Review ArticleCell therapy in myocardial infarction
Introduction
Heart failure is a leading cause of morbidity and mortality worldwide. There are an estimated 5 million Americans with a diagnosis of heart failure [1]. The overall prevalence ranges from 3 to 20 per 1000 people and exceeds 100 per 1000 people over the age of 65. The annual incidence of heart failure ranges from 1 to 5 per 1000 people and doubles each decade over the age of 45 [2]. Heart failure is responsible for roughly 20% of hospital admissions for patients over the age of 65 [1]. In the United States in 1991, the cost of treating heart failure in ambulatory patients was approximately $15 billion and the cost of inpatient treatment was roughly $23 billion. The total health care cost for treatment of heart failure neared 5% of health care expenditures that year [2].
Determining the etiology of heart failure can be complex due to a lack of consistent diagnostic criteria and patients with multiple morbidities who may contribute to the etiology. Despite this challenge, coronary artery disease (CAD) is currently the most common identifiable cause of heart failure. In over 20,000 patients enrolled in multicenter heart failure treatment trials from 1986 to 1997, CAD was the underlying etiology in 68% of cases [3]. In population-based studies, the prevalence of CAD varies from 28% to 36% [4], [5].
Mortality after myocardial infarction (MI) improves with early reperfusion of the infarct-related artery [6]. If this is not accomplished in a timely fashion, necrosis, scar formation, and left ventricular remodeling occur. Remodeling affects left ventricular function and, therefore, prognosis [7]. The best way to prevent this process from occurring is to minimize the initial insult with timely restoration of flow in the infarct-related artery; however, this is not always possible. Current procedures to treat heart failure once the infarct has occurred work toward prevention of further weakening of the myocardium. However, the primary problem of fibrosis is not addressed with these modalities. Cell-based therapy is an adjunctive treatment to improve left ventricular function after myocardial injury.
Traditional belief that the heart contains myocytes that have terminally differentiated has been questioned. Undifferentiated cells have been found in transplanted human hearts, and evidence of myocyte proliferation in the human heart exists as well [8], [9]. This proliferation is not sufficient to compensate for the up to 1 billion cardiomyocytes (CMCs) that are lost after MI [10]. Cellular cardiomyoplasty describes a method of transplanting stem or progenitor cells to damaged myocardium after infarction in order to regenerate myocardial tissue. The theory behind this method involves replacing degenerate myocardium with functional tissue. A number of different cell types, as well as methods of delivery, have been tested in both human and animal models.
Section snippets
Cell types
Multiple forms of stem and progenitor cells have been studied for use in cellular cardiomyoplasty. Each cell type has its own clinical, technical, and ethical considerations.
Intramyocardial injection
Intramyocardial injection of cells for cardiomyoplasty involves direct injection into the myocardium of the infarcted region. This delivery system has been used in a wide range of studies on cell therapy [20], [21], [22], [25], [28], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [57], [58], [59], [60], [61]. The advantage of intramyocardial injection (IMC) is that it provides a direct route of administration to the affected myocardium. Disadvantages include a low
Mechanism
The mechanism by which cell-based therapy causes beneficial effects on cardiac function remains unclear. Multiple theories have been described, including transdifferentiation, cell fusion, and release of paracrine mediators. The concept of stem cell plasticity describes stem cells from one tissue differentiating into that of another [10]. Both transdifferentiation and cell fusion are possible mechanisms to explain this plasticity in cell therapy. Transdifferentiation refers to differentiated
Menasche et al., 2003
The field of cell therapy is an exciting one that has gained significant attention recently. This interest has led to the conduction of several clinical trials. Menasche et al. conducted a Phase I trial utilizing autologous skeletal myoblasts delivered via direct intramyocardial route in 10 patients with LVEFs of <35%, history of MI, with residual akinetic scar. Myoblasts were injected during concomitant CABG; however, injection occurred in a different region than the one bypassed. Patients
Directions for future research
Cell therapy in the treatment of MI is a new and exciting concept that has been studied using numerous cell types, delivery systems, and strategies. Much progress has been made since the concept was first introduced; however, there are still many unanswered questions that need to be addressed before this technology can be properly instituted in a large patient population. The following is a brief list of issues that need to be addressed:
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The potential for stem cells to form fibroblasts or tumor
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Cited by (33)
A preliminary approach to the repair of myocardial infarction using adipose tissue-derived stem cells encapsulated in magnetic resonance-labelled alginate microspheres in a porcine model
2013, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :The mechanism by which transplanted stem cell based therapy causes beneficial effects is controversial. There are many hypotheses about the mechanisms involved in tissue regeneration, including transdifferentiation, cell fusion or secretion of paracrine mediators [17,36,37]. Some studies suggest that the improvement in cardiac function can be attributed mainly to the release of paracrine factors that mediate cell survival, neovascularization, remodelling and proliferation [2,38–41].
Effects of intracoronary stem cell transplantation in patients with dilated cardiomyopathy
2011, Journal of Cardiac FailureMicrocapsules and microcarriers for in situ cell delivery
2010, Advanced Drug Delivery ReviewsMyocardial injection of skeletal myoblasts impairs contractility of host cardiomyocytes
2010, International Journal of CardiologyCitation Excerpt :Over the past few years, a number of clinical trials investigated the potential of cell therapy for the treatment of heart failure [7].
The MRI assessment of intraurethrally - delivered muscle precursor cells using anionic magnetic nanoparticles
2009, BiomaterialsCitation Excerpt :Cell therapy has been envisaged in many muscle disorders, such as Duchenne's muscular dystrophy [1,2], infarcted myocardium [3,4], and striated urethral sphincter insufficiency [5–7] via restoration of contractile activity by direct intramuscular injection of muscle precursor cells (MPCs).
Embryonic stem (ES) cell-derived cardiomyocytes: A good candidate for cell therapy applications
2009, Cell Biology InternationalCitation Excerpt :A number of different cell types are currently being evaluated which include, cell therapies derived from primary cell isolates, established cell lines, adult stem cells namely bone marrow and mesenchymal stem cells, cord blood stem cells and of course ESC-derivatives (reviewed in Fodor, 2003). Several strategies of cell transplantation such as intramyocardial, intracoronary, transendocardial/transepicardial and intravenous injections (Collins et al., 2007) are being optimized. Nevertheless, ESC emerges as the most promising candidate in cell replacement therapy for heart disorders simply because they demonstrate reproducible differentiation, prolonged survival and site-specific engraftment.