Ann Thorac Surg 2005;79:S2238-S2247
© 2005 The Society of Thoracic Surgeons
Supplement
Current Status of Cellular Therapy for Ischemic Heart Disease
Shafie Fazel, MD, MS,
Gilbert H.L. Tang, MD,
Denis Angoulvant, MD, MS,
Massimo Cimini, PhD,
Richard D. Weisel, MD,
Ren-Ke Li, MD, PhD,
Terrence M. Yau, MD, MS*
Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, Department of Surgery, University of Toronto, Heart and Stroke Foundation/Richard Lewar Centre of Excellence, Toronto, Ontario, Canada
Accepted for publication February 21, 2005.
* Address reprint requests to Dr Yau, Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, 13EN-239, 200 Elizabeth St, Toronto, Ontario, Canada, M5G 2C4 (E-mail: terry.yau{at}utoronto.ca).
Presented at the 4th Annual Lillehei Heart Institute Symposium Celebrating the 50th Anniversary of Open-Heart Surgery by Cross Circulation, Minneapolis, MN, Oct 19–20, 2004.
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Abstract
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Cellular therapy for acute myocardial infarction and ischemic cardiomyopathy has entered clinical trials across the globe. Early promising results have now provided the justification for larger randomized and blinded trials to address the efficacy of cellular therapy. A variety of fresh or cultured autologous cells have been delivered by catheter-guided endocardial, catheter-guided intracoronary, catheter-guided transvenous, and direct epicardial routes. This review will summarize the clinical data and highlight salient basic science data that support the ongoing efforts to identify the optimal cellular therapy both for acute myocardial infarction and chronic ischemic cardiomyopathy patients.
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Introduction
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In the context of acute myocardial infarction (AMI), acute coronary thrombosis followed by reperfusion, which occurs in a large portion of patients after thrombolytic or percutaneous coronary intervention, elicits an intense inflammatory reaction. The damaged myocytes die by both necrosis and apoptosis as the infiltrating neutrophils and macrophages clear the necrotic debris. The injured myocardium elaborates a variety of chemotactic factors and cytokines that enables the movement of the various inflammatory cells into the infarcted zone. Similarly, the endothelium distal to the site of acute occlusion is rapidly activated to enable the firm adhesion and transmigration of the blood cells. The ischemically damaged endothelium becomes highly permeable as proteins seep through into the damaged myocardium. During this phase of acute injury, myocardial cellular delivery by intracoronary infusion is likely to be adequate [1–10]. Intramyocardial injections directly or using catheters may not be advisable because the infarcted area is at its least mechanical strength during the acute episode. Active inflammation will provide the molecular cues to the delivered cells to attach and transmigrate across the endothelium and to engraft in the infarcted segment.
In the context of established chronic ischemic cardiomyopathy, the clinical scenario is different. In these circumstances, the trend has been to combine cellular therapy with revascularization. The target region is typically not capable of being vascularized and is nonviable, precluding any obvious benefit to revascularization alone. The infarct core will be partially devoid of cardiomyocytes and vasculature and will be composed mainly of fibroblasts and collagen fibrils. Angiogenesis alone within the infarct core is not anticipated to improve cardiac regional or global function. Within the border zone, there will be a rim of hibernating myocardium that may be revived with revascularization or angiogenesis alone. Delivery of cells by the intracoronary route is unlikely to achieve significant engraftment of the delivered cells within the quiescent scar core where one anticipates the greatest benefit and response to cellular therapy. Electromechanical mapping using the NOGA catheter (Biosense Webster, Diamond Bar, CA) may enable the delineation of the electrically and mechanically silent areas, which would denote nonviable regions of the heart where the cells may be delivered using the endocardial approach [11–14]. Appropriate delivery of the cells in a uniform and reproducible fashion is difficult to achieve with this technique because of the uneven endocardial surface created by the papillary muscles and the ventricular trabecula. Other options include cannulation of the coronary venous system and intramyocardial transvenous delivery with intravascular ultrasound guidance [15, 16]. The advantage of this method is the relatively reliable manner in which the cells are delivered. The delivery location, however, is limited by the venous anatomy accessible to the catheter. The most reliable, uniform, and flexible manner in which the cells may be delivered is by direct surgical intramyocardial injection [17–21]. The obvious disadvantage of this technique is the requirement for an open-chest approach, but the procedure may be combined with coronary artery bypass grafting (CABG).
In general the timing of cell injection early after an AMI precludes the culture of the cells. In the setting of an AMI only bone marrow or peripheral blood cells may be used as a source of autologous cells [1–3, 5–10]. Because of the predominantly mature circulating cells, which are unlikely to participate in infarct repair above and beyond what already homes to the heart, harvesting and 2- to 3-day culture to expand blood endothelial progenitor cells has been used [1, 3, 5, 10]. Cytokine therapy to mobilize bone marrow stem and progenitor cells also allows purification of normally marrow-resident cells with simple phlebotomy [6], avoiding the discomfort associated with bone marrow aspiration.
In the chronic ischemic cardiomyopathy setting and elective nature of the intervention, it is possible to culture and expand the cells for a longer period of time. The available cell types for clinical use are greater than in the AMI setting. The cell types being transplanted in the middle of the scar will need to be able to modify the established local extracellular matrix and to induce angiogenesis to allow engraftment and survival of the cells. Myogenic cells are particularly adept at modification of their local matrix milieu and are considered prime candidates for myocardial cellular therapy. Clinical efforts thus far have focused on two major myogenic cell types: the skeletal myoblast or satellite cells [13, 15, 18–20, 22] and the bone marrow stromal cells or mesenchymal stem cells [4, 16, 17]. The skeletal myoblasts may be isolated from muscle tissue and expanded easily ex vivo to yield a large number of cells for implantation. Both in vitro and in vivo, the myoblasts are able to fuse and form myotubes. The bone marrow stromal cells or the mesenchymal stem cells exist at low frequencies in the bone marrow. However, they readily attach to plastic dishes and proliferate rapidly to yield large number of cells as well. The mesenchymal stem cell has been previously shown both to adopt a fibroblast-like morphology [23] to express myogenic markers [24, 25] and to give rise to cardiomyocyte-like cells [26]. Another myogenic cell type that has been tested extensively in the basic science laboratory but not in humans is the smooth muscle cell, which may be obtained from a variety of organs [27]. Notably, vascular smooth muscle cells appear to be unique in capably modifying the local matrix, inducing significant angiogenesis and improving cardiac function, and they may easily be obtained from pieces of saphenous vein or radial artery.
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Clinical Trials
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A summary of representative clinical trials is presented in Table 1.
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Bone Marrow or Circulating Progenitor Cell Therapy for Acute Myocardial Infarction
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The first report of bone marrow cell therapy for AMI was published in 2002 [8]. Strauer and colleagues infused bone marrow mononuclear cells after AMI using balloon inflation to stop flow within the infarct-related artery in 10 patients. After 3 months, the investigators found that cardiac function and cardiac geometry were significantly improved in the treatment group without any significant adverse events. This study proved that cell delivery is feasible, possibly safe, and perhaps efficacious.
In the same year, the group from Frankfurt, Germany, began reporting their results of bone marrow or circulating progenitor cell therapy in the TOPCARE-AMI (Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction) trial [1, 3, 5, 10]. In the initial study [1], 20 patients were randomly allocated to receive either circulating progenitor cells harvested from blood and cultivated for 3 days or bone marrow mononuclear cells. The treated patients were again compared with nonrandomized control patients receiving acceptable medical and interventional treatment. At 4 months’ follow-up, in both treated groups the ejection fraction determined by ventricular angiography improved from 0.516 to 0.601, whereas in the control group no significant improvement occurred. Dobutamine stress echocardiography and wall motion score indices confirmed the results of angiography. End-diastolic volumes did not differ significantly between the treated and control groups, suggesting that the functional benefits seen in this trial were secondary to improvement in contractility and not in ventricular remodeling. There were no significant differences between the cell groups.
In the 1-year follow-up [10], the investigators reported an extended series with 59 patients allocated to cell infusion treatment. Contrast-enhanced magnetic resonance imaging demonstrated better ejection fraction with an absolute increase of 0.08 and reduced infarct size in the cell-treated patients. No significant adverse events were reported, including an acceptable rate of in-stent restenosis in the treated lesion. On the basis of these promising results, the group in Frankfurt has embarked on a multicenter randomized, placebo-controlled, double-blind clinical trial (REPAIR-AMI trial).
In the first randomized but not blinded trial, entitled Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) study, conducted by Wollert and colleagues [9], investigators reported on 60 patients with acute ST-elevation myocardial infarction who were randomized to primary percutaneous intervention with or without intracoronary transfer of autologous bone marrow cells. At 6-month follow-up, there was a significant improvement of magnetic resonance imaging-measured ejection fraction in the cell group (from 0.50 to 0.567) compared with the control group (from 0.513 to 0.52), with the majority of the improvement seen in the myocardial segments adjacent to the infarcted region. No adverse events were reported during the 6-month follow-up. Similarly, Chen and associates [4] randomized 69 patients to receive intracoronary autologous bone marrow-derived cells cultured for 10 days or placebo. At 3-month follow-up, they also reported increased ejection fraction in the cell group by an absolute magnitude of 0.13, without significant adverse events.
Safety remains a major concern of myocardial cell transplantation. Ventricular arrhythmias have not been detected in patients who have received doses of bone marrow-derived cells, as opposed to the skeletal myoblasts (discussed below). However, a recent report by Kang and coworkers [6] highlighted other potential side effects of delivering bone marrow cells to the heart. These South Korean investigators reported that mobilization and intracoronary infusion of bone marrow cells after stenting is associated with heightened risk of in-stent restenosis of 70%. The stents had an average diameter of 3 mm and an average length 22.8 mm, with a significantly lower predicted incidence of in-stent restenosis. Considering that the stented culprit lesion was the site of fresh injury, amplification of the normal inflammatory response by the bone marrow-mobilizing cytokine, granulocyte colony-stimulating factor, likely led to the amplified restenosis response in this study. Another possible adverse event is distal embolization and microinfarction during the cell infusion. Neither of the studies by the groups in Hannover and Frankfurt observed a significant rise in cardiac enzymes or a disproportionate increase in the restenosis rate after the procedure [1, 8–10].
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Cell Therapy for Chronic Ischemic Cardiomyopathy
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Skeletal Myoblasts
Extensive preclinical data justified clinical trials that begun in Paris, France, on the implantation of autologous skeletal myoblasts in 2001. Ten patients with ischemic cardiomyopathy and left ventricular dysfunction were enrolled into a phase I trial of myoblast implantation at the time of CABG [19]. Cells were harvested, cultured, and injected into the nonviable regions of the left ventricle. Improvement in regional cardiac function was reported, but the confounding impact of revascularization obscured the analysis. One of the patients died 17 months after implantation because of a stroke, and the investigators performed a detailed histologic examination of the heart [18]. Skeletal muscle cells, which must have been the progeny of myoblasts, could be detected. The cells survived the hostile ischemic environment and engrafted over the long term, but remained isolated from adjacent cardiomyocytes. Four of the patients developed ventricular arrhythmias, raising concerns regarding cell implantation in patients who already have a high risk for ventricular arrhythmias. Subsequently, the skeletal myoblast has entered phase II multicenter randomized clinical trial (MAGIC trial—Myoblast Autologous Grafting in Ischemic Cardiomyopathy) in Europe to test efficacy. To monitor and terminate life-threatening ventricular arrhythmias, all patients will also receive an implantable cardioverter defibrillator in accordance with the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II criteria [28]. The MAGIC trial is proceeding, and the community eagerly awaits the final results.
Other investigators have attempted to implant skeletal myoblasts without concomitant revascularization procedures using percutaneous transendocardial cell delivery after electromechanical mapping [13], or using a catheter introduced into the coronary sinus for transvenous intramyocardial cell delivery [15]. Both of these studies proved that cell delivery is feasible, but the reliability of the cell delivery method was not evaluated and remains a major problem for catheter-guided delivery systems.
A particular patient population that may derive benefit with cell implantation may be the left ventricular assist device patients. Weaning of the left ventricular assist device and avoiding heart transplantation with cellular therapy may be possible. To address the feasibility of this approach, Pagani and colleagues [20] transplanted skeletal myoblasts into patients during support with left ventricular assist device. Histologic examination was later performed after explantation of the failing hearts at the time of heart transplantation. The skeletal myoblasts that were identified in the myocardium had differentiated into mature myofibers. These findings demonstrated engraftment and survival of injected myoblasts, but the impact on cardiac function was not clear.
Bone Marrow-Derived Cells
Similar to reports using skeletal myoblasts for ischemic cardiomyopathy, Stamm and associates [21] treated patients undergoing CABG with intramyocardial injections of bone marrow cells. The study demonstrated safety and feasibility of direct injection of bone marrow cells at CABG. In an interesting study, Galinanes and colleagues [17] treated left ventricular segments of the same hearts in 14 patients with one of three regimens: injection with bone marrow cells, CABG, or both. They used fresh bone marrow cells that were harvested from the cut sternum at the time of CABG. Only the areas that were injected with bone marrow cells and that received CABG showed improved segmental wall motion. Other investigators have used the NOGA-guided system to deliver bone marrow cells without concomitant revascularization with promising results as well [11, 12, 14]. Considering the small number of patients in these trials and the nonrandomized design, the strength of the conclusions that may be drawn, however, is strongly mitigated.
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Animal Data
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Clinical trials of cell therapy were initiated in 2001, on the foundation of almost a decade of preclinical work demonstrating consistent improvement in function in animal models of regional and global left ventricular dysfunction (Fig 1). The results of these preclinical studies have recently been reviewed [29, 30]. In the last 3 years, the concept of cell-based gene therapy for myocardial repair has been described and intriguing initial studies performed. This combination of cell and gene therapies may be the most promising avenue for future investigation. We will review the rationale and early investigations in this area, as well as the mechanisms by which cell and cell-based gene therapy strategies may exert their benefits.
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Fig 1. Cell implantation prevents heart failure. (Top) Mouse heart 28 days after coronary ligation, cut transversely (left) with the corresponding M-mode echocardiographic image (right). (Bottom) Mouse heart 28 days after coronary ligation and implantation of bone marrow stromal cells.
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Cell-Based Gene Therapy
Gene therapy was widely touted as a panacea for a host of disorders, including many that were not the result of a single-gene deficiency. The disappointing results of many gene therapy trials, however, highlighted the discrepancy between our ability to enhance the expression of a single transgene and the complex, multifaceted nature of most acquired diseases. One of the most appealing aspects of cell transplantation strategies is the idea that the implanted cells may respond appropriately to the local milieu in ways that could not have been foreseen by investigators, secreting cytokines to influence host cell migration, integration, angiogenesis, myogenesis, and extracellular matrix alterations. Although cell therapeutic approaches have shown consistent benefit, normalization of postinfarct ventricular morphology, perfusion, and function has yet to be achieved with this approach. It may be possible to enhance the ability of the transplanted cells to elicit the desired effects by modifying them ex vivo to express one or more beneficial transgenes. Unlike isolated gene therapy strategies, this approach does not rely on surviving native cells to express the transgene, and the combined approach is, therefore, of particular value in large infarcts with minimal viability. The cells, which can be efficiently transfected before implantation, may be able to enhance the angiogenic and myogenic effects of cell transplantation. Representative studies of cell-based gene therapy are listed in Table 2. In this section, we will focus on studies aimed at enhancing the impact of implanted cells on angiogenesis by expression of proangiogenic gene products.
In 2001, we [31] and Suzuki and coworkers [32] simultaneously reported that transplantation of vascular endothelial growth factor (VEGF) -transfected heart cells (a mixed culture of predominantly cardiomyocytes, with smaller proportions of smooth muscle cells, endothelial cells, and fibroblasts) [31] and skeletal myoblasts [32] resulted in greater angiogenesis and improvement in function than unmodified cells. Subsequently, a variety of transgenes have been evaluated. Most studies sought to enhance the angiogenic effect of cell transplantation through overexpression of VEGF [33–37], basic fibroblast growth factor [38], or hepatocyte growth factor [39, 40]. These studies have consistently demonstrated that cell-based angiogenic gene therapy results in greater angiogenesis and functional improvement than cell transplantation alone [31, 32, 37–40]. Askari and associates [33] and Chachques and coworkers [34] both concluded that cell-based VEGF gene therapy had greater effects on angiogenesis and function than VEGF gene therapy alone. In contrast, Sugimoto and colleagues [35] noted a further insignificant increase in vascular densities after implantation of 5 x 105 VEGF-expressing H9c2 myoblasts, compared with VEGF gene therapy alone. The promising results of most early studies, however, suggest that clinical application of this concept may soon follow.
Mechanism of Action
Transdifferentiation or fusion?
The concept that bone marrow cells may cross lineage boundaries to give rise to new cardiomyocytes was proposed in 2001 [41, 42] and formed the early rationale for performing clinical trials of bone marrow cell therapy (Fig 2). This concept has recently been challenged [43–45] and remains a source of ongoing controversy [46]. It has also been theorized that bone marrow cells may appear to have given rise to new myocytes by fusing with existing cardiomyocytes and passing on their markers to the myocytes [45]. At this time, it appears that the general belief is that neither transdifferentiation nor fusion of bone marrow stem cells and mature myocytes occur at frequencies that would significantly impact cardiac function.
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Fig 2. Proposed mechanisms by which implantation of cells may improve regional and global cardiac function. (ECM = extracellular matrix.)
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Mobilization of cardiac stem or progenitor cells?
If implanted cells do not become beating cardiomyocytes, it is possible that they incite or facilitate other cells to perform this function. The adult heart may be home to cardiac-specific stem or progenitor cells that are capable of cardiac regeneration. Anversa’s group, who first reported the possibility of bone marrow cell transdifferentiation into cardiomyocytes, isolated a subset of cells from adult myocardial tissue with characteristics of stem cells [47, 48]. The cells were capable of self-renewal and of differentiation into cardiomyocytes, endothelial cells, and smooth muscle cells, and could improve ventricular function when implanted into infarcted myocardium. Similarly, Schneider’s group reported on the characteristics of cardiac-resident progenitor cells (which may be the same cell type characterized by Anversa) [49]. The cells, when cultured in the presence of 5-azacytidine, were able to differentiate into cardiomyocytes, and when injected intravenously, homed to infarcted myocardium. These studies provided the rationale for further investigation and possible clinical trials. They also potentially identify a mechanism by which cell implantation can improve heart function, by recruitment of native cardiac resident stem or progenitor cells by paracrine mechanisms.
Angiogenesis?
It is becoming increasingly clear that cell implantation can improve cardiac function by other mechanisms as well. Implanted cells induce significant angiogenesis [50]. The signaling pathways that enable new blood vessel formation after cell implantation have not been rigorously assessed, but are likely to involve paracrine mechanisms. Skeletal myoblasts and heart cells expressing a VEGF transgene induce sequential upregulation of the VEGF receptors flk-1 and flt-1 in host cells after implantation, through an apparent paracrine effect [51]. Furthermore, some cell types, including bone marrow mononuclear cells or endothelial progenitor cells, play a direct role in new blood vessel formation by incorporation into either the endothelial or the smooth muscle layer of capillaries and arteriole-like structures. The magnitude of angiogenesis induced by cell transplantation generally correlates with the degree of improvement in ventricular function, leading some authors to argue that the major effect of cell implantation is induction of angiogenesis.
Stabilization of the extracellular matrix?
Another area that has recently come under investigation is the impact of cell implantation on the extracellular matrix [52]. Congestive heart failure is associated with progressive ventricular dilation. Ongoing myocyte loss is compounded by an imbalance of matrix-regulating enzymes that lead to gradual loss of tissue architecture. The role of the extracellular matrix in this adverse remodeling process is becoming more defined [53] as the fulcrum that defines cellular responses to both local and global stimuli including cytokines. In the heart, the extracellular matrix allows efficient myocyte coupling and the formation of a functional syncytium. Ongoing degradation of the matrix may therefore lead to progressive systolic dysfunction. Implanted cells may prevent this progressive ventricular dilation and may restore the balance of matrix-maintaining enzymes.
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Conclusions
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After a decade of pioneering preclinical studies, cell therapy has entered the clinical realm. The bulk of the data strongly suggests that it will be efficacious in patients with either AMI or chronic ischemic cardiomyopathy. It is imperative, however, that the next series of clinical trials be designed to minimize and closely monitor adverse events in patients, and that efficacy is maximized and carefully evaluated. Unfortunately, the potential for a few poorly designed trials to rapidly reverse a decade of progress exists. With appropriate, well-designed clinical trials, however, it is distinctly conceivable that cellular therapy for myocardial repair will become a routine intervention for cardiologists and surgeons alike.
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Acknowledgments
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This work is supported by the Heart and Stroke Foundation (HSF) of Ontario grants to Drs Li and Yau and the Canadian Institute Health Research (CIHR) grants to Drs Li and Fazel. Doctor Fazel is also a recipient of the joint HSF and CIHR TACTICS Fellowship, and a Physician Services Incorporated grant. Doctor Angoulvant is funded by a grant of the Fédération Française de Cardiologie.
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Abstract
Introduction
