Myocardial Repair and Regeneration: Bone Marrow or Cardiac Stem Cells?
Authors: Keith G Oldroyd, Colin Berry, Jozef Bartunek
Journal: Molecular Therapy (2012)

Following encouraging preclinical animal data, stem cell therapy has been tested in a variety of clinical trials in patients with both acute and chronic ischemic myocardial injury with the goal of repairing damaged myocardium and/or inducing the growth of new blood vessels so as to improve cardiac function and symptoms. Many cell types have been studied, but most clinical trials to date have utilized autologous bone marrow mononuclear cells (or cellular fractions thereof) with good safety data but heterogeneous results in terms of efficacy.1Malliaras K Marban E Cardiac cell therapy: where we've been, where we are, and where we should be headed.Br Med Bull. 2011; 98: 161-185Crossref PubMed Scopus (159) Google Scholar Two new studies using this cell type were recently completed by the Cardiac Cell Therapy Research Network established by the National Heart, Lung, and Blood Institute to accelerate the development of cell-based therapies in the USA. Both failed to demonstrate any beneficial effects on cardiac function.2Traverse JH Henry TD Ellis SG Pepine CJ Willerson JT Zhao DXM et al.Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function. The LateTIME Randomized Trial.JAMA. 2011; 306: 2110-2119Crossref PubMed Scopus (334) Google Scholar,3Perin EC Willerson JT Pepine CJ Henry TD Ellis SG Zhao DXM et al.Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function and perfusion in chronic heart failure. The FOCUS-CCTRN trial.JAMA. 2012; (e-pub ahead of print 24 March 2012)Google Scholar By contrast, two recently published trials using stem cells derived from the heart itself have reported positive results.4Makkar RR Smith RR Cheng K Malliaras K Thomson LEJ Berman D et al.Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.Lancet. 2012; 379: 895-904Abstract Full Text Full Text PDF PubMed Scopus (1121) Google Scholar,5Bolli R Chugh AR D'Amario D Loughran JH Stoddard MF Ikram S et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text Full Text PDF PubMed Scopus (1105) Google Scholar In this Commentary, we describe these trials in detail and provide possible explanations for their differing results. Acute myocardial infarctions (AMIs), or heart attacks, are caused by interruption of blood supply to a part of the heart, leading to death of heart tissue, most often due to rupture of an atherosclerotic plaque and blockage of a coronary artery. In most heart attack patients, the blocked coronary artery can be reopened using either thrombolytic drugs or percutaneous coronary intervention (PCI) employing balloon angioplasty and stents. However, depending mainly on the time delay between the attack and therapeutic intervention, many patients fail to achieve complete recovery of the damaged heart tissue and sustain substantial injury, leading to impaired cardiac function and heart failure. Several evidence-based drug therapies can improve the symptoms and cardiac dysfunction associated with the resulting ischemic cardiomyopathy, but there remains a need for new therapies to treat patients whose clinical condition fails to improve or continues to deteriorate. It is now recognized that both extracardiac (e.g., bone marrow) and intracardiac progenitor cells are mobilized and home to the site of the myocardial injury to participate in the compensatory healing response. There is also growing evidence that such cells participate in the maturation and induction of collateral vascular growth and neovasculogenesis and may acquire phenotypic properties of neighboring cardiac myocytes.6Bartunek J Vanderheyden M Hill J Terzic A Cells as biologics for cardiac repair in ischemic heart failure.Heart. 2010; 96: 780-792Crossref Scopus (38) Google Scholar However, these natural self-renewing processes, while sufficient to sustain normal homeostasis, are insufficient to salvage heart muscle following massive injury. This situation has prompted efforts to isolate, propagate, and reintroduce into the body various types of progenitor cells associated with the healing response. The LateTIME study is a randomized, double-blind, placebo-controlled trial of 150 million autologous nucleated bone marrow mononuclear cells administered by intracoronary injection to patients with AMI and a left ventricular ejection fraction (LVEF) below 45% (Table 1). Patients were recruited 2–3 weeks after their initial event, a time window chosen to determine whether patients who present to centers that lack expertise in cell therapy or who are initially too unstable to be treated could still benefit from the therapy. The same investigators are conducting a parallel study with a recruitment window of 3–7 days after the initial AMI (the TIME study). Patients randomized to placebo received 5% (v/v) human serum albumin–saline solution to which 100 ml of autologous blood was added to ensure that the color and consistency of the solution matched those of the experimental therapy. After 6 months' follow-up, the cardiac magnetic resonance imaging (MRI) data showed no effect of the treatment on either overall or regional cardiac function or infarct size2Traverse JH Henry TD Ellis SG Pepine CJ Willerson JT Zhao DXM et al.Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function. The LateTIME Randomized Trial.JAMA. 2011; 306: 2110-2119Crossref PubMed Scopus (334) Google Scholar (Table 2). These data contrast with those from the previously published double-blinded, placebo-controlled Repair-AMI trial, which reported a significant benefit on ejection fraction following intracoronary administration of bone marrow mononuclear cells at a median of 4 days after the clinical event.7Schächinger V Erbs S Elsässer A Haberbosch W Hambrecht R Hölschermann H et al.Intra-coronary bone marrow-derived progenitor cells in acute myocardial infarction.N Engl J Med. 2006; 355: 1210-1221Crossref PubMed Scopus (1682) Google Scholar Taken together, these two studies suggest that bone marrow mononuclear cell therapy may be efficacious only if administered early after AMI.Table 1Summary of design and methodologyName of study and referenceDesignControl (n)Treated (n)LVEF (%)Cell source (all autologous)Dose (millions of cells)SettingTimingRoute of administrationLateTIME2Traverse JH Henry TD Ellis SG Pepine CJ Willerson JT Zhao DXM et al.Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function. The LateTIME Randomized Trial.JAMA. 2011; 306: 2110-2119Crossref PubMed Scopus (334) Google ScholarDouble-blind2655<45Bone marrow mononuclear cells150PCI for acute MI2-3 weeks after MIIntracoronary FOCUS-CCTRN3Perin EC Willerson JT Pepine CJ Henry TD Ellis SG Zhao DXM et al.Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function and perfusion in chronic heart failure. The FOCUS-CCTRN trial.JAMA. 2012; (e-pub ahead of print 24 March 2012)Google ScholarDouble-blind3161<45Bone marrow mononuclear cells100Heart failure ± anginaChronic EndocardialinjectionCADUCEUS4Makkar RR Smith RR Cheng K Malliaras K Thomson LEJ Berman D et al.Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.Lancet. 2012; 379: 895-904Abstract Full Text Full Text PDF PubMed Scopus (1121) Google ScholarOpen-label817 (15)aFigures in parentheses are numbers for whom imaging data were available.25-45CDCs cultured from endomyocardial biopsies25PCI for acute MI~100 days post MIIntracoronarySCIPIO5Bolli R Chugh AR D'Amario D Loughran JH Stoddard MF Ikram S et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text Full Text PDF PubMed Scopus (1105) Google ScholarOpen-label716 (14)aFigures in parentheses are numbers for whom imaging data were available.<40c-kit + cells cultured from right atrial appendage1Elective CABG after MI~100 days after CABGIntracoronaryAbbreviations: CABG, coronary artery bypass graft; CDC, cardiosphere-derived cell; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention.a Figures in parentheses are numbers for whom imaging data were available. Open table in a new tab Table 2Summary of effects of cell therapyName of study and referenceNYHAMyocardial scar mass by CMRRegional wall motionLVEFLateTIME2Traverse JH Henry TD Ellis SG Pepine CJ Willerson JT Zhao DXM et al.Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function. The LateTIME Randomized Trial.JAMA. 2011; 306: 2110-2119Crossref PubMed Scopus (334) Google ScholarNot assessedNo differenceNo differenceNo differenceFOCUS-CCTRN3Perin EC Willerson JT Pepine CJ Henry TD Ellis SG Zhao DXM et al.Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function and perfusion in chronic heart failure. The FOCUS-CCTRN trial.JAMA. 2012; (e-pub ahead of print 24 March 2012)Google ScholarNo differenceNot assessedNo differenceNo differenceCADUCEUS4Makkar RR Smith RR Cheng K Malliaras K Thomson LEJ Berman D et al.Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.Lancet. 2012; 379: 895-904Abstract Full Text Full Text PDF PubMed Scopus (1121) Google ScholarNo difference28% ↓ at 6 monthsSignificant improvementNo difference (CMR)SCIPIO5Bolli R Chugh AR D'Amario D Loughran JH Stoddard MF Ikram S et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text Full Text PDF PubMed Scopus (1105) Google ScholarSignificant improvement24% ↓ at 4 monthsan = 7 treated patients in CMR substudy.Significant improvementSignificant increase (echo)Abbreviations: CMR, cardiac magnetic resonance; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association heart failure classification.a n = 7 treated patients in CMR substudy. Open table in a new tab Abbreviations: CABG, coronary artery bypass graft; CDC, cardiosphere-derived cell; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention. Abbreviations: CMR, cardiac magnetic resonance; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association heart failure classification. In the FOCUS-CCTRN trial, patients with chronic ischemic left ventricular dysfunction with heart failure and/or angina were entered into a randomized, double-blinded, controlled trial comparing 100 million autologous nucleated bone marrow cells or placebo administered by catheter-mediated intramyocardial injection using an existing electromechanical mapping system to identify appropriate sites for injection (Table 1). This trial had three co-primary end points: the change in left ventricular end-systolic volume assessed by echocardiography, maximal oxygen consumption, and reversal of myocardial perfusion abnormalities identified using single-photon emission tomography. After 6 months' follow-up, there were no statistically significant differences between the groups for any of the primary end points and no differences in patient symptoms3Perin EC Willerson JT Pepine CJ Henry TD Ellis SG Zhao DXM et al.Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function and perfusion in chronic heart failure. The FOCUS-CCTRN trial.JAMA. 2012; (e-pub ahead of print 24 March 2012)Google Scholar (Table 2). Regression analysis suggested a positive relationship between the CD34+ and CD133+ cell count in the cell population and absolute change in ejection fraction. In this regard, it should be noted that injection of purified CD34 cells previously yielded therapeutic benefit in a population of patients with chronic myocardial ischemia.8Losordo DW Henry TD Davidson C Lee JS Costa MAA Bass T et al.Intramyocardial autologous CD34+ cell therapy for refractory angina.Circ Res. 2011; 109: 428-436Crossref PubMed Scopus (391) Google Scholar In addition, it has been recognized that the functional properties of stem cells are impaired in older patients and in those with advanced ischemic heart disease and heart failure. In FOCUS-CCTRN, a prespecified subgroup analysis showed a statistically significant treatment effect on LVEF of patients younger than 62 years (the median age of the study population), with no benefit in those older than 62 years, suggesting that age is an important consideration for inclusion in such trials. Cardiac stem cells (CSCs) were first identified in the murine heart in 1999 and isolated and characterized in human myocardium by Messina et al. in 2004 (refs. 9Deisher TA Cardiac-derived stem cells.IDrugs. 2000; 3: 649-653PubMed Google Scholar, 10Messina E De Angelis L Frati G Morrone S Chimenti S Fiordaliso F et al.Isolation and expansion of adult cardiac stem cells from human and murine heart.Circ Res. 2004; 95: 911-921Crossref PubMed Scopus (1224) Google Scholar). The cardiac source of these cells may more readily ensure a therapeutic benefit as compared with naive bone marrow mononuclear cells. In animal models, CSCs injected into the heart have been shown to differentiate into all three major cardiac cell types—cardiomyocytes, endothelial cells, and vascular smooth muscle cells—and this led to improved cardiac function, suggesting that the delivered cells directly contributed to generation of new myocardial tissue. The results of two small prospective randomized first-in-human studies of stem cells derived from cardiac tissue and delivered back to the heart were recently reported. These studies employed two distinct CSC populations, but both purport to show, for the first time, evidence of myocardial regeneration within previously infarcted areas. In the CADUCEUS (Cardiosphere-Derived Autologous Stem Cells to Reverse Ventricular Dysfunction) study, 31 patients with AMI who had undergone successful PCI with stent implantation but were left with reduced cardiac function were randomized in a ratio of 2:1 to receive usual care or 12.5–25 million autologous cardiosphere-derived cells (CDCs) cultured from percutaneous endomyocardial biopsy tissues obtained approximately 2–4 weeks after the AMI4Makkar RR Smith RR Cheng K Malliaras K Thomson LEJ Berman D et al.Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.Lancet. 2012; 379: 895-904Abstract Full Text Full Text PDF PubMed Scopus (1121) Google Scholar (Table 1). Cell preparation required an average of 36 days, and most patients were treated 6–12 weeks after the MI (average 65 days). The cells were administered by intracoronary injection into the infarct-affected artery using a balloon catheter inflated at the site of the previously implanted stent. As might be expected in such a small trial, there were differences in the patient characteristics between the two groups, including racial origin, history of prior MI, and location of the damage within the heart. Although cardiac function was impaired in both groups, there was no description of the standard drug therapies used in such patients. Only 25 patients completed the study because of various modes of failure of the cell culture4Makkar RR Smith RR Cheng K Malliaras K Thomson LEJ Berman D et al.Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial.Lancet. 2012; 379: 895-904Abstract Full Text Full Text PDF PubMed Scopus (1121) Google Scholar, presence of an occluded artery at the time of planned cell therapy preventing delivery of the cell therapy1Malliaras K Marban E Cardiac cell therapy: where we've been, where we are, and where we should be headed.Br Med Bull. 2011; 98: 161-185Crossref PubMed Scopus (159) Google Scholar, or withdrawal of consent1Malliaras K Marban E Cardiac cell therapy: where we've been, where we are, and where we should be headed.Br Med Bull. 2011; 98: 161-185Crossref PubMed Scopus (159) Google Scholar. Importantly, the investigators report that the US Food and Drug Administration would not allow the use of a sham procedure, so this trial was not blinded. However, the MRI scans used to evaluate left ventricular function, volumes, and infarct size were analyzed in a blinded fashion by an independent "core" lab. The primary end point of the trial was a combination of safety outcomes, and in this respect the trial was positive with no reported adverse events at the time of cell infusion and no incidence of ventricular arrhythmias, sudden death, or the development of cardiac tumors during 6 months of follow-up. There was one new MI between 6 and 12 months in the cell-treated group but no other major adverse cardiac events. Serious adverse events were three times more common in the cell therapy group (36% vs. 13%), but this difference was not significant, clearly because of the small numbers involved. The efficacy outcomes are summarized in Table 2. No improvements in symptoms or quality of life were reported by the patients. The excitement generated by this study relates to the cardiac MRI results, which showed a marked reduction in the volume of myocardial scar assessed using the well-validated technique of late gadolinium enhancement. At 6 months, between-group differences in function in the infarct zones also favored the CDC-treated patients, although the within-subject changes in these parameters were not reported and overall left ventricular volumes and function were similar. In the SCIPIO (Stem Cell Infusion in Patients With Ischemic Cardiomyopathy) trial, the published work represents an interim report of 23 randomized patients from a study described as "ongoing"5Bolli R Chugh AR D'Amario D Loughran JH Stoddard MF Ikram S et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text Full Text PDF PubMed Scopus (1105) Google Scholar (Table 1). These patients all had remote MI an average of 3.7 years before recruitment and were scheduled to undergo elective coronary artery bypass graft surgery (CABG). During this surgery, the right atrial appendage is routinely removed and can be used to initiate cell culture. In each patient studied, it was possible to generate approximately 2 million c-Kit-positive CSCs over a period of several weeks. Patients randomized to cell therapy received 0.5–1 million cells by intracoronary injection via a native coronary artery or bypass graft approximately 4 months after surgery. Clearly, blinding would have been feasible in SCIPIO because the cardiac tissue was harvested under general anesthesia during cardiac surgery rather than percutaneously under local anesthesia as a separate procedure. However, the investigators indicated that they did not wish to undertake any additional invasive procedures in the control group, and so this trial was also not blinded. Cardiac function was assessed using three-dimensional echocardiography with only a subgroup undergoing cardiac MRI. Hence, there are only limited data on infarct size. Cell culture was successful in 80 of 81 patients screened for entry into the trial, although many subjects were excluded in the period between CABG and planned cell administration, mainly because of withdrawal of consent or an improvement in LVEF post CABG to >40%. Again, the primary end point was a combination of safety outcomes, and, like CADUCEUS, the trial was positive in this respect, with no reported incidence of ventricular arrhythmias, sudden death, or the development of cardiac tumors during up to 12 months of follow-up. There was one periprocedural adverse event due to catheter-related damage to a bypass graft that was being used as the conduit artery for cell administration to the heart. As a result, this bypass graft required treatment by additional coronary intervention. Other serious adverse events occurred with similar frequency in the two groups. The efficacy outcomes are summarized in Table 2. In contrast to CADUCEUS, cell-treated patients in SCIPIO demonstrated significant improvements in symptoms, quality of life, and LVEF at 4 months' follow-up. The seven treated patients who participated in the cardiac magnetic resonance (CMR) substudy showed a statistically significant reduction in myocardial scar mass from baseline to 4 months, which was further reduced in the six patients who underwent a second cardiac MRI at 12 months. Therefore, CADUCEUS and SCIPIO achieved their goal of demonstrating the feasibility and medium-term safety of culturing therapeutic doses of autologous CSCs from myocardial biopsy tissues and subsequently administering these cells by intracoronary injection to patients with prior MI. Although not powered for efficacy, both studies demonstrated a reduction in the volume/mass of scar on cardiac MRI, and this has been interpreted as showing replacement of the scar tissue with new viable heart muscle. If functionally important myocardial regeneration had taken place, an improvement in cardiac function and symptoms would have been expected. Despite similar reductions in scar volume (see Table 2), only the patients in SCIPIO showed improvements in quality of life and overall cardiac function. These findings may reflect differential efficacy of the two cell types.11Li T-S Cheng K Malliaras K Smith RR Zhang Y Sun B et al.Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells.J Am Coll Cardiol. 2012; 59: 942-953Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar In addition, the patients in CADUCEUS were treated 2–3 months after their original MIs as compared with 3–4 years in SCIPIO. In terms of translation and wider applicability, the intracoronary route of administration is obviously most attractive because it is easier and safer than direct injection of therapeutics into the heart muscle. In autologous CSC–derived therapy, the time taken for cell culture could mean that the window for optimal benefit may be missed in patients with recent AMI. If the efficacy of CSCs is confirmed in larger phase II studies, this would represent a paradigm shift in the management of patients with cardiac dysfunction due to prior MI. However, the results of LateTIME and FOCUS-CCTRN highlight the critical importance of study design. No matter how logistically difficult, future trials with CSCs should have a double-blind design with matched study procedures because proof of clinically meaningful efficacy will be required before wider adoption can be recommended.