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We are on the verge of an extraordinary and exciting time in cardiovascular medicine. Until recently, it was believed that tissue damaged during a myocardial infarction was permanently lost. We now understand that there is a stem cell-based repair process that attempts to repair the injured myocardium. Unfortunately, this is a clinically inefficient process because of the short period during which the molecular signals are expressed, too few stem cells and/or the wrong cell type entering the injured tissue, or the lack of coordinating and/or differentiation signals expressed in the injured tissue. Importantly, we are now actively developing strategies that we believe could not only recover cardiac function but regenerate myocardial tissue as well. Further development and clinical fruition of these strategies for the treatment and/or prevention of chronic heart failure will require a high level of collaboration between the basic scientist and clinician and a great deal of rigorous work on both sides. The combination of the increasing prevalence of congestive heart failure, the economic burden of caring for these patients and the morbidity and mortality associated with the diagnosis, the potential human and societal benefits of unlocking the potential of stem cell therapy as a treatment is extraordinary. [ABSTRACT FROM AUTHOR]

Angiogenesis and vasculogenesis are fundamental processes in embryonic development enabling multiorgan characteristics. Through the capillary net, the nutrient diffusion process is successfully achieved in complex cellular organisms. In adults the establishment, maintenance, and renewal of an efficient vascular net are required for the maintenance of normal, viable tissues. This requirement is especially important in the cardiovascular system, where vascular supply efficiency and endothelium normal function are affected in many different pathological entities. Impaired angiogenesis and endothelial dysfunction are the bases of many cardiovascular diseases such as hypertension, coronary artery disease, myocardial infarction, and chronic heart failure. Two different pathways of vessel development have been described: angiogenesis and vasculogenesis. Vasculogenesis is the process of new vessel development whereby primitive undifferentiated cells (angioblasts) differentiate to endothelial cells, which line a primitive network of embryological blood vessels. Angiogenesis describes the sprouting of differentiated preexisting endothelium into vascular tissue from preexisting capillaries. All blood vessels are lined with endothelial cells that must proliferate to form new vessels, migrate to reach remote targets, and survive in these different environments. Angioblast/endothelial progenitor cells (EPCs) represent the phenotypic equivalent of embryonic angioblasts because they can be derived from both endothelial and mural cell types. Angioblast/EPCs can be isolated from bone marrow aspirate, peripheral blood, umbilical cord blood, or human adipose tissue. Clinical applications of angioblast/EPCs in cardiovascular disease are oriented to neovascularization induction in ischemic tissues, generation of new vessel nets in regenerative therapies, and endothelization of denuded endothelium, vascular grafts, and tissue engineering devices. The role of angioblast/EPCs directly injected into the myocardium for the treatment of ischemic heart failure will be discussed here. [ABSTRACT FROM AUTHOR]

Previous dogma held that an acute myocardial infarction (MI) resulted in absolute death of the involved myocardium and could only be modulated by reperfusion therapy. Recent data demonstrating the presence of a natural repair process stimulated by the release of chemokines in response to injury have challenged that belief. Unfortunately, this natural repair mechanism occurs at a rate that precludes any meaningful recovery of myocardial tissue and function. The feasibility of myocardial repair/regeneration has been demonstrated through delivery of either exogenously expanded stem cells or endogenously mobilized stem cells expanded by growth factors (i.e., granulocyte-colony-stimulating factor). Although data regarding the use of various growth factors in order to attenuate the extent of damage or facilitate repair of injured myocardium remain limited, the early experiences have suggested safety. From these data, one may envision a potential therapeutic strategy that augments the naturally occurring repair process early following a MI through mobilization of stem cells that will minimize damage and limit the dysfunction for a substantial proportion of patients. [ABSTRACT FROM AUTHOR]

Clinical trials using autologous hematopoietic or whole bone marrow preparations in patients in the peri-infarct period are ongoing. These trials are attempting to improve myocardial function. Although it has been demonstrated in animal models that these stem cells do not differentiate into cardiac myocytes, there is now clear evidence in animal models and clinical human trials that their use is likely beneficial when delivered soon after acute myocardial infarction. It should be noted that all of these trials have been performed in days to less than 2 weeks from myocardial injury. The end product of myocardial injury translates into heart failure, an entity that may be minimized by this type of therapy. One comes to the conclusion that the data are promising, but there are still many questions to be answered, for example: What type of cell(s) should be transplanted, and what should be their mode of delivery, optimal time of transplant, etc. [ABSTRACT FROM AUTHOR]

Recent investigation of cell transplantation has provided new hope for the treatment of heart failure, a historically incurable disease. Although multiple cell types and delivery techniques have been employed, no clear consensus has been reached as to the superiority of any single method. Skeletal myoblasts have several unique properties that make them an attractive cell type for use in the clinical arena. Most importantly they are autologous, readily available, and easily harvested and expanded ex vivo. Furthermore, they can be modified genetically to optimize engraftment. Their successful use in animal studies has justified several clinical trials in the United States and Europe. Autologous engraftment of skeletal myoblasts in patients has been associated with modest improvements in cardiac function. The mechanisms by which these cells might exert their positive effect remain in question, but a direct contribution to contractile function seems unlikely. Enthusiasm for these cells has further been tempered by an apparent arrhythmogenic risk. This chapter explores the use of skeletal myoblasts for the treatment of heart failure. The preclinical and clinical data published to date are reviewed. The ultimate role of these cells in the clinical armamentarium of heart failure treatments will depend on the results of ongoing studies. Regardless of their future, the use of skeletal myoblasts has provided important insights in the burgeoning field of cell therapy for heart failure. [ABSTRACT FROM AUTHOR]

Ischemic heart disease remains a leading cause of morbidity and mortality despite advances in medical therapy and revascularization techniques. Born out of this burden of ischemic heart disease is a burgeoning body of literature in both the preclinical and clinical settings that demonstrates the benefits of cell therapy. Central to the acceptance of cell therapy as a viable treatment strategy is determining the fate of the cells employed, the overall effect on ventricular function, and, ultimately, clinical outcomes. Although these assessments are readily attainable through invasive hemodynamic studies and histological analysis in the preclinical setting, the use of clinical parameters and noninvasive imaging modalities have been employed in the clinical setting. In addition to establishing the safety of cell therapy by focusing on "hard endpoints," such as death, myocardial infarctiion, arrhythmias, the efficacy of cell therapy in achieving the outcome of myocardial regeneration may be feasible through advances in magnetic resonance and nuclear imaging as well as echocardiography. This chapter will discuss potential strategies that have been employed and those strategies that should continue to be utilized in the assessment of the cardiac response to cell therapy. [ABSTRACT FROM AUTHOR]

Treating ischemic heart failure remains one of the most challenging tasks in current cardiology practice. Despite recent technological advances, many heart failure patients are not ideal candidates for percutaneous or surgical revascularization. This so-called "no-option" patient group usually comprises those individuals who have undergone multiple revascularization procedures and have significant residual myocardial ischemia. The hallmark of the so-called no-option group of patients is that the current treatment approach yields unsatisfactory results once they continue to have unmanageable symptoms of refractory angina or heart failure. For treatment of no-option patients, clinical cardiology researchers have pursued different strategies, including percutaneous and surgical laser therapy and angiogenesis via delivery of growth factors, but limited and conflicting clinical results have been discouraging and led to the development of further therapies. As a result, stem cell therapy has emerged as an alternative for patients with end-stage heart disease. New insights into the mechanisms of cardiac repair have provided evidence that the heart can undergo a repair process in adulthood. Currently, several types of stem cells are under investigation for use in cardiac stem cell therapy. Bone marrow-derived stem cells were among the first to be studied in clinical trials. The present chapter will address current understanding of bone marrow-derived cardiac stem cell therapy for the treatment of ischemic heart failure and will discuss experimental and clinical evidence supporting its utilization. [ABSTRACT FROM AUTHOR]

The significant advances achieved over the past decade in the field of percutaneous coronary intervention have significantly increased our ability to use catheter-based techniques to modify cardiac physiology. The ongoing studies demonstrating the significant potential of cell-based therapy for the prevention and treatment of chronic heart failure has led to the development of multiple catheter-based systems for the delivery of cells to the injured myocardium. Advances have also been made in catheter-based systems that exploit electomechanical properties of the heart in order to direct the interventionalist as to the best areas in which to inject cells. In this chapter we will review the different catheter systems currently available or under development as well as discuss how different features of each may be optimal in the different settings of acute myocardial infarction and chronic heart failure. [ABSTRACT FROM AUTHOR]

Chronic heart failure has emerged as a major worldwide epidemic. Recently, a fundamental shift in the underlying etiology of chronic heart failure is becoming evident, in which the most common cause is no longer hypertension or valvular disease, but rather long-term survival after acute myocardial infarction (MI). The costs of this syndrome, both in economic and personal terms, are considerable. American Heart Association statistics indicate that chronic heart failure affects 4.7 million patients in the United States and is responsible for approx 1 million hospitalizations and 300,000 deaths annually. The societal impact of chronic heart failure is also remarkable. Patients with chronic heart failure often suffer a greatly compromised quality of life. About 30% of diagnosed individuals (i.e.,1.5 million in the United States) experience difficulty breathing with little or no physical exertion and are very restricted in their daily functions. This forced sedentary lifestyle inevitably leads to further physical and mental distress. However, it is evident, running through the different therapeutic strategies of chronic heart failure, that the appropriate treatment of patients with ischemic heart failure is still unknown. Since 1992, a revolutionary option to treat cardiac disease has come to the scene based on the possibility of using autologous cells, appropriately cultured and expanded, to replace or provide new contractile tissue as well as new sources of blood perfusion. Cell transplantation is currently generating a great deal of interest in that the replacement of akinetic scar tissue by viable myocardium should improve cardiac function, impede progressive left ventricular remodeling, and revascularize the ischemic area. From the original paper of Marelli and colleagues in 1992, presenting for the first time the concept of using autologous skeletal muscle cells to repair a damaged zone of the heart, a procedure termed "cellular cardiomyoplasty," supportive experimental as well as clinical evidence has been published in respect to the potential of cell transplantation for cardiac repair or regeneration. A variety of cell populations have been applied for cardiac repair either experimentally or clinically. Each cell type has its own profile of advantages, limitations, and practicability issues, particularly in the clinical setting. Several options are under evaluation in terms of mode of delivery. In this chapter we will discuss the fundamentals of the direct epicardial approach in cell transplantation using either an open- or closed-chest (endoscopy) technique. [ABSTRACT FROM AUTHOR]

Ischemic heart disease resulting from myocardial infarction (MI) is the leading cause of sudden cardiac death (SCD) in the United States. Recent clinical and basic science investigations have focused on replacing damaged myocardium with skeletal muscle myoblasts (SKMBs) and bone marrow-derived stem cells (BMCs). Such cell therapies for MI have been shown to improve cardiac function; however, it is unknown if electrical viability of damaged myocardium can be restored and, thus, reduce the risk for SCD. Presently, several studies suggest that SKMB therapy for damaged myocardium increases arrhythmia risk, which may be causally related to a lack of SKMB integration into the electrical syncytium of the heart. In contrast, BMCs demonstrate less arrhythmia risk, enhanced electrical viability, and evidence of electrical integration. Other cell types and delivery methods may offer an even greater potential for enhanced electrical viability and reduced arrhythmia risk. Considering that SCD associated with damaged myocardium is primarily caused by arrhythmias, it is clear that an important factor that will determine whether cell therapy will succeed or fail is its electrophysiological consequence. [ABSTRACT FROM AUTHOR]

Electromechanical coupling is crucial in the process of functional cardiomyocyte regeneration. Experimental and initial clinical studies have showed the high risk of arrhythmia in the animals and patients receiving cell transplantation from pluripotent stem cells. The mechanism underlying these arrhythmogenic properties is still unclear. The communications between the cells via gap junction formed by connexin proteins are essential for activating cardiac tissue, allowing propagation of electrical stimuli and related ionic currents. It has been shown that there is a functional gap junction between cardiomyocytes and most cells used for cell transplantation, such as human embryonic stem cells, human mesenchymal stem cells, bone marrow-derived mononuclear cells, and fibroblasts. Although it is still controversial, a recent study has shown that there are N-cadherin- and connexin-43-mediated junctions between skeletal myoblasts and cardiomyocytes, allowing them to induce synchronous beating. However, it should be emphasized that all of the cells mentioned above have been demonstrated to have pro-arrhythmogenic potentials. These factors must be weighed as we pursue the avenues of cell therapy for failed hearts. Experimental studies and initial clinical experience with cell transplantation has opened new perspectives for treatment of irreversibly injured myocardium. It must be pointed out that further studies, including experimental and clinical studies, are necessary to address the questions regarding the efficacy and long-term safety of cell transplantation. [ABSTRACT FROM AUTHOR]

Cell replacement therapy is emerging as a novel therapuetic paradigm for restoration of the myocardial electromechanical properties. This innovative strategy has been significantly hampered by the paucity of cell sources for human heart cells. The recent establishment of the human embryonic stem cell (hESC) lines may provide a possible solution for this cellsourcing problem. These unique pluripotent cell lines can be propagated in the undifferentiated state in culture and coaxed to differentiate into cell derivatives of all three germ layers, including cardiomyocytes. This chapter will focus on the derivation and properties of hESC and their cardiomyocyte cell derivatives. The potential applications of this unique differentiating system in several research areas will be discussed, with special emphasis on the steps required to fully harness their unique potential in the emerging field of cardiovascular regenerative medicine. [ABSTRACT FROM AUTHOR]

Understanding cardiac myocyte differentiation during embryonic heart development will provide insight into how to promote cardiac myogenesis in stem cell populations for cell-based therapies. This chapter reviews what is known about the embryonic origin of cardiac myocytes in vertebrates, the signals that induce myocardial cell specification, the factors that regulate transcription during cardiac myocyte differentiation, and the regulatory networks that connect them. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (MI) remains a leading cause of morbidity and mortality despite advances in treatment that have resulted in the lowest mortality rate to date. However, a significant proportion of patients do not receive these beneficial therapies because they are deemed ineligible or they present outside the window of opportunity for benefit. Thus, the prevalence of heart failure continues to rise. Although the treatments for heart failure have advanced tremendously, they simply focus on attenuating hemodynamic stimuli that induce deranged remodeling. The limitations of these therapies have prompted the search for additional treatments that may improve the outcomes experienced by patients stricken with an acute MI as well as those who have developed heart failure. Central to the development of novel therapeutic strategies to treat these two manifestations of ischemic heart disease is an understanding of the different goals for treatment in each situation as well as the differences in the molecular milieu present in each. Whereas targeting preservation of injured tissue and restoration of ample blood flow may be targets in the acute setting, restoring the deranged infrastructure as well as regenerating myocardium may be targets in the failing myocardium. Potent molecular signaling processes are present that respond to the initial insult of an acute MI and facilitate the initiation of the repair process. However, overactive or persistent expression of these factors may lead to altered myocardial matrix and, ultimately, facilitate the development of heart failure. This chapter will serve to expose the reader to this molecular signaling focusing on the acutely infarcted myocardium and the failing heart. [ABSTRACT FROM AUTHOR]

Limitations of revascularization for ischemic heart disease include incompleteness of revascularization, even for surgical revascularization, especially for calcified lesions in distal segments of small-caliber vessels. Revascularization has not been shown to regenerate functional, viable myocardium from scarred and infarcted myocardium. Previous alternatives to revascularization such as transmyocardial laser revascularization, gene therapy, and orthotopic heart transplantation also have many disadvantages that limit their use in high-risk patients such as those with recent myocardial infarction and advanced heart failure. Although preclinical and early clinical studies in cardiovascular disease of adult-derived stem cells have shown promise, many limitations remain. Umbilical cord blood (UCB)-derived stem cells have several advantages over adult stem cells, including ease of harvesting and storage and decreased risk for immune intolerance and transmission of infectious agents. Here we summarize our laboratory's preclinical in vitro and in vivo studies of UCB-derived stem cells: their phenotypic characterization, ability for neovascularization in a murine femoral artery ligation hindlimb ischemia model, reduced likelihood of stimulating an immune response, and interaction with stem cells of other origins. [ABSTRACT FROM AUTHOR]

In recent years, the evidence of myocardial regeneration in animal models as well as in humans has produced a paradigm shift in scientific opinion: cardiomyocytes can be generated ex novo in the adult heart. The origin of these dividing myocytes is still the subject of scientific debate. In fact, following the first observations of chimerism in transplanted heart and myocyte growth in cardiac hypertrophy and failure, studies of different groups pointed to the existence of local primitive stem (or progenitor) cells, which are able to proliferate and differentiate during the entire cardiac cell lineage. This chapter will focus on those resident cardiac cells claimed to be local sources of myocardial regeneration (endogenous cardiac stem cells). Different isolation procedures, characterization, and potential clinical application will be discussed. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are multipotential cells that can be isolated from a number of tissues but are readily isolated from bone marrow. These cells grow in culture as attached fibroblastic cells that expand readily in culture but maintain their contact inhibition as they reach confluence. Flow cytometry analysis of surface markers on MSCs shows that the cultured cells are very homogeneous, and differentiation assays indicate their potential to differentiate into a variety of cell types. Numerous experiments have demonstrated that these multipotential cells are not rejected by the immune system and therefore it may be possible to use the MSCs from one donor in multiple recipients. Additionally, these remarkable cells, found in all individuals, have the natural ability to migrate to sites of injury in the body, a finding the meaning of which is only beginning to be understood. Cardiac injury results in the loss of cardiomyocytes and reduced heart function. Cardiomyoplasty with MSCs is seen as a way to augment the myocardium with multipotential cells that may aid in repairing the heart and improving function. Animal studies have supported this approach, and human clinical trials have now begun. [ABSTRACT FROM AUTHOR]

Mammalian bone marrow contains mesenchymal lineage progenitors that have high proliferative capacity, are clonogenic in vitro, and demonstrate the ability to differentiate to multiple mesenchymal lineage tissue types, including bone, cartilage, fat, smooth muscle, and cardiac muscle. Isolation of these cells on the basis of their physical properties results in clonal outgrowth with functional in vitro heterogeneity. Prospective immunoselection of mesenchymal lineage precursor cells enhances reproducible functional outgrowth, and the phenotype STRO-1brightVCAM-1+ characterizes a multipotent mesenchymal precursor cell in vivo, which gives rise to a 50% frequency of multipotential clonal outgrowth in vitro. These cells are anatomically located in perivascular niches in the bone marrow and throughout the body and demonstrate phenotypic and genetic identity to vascular pericytes. Consistent with the pivotal role played by pericytes in formation of vascular structures during embryogenesis, cumulative data show that mesenchymal precursors regulate adult vasculature formation. In addition, under appropriate differentiation conditions, mesenchymal precursors give rise to new cardiomyocytes. Because vascular network formation is a prerequisite for long-term survival of cardiomyocyte precursors implanted into ischemic myocardium, mesenchymal lineage precursors appear to be ideal candidates for enhancing both cardiac neovascularization and myogenesis. Clinical protocols using these cells will require optimization of serum-free culture methodologies and biological scaffolds/matrices for enhancing survival of implanted cells. Finally, recent data indicating that mesenchymal lineage precursors evade immune recognition raise the exciting prospect that allogeneic use of these cells may be feasible. [ABSTRACT FROM AUTHOR]

In 2001 the laboratory of Catherine Verfaillie at the University of Minnesota described the multipotent adult progenitor cell (MAPC) as a novel progenitor cell present in adult marrow that is biologically and antigenically distinct from the mesenchymal stem cell (MSC). MAPCs represent a more primitive progenitor cell population than MSCs and demonstrate remarkable differentiation capability along the epithelial, endothelial, neuronal, myogenic, hematopoeitic, osteogenic, hepatic, chondrogenic, and adipogenic lineages. MAPCs thus embody a unique class of adult stem cells that emulate the broad biological plasticity characteristic of embryonic stem (ES) cells, while maintaining the characteristics that make adult stem cells more amenable to therapeutic application. MAPCs have been reported to be capable of prolonged culture without loss of differentiation potential, and of showing efficient, long-term engraftment and differentiation along multiple developmental lineages in nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice without evidence of teratoma formation. Based on these findings, there is great interest in evaluating the therapeutic value of MAPCs for a variety of human genetic and degenerative ailments, including cardiovascular disease. This chapter will focus on reviewing MAPCs and other adult stem cells displaying broad, pluripotent differentiation potential as cellular therapeutics with application for myocardial repair in heart disease. For clarity, the MAPC acronym will be used specifically to represent the cell population originally described by or acquired from the laboratory of Catherine Verfaillie and collaborators. Pluripotent adult stem cell cultures reported by other researchers will be referred to in accordance with designations used in the original publications. [ABSTRACT FROM AUTHOR]

Adult bone marrow consists of several populations of stem cells that are the focus of investigations into their potential to regenerate nonhematopoietic tissues. According to this hypothesis, bone marrow stem cells display a plasticity not previously recognized. Although data supporting bone marrow stem cell plasticity is extensive, many researchers dispute this concept. One of the most controversial aspects of stem cell plasticity relates to regeneration of heart muscle following acute myocardial infarction (MI). When experimentally induced MIs in rodents were analyzed for regeneration of the heart tissues, it was reported that cardiomyocyte renewal was achieved as a result of bone marrow stem cell infiltration of the damaged tissue. Evidence continues to accumulate in support of and against the potential for myocardial regeneration, indicating the need for a better scientific basis for the possible involvement of bone marrowderived stem cells in myocardial regeneration. In order to achieve a higher level of acceptance for myocardial regeneration, researchers must develop more exacting methodologies to monitor repair over time at the cellular level. A major effort must be undertaken to identify the signals required for stem cell mobilization and trafficking to infarcted cardiac tissue and to define the genetic mechanisms involved in stem cell plasticity. To answer these questions it will be necessary to establish the exact identity of the stem cell population involved. Controversies regarding myocardial regeneration in rodent models will require additional experiments using large animal models, with an emphasis on tracking of labeled donor cells. These preclinical experiments will also enable testing celldelivery devices and noninvasive modalities for detecting improvement in regional and global myocardial function. If key questions relating to transdifferentiation potential, cell survival, and function can be resolved, we may one day be able to fully exploit the potential of stem cells for myocardial repair. [ABSTRACT FROM AUTHOR]

Ischemic heart disease remains the leading cause of chronic heart failure (CHF). The prevalence of CHF has increased dramatically over the last three decades, with more than 10% of the US population over 65 years of age now carrying the diagnosis. Based on current trends, heart failure is predicted to increase to more than 6 million people in the United States by the year 2030 (1). One cause of the increased prevalence of CHF is our success in the treatment of acute myocardial infarction (MI). Mortality rates of transmural MI in clinical trials has decreased from more than 10% in clinical trials in the late 1980s to less than 5% in recent primary percutaneous coronary intervention trials. These advances, combined with the compelling data that cholesterol-lowering therapy significantly decreases the risk of MI, would lead one to hypothesize that the incidence of CHF should be on the decline. However, we are a population of increasing risk, given the increasing incidence of diabetes, hypertension, obesity, and sedentary lifestyle. Thus, although great advances have been made in the treatment of cardiovascular disease, there is a great need for stem cell therapy to prevent and treat CHF. [ABSTRACT FROM AUTHOR]

Stem cells are cells capable of proliferation, self-renewal, and differentiation into various organ-specific cell types. Stem cells are subclassified based on their species of origin (mice, rat, human), developmental stage of the species (embryonic, fetal, or adult), tissue of origin (hematopoietic, mesenchymal, skeletal, neural), and potential to differentiate into one or more specific types of mature cells (totipotent, pluripotent, multipotent). Embryonic stem (ES) cells are totipotent, primitive cells derived from the embryo that have the potential to become all specialized cell types. Conversely, adult stem cells are undifferentiated cells found in differentiated tissue that retain the potential to renew themselves and differentiate to yield organ-specific tissues. Stem cells are attractive candidates for novel therapeutics for patients with different heart diseases, including congestive heart failure, most commonly caused by myocardial infarction. The remarkable proliferative and differentiation capacity of stem cells promises an almost unlimited supply of specific cell types including viable functioning cardiomyocytes to replace the scarred myocardium following transplantation. [ABSTRACT FROM AUTHOR]