Autologous Skeletal Myoblasts Research Articles

Bone marrow cells for cardiac repair

Bone marrow cells for cardiac repair

Stem cells for clinical use in cardiovascular medicine

Cell transplantation is currently gaining a growing interest as a potential new means of improving the prognosis of patients with cardiac failure. The basic assumption is that left ventricular dysfunction is largely due to the loss of a critical number of cardiomyocytes and that it can be partly reversed by implantation of new contractile cells into the postinfarction scars. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials and now that the feasibility of the procedure is well established, efficacy data are expected from the ongoing randomized studies. Bone marrow stem cells are also generating a great deal of interest, particularly in patients with acute myocardial infarction, and are currently undergoing extensive clinical testing although recent data have raised a cautionary note about the transdifferentiation potential of these cells. While experimental studies and early-phase clinical trials tend to support the concept that cell therapy may enhance cardiac repair, several key issues still need to be addressed including (1) the optimal type of donor cells in relation to the clinical profile of the patients, (2) the mechanism by which cell engraftment improves cardiac function, (3) the optimization of cell survival, (4) the development of less invasive cell delivery techniques and (5) the potential benefits of cell transplantation in nonischemic heart failure. Current evidence suggests, however, that adult stem cells (myogenic or marrow-derived) fail to electromechanically integrate within the recipient heart, thereby mandating the search for second generation cell types able to achieve this goal which is the prerequisite for an effective enhancement of contractile function. Preliminary data suggest that cells that feature a true cardiomyogenic phenotype such as cardiac stem cells and cardiac-precommitted embryonic stem cells may fall in this category and carry the potential for ensuring a true regeneration of dead myocardium.

Feasibility and Safety of Autologous Myoblast Transplantation in Patients with Ischemic Cardiomyopathy

Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device implantation (LVAD). In addition, we sought to gain preliminary information on graft survival and any potential improvement of cardiac function. Eighteen patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twelve patients with a history of previous myocardial infarction (MI) and a left ventricular ejection of less than 30% were enrolled in the CABG arm. In a second arm, six patients underwent LVAD implantation as a bridge to heart transplantation and were required to donate their heart for testing at the time of heart transplant. Myoblasts were successfully transplanted in all patients without any acute injection-related complications or significant long-term unexpected adverse events. Follow-up PET scans showed new areas of viability within the infarct scar in CABG patients. Echocardiography measured an average improvement in left ventricular ejection fraction (LVEF) from 25% to 34%. Histological evaluation in four out of five patients who underwent heart transplantation documented survival and engraftment of the skeletal myoblasts within the infarcted myocardium. These interim results demonstrate survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality may offer a potential therapeutic treatment for end-stage heart disease.

Transcatheter Transplantation of Autologous Skeletal Myoblasts in Postinfarction Patients With Severe Left Ventricular Dysfunction

To report a case-controlled safety and feasibility study of transcatheter transplantation of autologous skeletal myoblasts as a stand-alone procedure in patients with ischemic heart failure. Six men (mean age 66.2+/-7.2 years) were eligible for transcatheter transplantation of autologous skeletal myoblasts cultured from quadriceps muscle biopsies. Six other men (mean age 65.7+/-6.3 years) were selected as matched controls (no muscle biopsies). A specially designed injection catheter was advanced through a femoral sheath into the left ventricle cavity, where myoblasts in solution (0.2 mL/injection) were injected into the myocardium via a 25-G needle. At baseline and in follow-up, both groups underwent Holter monitoring, a 6-minute walk test, New York Heart Association (NYHA) class determination, and echocardiography with dobutamine challenge. Skeletal myoblast transplantation was technically successful in all 6 patients with no complications; 19+/-10 injections were performed per patient (210 x 10(6)+/-150 x 10(6) cells implanted per patient). Left ventricular ejection fraction (LVEF) rose from 24.3%+/-6.7% at baseline to 32.2%+/-10.2% at 12 months after myoblast implantation (p=0.02 versus baseline and p<0.05 versus controls); in matched controls, LVEF decreased from 24.7%+/-4.6% to 21.0%+/-4.0% (p=NS). Walking distance and NYHA functional class were significantly improved at 1 year (p=0.02 and p=0.001 versus baseline, respectively), whereas matched controls were unchanged. Transcatheter transplantation of autologous skeletal myoblasts for severe left ventricular dysfunction in postinfarction patients is feasible, safe, and promising. Scrutiny with randomized, double-blinded, multicenter trials appears warranted.

Partial restoration of myocardial function and perfusion by cell therapy following myocardial infarction

In animals, both skeletal myoblasts and stem cells partially restore myocardial function after MI. This review provides a critical analysis of the initial clinical trials of these two therapeutic strategies. Direct injection of autologous skeletal myoblasts into the peri-infarct area has been performed at bypass surgery and by subendocardial injection in the catheterization laboratory. Both approaches appear to improve function significantly. Nonetheless, ventricular arrhythmias occur quite frequently in the first week after myoblast injection. In contrast, stem cells can be delivered to the injured myocardium by direct injection, by IV injection, or by bone marrow stimulation. The incidence of ventricular arrhythmia does not seem to increase. The magnitude of absolute improvement in cardiac ejection fraction, however, is only about 7%. The potential limitations of stem cell therapy are cell fusion, creating genetically abnormal cells, and the ability to deliver sufficient numbers of cells to have an important biologic effect. Cell replacement therapy after MI has considerable promise for restoration of cardiac function. Nonetheless because important theoretical and practical questions remain unanswered, the methodology is not yet ready for widespread clinical application.

Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: Phase I clinical study with 12 months of follow-up

Background Experimental studies have shown that skeletal myoblast transplantation into an area of postinfarction left ventricular injury results in an increase of segmental contractile performance that could be related to transplanted myoblasts. Initial experience with autologous skeletal myoblast transplantation in patients with postinfarction myocardial injury has also been obtained. Methods Patients who survived an acute myocardial infarction and were scheduled to undergo coronary artery bypass grafting were screened by means of dobutamine stress echocardiography and included into the study when no contractility changes within akinetic/dyskinetic segments were observed. Ten patients who gave informed consent were enrolled, and autologous myoblasts (satellite cells) were isolated from the skeletal muscle biopsy. Myoblast injections into the akinetic/dyskinetic area were performed after constriction of the anastomoses during the coronary artery bypass grafting procedure. Results Myoblast transplantations were performed after 3 weeks of in vitro culture in all patients. One patient died of a recent infarction at day 7 postoperatively because of a recent infarction in a remote area of the left ventricle. The left ventricular ejection fraction increased from 25% to 40% (mean, 35.2%) before the procedure to 29% to 47% (mean, 42.0%) during the 4-month visit ( P <.05), and the effect was maintained throughout 12 months of follow-up. Sustained ventricular tachycardia was observed in 2 patients in the early postoperative period and in the other 2 patients after 2 weeks of follow-up. Prophylactic amiodarone infusion was used in the remaining 8 patients and prevented sustained ventricular tachycardia episodes. Conclusions Autologous skeletal myoblast transplantation for the treatment of postinfarction heart failure is feasible. Our initial observations justify further research to validate this method in a clinical practice.

Autologous skeletal myoblasts restore the myocardial electrical impedance, but not the refractory period of infarcted myocardium: engraftment versus integration?

Introduction: Autologous skeletal myoblasts (ASM) can survive within areas of myocardial infarct. However, little evidence exists as to whether these skeletal fibers develop and become integrated (electromechanically coupled) with the host myocardium. Myocardial electrical impedance (MEI) is sensitive to physiological changes in regional tissue metabolism, while the myocardial refractory period (RP) is sensitive to changes in integrated intercellular electrochemistry of the myocardium. Methods: Myocardial infarction was created in sheep (N = 7) by means of coronary microembolization. Myocardial impedance electrodes were placed in remote (CTRL) and infarcted areas. Animals were injected (in the infarct) with up to 5.0 × 10^8 ASM (INF+ASM; N = 4) or cell-media (INF; N = 3). MEI and RP were measured in awake, unsedated animals at 1, 7, 14 and 21 days following ASM/cell-media injection. Random night-time ECG (telemetry) monitoring was conducted to evaluate for the presence of premature ventricular contractions (PVCs) or other ectopy. Results: ASM-derived myofibers were found aligned and apposed to cardiac myocytes, however, no connexin 43 was identified in skeletal myocytes. At Day 1, the MEI and RP of infarcted myocardium (361±20Ω & 178±4ms) differed (P<0.05) from that of remote myocardium (480±25Ω & 205±8ms). After 21 days, the MEI difference remained unchanged in cell-media animals (470±71Ω vs. 584±27Ω) but decreased significantly with ASM, reaching control (remote) values (503±20Ω vs. 522±24Ω, see figure). However, no significant change in RP or PVC count (21 pvc/hr; range: 3–38) was observed after Day 1. Discussion: The normalization of passive electrical properties (MEI) of the infarcted myocardium after ASM injection may represent ASM development, engraftment, and the revitalization of myocardial scar by skeletal myofibers. However, the lack of changes in measured RP suggests that engrafted skeletal myofibers may not impact active electrochemical properties of the myocardium.

Transplantation of autologous skeletal myoblasts as the treatment of patients with postinfarction heart failure

Transplantation of autologous skeletal myoblasts as the treatment of patients with postinfarction heart failure

481 Transplantation of autologous skeletal myoblasts in the treatment of patients with postinfarction heart failure ? One year experience

481 Transplantation of autologous skeletal myoblasts in the treatment of patients with postinfarction heart failure ? One year experience

Autologous skeletal myoblast implantation into heart. The myologist's experiences and directions

Autologous skeletal myoblast implantation into heart. The myologist's experiences and directions

New perspectives in the treatment of damaged myocardium using autologous skeletal myoblasts

Autologous skeletal myoblast transplantation may be used to ameliorate the healing process following myocardium infarct and, hopefully, cardiomyopathies. Despite successful animal experimentation, several issues need to be addressed in clinical settings, i.e., the impact of the delivery route, the extent of short- and long-term survival, and differentiation of the injected skeletal myoblasts. The authors offer some new hypotheses resulting from basic research, i.e., where and when to inject the myogenic cells, whatever their source, how to decrease new myofiber atrophy and improve their regeneration. Although these new hypotheses still need to be tested in humans, they may be decisive for future experimental studies and will lead to making endovascular cell implantation a more effective way to treat ischemic heart disease and failure.

Surgical ventricular restoration and other surgical approaches to heart failure

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.

1001-24 Long-term follow-up of safety and feasibility of autologous skeletal myoblast transplantation in patients undergoing coronary artery bypass graft surgery

1001-24 Long-term follow-up of safety and feasibility of autologous skeletal myoblast transplantation in patients undergoing coronary artery bypass graft surgery

Cellular transplantation: hurdles remaining before widespread clinical use.

The last few years have witnessed a growing interest in regenerative therapy of the failing heart by cell transplantation. Special emphasis has been put on skeletal myoblasts and bone marrow-derived stem cells, with a flurry of experimental studies generating overall positive but occasionally conflicting results. It is thus appropriate to review the most important of these studies in light of the major issues that still impede widespread clinical use of cell therapy. Recent laboratory data demonstrate the ability of autologous skeletal myoblasts to engraft into scarred myocardium and improve its function. Equally successful results have been reported with bone marrow-derived cells which, in contrast to myoblasts, are credited with a plasticity that might allow their transdifferentiation into cardiac or endothelial cells in response to organ-specific cues. However, some major questions remain unanswered; they include the choice of the optimal cell type in relation with the target patient population, the strategies for enhancing cell survival and functional integration, the clarification of the mechanisms of improvement, and the means of reducing invasiveness of cell delivery. Although laboratory research attempts to overcome these persisting hurdles, the accumulated body of evidence warrants implementation of clinical trials. The earliest ones have now documented the feasibility of cell therapy. It is now appropriate to conduct safety and efficacy studies which, if carefully done, should allow assessment of the extent to which this concept of regenerative therapy can be made a clinical reality.

Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure clinical experience with 6-month follow-up

Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure clinical experience with 6-month follow-up

Tissue implantation with autologous myoblast sheet improved cardiac performance in the impaired myocardium

The transplantation of autologous skeletal myoblasts (SM) using direct injection has been applied clinically. Loss of transplanted Cells and ECM due to direct injection limits SM’s number and potential. As for the clinical trial using autologous cell source, autologous myoblasts is a candidate. We hypothesized that tissue implantation rather than cell transplantation might be more advantageous to regenerate the impaired heart. The impaired heart was created in twenty eight rats by ligating LAD for 2 weeks. Polymers (N-isopropylacrylamide), a temperature responsive domain, were coated on culture dish. SM’s isolated from leg muscle were cultured and detached from the dishes as single monolayer cell-sheet at 20° C. Following therapies were conducted: Two myoblast sheets implantation (S group = 107 cells); Cell inject (I group = 107 cells); Non-cellular therapy (C group = collagen sheet). Two weeks after, the cell sheets showed attachment to myocardium and migration of the SM to the scar area. Histology in S-group revealed greater cellularity without scar formation, abundant widespread neo-capillaries and reduction of LV dilatation due to significant uniform thickened wall (S-group = 1168 ± 436μm vs I-group = 732 ± 204μm vs C-group = 696.9 ± 3.41μm) while I-group only showed small patches of grafted myoblasts with dispersed neo-capillaries and without significant reduction in LV dilatation. Eight week after, cardiac performance remained significantly improved in S-group. I group also showed recovery in cardiac performance but not as significant as showed by S-group. Technical loss of delivered cells was lesser in S-group as compared with I-group at 15 mins and 1 day as analyzed by RT-PCR for the presence of Y-chromosome. SM-sheet implantation improved global cardiac function by attenuating the cardiac remodeling and regenerating the impaired myocardium as compared to cell transplantation, suggesting a promising strategy for myocardial regeneration therapy.

Catheter-Based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: Clinical experience with Six-Month Follow-Up

ObjectivesWe report on the procedural and six-month results of the first percutaneous and stand-alone study on myocardial repair with autologous skeletal myoblasts. BackgroundPreclinical studies have shown that skeletal myoblast transplantation to injured myocardium can partially restore left ventricular (LV) function. MethodsIn 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). ResultsAll 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). ConclusionsThis 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.

Cellular cardiomyoplasty: a new therapeutic approach for regenerating the myocardium.

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.

Skeletal myoblast transplant in heart failure.

Despite recent advances in the prevention and treatment of ischemic heart disease (IHD), treatment of patients with heart failure secondary to myocardial infarction remains a therapeutic challenge. Heart transplantation has emerged as a viable option but is fraught with problems of supply. Mechanical assist devices are extremely expensive and dynamic cardiomyoplasty has shown only limited success in the clinical setting. Recent insights into the pathogenesis of myocardial diseases and the progress made in the field of molecular biology have resulted in the development of new strategies at molecular as well as cellular levels for cardiac muscle repair. One such strategy is to augment ventricular function by means of cellular cardiomyoplasty through intracardiac cell grafting using adult and fetal cardiomyocytes, stem cells, and autologous skeletal myoblasts.

Thérapie cellulaire et insuffisance cardiaque

Introduction. – Systolic heart failure is mainly due to a decreased left ventricular systolic function after myocardial infarction. Despite significant improvements in medical management of heart failure, the prognostic remains poor, with a 5-years survival only of 30%. Purpose. – Current treatments are only able to delay progression toward end-stage heart failure. Heart transplantation is accessible only for selected patients. Thus, in the context of post-myocardial infarction, cell therapy appears to be a new original technique, available for the majority of patients and potentially non-invasive. Conclusion. – After promising results in experimental models, a phase I clinical trial has been conducted in France, showing the feasibility of intracardiac autologous skeletal myoblast implantation. Other studies in Europe and USA are currently testing a variety of cells and delivery systems. A phase II-trial will begin in France.