone marrow aspirates and reinjected into the infarct-related artery a few days after its recanalization by balloon angioplasty and stenting. Not unexpectedly, the enthusiasm raised by the consistently positive results of early-phase uncontrolled and usually small-sized studies has been dampened by the data yielded by the following wave of randomized trials. The most recent meta-analysis has compiled the data of 811 patients included in 13 randomized trials.21Martin-Rendon E Brunskill SJ Hyde CJ Stanworth SJ Mathur A Watt SM Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review.Eur Heart J. 2008; 29: 1807-1818Crossref PubMed Scopus (456) Google Scholar Overall, stem-cell therapy was found to improve LVEF by 2.99% (95% confidence interval, 1.26–4.72%, P = 0.0007), despite a considerable degree of heterogeneity in LVEF comparisons, and reduce LV endsystolic volume by 4.74 ml (95% confidence interval, −7.84 to −1.64 ml, P = 0.003) and myocardial lesion area by 3.51% (95% confidence interval, −5.91 to −1.11%, P = 0.004) compared with controls. Subgroup analysis revealed that the benefit of cell therapy was greater when cells were infused within 7 days following infarction and when the dose administered was higher than 108. However, bone marrow–cell therapy failed to alter postinfarction remodeling, which is a major predictor of late adverse outcomes22Udelson JE Konstam MA Relation between left ventricular remodeling and clinical outcomes in heart failure patients with left ventricular systolic dysfunction.J Card Fail. 2002; 8: S465-S470Abstract Full Text PDF PubMed Scopus (75) Google Scholar and should, thus, be logically the primary target of interventions adjunctive to current percutaneous revascularization procedures. Indeed, a more focused analysis of the large randomized controlled trials shows that the 204-patient REPAIR-AMI study23Schächinger V Erbs S Elsässer A Haberbosch W Hambrecht R Hölschermann H et al.Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial.Eur Heart J. 2006; 27: 2775-2783Crossref PubMed Scopus (499) Google Scholar is the only one to have unequivocally shown the benefits of intracoronary infusions of bone marrow–derived MNC, particularly in the subgroup of patients with an LVEF at or below the median value of 49% (absolute improvement in LVEF, 5.0; 95% confidence interval, 2.0–8.1). Furthermore, in this trial, cell therapy was reported to have reduced the 1-year prespecified combined clinical endpoint of death, recurrence of myocardial infarction, and any revascularization procedure (P = 0.01). In the other large studies, the alleged benefits of stem-cell therapy have been less straightforward, totally negative (ASTAMI),24Lunde K Solheim S Aakhus S Arnesen H Abdelnoor M Egeland T et al.Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.N Engl J Med. 2006; 355: 1199-1209Crossref PubMed Scopus (1142) Google Scholar mixed like in the Belgium25Janssens S Dubois C Bogaert J Theunissen K Deroose C Desmet W et al.Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial.Lancet. 2006; 367: 113-121Abstract Full Text Full Text PDF PubMed Scopus (1151) Google Scholar trial, where EF failed to improve despite a reduction in infarct size (similar to what has been observed in a swine model duplicating the clinical scenario)26Moelker AD Baks T van den Bos EJ van Geuns RJ de Feyter PJ Duncker DJ et al.Reduction in infarct size, but no functional improvement after bone marrow cell administration in a porcine model of reperfused myocardial infarction.Eur Heart J. 2006; 27: 3057-3064Crossref PubMed Scopus (53) Google Scholar or transient, like in the BOOST trial, where the better outcomes seen at 4 months after cell infusions were not apparent 14 months later because of a gradual improvement in the control group.27Meyer GP Wollert KC Lotz J Steffens J Lippolt P Fichtner S et al.Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrow transfer to enhance ST-elevation infarct regeneration) trial.Circulation. 2006; 113: 1287-1294Crossref PubMed Scopus (905) Google Scholar The interpretation of results also needs to be cautious; for example, in the recently published FINCELL trial