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Ann Thorac Surg 2009;88:1714-1722. doi:10.1016/j.athoracsur.2009.05.079
© 2009 The Society of Thoracic Surgeons
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Review

Cell-Based Therapy for Ischemic Heart Disease: A Clinical Update

Jeremy L. Herrmann, MDb, Aaron M. Abarbanell, MDb, Brent R. Weil, MDb, Yue Wang, PhDb, Meijing Wang, MDb, Jiangning Tan, MD, PhDb, Daniel R. Meldrum, MDa,b,c,d,*

a Clarian Cardiovascular Surgery, Indiana University School of Medicine, Indianapolis, Indiana
b Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
c Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
d Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

* Address correspondence to Dr Meldrum, 635 Barnhill Dr, Van Nuys Medical Science Bldg, Room #2017, Indianapolis, IN 46202 (Email: dmeldrum{at}iupui.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 
Progenitor cell therapy is a promising treatment for ischemic heart disease. Early clinical trials of autologous bone marrow-derived progenitor cell therapy for acute and chronic myocardial ischemia showed modest functional improvements after cell delivery; however, the duration of these benefits remains unclear. Ongoing investigations continue to enhance our understanding of the mechanisms by which progenitor and stem cells function and how their survival and cardioprotective abilities can be improved. This review discusses: (1) relevant progenitor and stem cells in myocardial regenerative therapy, (2) routes of cell delivery to ischemic myocardium, (3) clinical trials investigating bone marrow-derived progenitor cell therapy for myocardial ischemia, and (4) future directions of the field.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 
Cardiovascular disease remains a leading cause of morbidity and mortality in developed countries. Cardiomyocytes have a limited capacity for self-renewal, and current medical therapy and revascularization procedures can not re-supply significant functional contractile tissue after infarction. Heart transplantation is the only clinically feasible method of replacing infarcted myocardium, but it is limited by donor supply. Given the need to overcome the limitations of these treatments, cell-based therapy has emerged in the past 2 decades as a novel regenerative therapy for ischemic heart disease. Although progenitor cells were initially hypothesized to regenerate injured tissue by differentiating into functional cardiomyocytes [1–4], additional investigations have revealed other complementary abilities of these cells including homing to injured tissue [5–8], production of protective growth factors and anti-inflammatory cytokines [9–11], and promotion of neoangiogenesis and cell survival [12].

Several clinical trials have investigated the delivery of autologous bone marrow-derived progenitor cells to the myocardium through multiple delivery methods in patients suffering from acute and chronic myocardial ischemia, as well as congestive heart failure (Table 1). Patients not eligible for revascularization procedures and patients who are undergoing planned cardiac procedures have received particular attention in the latter group. In general, results of these early trials demonstrated modest improvement in cardiac function after cell therapy that have persisted up to 12 months in the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) study; however, the benefits in functional recovery did not persist in the 18-month follow-up of the bone marrow transfer to enhance ST-elevation infarct regeneration (BOOST) study (Table 1) [13, 14]. Although longer-term follow-up studies are ongoing, there has been renewed interest in discerning the mechanisms by which progenitor cells mediate therapeutic benefits and the ways in which they function are optimized. To provide an update of the role of progenitor cell therapy in cardiac surgery, this review will discuss: (1) relevant progenitor and stem cells in myocardial regenerative therapy, (2) routes of cell delivery to ischemic myocardium, (3) clinical trials investigating bone marrow-derived progenitor cell therapy for myocardial ischemia, and (4) future directions of the field.


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  		Table 1 Representative Human Clinical Trials of Cell-Based Therapy for Myocardial Ischemia
 

   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 
A literature search was performed using the MEDLINE and PubMed databases in the English language until October 2008. Keywords used included the medical subject heading terms: "myocardial ischemia," "stem cells," and "tissue therapy." Studies were also identified from references cited in publications found using the search terms and in published review articles. When multiple studies were published by a single institution, the largest or most informative study was included. Current clinical trials were identified at ClinicalTrials.gov using the same search terms [5].


   Overview of Cell Types
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 
Early clinical trials have used skeletal myoblasts, circulating endothelial progenitor cells, and other bone marrow-derived mononuclear cell populations for treatment of myocardial ischemia. However, other numerous progenitor and stem cell types have been studied in animal models to assess their ability to restore cardiac function, including embryonic stem cells (ESCs), hematopoietic stem cells, mesenchymal stem cells (MSCs), endothelial progenitor cells, and, most recently, resident cardiac stem cells [16, 17]. These cell types possess unique profiles regarding ease of isolation and culture, cell surface marker expression, and ability to differentiate into other cell types.

Embryonic stem cells are undifferentiated, pleuripotent cells obtained from the inner cell mass of blastocysts. Their extensive capacity for differentiation has garnered tremendous interest for their use in regenerative medicine. Early studies of myocardial transplantation of undifferentiated murine ESCs showed improved cardiac recovery after ischemia primarily through the paracrine release of growth factors [11, 18]. However, transplantation of undifferentiated ESCs may result in teratoma formation and intramyocardial immune reactions [19, 20]. This potential for disorganized regeneration spawned interested in using more differentiated, ESC-derived cardiomyocytes that exhibit similar functional and molecular characteristics as cardiomyocytes obtained from post-natal tissue with theoretically less potential for disorganized growth. These ESC-derived cardiomyocytes seemed to improve cardiac function and decrease left ventricular remodeling in post-infarcted rat hearts without teratoma formation [21, 22]. Further studies are needed to fully define the restorative, immunogenic, teratomatous properties of ESCs of various differentiated states.

Adult progenitor and stem cells from the peripheral circulation, bone marrow, and other tissues have been more commonly used in cell-based treatments for ischemic heart disease. Generally, adult stem cells are multipotent with more limited differentiation potential than ESCs. Of primary interest have been bone marrow-derived hematopoietic stem cells and mesenchymal stromal cells that encompass MSCs, fibroblasts, and other progenitors. Compared with other progenitor cell types, these cells are present in greater numbers in vivo and pose less risk of inducing immune reactions. Hematopoietic stem cells and MSCs comprise approximately 0.01% of the total cell population in mammalian bone marrow and may be distinguished by cell surface marker expression [23, 24]. Hematopoietic stem cells have shown the ability to home to injured myocardium, but whether they differentiate into endothelial cells and cardiomyocytes or fuse with cardiomyocytes has been debated [25, 26].

Mesenchymal stem cells are pleuripotent, and their ability to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro has been advocated as one criterion for their characterization [27]. Mesenchymal stem cells have also demonstrated immunoprivilege through their abilities to evade host immune reactions and even suppress lymphocyte activation [28, 29]. Human mesenchymal stem cells transplanted into fetal sheep before and after development of immune competence demonstrated long-term survival and pleuripotency [30]. More recently, Atoui and colleagues [31] observed survival of human MSCs 8 weeks after injection into the hearts of immunocompetent rats without evidence of local immune response. In contrast, allogeneic male rat MSCs injected into female hearts after myocardial infarction resulted in improved cardiac recovery seen, but no transplanted cells survived beyond 28 days [32]. However, no activated T-cells were observed around donor allogeneic MSCs. These conflicting reports highlight the ongoing controversy of the capacity of MSCs to survive after allogeneic transplantation, and further work is needed to determine their use as a potential readily available, allogeneic, "off-the-shelf" source for stem cell-based therapy.

Endothelial progenitors comprise a circulating cell population derived from multiple origins, including bone marrow [33]. Although they may be home to the injured myocardium, they demonstrate very little ability to differentiate into cardiomyocytes in vitro [34, 35]. Their levels in the peripheral circulation seem to increase after elective cardiac surgery [36]; however the clinical effect of this observation is uncertain.

Most recently, a population of resident cardiac stem cells has been described [37, 38]. Their levels increased several fold after myocardial cryo-injury, but they are acutely depleted after myocardial infarction in mice [39]. They are relatively rare (comprising < 1% of cells in the mouse heart), and they have been subclassified according to surface marker or transcription factor expression [40]. The c-Kit+ cells have demonstrated capacity for self-renewal, clonogenicity, and pleuripotency through differentiation into myogenic, endothelial, and smooth muscle lineages in vitro and may regenerate ischemic myocardium [38]. A second population of CSCs that express stem cell antigen-1 (Sca-1) have been induced to differentiate into cells expressing cardiac specific markers in vitro, as well as at home to infarcted myocardium [37]. The Isl1+ cells isolated from postnatal rat, mouse, and human myocardium were shown to display mature cardiac phenotype including expression of myocytic markers in the absence of cell fusion, intact calcium cycling, and generation of action potentials in co-culture experiments with neonatal cardiomyocytes [41]. In addition, Isl1+ progenitor cells have been implicated in the development of specific cardiac lineages particularly in the right heart; however their capacity to regenerative myocardium remains undefined [42].


   Routes of Cell Delivery
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 
Progenitor cells may be transplanted through several delivery methods, each with its own accompanying risks and benefits. Systemic intravenous infusion involves injecting a progenitor cell suspension into a central or peripheral vein followed by homing of the cells injured tissue [43]. This technique is the least invasive; however, cells may be trapped by the lungs, the significance of widespread stem cell distribution remains unknown, and this approach has garnered less interest than more directed options [7].

Targeted deliveries involve injecting cells into known ischemic myocardium or relevant vascular territories. Direct intramyocardial injections can be made through the epicardium into the underlying ischemic myocardium. This technique may be performed during cardiac surgery when the heart is fully exposed, and the primary advantage of this approach is the ability to target specific areas of myocardium and scar under direct visualization. However, applications for larger areas require multiple injections, and the benefit may be limited by poor cell diffusion [44].

Percutaneous cell delivery poses less risk of morbidity compared with operative interventions, and this is now the most widely used route. During percutaneous intracoronary infusions, the target vessel for the ischemic territory is accessed and cells are injected through an over-the-wire balloon catheter. The balloon is intermittently inflated to transiently stop coronary flow to allow for cell distribution which may actually induce microinfarctions [45]. This approach is well-suited for larger regions of dysfunctional myocardium. However, diffusion and distribution of transplanted cells may be limited by the coronary epithelium [44]. This approach showed greater engraftment of transplanted MSCs in pigs after infarction compared with subendocardially or intravenously transplanted cells [46].

Percutaneous transendocardial delivery involves the direct injection of cells into the myocardium through the use of custom percutaneous catheters equipped with small injection needles. When combined with electromechanical mapping to identify ischemic territories, this technique offers greater precision in targeting at-risk regions [47]. Similarly with percutaneous coronary infusion, percutaneous transendocardial delivery offers less morbidity risk compared with surgical intervention.


   Clinical Trials
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 
After the initial demonstration of safety and efficacy in animal and human pilot studies, several randomized and nonrandomized studies of cell therapy for acute myocardial ischemia, chronic myocardial ischemia, and congestive heart failure and ischemic cardiomyopathy were conducted (Table 1). In these studies, mononuclear cells or myoblasts were harvested from patients' bone marrow or skeletal muscle (cultured for 3 to 7 days), and then infused or injected into the myocardium. The semi-fractionated bone marrow mononuclear cell populations were likely comprised of endothelial cells, hematopoietic stem cells, MSCs, and other stromal cells, although the exact proportions of these cells have not been routinely analyzed or reported, or both.

Two recent meta-analyses evaluated the results of several clinical studies of percutaneous intracoronary infusion of bone marrow-derived progenitor cells for the treatment of acute myocardial infarction. Abdel-Latif and colleagues analyzed 18 controlled studies including 12 randomized trials [48]. Overall, percutaneous intracoronary cell transfer showed no increase in adverse events, although one study did report a greater in-stent re-stenosis rate in the cell group than in the control group (47% vs 25%; p < 0.05). Improvements in cardiac function with cell transplantation included a 3.66% increase in left ventricular ejection fraction (95% confidence interval [CI], 5.40% vs 1.93%; p < 0.01), a 5.49% reduction in infarct size (95% CI, –9.10% to –1.88%; p = 0.003), and decreased left ventricular end-systolic volume (–4.80 mL; 95% CI, –8.20 to –1.41; p = 0.006).

The meta-analysis by Lipinski and colleagues [49] included 10 studies, 7 of which were randomized. In their analysis, intracoronary cell therapy showed a significant decrease in recurrent myocardial infarction, but no difference in mortality risk and rehospitalization for heart failure. Patients who received cell infusions showed a 2.97% increase in ejection fraction (95% CI, –4.04% to –1.88%; p < 0.001), decreased end-systolic volume (–7.43 mL; 95% CI, –12.21 vs –2.66 mL; p = 0.002), and a 5.28% reduction in perfusion defect size. A nonsignificant dose-response relationship between injected cell volume and left ventricular ejection fraction was also observed.

Martin-Rendon and colleagues [50] performed a Cochrane systematic review of 13 randomized controlled trials from 9 countries, including 880 patients investigating the use of autologous bone marrow stem and progenitor cells for the treatment of acute myocardial infarction. All studies used percutaneous intracoronary infusion for delivery. Left ventricular ejection fraction (LVEF) was the primary outcome evaluated, and cell engraftment and survival, left ventricular end-systolic volume, left ventricular end-diastolic volume, infarct size (scar size), and wall motion abnormalities were evaluated as secondary outcomes. They concluded that autologous bone marrow-derived stem and progenitor cell therapy for acute myocardial infarction may be safe and moderately beneficial. However, the trials included were too small to demonstrate whether this therapy may have an effect on the incidence of mortality and morbidity (eg, incidence of reinfarction, arrhythmias, re-stenosis, hospital readmission, and target vessel revascularization).

Of the included studies in these analyses, most were nonblinded, included small sample sizes (ie, 20 to 204 patients), had short follow-up periods (range, 3 to18 months), involved variable timing of transplantation after revascularization, and used various types and numbers of cells. In addition, only studies using percutaneous intracoronary infusion were included. To address these issues, numerous controlled clinical studies are ongoing for acute (Table 2) and chronic myocardial ischemia (Table 3). Specifically, these studies aim to determine the optimal timing, dosage, and route of cell delivery.


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  		Table 2 Active Randomized Clinical Trials for Autologous Cell Therapy for Acute Myocardial Ischemia
 

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  		Table 3 Active Randomized Clinical Trials for Autologous Cell Therapy for Congestive Heart Failure and Chronic Myocardial Ischemia
 
Since the publication of these analyses, a substudy of the REPAIR-AMI trial was completed that used magnetic resonance imaging to measure myocardial functional and size parameters following percutaneous revascularization with or without intracoronary bone marrow cell injection [51]. Fifty-four of the 204 patients in the REPAIR-AMI trial were included. The results demonstrated that intracoronary bone marrow cell infusion in patients with a baseline ejection fraction of less than 48.9% did result in significantly improved LVEF, left ventricular end-diastolic volume, and left ventricular end-systolic volume compared with the percutaneous intervention with cell infusion group at 12 months of follow-up.

To date, surgical trials using bone marrow-derived cell therapy have focused on chronic stable myocardial ischemia. These trials have generally included patients with a remote history of myocardial infarction (> 4 weeks prior), evidence of akinetic or dyskinetic infarct scars, and an indication for elective coronary artery bypass grafting (CABG). The results of these relatively small studies appear divided over whether the addition of bone marrow cell-based therapy with CABG offers clinical benefit.

Stamm and colleagues [52] completed a safety and efficacy study of 43 patients assigned to receive intramyocardial injection of CD133+ bone marrow cells during CABG or CABG alone. At 6 months, there was significant improvement in LVEF after CABG with cell injection versus CABG alone (mean change, +9.7% ± 8.8% vs +3.4 ± 5.5%; p = 0.02), and no adverse effects were observed. Zhao and colleagues [53] completed a randomized trial of 36 patients assigned to undergo CABG alone or CABG plus intramyocardial injection of bone marrow cells. At 6 months, the CABG plus cell injection group demonstrated significantly improved New York Heart Association classification, LVEF, wall thickness, and regional contractility in the infarct region. One late mortality and two incidents of ventricular arrhythmia occurred in the cell infusion group compared with none in the control group.

A randomized controlled trial by Hendrikx and colleagues [54] included 20 patients who underwent elective CABG with or without injection of bone marrow cells into the border zone of infarct scar. In this study, there was no significant change in LVEF at 4 months between the control group (39.5 ± 5.5% to 43.1 ± 10.9% increase) and the cell injection group (42.9 ± 10.3% to 48.9 ± 9.5% increase). However, wall thickness and contractility in the infarct area showed significant improvement after cell injection. Similarly, a randomized controlled trial by Ang and colleagues [55] included 63 patients who underwent CABG alone or CABG with intramyocardial injection or intracoronary infusion of bone marrow-derived mononuclear cells obtained at the beginning of the procedure. As with the Hendrikx [54] study, there was no significant change in global LV function.

The discrepancy in these early findings remains unclear. Whereas, the bone marrow cells in the Stamm [52] study were harvested the day before surgery and cultured overnight, cells were harvested after induction of anesthesia for the CABG procedure in the other randomized studies. Stamm and colleagues [52] also isolated CD133+ bone marrow cells, which may specifically give rise to endothelial cells, whereas the randomized studies used less fractionated cell populations similar to the percutaneous intracoronary infusion trials. In addition, the number of cells injected and timing of injection were variable between these studies. It is clear that larger, randomized studies with more standard protocols will be necessary to fully determine whether this therapy may hold clinical benefit for this population of patients.


   Future Directions of Mesenchymal Stem Cell-Based Therapy
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
Comment
 Acknowledgments
 References
 
The development of cell-based therapies for ischemic heart disease faces several practical challenges. Once transplanted, MSCs demonstrate retention rates of less than 5% to 6% likely due to poor incorporation and diminished survival in the inflammatory milieu [46]. As MSCs represent a small fraction of bone marrow cells, the process of expanding them in culture to numbers adequate for transplantation may require several weeks. Most clinical studies to date have used semi-fractionated populations of bone marrow cells and further work to improve efficiency of collection, culture, and survival will be crucial to optimizing this therapy. Moreover, as the number and function of bone marrow-derived mononuclear cells may decline in the setting of ischemic cardiomyopathy or other chronic disease states, it may also be necessary to continue to explore other potentially therapeutic populations, such as hematopoietic stem cells and endothelial progenitor cells.

Treating MSCs during ex vivo expansion with hypoxia or growth factors is another strategy for overcoming the post-transplant diminished cell survival and potentially function. These relatively simple techniques involve subjecting the cells to hypoxia or media containing growth factors or agents while in culture to stimulate their paracrine function and survival. In animals, preconditioned MSCs have demonstrated improved survival and engraftment, attenuation of negative myocardial remodeling, and improved myocardial functional recovery [56–58]. It remains to be seen whether these treatments will also confer long-term benefits.

The variable outcomes of the early clinical progenitor cell therapy studies, as well as the limited duration of benefit, have generated interest in optimizing donor cell function. The process of altering specific protein expression through ex vivo modifications has offered insight into the important receptors and molecules involved in progenitor cell paracrine signaling, homing, and survival. Although numerous techniques for altering gene and protein expression exist, much of this work has used viral transfection. Numerous investigators have modified MSCs to overexpress protective growth factors such as VEGF [59], upregulate homing receptors [60], upregulate cell survival signaling pathways involving Akt [61], and overexpress ischemia-protective proteins including heme oxygenase-1 [62]. The cumulative benefits of these animal studies include increased stem cell and cardiomyocyte survival, decreased infarct size, decreased remodeling, and increased recovery of cardiac ischemia.

One of the current limitations of surgically delivering cells to the myocardium is that it must be performed in combination with CABG or other cardiac procedures. However, currently under development are minimally invasive thoracoscopic techniques that use video assistance, and even robotic assistance, to maximize the surgical benefits of precise cell delivery through direct visualization of the infarct region [63, 64]. The development of new delivery methods that minimize morbidity and optimize direct cell injection or infusion may enable this application to be performed as a stand-alone procedure and for patients who are not otherwise candidates for surgical revascularization. In addition, surgically delivering cells without concomitant revascularization will enable investigators to more clearly discern the benefits of stem cell-based therapy for myocardial ischemia in the absence of those derived from revascularization.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
Acknowledgments
 References
 
Ischemic heart disease remains a major health care challenge, and progenitor cell-based therapy holds potential for treating the spectrum of myocardial ischemia. Early clinical trials demonstrated the safety of myocardial progenitor cell transplantation with associated improvements in cardiac function and remodeling. Further studies to evaluate the optimal cell type, dose, and delivery route are ongoing, but the need for larger, randomized, multicenter trials clearly remains. In addition, elucidating and modifying the signaling properties of stem cells to enhance their survival and function may further increase their therapeutic potential.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
References
 
This work was supported in part by NIH R01 GM070628, NIH R01 HL085595, NIH K99/R00 HL0876077, NIH F32 HL092718, NIH F32 HL092719, and an American Heart Association Grant-in-aid.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Overview of Cell Types
 Routes of Cell Delivery
 Clinical Trials
 Future Directions of Mesenchymal...
 Comment
 Acknowledgments
 References
 

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