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Objective. Improvement of the treatment results in patients with refractory angina, complicated by the heart insufficiency, using new methods of correction of the heart pumping function elaborated. Materials and methods. Clinical investigation was performed, basing on retro- and prospective analysis of the treatment results in 156 patients: efficacy of myocardial remodeling was studied, using mesenchymal stem cells in patients, suffering refractory angina. For determination of the cellular therapy efficacy a navigation system NOGA XP was applied. Results. There were presented the results of investigation of efficacy of intravenous injections of autologous mesenchymal stem cells to patients, suffering refractory angina, complicated by lowering of the heart pumping function, and immediate results of cardiomyoplasty using stem cells as well. For the first time a navigation system NOGA XP for determination of myocardial hibernation zones was applied in patients, suffering refractory angina. Also, using navigation system NOGA XP, the results of cellular cardiomyoplasty were obtained, while comparing electro-mechanical schemes before and after cellular therapy. Conclusion. There was established the improvement of indices of the heart pumping function and the patients’ quality of life.

Despite a significant arsenal of medications and methods of surgical correction of myocardial blood supply, treatment of some forms of coronary heart disease remains relevant. The purpose of the work is to analyze the effectiveness of the use of stromal stem cells (SSC) of bone marrow in autologous transendocardial transplantation in some forms of IHD. Material and methods. In the near and long-term results, we analyzed the histories and diseases and conducted a survey of 68 patients. Of the 68 patients, the largest group was men - 53 (77.9%), women were much fewer - 15 (22.1%). Then we formed 4 groups (17 patients each): 1 group - control - patients received standard drug therapy; Group 2 - to patients who received standard therapy, empty myocardial injections were performed using a catheter and the NOGA XP navigation system; Group 3 - auto-CCK was administered intravenously to patients; 4 group - against the background of therapy, transendocardial auto-SSK was administered. Results and its discussion. When analyzing the patient's subjective sensations in group I, after 3 months in group 1, 4 patients (32%) noted improvement, unchanged - 11 (64.7%), worsening - 2 (11.8%) and significant worsening 1 ( 5.9%). In group II, improvement was in 1 patient, which was 5.9%, unchanged - 13 (76.5%), worsening - 2 (11.8%) and significant deterioration - 2 (11.8%). In group III, improvement was observed in 5 patients - 29.4%, significant improvement in 1 (5.9%), deterioration and significant deterioration in 1 patient (5.9% each, respectively). In group IV unchanged - 6 (35.3%) patients, improvement - 7 (41.2%), significant improvement - 4 (32%), worsening - 1 (5.9%). Cell transplantation, regardless of the method of administration, increases the EF and reduces the EDV of the left ventricle, more significantly in the group with a transendocardial route of administration. Conclusion. In accordance with published data, we obtained similar data - transplantation of human bone marrow SSC with autologous administration causes a positive effect in the form of increased EF LV, decreased EDV of the LV, increased exercise tolerance and a significant improvement in patients' well-being. It should be noted that intravenous and intracoronary administration of auto-SSC is much less effective in the studied parameters than transendocardial introduction of cells into the myocardium.

Heart disease is one of the leading causes of morbidity and mortality worldwide. Two of these diseases are heart failure and myocardial infarction. In America alone, there are about 6.2 million people with heart failure, and every 40 seconds, a patient with a heart attack is recorded. Myocardial infarction, known as a heart attack, occurs after the blocking or occlusion of a coronary artery, disabling the delivery of oxygenated blood to regions of the heart. Heart failure, usually occurring after ischemic diseases like myocardial infarction, is where the heart loses the ability to pump a sufficient blood supply to meet the body’s needs. The major ways of treating heart failure and myocardial infarction today are either too expensive or hard to come by, so a new sort of treatment is direly needed. Cellular cardiomyoplasty, a form of cell therapy, is being looked into as a new way to treat these two and other cardiomyopathies. Additionally, though there have been a few cells that have shown a possibility of use for cardiomyoplasty, this review focuses on mesenchymal stem cells, specifically called mesenchymal stromal cells. The purpose of this review is to look into what cellular cardiomyoplasty is, how it may be used in the future, and how mesenchymal stromal cells have shown potential to be used for it.

Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.

The aim was to create a model of myocardial infarction with a borderline myocardial impairment which would enable evaluation of the retrograde cellular cardiomyoplasty through the venous coronary sinus in a large animal model.Fifteen (study group) and 10 juvenile farm pigs (control group) underwent distal left anterior descending artery ligation. One month later the study group animals underwent sternotomy and a murine myoblastic line C2-C12 was injected at a constant pressure of 30mmHg, into the coronary sinus. Thirty days later all animals that survived from both groups underwent transthoracic echocardiography and 99Tc scintigraphy and were later euthanized and specimens were taken for microscopic evaluation.Cardiac output decreased significantly after ligation (p0.001) and increased significantly after cardiomyoplasty (p0.001). In all animals, the surgical induction of myocardial infarction caused a marked decline in the echocardiographic values of cardiac function; however, the cardiac function and dimensions were significantly improved in the study group after cardiomyoplasty versus the control group. All animals undergoing cardiomyoplasty demonstrated a significant reduction of the perfusion deficit in the left anterior descending artery territory, instead such data remained unchanged in the control group. The histological examination demonstrated the engrafted myoblasts could be distinguished from the activated fibroblasts in the scar tissue because they never showed any signs of collagen secretion and fiber buildup.In conclusion, the venous retrograde delivery route through the coronary sinus is safe and effective, providing a significant improvement in function and viability.

Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. Especially, cell sheet technology has been developed and has already been introduced to clinical situation. As the first step in development of cell sheet, neonatal cardiomyocyte sheets were established and these sheets showed electrical and histological homogeneous heart-like tissue with contractile ability in vitro and worked as functional heart muscle which has electrical communication with recipient myocardium in small animal heart failure model. Next, as a preclinical study, noncontractile myoblast sheets have been established and these sheets have proved to secrete multiple cytokines such as HGF or VEGF in vitro study. Moreover, in vivo studies using large and small animal heart failure model have been done and myoblast sheets could improve diastolic and systolic performance by cytokine paracrine effect such as angiogenesis, antifibrosis, and stem cell migration. Recently evidenced by these preclinical results, clinical trials using autologous myoblast sheets have been started in ICM and DCM patients and some patients showed LV reverse remodelling, improved symptoms, and exercise tolerance. Recent works demonstrated that iPS cell-derived cardiomyocyte sheet were developed and showed electrical and microstructural homogeneity of heart tissue in vitro, leading to the establishment of proof of concept in small and large animal heart failure model.

Heart failure is a life threatening disorder in worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. This review article provides summary about recent basical and clinical advances about myocardial regeneration induced by bioengineered cardiac tissue.

Background: The polyamine spermine enhances differentiation of mouse embryonic stem cells into cardiac lineage. The aim of this study was to determine the effects of spermine on the differentiation of human adipose tissuederived multi-lineage progenitor cells (hADMPCs) into cardiomyocytes both in vitro and in vivo and any subsequent functional effect in a swine model of chronic myocardial infarction. Methods and results: Spermine increased the expression of cardiac markers nkx2.5, islet-1, α-cardiac actin and cardiac troponin I (to 11.2-, 27.5-, 43.6- and 19.1-fold, relative to baseline, respectively) in hADMPCs. Chronic myocardial infarction model with left ventricular dysfunction was induced by balloon occlusion of the diagonal coronary artery followed by reperfusion, with subsequent similar procedure conducted one week later in the left ascending coronary artery (#6). Four weeks later, the immunosuppressed animals (with CyA 5.0 mg/kg intramuscularly (i.m) body weight/day) were transplanted with spermine-treated hADMPC (1×105 , 3×105 , 1×106 or 3×106 cells/kg body weight) via the coronary artery (#6). Cardiac function was assessed by echocardiography at 0, 4, 8 and 12 weeks post-transplantation. Transplantation of these cells improved cardiac function and the most effective dose was 3x105 cells/kg (ejection fraction; 33.4%, 47.0%, 51.5% and 52.9% at 0, 4, 8 and 12 weeks post-transplantation, respectively). At 12-week post-transplantation, spermine-treated hADMPCs differentiated into human-specific troponin I- and α-cardiac actin-positive cells in vivo. Conclusion: Spermine induced differentiation of hADMPCs into cardiomyocytes both in vitro and in vivo and cellular cardiomyoplasty improved cardiac function. Cellular cardiomyoplasty using hADMPC could be potentially effective cell-based therapy.

Cellular cardiomyoplasty employs stem cell therapy to regenerate myocardium. Characterized by their potential for proliferation, differentiation and capacity for self-renewal, stem cells are ideally suited for use in regenerative medicine. Supplementing traditional therapeutic modalities aimed at the palliation of congestive heart failure, cellular cardiomyoplasty is an innovative approach aimed at producing functional, viable myocardium following an acute infarction. The primary focus is to prevent the onset of congestive heart failure; however, potential applications aimed at reversing ischemic heart disease are concurrently in development. After decades of research, cellular cardiomyoplasty has moved beyond traditional in vitro and animal models; it is currently being implemented in clinical trials. Despite this monumental advance, certain limitations remain inherent in this process, preventing stem cell therapy from reaching its full potential. On a cellular level, stem cell retention and viability postimplantation continues to be problematic. Solutions under investigation include pioneering advances in cell delivery, in vitro pretreatment, and tissue engineering. Moreover, questions surrounding optimal cell type and cellular mechanisms concerning cellular cardiomyoplasty remain unanswered. Clarification of these issues is essential to ensure continued progression of this new technology. Stem cell therapy has been highly successful within the in vitro and in vivo environment. However, as clinical trials abound, cellular cardiomyoplasty must transition from an experimental concept to an effective therapeutic treatment. This process is hindered by discordance between scientific accrue and practical applicability. This review will provide a comprehensive summary of current innovations on cellular cardiomyoplasty, and future prospects. There will be a particular emphasis on the clinical aspects of stem cell therapy in an attempt to bridge the gap between science and medicine. Overcoming this barrier will render cellular cardiomyoplasty accessible to patients on a global basis.

Heart disease is one of the leading causes of death worldwide and the number of patients with the disease is likely to grow with the continual decline in health for most of the developed world. Heart transplantation is one of the only treatment options for heart failure due to an acute myocardial infarction, but limited donor supply and organ rejection limit its widespread use. Cellular cardiomyoplasty, or cellular implantation, combined with various tissue-engineering methods aims to regenerate functional heart tissue. This review highlights the numerous cell sources that have been used to regenerate the heart as well as cover the wide range of tissue-engineering strategies that have been devised to optimize the delivery of these cells. It will probably be a long time before an effective regenerative therapy can make a serious impact at the bedside.

Heart failure (HF) is one of the leading death causes in patients with myocardial infarction (MI). The modern methods of reperfusion MI therapy, such as thrombolysis, surgery and balloon revascularization, even when performed early, could fail to prevent the development of large myocardial damage zones, followed by HF. Therefore, the researches have been searching for the methods which improve functional status of damaged myocardium. This review is focused on stem cell therapy, a method aimed at cardiac function restoration. The results of experimental and clinical studies on stem cell therapy in coronary heart disease are presented. Various types of stem cells, used for cellular cardiomyoplasty, are characterised. The methods of cell transplantation into myocardium and potential adverse effects of stem cell therapy are discussed.

Our study aimed to elucidate whether bone marrow stem cell (BMC) treatment might result in a cellular response in cardiomyocytes IN VITRO. Subconfluent neonatal rat cardiomyocyte cultures were cocultured for three days with Vybrant CM-DiI labeled BMC from human sternal bone marrow and underwent immunohistological staining for the proto-oncogene c-Myc and the cell cycle proteins CDK2, CDK4 and ATF-3. β-adrenoceptor density was analyzed using [125I]-iodocyanopindolol (ICYP) histoautoradiography. Quantitative analysis of immunohistochemical images revealed significantly increased expression and upregulation of c-Myc, and its downstream targets ATF-3, CDK2 and CDK4 in neighboring cardiomyocytes to BMC, depending on their distance to the BMC compared to cardiomyocytes far from the BMC. Histoautoradiography revealed a significantly higher β-adrenoceptor density in cardiomyocytes in the immediate vicinity to the BMC. With increasing distance to the BMC, β-adrenoceptor density in cardiomyocytes declined. Thus, a small number of BMC can affect a larger number of cardiomyocytes by activating an intracellular signaling cascade and enhancing β-adrenoceptor density.

Cellular cardiomyoplasty is under extensive investigation as a potential therapeutic strategy after myocardial infarction, in congestive heart failure and chronic ischemic heart disease. Various cell sources and techniques for transplantation have been studied in animal models of cardiac disease. The initial goal of replacing myocardial scar tissue by vital myocardial cells, integrated into the host, simultaneously beating and contributing to systolic force, has not yet been accomplished. However, most experimental models provided evidence for enhanced vascularization after cell transplantation. In some investigations, neovascularization was also shown to be accompanied by increased myocardial perfusion. Mechanisms by which vascularization occurs have not been fully elucidated: either the transplanted cells provide an angiogenic stimulus, involving various paracrine or hormone-like factors, which induces the formation of a new vasculature or, depending on the source of transplanted cells, the cells incorporate into the vascular network after proliferation and differentiation. This review summarizes research that specifically studied the occurrence, magnitude and mechanisms of enhanced myocardial blood supply after cellular cardiomyoplasty

Autologous or allogeneic mesenchymal stem cells (MSCs) have been used as one of the potential cell sources for cellular cardiomyoplasty. The adverse microenvironment in acute myocardial infarction, however, is considered a deleterious factor for MSC transplantation and cell survival. Tumor necrosis factor (TNF)-α is an inflammatory mediator produced during ischemia that may affect the survival of MSCs. In this study, we investigated the enhancement of MSC survival by transfecting cells with the TNF receptor (TNFR) gene, leading to the overproduction of TNFR and the binding of TNF-α. Rats with acute myocardial infarction, induced by the occlusion of the left coronary artery, were transplanted with MSC or MSC-TNFR. After 2 weeks of acute myocardial infarction, cardiac function was assessed. Engrafted MSC survival and localization of TNF-α protein in infarction myocardium were evaluated. The levels of TNF-α and TNFR in the infarction zone were assessed. The results indicate that MSC-TNFR transplantation (1) improved left ventricular function; (2) enhanced engrafted MSC survival in the infarcted myocardium; (3) attenuated the level of TNF-α in serum and cardiac tissue; and (4) increased TNFR protein production in the infarcted myocardium. Our results showed that MSC modified by the TNFR gene improved cell viability and thereby has the potential to improve the efficiency of MSC transplantation therapy in the ischemic heart.

Heart diseases, including myocardial infarction (MI) and congestive heart failure (CHF), have high mortality rates. Both MI and CHF are characterized by cardiac muscle damage caused by massive cardiomyocyte death and reduced cardiac function. Cellular therapy aimed at using cells to improve cardiac function and/or regenerate new myocardium, has been extensively investigated for cardiac repair. Two strategies have been currently taken for cellular transplantation, including in situ cellular cardiomyoplasty and cardiac tissue engineering. The in situ cellular cardiomyoplasty strategy delivers cells directly into the infarcted myocardium. A variety of cell types has been shown to be beneficial in cardiac repair. However, this strategy is limited in terms of cell retention, survival of the engrafted cells, cell differentiation, and integration of transplanted cells with host tissue. Cardiac tissue engineering is an alternate strategy to in situ cellular cardiomyoplasty, which is designed to repair infarcted myocardium using cells, biomaterials and regulative factors (for example growth factors). There are currently various approaches for cardiac tissue engineering, such as, in situ delivering cells with injectable biomaterials into the infarcted myocardium, in vitro engineering of contractile tissue constructs followed by in vivo implantation, in vitro engineering of stem cell loaded tissue constructs for in vivo myocardium regeneration, and cell sheet tissue engineering. This review provides a comprehensive progress of in situ cellular cardiomyoplasty and cardiac tissue engineering for cardiac repair.

Cellular cardiomyoplasty is a promising approach for the treatment of severe heart failure. However, the question which cell line is the best to use is still a matter of debate. In this study, we aimed to evaluate the efficacy of arterial media-intima cell suspension (AMICS) transplantation in rabbit myocardial infarct model. The study was divided into 2 groups: group A (the cell-treated group, n = 9) and group B (the medium injection group, n = 8). Group A was further divided into 2 subgroups as branch-1 (treated with unlabeled cells) and branch-2 (treated with iron-labeled cells). The experimental myocardial infarction (MI) was induced by ligation of left anterior descending coronary artery with a combination of cryoinjury. Ten days after the MI, cells obtained from autologous femoral arteries were injected into the injured myocardium of group A, while group B received an injection of only DMEM medium. Clinical, echocardiographic, and histopathologic evaluations were done. As compared to the ninth day values, echocardiography showed a significant improvement in systolic functions and left ventricular (LV) dimensions of the cell-treated group on the 30th day. In the heart biopsy sections of branch-1, the immunostained injected cells were observed to exist closely, suggesting an organization. Cells existing separately and lumen-like structure organizations stained positive with both smooth muscle cell (SMC) alpha-actin and Prussian Blue were also showed in the histological observation of branch-2. Autologous AMICS transplantation seems to be a feasible and efficacious method for cellular cardiomyoplasty in our rabbit model.

This study was designed to compare the efficacy of intraventricular (IV), intramyocardial (IM) or combined IV and IM injections of human adipose tissue-derived stem cells (hADSCs) administered either immediately, 5, or 10 days after induction of acute myocardial infarction (AMI) in a nude rat model. Acute myocardial infarction was induced in 99, adult (250–350 g BW), male nude rats strain Crl:NIH-Fox1RNU. Rats received either no cells (group I, n = 15) or 2 million, hADSCs as follows: group II (n = 19) IV injection immediately after AMI; group III (n = 18) IV injection 5 days after AMI; group IV (n = 15) IV injection 5 days and IM injection 10 days after AMI; group V (n = 17) IV injection immediately after AMI and IM injection 10 days after AMI and group VI (n = 15) IM injection 10 days after AMI. Tissue sections from hearts were studied using H&E and immunohistochemistry. In the control group, there was a tendency toward granulation tissue formation, active phagocytosis, and variable angiogenesis when evaluated at 10 days, early fibrosis when evaluated at 30 days, and established fibrosis when evaluated at 60 days. However, hADSC-treated groups showed a tendency toward cardiomyocyte regeneration and prominent angiogenesis when evaluated at 10 days and smaller infarction size when evaluated at 30 and 60 days. The present study showed a significantly decreased amount of scar tissue following myocardial infarction and enhanced regenerative capacity of myocardial cells following a single, intraventricular injection of 2 million hADSCs immediately after AMI.

Background Until now, cell therapy has constituted a passive therapeutic approach; the only effects seem to be related to the reduction of the myocardial fibrosis and the limitation of the adverse ventricular remodeling. Cardiac resynchronization therapy is indicated in patients with heart failure to correct conduction disorders associated with chronic systolic and diastolic dysfunction. The association of electrostimulation with cellular cardiomyoplasty could be a way to transform passive cell therapy into "dynamic cellular support." Electrostimulation of ventricles following skeletal myoblast implantation should induce the contraction of the transplanted cells and a higher expression of slow myosin, which is better adapted for chronic ventricular assistance. The purpose of this study is to evaluate myogenic cell transplantation in an ischemic heart model associated with cardiac resynchronization therapy. Methods Twenty two sheep were included. All animals underwent myocardial infarction by ligation of 2 coronary artery branches (distal left anterior descending artery and D2). After 4 weeks, autologous cultured myoblasts were injected in the infarcted areas with or without pacemaker implantation. Atrial synchronized biventricular pacing was performed using epicardial electrodes. Echocardiography was performed at 4 weeks (baseline) and 12 weeks after infarction. Results Echocardiography showed a significant improvement in ejection fraction and limitation of left ventricular dilatation in cell therapy with cardiac resynchronization therapy as compared with the other groups. Viable cells were identified in the infarcted areas. Differentiation of myoblasts into myotubes and enhanced expression of slow myosin heavy chain was observed in the electrostimulated group. Transplantation of cells with cardiac resynchronization therapy caused an increase in diastolic wall thickening in the infarcted zone relative to cells-only group and cardiac resynchronization therapy–only group. Conclusions Biventricular pacing seems to induce synchronous contraction of transplanted myoblasts and the host myocardium, thus improving ventricular function. Electrostimulation was related with enhanced expression of slow myosin and the organization of myoblasts in myotubes, which are better adapted at performing cardiac work. Patients with heart failure presenting myocardial infarct scars and indication for cardiac resynchronization therapy might benefit from simultaneous cardiac pacing and cell therapy.

OBJECTIVE. This article aims to familiarize radiologists with novel treatment options for chronic heart failure that is unresponsive to medical therapy, such as mechanical cardiac assist devices, surgical procedures, resynchronization therapy with biventricular pacing, and cellular cardiomyoplasty, and their radiographic appearances.CONCLUSION. Heart transplantation as a treatment of debilitating heart failure provides an opportunity for meaningful long-term survival but is limited by a shortage of donor hearts. This has spurred the development of new treatment options for chronic heart failure that is unresponsive to medical therapy.

Cellular cardiomyoplasty is an investigational technique that may have the potential to reduce myocardial infarct size and improve cardiac function in patients with ischemic heart disease. However, experience with this approach is still limited to a few small trials, some of which were not blinded or had other design problems. The mechanism of benefit, long-term safety, and clinical efficacy of cellular cardiomyoplasty require further study.

Despite of vast improvements in treatment, myocardial infarction often leads to heart failure (HF) which remains the leading cause of death in developed countries. Other than heart transplantation, therapeutic options have a limited role in improving out comes in patients with severe HF. It is therefore no surprise that cardiac cell therapy has raised many hopes as a novel therapeutic approach aimed at cardiac myocyte replacement/regeneration termed “cellular cardiomyoplasty”. However, the ideal source, cell type, critical cell number, and mode of application for optimal therapeutic effect have not been defined thus far. Recent observations of the beneficial effect of cell transplantation in animal experiments have generated tremendous excitement and stimulated clinical studies suggesting that this approach is feasible, safe, and potentially effective in humans. Cell-based myocardial regeneration is currently being explored for a wide range of cardiac disease states, including acute and chronic ischemic myocardial damage, cardiomyopathy and as biological heart pacemakers. The main purpose of this article is to review recent literature on the use of various cells for the examination of their in vitro cardiogenic potential and their in vivo capacity to engraft and improve the functional properties of the infarcted heart.

Background Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy, the extracellular matrix is deeply altered; therefore, it could be important to associate a procedure aiming at regenerating myocardial cells and restoring the extracellular matrix function. We evaluated the feasibility and safety of intrainfarct cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted ventricles. Methods In 20 consecutive patients presenting with left ventricular postischemic myocardial scars and indication for coronary artery bypass graft surgery, bone marrow cells were implanted during surgery. In the last 10 patients, we added a collagen matrix seeded with bone marrow cells, placed onto the scar. Results There was no mortality and any related adverse events (follow-up 10 ± 3.5 months). New York Heart Association functional class improved in both groups from 2.3 ± 0.5 to 1.3 ± 0.5 (matrix, p = 0.0002) versus 2.4 ± 0.5 to 1.5 ± 0.5 (no matrix, p = 0.001). Left ventricular end-diastolic volume evolved from 142.4 ± 24.5 mL to 112.9 ± 27.3 mL (matrix, p = 0.02) versus 138.9 ± 36.1 mL to 148.7 ± 41 mL (no matrix, p = 0.57), left ventricular filling deceleration time improved significantly in the matrix group from 162 ± 7 ms to 198 ± 9 ms ( p = 0.01) versus the no-matrix group (from 159 ± 5 ms to 167 ± 8 ms, p = 0.07). Scar area thickness progressed from 6 ± 1.4 to 9 mm ± 1.1 mm (matrix, p = 0.005) versus 5 ± 1.5 mm to 6 ± 0.8 mm (no matrix, p = 0.09). Ejection fraction improved in both groups, from 25.3% ± 7.3% to 32% ± 5.4% (matrix, p = 0.03) versus 27.2% ± 6.9% to 34.6% ± 7.3% (no matrix, p = 0.031). Conclusions This tissue-engineered approach is feasible and safe and appears to improve the efficiency of cellular cardiomyoplasty. The cell-seeded collagen matrix increases the thickness of the infarct scar with viable tissue and helps to normalize cardiac wall stress in injured regions, thus limiting ventricular remodeling and improving diastolic function.

Background Cellular cardiomyoplasty is emerging as a potentially novel therapeutic option for heart failure and typically involves direct intramyocardial injection of donor cells into a beating heart. Yet, limited rates of cell engraftment remain an obstacle to be overcome before cell therapy is fully recognized. Mechanical and biological mechanisms may account for observed donor cell loss. This study examines acute mechanical loss during intramyocardial injections in beating and arrested hearts. Materials and methods A porcine cardiopulmonary bypass model was used. Animals underwent either beating ( n = 5) or arrested ( n = 5) intramyocardial injections into the left ventricle. Fluorescent microspheres were used in lieu of cells because they are biologically inert. Thirty minutes after delivery, animals were euthanized. Microspheres in cardiac and peripheral tissues were quantified using flow cytometry. Results Approximately 10% of microspheres were retained within the site of injection in both groups. There was no statistical difference between microsphere retention rates in either the beating or the arrested heart group. Microspheres were found in peripheral organs, pericardial fluid, and the delivery device. Conclusions The majority of microspheres injected intramyocardially are lost in both beating and arrested hearts. Cardiac standstill does not enhance microsphere retention. Possible mechanisms include leakage from the injection site and washout via the cardiac venous/lymphatic system. Delivery strategy will need to be modified if more cells are to be retained within the target organ.

BACKGROUND Treatment of ischemic heart disease remains an important challenge, though there have been enormous progresses in cardiovascular therapeutics. This study was conducted to evaluate whether Tongxinluo (TXL) treatment around the transplantation of mesenchymal stem cells (MSCs) can improve survival and subsequent activities of implanted cells in swine hearts with acute myocardial infarction (AMI) and reperfusion. METHODS Twenty-eight Chinese mini-pigs were divided into four groups including a control group (n = 7); group 2, administration of low-dose TXL alone from the 3rd day prior to AMI to the 4th day post transplantation (n = 7); group 3, MSCs alone (n = 7) and group 4, TXL + MSCs (n = 7). AMI models were made by occlusion of the left anterior descending coronary artery for 90 minutes. Autologous bone marrow-MSCs (3 x 10(7) cells/animal) were then injected into the post-infarct myocardium immediately after AMI and reperfusion. The survival and differentiation of implanted cells in vivo were detected by immunofluorescent analysis. The data of cardiac function were obtained at baseline (1 week after transplantation) and endpoint (6 weeks after transplantation) by single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Apoptosis was detected by TUNEL assay and the oxidative stress level was investigated in the post-infarct myocardium at endpoint. RESULTS At endpoint, there was less fibrosis and inflammatory cell infiltration with more surviving myocardium in group 4 than in the control group. In group 4 the survival and differentiation of implanted MSCs were significantly improved more than that seen in group 3 alone (P < 0.0001); the capillary density was also significantly greater than in the control group, group 2 or 3 both in the infarcted zone (P < 0.0001) and the peri-infarct zone (P < 0.0001). MRI showed that parameters at baseline were not significantly different between the 4 groups. At endpoint, regional wall thickening and the left ventricular ejection fraction were increased while the left ventricular mass index, dyskinetic segments and infarcted size were decreased only in group 4 compared with control group (P < 0.0001). SPECT showed that the area of perfusion defect was significantly decreased at endpoint only in group 4 compared with control group (P < 0.0001). TUNEL assay indicated that TXL administration significantly decreased cell apoptosis in peri-infarct myocardium in groups 2 and 4. Furthermore, superoxide dismutase (SOD) significantly increased and malondialdehyde (MDA) decreased in groups 2 and 4 by the administration of TXL. CONCLUSIONS Our study demonstrates the following: (1) immediate intramyocardial injection of MSCs after AMI and reperfusion resulted in limited survival and differentiation potential of implanted cells in vivo, thus being incapable of beneficially affecting post-hearts; (2) TXL-facilitation resulted in a significant survival and differentiation potential of implanted cells in vivo via inhibition of apoptosis and oxidative stress, accompanied by significant benefits in cardiac function.

The stem cell transplantation is emerging as a potential therapeutic modality for patients with heart failure. It has been demonstrated that intracoronary stem cell transplantation had beneficial effects on left ventricular perfusion and contractile functions. We hypothesized that patients with end-stage ischemic cardiomyopathy, who are candidates for heart transplantation, could also benefit from autologous intracoronary stem cell transplantation. We performed a prospective, open-labeled study in 10 patients with end-stage ischemic cardiomyopathy, who were on the waiting list for heart transplantation. Each patient received bone marrow-derived mononuclear cell infusion via balloon catheter in the target vessel, which had been revascularized by percutaneous intervention and was patent before the procedure. Clinical and laboratory evaluations, a treadmill exercise test, echocardiography, and single photon emission tomography (SPECT) were performed to the patients at baseline and 6 months after stem cell infusion. At 6-month follow-up of the eight patients who were able to complete the study, we revealed a significant increase in ejection fraction (from 30.0 +/- 6.6% to 36.2 +/- 7.3%; p = 0.001) in echocardiographic evaluation. SPECT evaluation also displayed a reduction in infarct area (50.4 +/- 16.1% to 44.1 +/- 12.5%; p = 0.003). Both myocardial oxygen consumption (p = 0.001) and metabolic equivalents (p = 0.001) were significantly increased at 6-month follow-up. These results demonstrate that intracoronary stem cell transplantation ameliorates heart failure symptoms and improves left ventricular function and perfusion. Therefore intracoronary stem cell transplantation may be used as an alternative treatment option for heart transplant candidates.

Purpose Cellular cardiomyoplasty is a potential therapeutic approach to preventing left ventricular remodeling after myocardial infarction and has shown encouraging results such as induction of neoangiogenesis and functional improvement of diseased hearts. We report the results of a pilot study on progenitor cells in five patients with acute myocardial infarction (AMI). Materials and Methods Patients with single-vessel disease who had their first episode of myocardial infarction and underwent angioplasty after 48 h (an average of 17 days following myocardial infarction) were included in the study. Mononuclear cells (MNCs) (1×10 7 ) were isolated by Ficoll Hypaque method from 60 ml of bone marrow (BM) obtained from the iliac crest of 5 patients (aspiration was performed under local anesthesia). The mean CD34 count was 1–4%. After confirming the patency of the affected vessel postangioplasty, cellular concentrate was injected into the affected artery in 3-ml boluses (three to four injections), with intermittent occlusion. Results The mean age of all five male patients was 48.6+13.7 years. At 1 year, five patients were asymptomatic, and one had Class II dyspnea on exertion. The results of an echocardiogram performed at 6 months showed an improvement in ejection fraction (EF) from 35.3% to 43.13% and in fractional shortening from 24.75% to 28.33%. End-systolic volume decreased from 115.5 to 92.3 ml, end-diastolic volume decreased from 177.5 to 170 ml, and end-systolic dimensions also decreased from 4.26 to 4 mm, demonstrating positive left ventricular remodeling. Repeat echocardiogram at 1 year showed persistent improvement in EF. No adverse events were noted either before or after the procedure. Conclusion The injection of autologous BM MNCs is a safe and efficacious therapy following early revascularization in AMI patients.

Transplantation of autologous skeletal myoblasts (SKMB) into infarcted heart (or cellular cardiomyoplasty, CCM) augments myocardial performance in animal models of myocardial infarction. However, the effect of CCM in the setting of ventricular aneurysm has not been evaluated. This study analyzes the effects of transplanted SKMB on regional wall motion in a rabbit model of postinfarct ventricular aneurysm. We hypothesize that CCM, performed early after myocardial infarction, prevents the progression of dyskinetic wall motion.Twenty-six rabbits underwent apical left ventricular cryoinfarction and soleus muscle biopsy for in vitro isolation of skeletal myoblasts. At 2 weeks postinfarct, the presence of ventricular aneurysm was detected in 23/26 animals by sonomicrometry and micromanometry. Seventeen of 23 animals were randomized to receive either 108 autologous myoblasts (CCM) or vehicle. Regional stroke work, percent systolic shortening, and synchronicity of regional wall motion were determined prior to, and four weeks following, injection (CCM; n = 9; vehicle, n = 8). Wall motion was evaluated under baseline and stress (dobutamine, 10 (g/kg/min) conditions. Six animals did not undergo randomization, but their hearts were used to measure the size of infarction.Four weeks following treatment of animals with ventricular aneurysm, systolic contractile activity was present in most animals treated with myoblasts but in none treated with vehicle (5/7 versus 0/6, respectively, P0.05). Dobutamine tended to accentuate the differences seen at baseline between the groups.This study demonstrates a high incidence of systolic contractile activity in a previously aneurysmal region of myocardium following CCM and may represent a novel therapy for the prevention and treatment of postinfarct aneurysm.

Cellular therapy for myocardial injury has improved ventricular function in both animal and clinical studies, though the mechanism of benefit is unclear. This study was undertaken to examine the effects of cellular injection after infarction on myocardial elasticity. Coronary artery ligation of Lewis rats was followed by direct injection of human mesenchymal stem cells (MSCs) into the acutely ischemic myocardium. Two weeks postinfarct, myocardial elasticity was mapped by atomic force microscopy. MSC-injected hearts near the infarct region were twofold stiffer than myocardium from noninfarcted animals but softer than myocardium from vehicle-treated infarcted animals. After 8 wk, the following variables were evaluated: MSC engraftment and left ventricular geometry by histological methods, cardiac function with a pressure-volume conductance catheter, myocardial fibrosis by Masson Trichrome staining, vascularity by immunohistochemistry, and apoptosis by TdT-mediated dUTP nick-end labeling assay. The human cells engrafted and expressed a cardiomyocyte protein but stopped short of full differentiation and did not stimulate significant angiogenesis. MSC-injected hearts showed significantly less fibrosis than controls, as well as less left ventricular dilation, reduced apoptosis, increased myocardial thickness, and preservation of systolic and diastolic cardiac function. In summary, MSC injection after myocardial infarction did not regenerate contracting cardiomyocytes but reduced the stiffness of the subsequent scar and attenuated postinfarction remodeling, preserving some cardiac function. Improving scarred heart muscle compliance could be a functional benefit of cellular cardiomyoplasty.

We tested the hypothesis that granulocyte colony-stimulating factor (G-CSF) administration would enhance the efficacy of cellular cardiomyoplasty with embryonic stem (ES) cell-derived cardiomyocytes in infarcted myocardium. Three weeks after myocardial infarction by cryoinjury, Sprague-Dawley rats were randomized to receive either an injection of medium, ES cell-derived cardiomyocyte transplantation, G-CSF administration, or a combination of G-CSF administration and ES cell-derived cardiomyocyte transplantation. Eight weeks after treatment, the cardiac tissue formation, neovascularization, and apoptotic activity in the infarct regions were evaluated by histology and immunohistochemistry. The left ventricular (LV) dimensions and function of the treated heart were evaluated by echocardiography. Transplanted ES cell-derived cardiomyocytes survived and participated in the myocardial regeneration in the infarcted heart. A combination of G-CSF treatment and ES cell-derived cardiomyocyte transplantation significantly promoted angiogenesis and reduced the infarct area and cell apoptosis in the infarcted myocardium compared with ES cell-derived cardiomyocyte transplantation alone. The combination therapy also attenuated LV dilation, as compared with ES cell-derived cardiomyocyte transplantation alone. G-CSF treatment can enhance the efficacy of cellular cardiomyoplasty by ES cell-derived cardiomyocyte transplantation to treat myocardial infarction.

Heart failure is one of the most prominent causes of morbidity and mortality worldwide. According to the World Health Organization, coronary artery disease and myocardial infarction (MI) are responsible for 29% of deaths worldwide. MI results in obstruction of the blood supply to the heart and scar formation, and causes substantial death of cardiomyocytes in the infarct zone followed by an inflammatory response. Current treatment methodologies of MI and heart failure include organ transplantation, coronary artery bypass grafting, ventricular remodeling, cardiomyoplasty, and cellular therapy. Each of these methodologies has associated risks and benefits. Cellular cardiomyoplasty is a viable option to decrease the fibrosis of infarct scars, adverse post-ischemic remodeling, and improve heart function. However, the low rate of cell survival, shortage of cell sources and donors, tumorigenesis, and ethical issues hamper full exploitation of cell therapy for MI treatment. Consequently, the mobilization and recruitment of endogenous stem/progenitor cells from bone marrow, peripheral circulation, and cardiac tissues has immense potential through harnessing the host's own reparative capacities that result from interplay among cytokines, chemokines, and adhesion molecules. Therapeutic treatments to enhance the mobilization and homing of stem cells are under development. In this review, we present state-of-the-art approaches that are being pursued for stem cell mobilization and recruitment to regenerate infarcted myocardium. Potential therapeutic interventions and delivery strategies are discussed in detail.

Objective: Recent progress in the field of cellular cardiomyoplasty has opened new prospects for the treatment of ischemic heart disease and currently moves from bench to bedside. The aim of the present study was to develop a novel cell delivery technique, reducing target tissue damage and improving cell dispersion and engraftment. Methods: In 30 male Fischer F344 rats an infarction of the left ventricle was generated by ligation of the left anterior descendent artery. Seven days after infarction, either 15 microdepots of 10 ml myoblast cell suspension (microdepot group) or culture medium (control group) were injected into the infarcted region using an automatic pressure injection device, or three depots of 50 ml myoblast cell suspension (macrodepot group) were injected using the standard surgical technique. Echocardiography was performed in all rats before and 6 weeks after cell injection. In all groups the perioperative mortality was below 20%. Six weeks after cell transplantation, a significant improvement of ejection fraction was seen in both myoblast treated groups compared to controls (macrodepot, microdepot, control; 53.7G11.9, 70.7G2.0, 39.1G6.4; PZ0.026, P!0.001). The microdepot group showed a more decent improvement than the macrodepot group (70.7G2.0 vs. 53.7G11.9, PZ0.013). In both treated groups, grafted myoblasts differentiated into multinucleated myotubes within host myocardium, however, the engraftment pattern was different and angiogenesis was enhanced in the microdepot group. Conclusions: Intramyocardial multisite pressure injection allows the safe and reliable transplantation of several myoblast microdepots into an infarcted myocardium and improves the efficacy of myoblast transplantation compared to the standard technique. Q 2005 Elsevier B.V. All rights reserved.

Background Cellular cardiomyoplasty (CCM) is a major method for the treatment of heart failure because adult cardiomyocytes do not regenerate after ischemic injury, which results in heart failure. There is a great deal of interest in finding suitable new cell sources for use in CCM. Here, we report that human amniotic mesenchymal cells (hAMC), which are multipotent cells derived from fetal mesoderm, may be a suitable cell source for CCM. Methods Freshly isolated hAMC were examined to detect the expression of cardiac-specific genes by reverse-transcription polymerase chain reaction and immunocytochemistry. hAMC were cocultivated with neonatal rat heart explants and transplanted into myocardial infarcts in the rat heart. Results hAMC expressed cardiac-specific transcription factor GATA4, cardiac-specific genes, such as myosin light chain (MLC)-2a, MLC-2v, cTnI, and cTnT, and the alpha-subunits of the cardiac-specific L-type calcium channel (alpha1c) and the transient outward potassium channel (Kv4.3). After stimulation with basic fibroblast growth factor (bFGF) or activin A, hAMC expressed Nkx2.5, a specific transcription factor for the cardiomyocyte and cardiac-specific marker atrial natriuretic peptide. In addition, the cardiac-specific gene alpha-myosin heavy chain was detected after treatment with activin A. Coculture experiments confirmed that hAMC were able to both integrate into cardiac tissues and differentiate into cardiomyocyte-like cells. After transplantation into the myocardial infarcts in rat hearts, hAMC survived in the scar tissue for at least 2 months and differentiated into cardiomyocyte-like cells. Conclusion The results of the present study suggest that hAMC possess some characteristics of cardiomyocytes.

Myocardial infarction may be complicated by the formation of a left-ventricular aneurysm that distorts the normal elliptical geometry of the ventricle to produce a dilated spherical ventricle with limited contractile and filling capacities. One of the consequences is congestive heart failure, which may be refractory to medical therapy and require surgical treatment. Surgical methods to restore the volume and shape of the left ventricle have evolved over the years. Nevertheless, although surgery for left-ventricular aneurysms has been performed for almost 50 years, the most appropriate approach is still controversial. This review gives an overview of the postinfarction left-ventricular aneurysm, tackling issues from the disease itself to surgical and other techniques of ventricular remodeling.

Background: Contraction of transplanted myoblasts and their effects on function and remodeling after myocardial infarction remain controversial. Aim: We used magnetic resonance imaging (MRI) to study wall thickening and left ventricular (LV) function and geometry after myoblast transplantation. Methods and results: Three weeks after cryo-infarction rabbits were randomized to receive an injection of f2 � 10 8 myoblasts (n=8) or medium (n=9) into the scar. Cine MRI and contrast enhanced (ce) MRI images were acquired before injection (baseline) and 4 weeks later (endpoint). Regional wall thickening was measured at the site of transmural hyperenhancement. In the control group, regional wall thickening decreased to � 15.3F8.6% at baseline, which further decreased to � 18.3F5.7% at endpoint. Further, end-diastolic volume increased from 3.96F0.27 to 5.00F0.46 ml and end-systolic volume from 2.23F0.19 to 2.96F0.30 ml (both P

In a small town in northern Montana, a 64-yearold retired nurse, physically active, but moderately obese, had been having episodes of angina related to physical stress for 1 week. When a more severe attack of angina persisted, she immediately chewed and swallowed 325 mg of aspirin and called her family practitioner, who arrived at her home promptly and administered 5 mg of intravenous morphine sulfate. The chest pain was alleviated soon after, and she was given 20 mg of atorvastatin and then transported by medical air ambulance 150 miles to a tertiary hospital equipped to care for acute coronary events. The admitting electrocardiogram revealed an acute ST elevation anterolateral infarction with several multifocal ventricular premature beats and a heart rate of 100 beats/ minute. The duration of the acute myocardial infarction (MI) (from onset of chest pain to arrival at the hospital emergency department) was estimated to be 3 1 ⁄2 hours. Primary percutaneous transluminal angioplasty and drug eluting stenting of a proximal left anterior descending artery thrombotic occlusion was successfully performed. The cardiologist in attendance was a member of a national team investigating the therapeutic benefits of transplanting bone marrow‐derived endothelial progenitor cells (EPCs) into the myocardium of patients with an acute MI. The patient agreed to participate in this investigation. QUESTIONS 1. Which of the following improve cell viability and reduce ventricular remodeling and as a result increase survival in patients with heart failure and following an MI? a. pharmacological therapy b. coronary artery bypass graft surgery c. cardiac catheterization d. mechanical assist devices e. cardiac transplantation f. cellular cardiomyoplasty g. all of the above

An adult heart injured by an ischemic episode has a limited capacity to regenerate. We administered three types of adult guinea pig cells [cardiomyocytes (CMs), cardiac fibroblasts (CFs), and skeletal myoblasts (Mbs)] to compare their suitability for repair of acute myocardial infarction. We used confocal fluorescent microscopy and a variety of specific immunomarkers and echocardiography to provide anatomic evidence for the viability of such cells and their possible functional beneficial effects. All cells were transfected with adenovirus-containing β-galactosidase gene so that migration from the injection sites could be traced. Both freshly isolated CMs as well as CFs were found concentrated in the infarcted zone; these cells survived for at least 2 wk posttransplantation. Transplanted CMs were regularly striated and grew long projections that could form gap junctions with native CMs, which was evidenced by connexin43 labeling. In addition, CM transplantation resulted in increased angiogenesis in the infarcted areas. In contrast, transplanted CFs did not appear to make any gap junctional contacts with native CMs nor did they enhance local angiogenesis. Mbs cultured for 7 days and transfected Mbs were identified 7 days posttransplantation in the infarcted area. During that time and thereafter, Mbs proliferated and differentiated into myotubes that formed new, regularly striated myofibers that occupied most (50–70%) of the infarcted area by 2–3 wk. These newly formed myofibers maintained their Mb skeletal muscle origin as evidenced by their capacity to express myogenin and fast skeletal myosin. This skeletal phenotype appeared to downregulate with time, and Mbs partially transdifferentiated into a cardiac phenotype as indicated by labeling for cardiac-specific troponin T and cardiac myosin heavy chain. By the third week posttransplantation, new myofibers formed apparent contacts with the native CMs via putative gap junctions that expressed connexin43. Myocardial performance of animals that were successfully transplanted with Mbs was improved.

BACKGROUND: Cell-based regenerative therapy is undergoing different experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction. METHODS: An overview of the actual status quo. RESULTS: Over 200 patients have been treated worldwide with cell-based procedures for myocardial regeneration. Results are preliminary. CONCLUSIONS: Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility.

Historically, few patients with ischemic congestive heart failure (CHF) have been considered for cardiac surgical intervention unless there was an obvious need for coronary revascularization or valve repair. New surgical procedures and non-mechanical assist devices are being used and tested in patients with end-stage CHF. We report on The Ohio State University Medical Center's early involvement in the international and multi-institutional Surgical Treatment for Ischemic Heart Failure (STICH) trial, which is evaluating the value of coronary artery bypass in patients with ischemic CHF as compared to medical therapies alone, and whether surgical ventricular restoration (SVR) offers additional benefit to patients with dilated hearts undergoing revascularization. Beyond standard coronary revascularization and SVR, new surgically deployed devices that attempt to augment ventricular performance by direct restraint of left ventricular dilatation or by reducing ventricular wall stress through altering ventricular shape are reviewed. The growing clinical and experimental experience with cellular cardiomyoplasty (in particular, autologous skeletal myoblast and adult-derived stem transplantation) also is reviewed. This review is intended to express the institutional insights of the authors, who have been involved in clinical trials and basic science research in each of these areas.

Background Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. Supplementing infarcted myocardium with neonatal myocyte would attenuate deleterious remodeling and so the present study used Doppler echocardiography and histology to analyze the cardiac function and histological regeneration of the damaged myocardium after cellular cardiomyoplasty. Methods and Results Experimental MI was induced by 24-h coronary ligation followed by reperfusion in adult male Lewis rats and neonatal myocytes were injected directly into the infarct and peri-infarct regions. Three groups of animals were studied at 4 weeks after cellular cardiomyoplasty: noninfarcted control (control), MI plus sham injection (MI), and MI plus cell injection (MI + cell). Ventricular remodeling and cardiac performance were assessed by Doppler echocardiography or contrast echocardiography. At 4 weeks after cellular cardiomyoplasty, MI + cell hearts exhibited attenuation of global ventricular dilation and cardiac function compared with MI hearts not receiving cellular cardiomyoplasty. Immunohistochemically, connexin-43-positive small cells were observed in the vicinity of the infarction in MI + cell heart. By electron microscopy, these cells contained myofilaments with Z-bands and poorly developed intercalated disks, suggesting neonatal myocardial cells. Furthermore, the myocardial cells were often making close contact with interstitial cells. Conclusions Implanted neonatal myocytes form viable grafts after MI, resulting in attenuated ventricular dilation and enhanced contractile function. Echocardiography, electron microscopy, and immunohistochemistry are useful methods for assessing the functional and histological regeneration of the damaged myocardium. (Circ J 2004; 68: 580 - 586)

One of the most promising new therapeutic techniques for the augmentation and regeneration of the myocardium is cellular cardiomyoplasty. Reports from animal and clinical investigations indicate that the transplant of different cell types, such as autologous skeletal myoblasts and adult stem cells, into injured myocardium results in the generation of new cardiac myocytes and improvement in myocardial performance. Although there is no consensus with regard to the best cell type to transplant or the extent of myocardial renewal and regeneration, the technique of cardiac cellular myoplasty may become one of the most important advancements in the treatment of cardiovascular diseases such as myocardial infarction and heart failure.

Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardial infarction. However, the angiogenic potential of transplanted immature cardiomyocytes and their effect on regional myocardial blood flow (RMBF) after coronary artery occlusion remain to be evaluated.Intramyocardial injection of cultured neonatal cardiomyocytes (4 x 10(6) cells/50-70 microliter) into the scar 1 week after permanent coronary occlusion in rats resulted in improved RMBF in the infarct 4 weeks after transplantation (radioactive microspheres, 0.97 +/- 0.18 ml/min/g) in comparison to medium-injected hearts (0.61 +/- 0.11 ml/min/g, P0.047). The macroscopic perfusion defect after in vivo staining with the blue dye 50% Uniperse blue was significantly smaller in the cell transplantation group (1.5 +/- 0.3% of the heart) compared to the medium group (3.0 +/- 0.6%, P0.017). Clusters of engrafted cells within the scar demonstrated a high capillary density (1217 +/- 114 perfused (blue) capillaries/mm(2)); however, in the scar tissue itself capillary density in the cell group (156 +/- 62/mm(2)) did not significantly differ from the medium group (125 +/- 10/mm(2)), suggesting that neo-angiogenesis was confined to regions of successful engraftment (non-infarcted tissue: 1924 +/- 114 perfused capillaries/mm(2)). The transplantation group was characterized by smaller diastolic and systolic left ventricular volumes, as assessed by intravenous ventriculography, along with thickened infarcts (0.93 +/- 0.07 vs. 0.75 +/- 0.04 mm, P0.020) and lower infarct expansion indices (0.64 +/- 0.07 vs. 0.83 +/- 0.06, P0.023), as determined by post-mortem morphometry of histologic slides.Transplantation of neonatal cardiomyocytes induced neo-angiogenesis in zones of successful cell engraftment within the scar, which effectively enhanced tissue perfusion.

Time for primary review 23 days. In newts, excision of up to 50% of the ventricular myocardium results in spontaneous regeneration and rebuilding of the heart, a process that involves de-differentiation of the remaining cardiomyocytes, de-novo synthesis of DNA followed by proliferation and mitotic cell division of both cardiomyocytes and connective tissue, and subsequent replacing of the lost tissue [1–3]. In contrast, the mammalian heart loses its capability of a quantitatively sufficient proliferative response to various injuries soon after birth [4–6]. Interestingly, recent studies reported a certain degree of cardiomyocyte regeneration in various pathologic conditions, such as heart failure [7], orthotopic heart transplantation [8,9], or myocardial infarction [10,11], and even surmised the existence of resident cardiac stem cells [12], or extracardiac cardiomyocyte progenitor cells [13] in the mammalian heart. However, these findings are still controversial [14]. In some of these studies, the presence of the Y-chromosome in hearts from female donors after gender-incompatible heart transplantation was used as evidence for population of the hearts by extracardiac progenitors. However, recent in vitro studies reported the occurrence of spontaneous cell fusions of putative stem cells, such as bone-marrow [15] or neural stem cells [16], with embryonic stem cells when cultured together, which challenges the concept of transdifferention and requires additional investigations in this field. Nevertheless, the mechanisms of re-activated or preserved cardiomyocyte proliferation and regeneration in humans (for review see [17]) are obviously not sufficient to prevent extensive scar formation and the relentless disease progression of heart failure after myocardial infarction or loss of contractile function with pressure or volume overload [18,19]. Despite progress in pharmacological treatment of the syndrome of heart failure [20], mortality and curtailment of quality of life in advanced stages of congestive heart failure are significant [21], … *Corresponding author. Tel.: +1-213-977-4050; fax: +1-213-977-4107. rkloner{at}goodsam.org

Background: Cellular cardiomyoplasty is the method of transplanting myogenic cells into injured myocardium to restore the lost heart muscle cells and to improve ventricular function. Method: Three patients, all with a history of coronary heart disease, underwent coronary artery bypass grafting and implantation of autologous satellite cells. A muscle biopsy of 2-4 g from the right vastus lateralis muscle was obtained for satellite cell (myogenic stem cell from skeletal muscle) isolation and proliferation before implanted into the donor's heart. The cells were suspended in serum-free medium and injected into 30-40 sites at and around the ischemic areas just before reversing the hypothermic cardioplegia to eliminate arrhythmia and to improve retention. After recovery, each patient was maintained at the intensive care unit for 3-4 days with ECG monitoring before transferring to the patient floor. Results: All patients survived the procedure with an uneventful recovery and were discharged from the hospital. At 3-4 months follow-up examination, increased left ventricular ejection fraction of 11% (35-46%), 5.4% (40-45.4%) and 1% (40-41%) and decreased left ventricular diastolic diameter of 4, 2 and 9 mm were observed for the patients, respectively. Arrhythmia was not detected during the follow-up evaluation by ECG. Improved perfusion ({sup 99m}TC-MIBI) andmore » increased metabolic activity ({sup 18}F-deoxyglucose) were found at the sites of satellite cell implantation. Significant increase of wall thickness and movement at the areas of cell injection was also observed using 2D-echo. Conclusion: Cellular cardiomyoplasty using autologous satellite cells is a safe procedure with encouraging beneficial outcomes in patients.« less

Heart failure, frequently the consequence of irreversible myocardial damage with subsequent formation of akinetic scar tissue, is a highly prevalent disease, and in its advanced stages associated with high mortality. The transplantation of exogenous cells with the inherent ability to contract has been put forward as one potential treatment strategy to increase contractility and cardiac performance. Besides skeletal myoblasts or stem cells from various sources, immature cardiomyocytes, such as fetal or neonatal cardiomyocytes, have been transplanted into normal, cryoinjured, infarcted myocardium, as well as into models of global heart failure. Survival of transplanted immature cardiomyocytes has been demonstrated up to 6–7 months, accompanied by vascularization of the grafted tissue. Transplants developed sarcomeric structures and other morphological features of differentiation. The principal possibility of cell-to-cell coupling between graft and host cells was demonstrated after cardiomyocyte transplantation into normal hearts and in some studies in damaged myocardium. But most long-term follow-up investigations in models of myocardial infarction reported that optimal integration of the engrafted cells appeared to be hindered by scar tissue, separating the transplant from the host. Nonetheless, in several studies, improved parameters of cardiac performance were demonstrated ex-vivo and in vivo. Potential mechanisms might involve beneficial effects on the remodeling process. In this review, we critically evaluate the potential value of cardiomyocyte transplantation as a new approach in the treatment of the syndrome of “heart failure”.

Objectives We report on the procedural and six-month results of the first percutaneous and stand-alone study on myocardial repair with autologous skeletal myoblasts. Background Preclinical studies have shown that skeletal myoblast transplantation to injured myocardium can partially restore left ventricular (LV) function. Methods In a pilot safety and feasibility study of five patients with symptomatic heart failure (HF) after an anterior wall infarction, autologous skeletal myoblasts were obtained from the quadriceps muscle and cultured in vitro for cell expansion. After a culturing process, 296 ± 199 million cells were harvested (positive desmin staining 55 ± 30%). With a NOGA-guided catheter system (Biosense-Webster, Waterloo, Belgium), 196 ± 105 million cells were transendocardially injected into the infarcted area. Electrocardiographic and LV function assessment was done by Holter monitoring, LV angiography, nuclear radiography, dobutamine stress echocardiography, and magnetic resonance imaging (MRI). Results All cell transplantation procedures were uneventful, and no serious adverse events occurred during follow-up. One patient received an implantable cardioverter-defibrillator after transplantation because of asymptomatic runs of nonsustained ventricular tachycardia. Compared with baseline, the LV ejection fraction increased from 36 ± 11% to 41 ± 9% (3 months, p = 0.009) and 45 ± 8% (6 months, p = 0.23). Regional wall analysis by MRI showed significantly increased wall thickening at the target areas and less wall thickening in remote areas (wall thickening at target areas vs. 3 months follow-up: 0.9 ± 2.3 mm vs. 1.8 ± 2.4 mm, p = 0.008). Conclusions This pilot study is the first to demonstrate the potential and feasibility of percutaneous skeletal myoblast delivery as a stand-alone procedure for myocardial repair in patients with post-infarction HF. More data are needed to confirm its safety.

Myocardial infarction is the leading cause of heart failure in developed countries, because even the advanced therapeutic measures of today are usually not sufficient to prevent left ventricular remodeling as they fall short of actual replacement of necrotic cardiac myocytes. Recent new insights into stem cell biology have changed our understanding of regenerative activities in the infarcted heart and have raised considerable hopes for novel therapeutic approaches aimed at cardiac myocyte replacement/regeneration through cell transplantation ("cellular cardiomyoplasty"). CELL-BASED THERAPEUTIC CONCEPTS: This review summarizes our present understanding of physiological stem cell/precursor cell mobilization to the infarcted heart and discusses the main therapeutic concepts for cell-based regeneration of myocardial infarction (adult/embryonic stem cells, skeletal myoblasts, endothelial precursors and others), including a brief overview of ongoing clinical trials. Finally, a shortlist of central clinical and research goals is provided, which should be addressed by stringently designed patient trials.

Cell transplantation is a novel experimental strategy to treat heart disease, such as myocardial infarction and heart failure. Its beneficial effects may include active contribution of transplanted cells to contractile function, passive improvement of the mechanics of the heart, induction of neoangiogenesis or other indirect influences on the biology of the heart. Several cell types have been used for cardiac cell transplantation including cardiac cells from fetal or newborn animals and cardiac muscle cell lines, skeletal myoblasts and skeletal muscle cell lines, smooth muscle cells, and a variety of stem cells, either adult or embryonic. With many of these cells, encouraging results in experimental ischemic and nonischemic heart disease have been obtained including successful cell survival after transplantation, integration into the host myocardium, and improvement of the function of diseased hearts. Most of these studies found cardiac contractility improved and some found enhanced angiogenesis. However, the mechanisms of these effects remain obscure, and the impact of dosage (cell number) on functional response is completely unclear. In addition, not enough comparative studies were performed to allow preference of one cell type over the other. The current data suggest that whatever cell species is used, the best survival and integration may be accomplished if immature and undifferentiated cells are used. Any kind of stem cell has obvious advantages in terms of endless reproducibility and plasticity, but the complete differentiation and maturation into cardiac myocytes still needs to be proven. At present several clinical studies are exploring the therapeutic benefits of cellular cardiomyoplasty in patients with ischemic heart disease, but it has to be noted that there are many issues that need to be addressed before this strategy will add to the therapeutic options for patients with heart disease.

Dynamic Cardiomyoplasty. Latissimus dorsi dynamic cardiomyoplasty has been used in our institution for heart failure patients refractory to medical therapy; 113 cases were operated at Broussais and Pompidou Hospitals and 75 patients by our team abroad, in the scope of an international cooperative program. Cardiomyoplasty has been associated with better results due to technical improvements, the most significant mini-invasive techniques, the latest the use of growth factors to enhance muscle vascularization. Risk factors have been identified, resulting in more precise indications, a lower hospital mortality, and a wider use of this operation. There has been a new tendency to associate cardiomyoplasty with electrophysiological therapies: implantation of ventricular defibrillators and multisite cardiac pacing (for atrioventricular and interventricular resynchronization). Cellular Cardiomyoplasty. Adult myocardium cannot repair after infarction due to the absence of stem cells. Cell transplantation strategies for heart failure have been designed to replace damaged cells with cells that can perform cardiac work. Current possibilities in cell therapy for heart failure is the transplantation into the infarcted myocardium of autologous myoblasts (satellite cells originated from skeletal muscle), fetal cardiomyocytes, autologous heart cells, cells derived from bone marrow stem cells, and smooth muscle cells. Experimental studies demonstrated that cell transplantation into the myocardium was associated with the recovery of myocardial contractility and compliance, as well as the diastolic pressure-strain relationship in animal models (infarctlike myocardial lesions and dilated cardiomyopathy models). Healthy myoblasts and myotubes were observed 2 months after myocardial implantation. Clinical studies are now in progress.

Objective: Skeletal myoblast transplantation is a promising alternative to treat heart failure. A single fiber, the minimal functional unit of skeletal muscle, retains skeletal myoblasts beneath the basal lamina. When surrounding muscle is injured, myoblasts migrate from the fiber into the damaged area to regenerate muscle. We hypothesized that such isolated fibers could be used as an efficient vehicle to deliver myoblasts into damaged myocardium, resulting in improved cardiac function. Methods: Living single fibers of rat skeletal muscle were isolated, and their behavior was characterized in vitro. Single fibers were injected into the myocardium (at 4 sites, each receiving a single fiber) of rats in 2 models of heart failure induced either by means of doxorubicin administration or left coronary artery occlusion. Results: Skeletal myoblasts dissociated from an isolated single fiber, proliferated, and differentiated into multinucleated myotubes in vitro. Within 3 days after grafting in vivo, original fibers provided putative myoblasts and disappeared. At 4 weeks, discrete loci consisting of several multinucleated myotubes were observed. Furthermore, single-fiber transplantation significantly improved cardiac function compared with the control treatment in either doxorubicin-treated hearts (maximum dP/dt, 4013.9 ± 96.1 vs 3603.1 ± 102.3 mm Hg/s; minimum dP/dt, −2313.7 ± 75.1 vs −2057.1 ± 52.4 mm Hg/s) or ischemic hearts (maximum dP/dt, 3905.6 ± 103.0 vs 3572.6 ± 109.7 mm Hg/s; minimum dP/dt, −2336.1 ± 69.7 vs −2106.4 ± 74.2 mm Hg/s). Conclusion: Single-fiber transplantation acts as a vehicle for delivering putative skeletal myoblasts that appear to differentiate into myotubes within the myocardium. This was associated with improved function of failing hearts, suggesting its efficacy as a novel graft for cellular cardiomyoplasty. J Thorac Cardiovasc Surg 2002;123:984-92