Cardiovascular & Haematological Disorders - Drug Targets - Volume 10, Issue 3, 2010

Cell and tissue repair is an essential mechanism not only to the survival of organisms in their constant struggle to preserve homeostasis, but also for the evolution of life in Earth's often harsh environment. In some tissues this ability to regenerate is extremely effective, while in others it is virtually nonexistent. Some organisms, such as the zebrafish and newt, have excellent regenerative capacities and can completely regrow an amputated limb or tail [1]. They can even regenerate part of the heart that has been excised, by producing a mass of undifferentiated cells [1]. Unfortunately, under normal conditions mammals do not possess this extraordinary ability [2]. However, the inability of mammals to regenerate cardiac tissue can, at least in theory, be circumvented by various mechanisms [3]. The potential role of stem cells in cardiovascular diseases is well recognized. Stem cells contribute to cardiac repair, but they only have a limited capacity to achieve this effect. Stem cells use has been an important area of both basic and clinical research during the last years. Various types of cells have been used for transplantation targeting cardiac repair, including bone marrow cells, resident cardiac stem cells, endothelial progenitor cells, skeletal myoblasts, adipose progenitor cells, mesenchymal progenitor cells, and embryonic stem cells. Besides intracoronary administration, two other methods are used to apply stem cells: percutaneous endocardial (intramyocardial) and surgical (epicardial). The advantage of intracoronary application is that the cells reach the infarct border zone, an environment where they are likely to develop. However, this route means that the cells must migrate through the arterial wall to myocardial tissue, and so ischemic areas will receive fewer cells than non-ischemic areas. In addition, while stem cells derived from bone marrow or blood are able to migrate through the vessel wall, this is not the case with skeletal myoblasts, which can obstruct coronary microcirculation and cause microinfarctions. Intramyocardial administration has the advantage of applying the cells directly at the desired site without the need for migration and without provoking distal embolization. However, this requires perforation of the myocardium, and cells are less likely to survive in necrotic tissue with limited perfusion, particularly in the first few days post-MI. Most cells injected in these circumstances in fact die [4]. Moreover, a recent study showed that intravenous bone marrow mononuclear cell injection was ineffective to target myocardium and that the presence of myocardial infarction did not affect myocardial cell distribution [5]. Another important point is that stem cells mainly home to the spleen [6]. In fact, in one study, myocardial regeneration was only induced in splenectomized animals [7]. Safety is an essential consideration in any new therapy introduced into clinical practice. Stem cells have the potential to transform not only into cardiomyocytes but also into fibroblasts, which may worsen myocardial scarring and create a substrate for malignant arrhythmias [8]. This pro-arrhythmic effect may be strengthened by the incomplete integration of stem cells into myocardial tissue, which could affect electrical conduction and hence the synchronicity of myocardial contraction. This effect of stem cell therapy had not been seen in animal studies before its use in humans [9, 10]. However, enthusiasm for injecting skeletal myoblasts into myocardial scar, with the aim of repairing the damaged tissue, has waned after patients receiving the treatment began to suffer from malignant arrhythmias [11]. These may be caused by the failure of skeletal myoblasts to produce connexin-43, preventing electrical coupling with the surrounding myocardium [12]. Intracellular monitoring of skeletal myoblasts transplanted into infarcted myocardium in rats showed that the myoblasts' contractile activity was independent of neighbouring cardiomyocytes [13]. This could trigger fatal arrhythmias. As a consequence, intramyocardial administration of skeletal myoblasts must be accompanied by implantation of a cardioverter-defibrillator [11]. Teratomas can also form as a result of stem cell therapy. The application of unselected cell populations from bone marrow, containing stem cells that are specific to various organs, can result in the development of non-cardiac tissues [14]. Furthermore, four weeks after intramyocardial administration of unselected bone marrow cells in rats, myocardial calcification was found in 30% of the animals [15].

Endothelial progenitor cells (EPCs) are a special type of stem cells, derived from bone marrow that can be mobilized to the peripheral circulation in response to many stimuli. EPCs play a crucial role in the vascular repair, as well as in neovascularization processes. Recent studies have shown that EPCs are impaired, both in number and function, in diabetic patients independently of other cardiovascular risk factors. Accelerated atherosclerosis is probably the most devastating among diabetes complications and endothelial dysfunction might be the beginning of the atherosclerosis. The impairment of EPCs seems to significantly contribute to atherogenesis and atherosclerotic disease progression in diabetes. Autologous EPCs therapy is a promising treatment option for vascular complications requiring therapeutic revascularization and vascular repair. Diabetic patients represent a population that may benefit from cell-based therapy; however, the dysfunction of their endogenous cells may limit the feasibility of this approach. In fact, EPCs isolated from these patients for autologous cell transplantation may retain their dysfunctional characteristics in vivo and as a consequence display a reduced capacity to improve therapeutic neovascularization. In the present review, we summarize the most relevant mechanisms underlying EPC dysfunction in diabetes.

A growing number of clinical trials are evaluating the effects of stem cell therapy in patients with chronic ischemic heart dysfunction. As most of the clinical trials included a limited and different number of patients, various stem cell sources and several delivery approaches, results vary substantially between these studies. We analyse whether the assessment of myocardial viability may be important when evaluating effects of stem cell transplantation on parameters of left ventricular remodeling. Viability assessment could help to find the best type of stem cell and the best method of cell delivery to be used in chronic ischemic heart dysfunction.

Stem cell-based therapies represent a promising therapy for myocardial infarct. Pre-clinical and clinical tests performed in the last 10 years indicate that several types of stem cells and their progenies reduce infarct size and improve cardiac contractile function. The mechanism is dependent on the type of cell and involves a combination of several factors, such as: (i) the formation of new blood vessels, (ii) the release of pro-survival, pro-angiogenic and antiinflammatory factors (paracrine effect), and (iii) the functional contribution of cardiomyocytes. With the exception of cardiac progenitor cells and pluripotent stem cells (human embryonic stem cells and inducible pluripotent stem cells) that have the unquestioned ability to give rise to cardiomyocytes, the other stem cells, including bone marrow stem cells and fetal stem cells, have none or very limited capacity to differentiate into contractile cells. For both cases, it is of the utmost importance to develop strategies to promote cell survival and in vivo engraftment as well as to unravel the therapeutic mechanism of stem cells. This review focuses on the recent developments of stem cells and on the use of biomaterials for efficient stem cell delivery and tracking.

With increasing focus on the advance towards curative solutions, it is hard not to be excited by the potential of stem cell-based therapy. Application of the stem cell paradigm to cardiovascular medicine has fostered the evolution of novel approaches aimed at reversing injury caused by ischemic and non-ischemic cardiomyopathy. The feasibility and safety of stem cell use has been established in over 3, 000 patients with either recent myocardial infarction or chronic organ failure. Nonetheless, the efficacy of stem cell therapy continues to remain in question. Initial clinical trials have focused on evaluation of multiple adult stem cell phenotypes in their unaltered, naive state as a “first generation” resource for repair. Though significant strides in perfecting delivery of these biologics to the diseased heart have been achieved, the benefits with regard to myocardial functional recovery have been modest at best. One approach towards optimizing outcome may lie upon preemptive guidance of stem cells down the pathway of myocyte regeneration. As seen with pharmacotherapeutics in the last century, successful translation of “second generation” biotherapeutics in the 21st century will require close integration of a community of practice and science to ensure broad application of this emerging technology in the treatment of heart disease.

Cardiovascular disease is the leading cause of death in developed countries. Acute myocardial infarction (AMI) is the result of hypoxia leading to cardiomyocyte death. This causes loss of function of contractile tissue, which is replaced by non-contractile fibrous tissue affecting left ventricular ejection fraction (LVEF). One of the current approaches to recover LVEF after an AMI is focused on the search for functional cells to replace the dead tissue, via implantation in the heart of autologous progenitor cells with a regenerative capacity. This review classifies these cells into two types: a) non-resident cells and b) resident cells within the cardiac tissue. We provide an overall view of the various subpopulations and their markers, based, in humans and animal models from the early pioneering work to the latest findings.

The crucial role played by the endothelium in cardiovascular disorders has been repetitively recognised. Endothelium injury has been implicated in atherosclerosis, thrombosis, hypertension and other cardiovascular diseases. Recently, however, research has undertaken a new avenue. As mature endothelial cells posses limited regenerative capacities, the interest has been switched to the circulating endothelial progenitor cells (EPCs). Indeed, the scientific community has made progress in understanding the role of EPCs in the maintenance of endothelial integrity and function as well as post natal neovascularisation. It has been suggested that these cells are able to home in the site of heart injury / damage and that they might take part in angiogenesis, giving hope for new treatment opportunities. There is evidence that reduced availability of EPCs or impairment of their function is associated with more severe CV disease and to comorbid risk factors. Different current drug regimes are able to influence bone marrow production and release of EPCs and several growth factors are considered for possible useful new therapeutic approaches. Thus, many studies into the potential use of EPCs in the clinical setting have recently been conducted with conflicting results. The goal of this review article is to discuss current therapies to regenerate new vessels and therefore to enhance myocardial function. The article overviews the search strategy and the pathophysiological aspects behind this therapy, consider the target currently under investigation and set the stage for new ideas.

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in cardiovascular disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug needs further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in platelet responsiveness to drugs. The historical “gold standard” test of platelet function (optical aggregation) has been extensively used for measuring the effect of antiplatelet drugs, but has limitations. New tests developed (i.e. PFA-100®, VerifyNow®) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity of a consensus regarding the definition of resistance and the relevant test, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of individually adjusting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.