Gallegos
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Bolman
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. Stem Cell–Induced Regeneration of Myocardium.
Cohn Lh, ed. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2008:1657-1668.
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CHAPTER 71 |
INTRODUCTION TO CELLULAR THERAPY
Cardiovascular disease remains the leading cause of death in industrialized nations despite major advances over the past 60 years in medical and surgical therapy. Largely this relates to the growing worldwide epidemic of congestive heart failure (CHF) currently affecting ~15 million patients and which carries a 5-year mortality of 50%.1 Heart failure—severe ventricular dysfunction—has numerous etiologies but is most often seen as a result of ischemic cardiomyopathy. The hallmark of end-stage CHF is cardiomyocyte loss unmatched by myocyte regeneration following myocardial infarction (MI). Early rapid revascularization—be it with pharmacotherapy, stenting, or surgery—may potentially improve myocardial blood flow with resultant improvement in the function of remaining viable myocardium. However, current therapeutics cannot regenerate myocytes lost to necrosis. As a result, complete cardiovascular functional restoration remains unattainable with the currently available conventional therapies.
Myocardial regeneration—the replacement of lost myocytes—is seen in organisms such as the newt and zebra fish. In higher mammals, dogma has dictated the impossibility of such myocyte regeneration, as the heart was viewed as a terminally differentiated organ. This lack of regeneration prompted interest in organ transplantation as a means of complete replacement of the failing organ. The successful development and implementation of heart transplantation by Barnard and Shumway has greatly improved the clinical outcome for patients diagnosed with end-stage CHF.2 Unfortunately, several constraints associated with the origin of the donor heart limit the potential for broad application of transplantation in the affected CHF population. The most significant limitation remains the limited availability of donor organs (Fig. 71-1).3 Complications of immune rejection and immunosuppression also limit the long-term benefits of heart transplantation. Efforts to eliminate the limitations of organ transplantation with the use of mechanical left ventricular assist devices (bridge to transplantation or destination therapy) have similarly been thwarted by finite device durability or device-related complications.4
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Cardiovascular disease remains a formidable clinical challenge for which no absolute solution is currently available. Cellular-based tissue regeneration may be of significant importance but remains to be developed further before its true potential may be realized. The following discussion will review the development of cell-based therapy from animal models to current clinical trials.
The potential therapeutic benefit offered by cell-based therapies has spurred numerous investigators to search for the ideal stem cell population. This stem cell would effectively engraft and integrate into regions of damaged myocardium and restore cardiac function without improper differentiation into other contaminating cell types. This would require not only neomyogenesis, but also accompanying neoangiogenesis, either as direct or indirect consequence of the implanted cell.
Many cell types with the potential to repair the injured heart have been considered, including differentiated (e.g., fetal myocytes and satellite muscle cells) and undifferentiated primordial cell lines (e.g., embryonic or adult stem cells). Primordial cell lines, or stem cells, that might be utilized for cell-based therapy were first developed from embryonic tissue.13,14 Embryonic stem (ES) cells are pluripotential (i.e., capable of functional plasticity with the ability to differentiate into all cell types found in the fetus and placenta in vitro). Once established, the cell lines can be propagated in cultures to provide a continuous source of material for transplantation. In fact, ES line–derived cells have shown the ability to form myocytes that generate stable cardiac engraftment.15 Unfortunately, extensive experimentation in vivo is still necessary to properly direct the formation of integrated, functional cardiac tissue at the site of injury without improper differentiation to form teratomas or other noncardiac cell types. In addition, numerous obstacles that plagued organ transplantation will also likely prevent the widespread use of ES cell therapy. These issues are directly related to the origin of the cell line. First is the issue of allogenicity, which might confer a small potential for rejection, thereby requiring lifelong immunosuppression. But more importantly, the lack of general availability of embryonic stem cells, not dissimilar to the lack of donor hearts, may be most limiting. Current ethical obstacles surrounding the use of embryonic tissue and the current governmental ban on the development of new cell lines will limit the availability of tissue for transplantation.16–21 New discoveries that have allowed the cloning of ES cells may alleviate this limitation,22,23 but realization of this potential will await further investigation. Consequently, to utilize stem cell transplantation in a clinical setting, stem cells derived from other sources require investigation.
Stem cells have been demonstrated to be present within various organ tissues in the adult.24–27 Recent interest has been focused on these cell lines, and the term adult stem cell has been used to differentiate these from ES cell lines. Adult stem cell lines, on exposure to specific signal molecules, have demonstrated the capability of generating myocytes in vitro.28,29 In addition, the ability to induce in vivo transformation of bone marrow–derived mesenchymal stem cells into myocytes in the rat has been reported.30,31 Rather than forcing differentiation to take place in vitro prior to transplantation, it appears that stem cell transplantation, in itself, is a sufficient trigger for differentiation. The implicit assumption made is that the desired native tissue offers to the stem cell an environment rich in the signals of differentiation. Hence adult stem cells may be viewed as the primordial building blocks for selective regeneration of injured myocardium.
Multipotent tissue-specific cells that have already committed to a distinct lineage, such as hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells, have also produced encouraging results when used for cell-based cardiac regeneration therapy.10 However, to date, the use of these cells often results in incomplete engraftment and a failure to restore cardiac function over time.32
Multiple methods for stem cell delivery have been investigated, including direct myocardial injection, peripheral transfusion, and/or stem cell mobilization.33 No current study to date is available to elucidate which approach is superior, though only endocardial and epicardial injections would likely be relevant to cardiac surgeons. Both transfusion and mobilization of resident stem cells offer the least invasive means of stem cell delivery. However, this requires the availability of effective homing signals to direct the correct location for engraftment while preventing the potential for adverse engraftment in other regions (e.g., promoting tumor growth). This impediment is avoided by using direct myocardial injections, either surgically or via interventional catheter techniques (Fig. 71-3). Direct epicardial myocardial injection can be consistently completed intraoperatively during concomitant procedures (e.g., coronary arterial bypass, arrhythmia surgery, mechanical assist device implantation, and valve operations) or via minimally invasive approaches for isolated cell therapy. Direct endocardial injection will likely be accomplished by using commercially available radiographic stem cell injection catheters (Fig. 71-4). Currently, we believe that multiple stem cell injections may be required to achieve full therapeutic myocardial regeneration. As a result, the use of stem cell injection catheters may become the standard of practice following initial open chest cell injection therapy. In addition, the use of advanced imaging techniques (magnetic resonance imaging [MRI] and electromechanical catheters) will likely be used to allow for real-time image-guided smart injection (in a manner akin to guidance of "smart" bombs) at areas of identified myocardial damage. Further investigation is required to identify the best delivery method, number of cells, and treatment regimen. It is likely this information will be gleaned from ongoing clinical trials (Table 71-1) and animal experimentation.
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Regardless of the cell type used in cell-based therapy, it is clear that animal models will play a critical role in the translational research that will be necessary to advance this theory out of the lab and into clinical practice. Multiple animal species from rodents to humans have now been used for the study of cell-based therapy. Although many anticipate that cellular therapy will be a panacea for multiple forms of cardiovascular disease, few disease models have actually been rigorously investigated. Much of the early basic and clinical research has been conducted in acute ischemia models. However, while effective treatment options for acute ischemia do exist (thrombolytics, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft [CABG]), only limited options are available for chronic myocardial ischemia. This observation strongly suggests that further development of the chronic cardiovascular disease models using cell-based therapy is warranted. This observation has clearly been recognized, as numerous investigators are now incorporating cellular therapy in combination with mechanical assist device insertion.
As with most research, the experimental hypothesis will remain fundamental in choosing the correct animal model. However, the availability of appropriate stem cell lines in the desired species will add additional limitations in the field of cellular cardiovascular therapy. Full characterization of the cell lines is critical to allow for safety evaluation and is advantageous in correctly ascribing functional changes to the appropriate precursor cell. The multiple types of stem cells available for the rodent have made small-animal models effective for investigations of stem cell engraftments. However, significant differences in myocardial anatomy and physiology raise serious concerns that findings may not be directly translatable to humans. Ultimately, large-animal models that better approximate the diseased human heart will be required to fully assess stem cell engraftment, differentiation, and/or functional improvement. In general, large-animal models are considered better suited for assessment of myocardial function via angiography, echocardiography, or MRI; however, the limited availability of appropriate stem cell lines for use in these models has prevented the widespread use of large-animal models.
The ability to track the implanted cell is critical not only to assess the potential of engraftment, but also for later determination of differentiation and incorporation into the native tissue. Multiple cell-labeling techniques are under investigation, including the use of viral gene transduction (e.g., green fluorescent gene and lacZ), incorporation of dyes, and the use of metallic microparticles.34,35 Gene insertion can be fairly easily accomplished, allowing for fluorescence microscopy or quantitative polymerase chain reaction identification of the stem cell. However, the exact insertion site into the DNA of the cell cannot currently be well controlled, introducing the possibility for non-expression of the gene or potential disruption of normal cellular transcription and translation processes. The use of dyes incorporated into the cells by pinocytosis has been reported (e.g., 4,6-diamino-2-phenylindole; DAPI). The primary disadvantage of this technique has been the potential for dye incorporation into native cells in vivo. The use of metallic microparticles has received recent attention, in that such particles may allow for real-time identification of cells by MRI imaging and later pathologically by staining. However, information about the potential disruption of cellular function and possible uptake in vivo by native cells has yet to be fully elucidated.
Several clinical trials utilizing various cell types and disease models have now been completed (see Table 71-1). Unfortunately, these studies have been limited by the recovery of insufficient postimplantation tissue. This limitation is a direct result of study design—cell-based therapy in patients undergoing revascularization. Few patients having received cell therapy have experienced adverse events resulting in death. As a result, no tissue has been available for autopsy evaluation. Future studies involving end-stage CHF patients utilizing mechanical assist device implantation as a bridge to transplantation may alleviate this limitation.36 In these patients, myocardial samples will be taken pre–cell implantation at the time of mechanical device insertion or cell injection. Similarly, post–cell-treated myocardium will be available at the time of device explantation or orthotopic heart transplantation.
Functional Assessment of Stem Cell Therapy
Numerous researchers have dedicated their efforts to demonstrating improvement in cardiac function following cell-based therapy. Each author has utilized their preferred method of assessing cardiac function. Regardless of the specific method used by any given investigator (pressure measurements, ultrasonic microcrystal placement, echocardiography, or MRI), all have been able to conclude that cell therapy positively impacts some element of cardiac function. However, long-term follow-up studies directly comparing cardiac assessment techniques specifically for the assessment of cell-based therapy do not currently exist in the literature. Therefore, no conclusions may currently be drawn regarding the superiority of any individual technique of cardiac assessment. It is the authors’ opinion that cardiac MRI offers the greatest ability to follow long-term patient outcome. MRI allows for a noninvasive serial assessment of cardiac perfusion, contractility (global and regional), wall motion, infarct size, and chamber size. In addition, the use of real-time MRI may allow for precise delivery of cells using MR-safe injection catheters currently in development.37 Finally, the use of metallic microparticles, as mentioned above, may allow for cell tracking following cell injection.34,35 Drawbacks to MRI of course do exist, including the inability to scan patients with newly implanted pacemaker leads and other prohibitive patient contraindications to MRI. More research and further refinements in measurement techniques will likely offer additional strategies that will ultimately be universally applicable.
Mechanism of Myocardial Repair Following Cell Therapy
The concept of myocardial cellular therapy was originally conceived based on the example set by the success of whole organ transplantation—replace what has been lost. However, with the need for whole organ transplantation far exceeding the organs available for donation (see Fig. 71-1), the goal of cell-based therapy is to restore cardiac function by the replacement of only the sections of dead myocardium. Here the replacement of lost myocytes would be accomplished by the implantation of a population of readily available cells that integrate into the existing matrix and provide synchronized contractile activity.38 To date, both animal and human studies have been reported demonstrating improvement in various parameters of heart function in support of this goal. However, the means by which cellular transplantation has provided this benefit to cardiac function remains unclear and hotly debated.39 A significant problem in understanding the mechanism is undoubtedly related to the limited ability to track implanted cells. No universally reliable technique has thus far allowed tracking of implanted cells, particularly in human trials. Furthermore, as mentioned previously, limited tissue has been available for engraftment studies.
The implantation of adult and fetal cardiomyocytes has been attempted experimentally, with limited success. In these instances, cellular replacement would require only engraftment and integration into the conglomerate contractile apparatus to potentially repair the damaged myocardium. This is not the case for naïve stem cells, which have been intently used for myocardial cell transplantation. In this scenario, implanted stem cells (e.g., embryonic, bone marrow, or skeletal stem cells) would require not only engraftment and integration, but also, most importantly, transdifferentiation into cardiomyocytes. Chiu proposed the notion that transdifferentiation could result from some unknown signaling process commenced by exposure to the local milieu present in the region of injured myocardium.40,41 This concept does have some support from studies following cardiac transplantation in sex-mismatched pairs where the presence of integrated cardiomyocytes of recipient origin has been identified, presumably following engraftment of circulating stem cells or resident stem cells.11,12 The importance of the local milieu was highly suggestive, if one considers that the number of engrafted recipient cells increased with the greater incidence of donor organ rejection. This observation emphasized the requirement for myocardial injury as a strong factor involved in the recruitment and engraftment of stem cells.
Several in vitro and in vivo studies exist in the literature that support the hypothesis of the transdifferentiation of stem cells into cardiomyocytes.28,31,42 At the bench, various forms of bone marrow–derived stem cells (e.g., hematopoietic stem cells, bone marrow mesenchymal stem cells, and multipotent adult progenitor cells) have been successfully induced into a cardiomyocyte phenotype.43–45 Animal studies using injected cultured stem cells or mobilized stem cells (induced by stem cell factor treatment) have demonstrated rapid regeneration of myocardium, the first being reported by Orlic and colleagues.31,42,46 In this seminal effort, the expression of cardiomyocyte-specific genes in labeled implanted stem cells was strongly suggestive for integration of the implanted cells with the host myocardium and supported the potential for synchronous contraction. Since the publication of this report, numerous preclinical and clinical trials have demonstrated myocardial repair and regeneration.
Unfortunately, the number of engrafted cells following injection is typically insufficient to account for the degree of improvement in myocardial function. Furthermore, the mere presence of cardiomyocyte-specific gene products alone is insufficient evidence that the transplanted cells actually regenerate myocardium that electromechanically integrates with host myocardium. Finally, the concept of transdifferentiation itself has been called into question. Opponents point to reports demonstrating stem cell fusion with native parenchymal cells, producing a hybrid cell containing both stem cell and myocyte-specific markers, accounting for prior observation of supposed "neomyogensis."47–49 Additional negative evidence has recently been offered by recent independent reports where the transdifferentiation of bone marrow stem cells into cardiomyocytes did not occur after implantation.50–52 The credence of current evidence does not fully support the concept of stem cell transdifferentiation, although sufficient evidence does not exist to dispel this concept. In addition, it is not clear that the observed improvement in cardiac function is the direct consequence of electromechanical integration of the implanted cell. This is certainly the case with skeletal myoblast therapy, in which cell injection results in the formation of isolated skeletal myotubes within the scar. Although the myotubes remain electrically and functionally isolated from the host myocardium, both preclinical and clinical trials have provided documented improvement in cardiac function.51,53–55
Alternative Mechanisms of Repair
The lack of absolute evidence to support transdifferentiation of implanted cells into myocytes as the sole mechanism, or even one of the mechanisms, for the observed functional improvement in cardiac function has spawned ongoing interest in both preclinical and clinical research. Regardless of the direct contribution of the injected cells to myocyte mass, it is clear that cellular transplantation results in neomyogenesis, neoangiogenesis, and alterations in ventricular remodeling.40,56–60
Recent work has suggested that the mechanisms of cellular therapy may involve cytokines and growth factor–mediated endogenous stem cell mobilization, improved homing of stem cells to sites of injury, and induction of antiapoptotic pathways.61,62 All mechanisms may contribute to an overall increase in functional myocardial mass salvage in the area of injury. Release of these factors may occur systemically or locally at the site of injury both from and as a result of cellular transplantation. In addition, some have theorized that observed cell fusion could be responsible for the release of factors. Research involving infusion of pharmacologic agents with anti-apoptotic properties (e.g., ursodeoxycholic acid [bear bile]) suggests improvement in survival of ischemically damaged cardiomyocytes, supporting this mechanism. The exact contribution of these mechanisms to the overall effect of cellular therapy remains to be elucidated.
Induction of neovascularization, a crucial component of cellular therapy, is mediated by both cytokine release and potentially by direct cellular contribution of endothelial progenitors, as has been observed following bone marrow stem cell therapy.10,63,64 Increased angiogenesis provides not only the potential for improved perfusion in the region of myocardial injury, but may also prevent myocyte apoptosis and maladaptive remodeling of the myocardial matrix.40,57,63,65 Overall, neovascularization could improve cardiac function by preventing cell loss and ventricular dilatation while also recruiting hibernating myocardium. Both preclinical and clinical studies using bone marrow–derived stem cell injections following MI support this theory, with documented increased capillary density in conjunction with an improvement of myocardial contractility.66,67
In addition to improved myocardial perfusion, cellular therapy appears to be an integral factor in the preservation of the integrity of the extracellular matrix (ECM) following myocardial injury. Myocyte loss results not only from the initial acute ischemic injury, but also from degradation and maladaptive remodeling of the ECM. As a result, disruption of the matrix network impairs support for heart cells, leading to further cell loss and ventricular dilatation, ultimately culminating in CHF.57,68,69 Cellular transplantation may prevent ECM degradation or may induce the restoration of the ECM, or a combination of both scenarios. This may result from direct secretion of new matrix elements by the injected cells or by secretion of cytokines that result in activation of the biochemical cascades ultimately responsible for ECM stabilization.53,70–72 In any event, stabilization of the ECM provides structural support for host heart cells, limiting infarct expansion and improving regional ventricular compliance and function.57,73–75 Numerous reports offer evidence of a beneficial effect following cellular therapy on the ECM, not only in the infarct zone but also in regions of normal myocardium.57 Functional improvement has been reported following the injection of various types of cells, in spite of a lack of a complete understanding of the true mechanism by which stem cells improve cardiac function. Certainly much more additional investigation at the bench side and bed side is required before the true mechanism is elucidated.
CLINICAL TRIALS IN CELLULAR THERAPY
Scattered individual case reports of patients receiving "cell injections" rapidly appeared in the literature following positive reports in preclinical animal studies.76–78 This rapid transition of bench-side research into the clinical realm was felt to be justified based on the need for a broadly applicable approach to counteract the ever-increasing incidence of CHF following MI. Though numerous authors reported significant improvement in cardiac function, most of these case studies were severely limited, being confounded by concomitant revascularization and poor characterization of the injected cells. Furthermore, follow-up periods were short and conclusions regarding improvement in cardiac function were based on a variety of clinical nonstandardized end points.
Despite the questionable validity of these preliminary case reports, interest in cellular therapy has steadily increased. The first results from an organized human cellular therapy trial were reported by Menasche and colleagues.79 Since its publication in 2001, 13 trials involving over 170 enrolled patients have been reported (see Table 71-1) and are discussed in the remainder of this section. As with the animal trials that proceeded, various cell delivery methods, cell types, disease states, and cardiac function assessment methods were utilized in these preliminary phase I feasibility trials (Table 71-2).78,80–93 Again, all trials supported the feasibility of cell therapy, indicating a positive impact on cardiac function after cell implantation.
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Skeletal myoblasts (SMs) are primordial cells that are precursors to skeletal myocytes. These cells can be obtained readily by small biopsy of peripheral skeletal muscle and can be expanded by in vitro culture to obtain an adequate number of cells for use in cellular therapy.94 The first patients to be involved in human cellular therapy trials received direct epicardial SM injections following MI. In this pivotal trial, Menasche and associates injected autologous SMs into a segment of non-revascularizable, nonviable infarcted myocardium in 10 patients with ischemic heart failure who were undergoing planned CABG.93 At the end of the 11-month follow-up period, all patients demonstrated an improvement in the New York Heart Association functional class and left ventricular ejection fraction (LVEF) with an associated increased viability of the grafted scar. No immediate perioperative deaths were reported, with only one late death occurring secondary to stroke more than a year after transplant. Most concerning was the development of sustained ventricular tachycardia in four patients. These results were supported by Herreros and coworkers, demonstrating similar improvements in cardiac function by 3 months following injection in 12 patients undergoing CABG after MI.85 Here only 1 of 12 patients developed a nonsustained ventricular tachycardia. Both trials suffered significantly from the inability to rigorously evaluate the cell-treated region, as little tissue was available for pathologic review.
This problem was ameliorated by Pagani and associates who injected SMs in five patients undergoing left ventricular assist device (LVAD) implantation for severe ischemic cardiomyopathy and refractory heart failure.87 Following explantation of the hearts, histologic evaluation demonstrated the formation of viable islands of muscle grafts in the scarred myocardial tissue where SM injection was performed. Again, 3 of 5 patients experienced documented ventricular tachyarrhythmias. Nonsurgical catheter-based percutaneous injection of SMs have also been successfully accomplished in humans. Using this technique, mapping of damaged regions of myocardium can be performed, allowing for precisely guided injection of cells using stem cell injection catheters. Smits and colleagues treated five patients with ischemic CHF after MI in this fashion, injecting SMs using a catheter-based endocardial approach.88 On follow-up 6 months after treatment, imaging demonstrated improved myocardial wall thickening within the injection region and an overall improvement in LVEF. As seen with the open surgical technique, 1 of 5 patients developed nonsustained ventricular tachycardia, reflecting that the cell injection and not technique was likely responsible for the dysrhythmia. In summary, these early feasibility trials in humans supported the potential efficacy of SM-based cellular therapy. Importantly, the LVAD trial conducted by Pagani identified the ideal initial candidates for future trials. Critical histologic data not previously obtainable with outpatient death are possible now for the entire heart following heart transplantation rather than relying on small tissue biopsies. The trials have not yet provided data supportive of any apparent obvious superiority of one delivery method over another. Most concerning, the trials also raised serious safety concerns with regard to the induction of severe ventricular arrhythmias, necessitating the use of antiarrhythmics or automated implantable defibrillators.
Blood- and Bone Marrow–Derived Stem Cell Trials
Shortly after the reports of success with SM injection, bone marrow– and blood-derived stem cells were explored as a new potential cell source. The first group trial was reported by Hamano and colleagues, who performed autologous mononuclear bone marrow cell injection in 5 patients undergoing CABG.81 One year following cell injection, 3 of 5 patients demonstrated improved perfusion in the region of injury. Benefit to cardiac function was suggested by Strauer and Assmus and their coworkers (Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction; TOPCAREAMI), who performed separate nonrandomized trials of autologous cell injection with concomitant percutaneous transluminal coronary angioplasty for recent acute ST-elevation myocardial infarction (MI).80,82 Strauer infused autologous bone marrow mononuclear cells (n = 10 patients), while Assmus evaluated the use of either autologous circulating blood-derived or bone marrow–derived progenitor cells (n = 20 patients). All patients were evaluated 3 to 4 months post–cell infusion and were compared with matched historical control patients. Cell infusion was associated with a reduction in infarct size and left ventricular end-systolic volume, and was coupled with an improvement in myocardial perfusion and contractility (global and regional). The TOPCARE-AMI trial offered additional conclusions regarding the need for exact stem cell characterization. In this trial, serial contrast-enhanced MRI and ex vivo migratory capacity assay of the implanted cells confirmed that implantation of cells with high migratory capacity was associated with higher beneficial effects on infarct size and left ventricular remodeling.95 Importantly, no death was directly attributed to cell injection. No significant morbidity attributable to arrhythmia was reported.
The use of bone marrow– and blood-derived stem cells has also been explored in patients with chronic cardiac disease. Tse and colleagues offered cell therapy to eight patients with stable refractory angina.84 Patients in this trial received autologous bone marrow mononuclear cells via percutaneous catheter-based myocardial injections guided by electromechanical mapping. Consistent with the trials completed in the acute MI series, patients demonstrated increased myocardial perfusion and contractility, and reported reduced anginal episodes and nitroglycerin usage by 3-months’ follow-up. No adverse events were reported, suggesting a higher degree of relative safety compared with SM injection. However, this conclusion was questioned by Perin and associates, who conducted a similar trial, treating patients (n = 14) with severe chronic ischemic heart failure with autologous mononuclear cells.89 Cell injection resulted in improved cardiac function at the 4-month evaluation consistent with prior studies; however, one fatality was attributed to sudden cardiac death.
Unlike SMs, blood- and bone marrow–derived stem cells can be mobilized using drug infusion with stem cell colony-stimulating factors. Kang and coworkers randomized patients (n = 27) with MI who underwent percutaneous transluminal coronary intervention into three experimental groups to determine if there was any benefit to granulocyte colony-stimulating factor with or without intracoronary infusion of peripheral blood stem cells compared to the control percutaneous coronary intervention group.78 At the 6-month follow-up, a high rate of in-stent restenosis was observed in patients who received granulocyte colony-stimulating factor.
Success achieved with initial trials was encouraging and ultimately led to the first true randomized controlled trial examining the safety and efficacy of cell therapy for acute ST-elevation MI, completed by Wollert and colleagues.90 Patients (n = 60) included in the BOOST trial (Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration) were randomized to primary percutaneous intervention with or without intracoronary infusion of autologous bone marrow cells. At the 6-month follow-up, no adverse events were reported. All patients were followed with cardiac MRI, which demonstrated significant improvement in LVEF in the cell treatment group (from 50 to 56.7%) compared to the control group (from 51.3 to 52%). To further explore the conclusions drawn from the BOOST trial, Chen and colleagues randomized patients (n = 69) undergoing primary percutaneous coronary intervention after acute MI to receive intracoronary infusion of autologous bone marrow–derived mesenchymal stem cells or cell-free saline injection.91 At the 3-month follow-up, patients having received cell therapy were noted to have a greater improvement in LVEF, myocardial perfusion, and wall motion relative to the saline-treated group.
The initial available data involving blood- and bone marrow–derived stem cell therapy are encouraging and should pave the way for larger phase II/III trials aimed at assessing when, how, and to whom cells should be delivered after MI. These future trials will address safety concerns including postimplantation incidence of severe ventricular arrhythmias, though current studies would suggest this to be less concerning with these types of stem cells.
Significant translation of bench research in cellular therapy into clinical trials has occurred, offering the cardiovascular physician a new weapon in the armamentarium for prevention and treatment of myocardial injury. Numerous reports in both preclinical and clinical studies demonstrate that cellular therapy is safe and may be efficacious as a treatment option to treat both acute and chronic myocardial injury. Although specific safety concerns remain related to induction of clinically relevant ventricular arrhythmias, preliminary clinical trials suggest that cellular therapy may be routinely engaged for the treatment of myocardial injury with the ultimate goal of prevention of end-stage cardiac failure. Several questions remain to be evaluated, including identification of the ideal cell type or types, the exact cell dose, timing and number of treatments, and most importantly, careful determination of each of these variables as they relate to specific disease states. Certainly both the type (acute versus chronic) and severity of disease will dictate the overall treatment protocol. Additional research is required not only in clinical trials, but also at the bench side to determine the exact mechanism by which cellular therapy improves cardiac function. Cellular therapy likely induces neoangiogenesis, neomyogenesis, anti-apoptotic pathways, and stabilization of the ECM—all contributing to improved cardiac function. Once the specific mechanisms are identified, either the use of purified cytokines or genetic manipulation of the injected cells may add further efficacy while providing an increase in safety by minimizing or eliminating the use of cellular injection itself.
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