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Objectives Myocardial autophagy has been recognized as an important factor in heart failure. It is not known whether changes in ventricular geometry by left ventriculoplasty influence autophagy in ischemic cardiomyopathy. We hypothesized that myocardial autophagy plays an important role in left ventricular (LV) redilation after ventriculoplasty. Methods Four weeks after ligation of the left anterior descending artery, ventriculoplasty or sham operation was performed. The animals were euthanized at 2 days (early) or 28 days (late) after the second operation. Ventricular autophagy was evaluated by protein expression of microtubule-associated protein light chain 3 II, an autophagosome marker. Cardiomyocyte area was assessed by histologic examination. LV function was evaluated by echocardiography. To examine the implications of autophagy, an autophagy inhibitor (3-methyladenine) was injected intraperitoneally for 3 weeks before sacrifice. Results The LV was reduced in size early and redilated late after ventriculoplasty. LV systolic function was improved early and later worsened after ventriculoplasty. Light chain 3 II expression decreased early after ventriculoplasty and increased in the late period. Myocyte area increased from the early to late stage after ventriculoplasty. Autophagic inhibition exaggerated the increased myocyte hypertrophy and LV redilation. Conclusions In a rat model of myocardial infarction, autophagy decreased early after ventriculoplasty and increased again during LV redilation. These results provide new insights into the mechanism underlying the late failure of ventriculoplasty.

Over time, various surgical treatment strategies have evolved to manage advanced heart failure (HF). Scientific and technological breakthroughs through the last 50 years have put forward various surgical alternatives to patients with advanced HF encompassing surgical ventricular restoration to surgical gene therapy and stem cell replacement of the diseased ventricles. Organ-saving surgical options which used to be promising included dynamic cardiomyoplasty, partial resection of ventricle and cardiac wrapping with Acorn CorCap cardiac support device. These procedures were eventually abandoned due to negative outcomes and without proven disadvantages. Another organ-saving surgical option currently being considered but still make little sense is cardiac regeneration by stem cell therapy, i.e., cardiomyocyte restoration and replacement. Presently, the organ-saving surgical alternatives to treat end-stage HF are revascularization for ischemic cardiomyopathy, mitral valve surgery (repair or replacement) for ischemic mitral incompetence (IMI), left ventricular (LV) aneurysmectomy (surgical ventricular restoration) and mitral valve repair for IMI. These aforementioned procedures have become quite established approaches and with increasing experience are continuously being modified to improve outcome. Various mechanical circulatory support systems have emerged over time to improve functional status of patients with advanced HF, either as a bridge to heart transplantation or as a bridge to myocardial recovery. Likewise offered in those with contraindications to transplantation. Ventricular assist devices (VAD) can keep patients alive until an eventual transplantation. This article reviews the variety of the myriad of alternative organ-saving surgical alternatives that have been available or are currently available provided to patients with end-stage HF, their advantages and deficiencies, as well as prospects in HF therapy.

In coronary heart disease, the use of stem cells for regeneration purposes has been broadly studied. Whereas bone marrow mesenchymal stem cells remain the most extensively investigated, other cell sources have been reported. Here we discuss and compare the characteristics of placenta-derived mesenchymal stem cells as a novel alternative cell source for cellular cardiomyoplasty. These cells are isolated from the human term placenta, which is normally discarded post partum. With their lack of ethical conflicts and young age, the readily available placenta-derived mesenchymal stem cells could be more suitable for myocardial regenerative therapy.

Heart failure is the end-stage of many cardiovascular diseases—such as acute myocardial infarction—and remains one of the most appealing challenges for regenerative medicine because of its high incidence and prevalence. Over the last 20 years, cardiomyoplasty , based on the isolated administration of cells with regenerative capacity, has been the focal point of most studies aimed at regenerating the heart. Although this therapy has proved feasible in the clinical setting, the degree of infarcted myocardium regenerated and of improved cardiac function are at best modest. Hence, tissue engineering has emerged as a novel technology using cells with regenerative capacity, biological and/or synthetic materials, growth, proangiogenic and differentiation factors, and online registry systems, to induce the regeneration of whole organs or locally damaged tissue. The next step, seen recently in pioneering animal studies, is de novo generation of bioartificial hearts by decellularization and preservation of supporting structures for their subsequent repopulation with new contractile, vascular muscle tissue. Ultimately, this new approach would entail transplantation of the “rebuilt” heart, reestablishing cardiac function in the recipient.

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.

In adult organisms, when stimulation of skeletal muscle is stopped, all changes revert to control after 10–14 days. This is the reason that training of the skeletal muscle before cardiomyoplasty is not done. We hypothesized that the muscle of a growing organism would not revert during a delay. Four lambs received 8 weeks of electrical stimulation of the left latissimus dorsi muscle (LDM) with the right LDM as control. Contractility force and positive and negative dF/dt were measured after 8 weeks conditioning, 2 weeks delay, and control. Conditioned muscle during a 30-minute fatigue test had decreased contractile force on an average of 7±2%; control muscle had decreased contractile force on an average of 39±4%; and after 2 weeks delay, there was a decrease in the contractile force of 12±2%. A stronger fatigue test was performed after 10 minutes of rest. Conditioned muscle lost an average of 15±5% of their contractile force, 16±2% positive dF/dt, and 14±2% negative dF/dt. Control muscle lost 40±3%, 39±4%, and 42±5%, respectively. After 2 weeks delay, previously conditioned muscle showed the following decreases: contractile force 21±3%, positive dF/dt 19±3%, and negative dF/dt 16±3%. Skeletal muscle biopsies were also taken and levels of lactate dehydrogenase (LDH) fractions were measured. LDH fractions one and two (LDH-1 + 2) after 8 weeks conditioning consisted of 6.7±1.9% (p

La insuficiencia cardíaca es uno de los problemas de salud de mayor relevancia por su incidencia creciente y sus repercusiones sociales, económicas y sobre todo humanas. El trasplante cardíaco es un abordaje excelente y un tratamiento consolidado para estos pacientes. Sin embargo, la desproporción entre el número de pacientes con una insuficiencia cardíaca terminal y los donantes potenciales restringe el trasplante a aquellos pacientes sin otras posibilidades de tratamiento y ha generado alternativas terapéuticas para mejorar el pronóstico y los síntomas de estos pacientes con alto riesgo. El interés creciente del estudio de la reversibilidad de varias formas de insuficiencia cardíaca terminal y la aplicación de la biología al tratamiento de estos pacientes ha inducido el desarrollo de estrategias terapéuticas, diseñadas para integrar la biología y las nuevas tecnologías médicas, para así intervenir sobre los modelos biomecánicos, moleculares y neurohormonales de la insuficiencia cardíaca. Estos tratamientos incluyen la cardiomioplastia celular, la ingeniería tisular, la cirugía de restauración del ventrículo izquierdo, la inmunoadsorción y la constricción mecánica pasiva ventricular como puente a la recuperación. La integración de estos abordajes puede ofrecer alternativas válidas al trasplante cardíaco.Chronic heart failure is one of the major health care issues in terms of increasing number of patients, rate of hospitalizations and costs. Heart transplantation is an excellent approach and a consolidated treatment for these patients. furthermore, the disproportion between the incidence of heart failure and the number of heart donors makes necessary to restrict cardiac transplant to patients with no other treatment possibilities and has generated alternative treatments to improve prognosis and symptomatology in this high risk patients. The interest in the reversibility of certain forms of end-stage heart failure and the application of biology to the treatments of these patients has generated therapeutic strategies designed to integrate biology and medical technologies in order to act to the biomechanical, the molecular and the neurohormonal model of heart failure. These treatments include cellular cardiomyopathy, tissue engineering, surgical left ventricular restoration and passive mechanical ventricular assistance as a bridge to recovery. The integrated development of these approaches could offer hopeful treatment as alternative to heart transplantation.

Objective: Previous regenerative studies have demonstrated massive cell losses after intramyocardial cellular delivery. Therefore, efforts at reducing mechanical losses may prove more successful in optimising cellular therapy. In this study, we hypothesized that escalating mesenchymal stem cells (MSCs) dose will not produce corresponding improvement in cardiac function due to washout of the small cells in microcirculation. Using microspheres similar in size to MSCs, that are encapsulated in alginate-poly-L-lysine-alginate (APA), we tested the hypothesis that size is an important factor in early losses. Methods:In experiment I, five groups of rats (n = 9 each) underwent coronary ligation; group I had no treatment; the other groups received escalating 0.5 � 10 6 , 1.5 � 10 6 ,3 � 10 6 and 5 � 10 6 of MSCs each. Echocardiogram was performed at baseline, 2 days and 7 weeks after surgery. In experiment II, cell-sized microspheres (10 mm) were encapsulated in APA microcapsules. In group I (n = 16), rats received bare microspheres, group II (n = 16) microspheres within 200 mm microcapsules and in group III (n = 16), microspheres within 400 mm microcapsules. After 20 min, hearts were quantified for the amount retained. Results: Myocardial function did not improve further with escalatingcell dosesbeyondan initialresponse at1.5 � 10 6 cells.Encapsulatedmicrospheresin200 mm and 400 mm microcapsules demonstrated a fourfold increase in retention rate compared with 10 mm microspheres. Conclusion: We concluded that suboptimal functional improvement in this animal model starts at 1.5 � 10 6 cells and does not respond to escalating cell doses. Improving mechanical retention is possible by increasing the size of the injectate. Microencapsulation could be used to encapsulate donor cells and facilitate functional improvement in cellular heart failure therapy. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Chronic heart failure is one of the major health care issues in terms of increasing number of patients, rate of hospitalizations and costs. Heart transplantation is the best established therapy for patients with severe heart failure. However, the number of donors limits the activity to 5000 heart transplants performed annually worldwide. This limitation has generated alternative treatments. The increase of the interest in the reversibility of the heart failure and the application of new biological alternatives has generated therapeutic strategies designed to integrate biology and medical technologies in order to act to the biomechanical, the molecular and the neurohormonal mechanisms of heart failure. These treatments include cellular cardiomyoplasty, tissue engineering, surgical left ventricular restoration as well as passive and active mechanical ventricular assistance as destination therapy, bridge to recovery or bridge to transplantation. The integrated development of these approaches could offer hopeful treatments, although there is still much to be learned regarding the optimal use of these strategies.

Several recent basic research studies have described surgical methods for cardiac repair using tissue cardiomyoplasty. This review summarizes recent advances in cardiac repair using bioengineered tissue from the viewpoint of the cardiac surgeon. We conclude that the results of many basic and preclinical studies indicate that bioengineered tissue can be adapted to conventional surgical techniques. However, no clinical studies have yet proved bioengineered tissue is effective as a treatment for human heart failure. Today's cardiac surgeons can look forward to the advent of new techniques to benefit patients who respond poorly to existing treatment for heart failure.

GIL, J. & OLIVARES, R. A biceps muscle Latissimus dorsi in a dog. Int. J. Morphol., 32(4):1464-1466, 2014.SUMMARY: This article reports the finding of a twin unreported muscle begin. In one dog, both, left and right muscle latissimusdorsi were biceps. The thin second head of m. latissimus dorsi that we founded, could be an intermediate step of comparative anatomychanges from reptilian to mammal. Man breast surgery and cardiomyoplasty, use dog latissimus dorsi as experimental, to know thisinformation can be useful to these situations.KEY WORDS: Muscle; M. Latissimus dorsi; Dog; M. Biceps; Arm.

Sudden death represents a common event in the natural history of patients affected by chronic heart failure. Such an outcome also has been shown to characterize the follow-up of the cardiomyoplasty procedure. We report two cases of patients who had cardiomyoplasty and experienced witnessed episodes of ventricular arrhythmia at variable times after surgery (2 years and 2 months, respectively). In the first case, an implantable cardioverter defibrillator (ICD) was implanted subsequent to the arrhythmic episode, whereas the second patient had a combined cardiomyoplasty and ICD implantation procedure. In particular, this patient underwent a modified wrapping technique, herein described, because of a large left ventricular dilatation. In both cases, ventricular defibrillation did not affect the correct functioning of the implanted cardiomyostimulator. Our article confirms that ventricular arrhythmia is common in cardiomyoplasty patients. The combined use of a skeletal muscle stimulator and implantable defibrillator may therefore be effective in preventing arrhythmia-related sudden death without any concurrent effect on the correct functioning of the wrapped muscle/heart circuit, with likely benefit on long-term cardiomyoplasty patient survival.

Muscle necrosis has been frequently observed in cardiomyoplasty patients and in experimental animal studies. The purpose of this study was to determine if heat shock could provide protection to skeletal muscle as has been shown in cardiac muscle. A 15-minute heat shock at 42 degrees C resulted in an immediate increase in HSP72 mRNA and was followed within 3 hours by a two-fold increase in HSP72. Surgical dissection of the latissimus dorsi muscle (LDM) followed by an ischemic period resulted in a two-fold increase in HSP72 in control LDM, whereas the already high levels in the heat-shocked LDM increased only slightly with surgery and ischemia. Citrate synthase activity and tissue histology indicated that heat shock did not protect the LDM from the imposed surgical trauma and ischemia insults used in this study.

The concept of bionics was developed 50 years ago and represented the development of engineering and technology based on natural biological systems. Traditional applications of bionics in healthcare include artificial bionic organs that apply engineering principles to replace or augment physiological functions by integrating electronic, mechanical or electromechanical components to inherent body tissues/organs (we term this as ‘exobionics’). Recently, there has been a new wave of bio-inspired treatments that act through the reorganization of the existing biological organs in an individual to enhance physiology. Here, the technology does not replace biological tissue, but rather applies engineering principles to replace or augment physiological functions by the rearrangement and manipulation of inherent tissue/organs; we term this autobionics. Examples include: dynamic cardiomyoplasty (artificial heart pump using skeletal muscle), the Ross procedure (pulmonary autograft), dynamic graciloplasty (artificial sphincter) and metabolic gastric bypass (rearranging the gastrointestinal tract to modify gut- and pancreatic-hormone release). Autobionic therapies can be classified into dynamic, static and metabolic procedures. This results in tissue redesignation (one tissue used in place of another), tissue replacement and systems reorganization (rearranging inherent organ/tissue anatomy). In some cases autobionic procedures can enhance physiological function beyond normality and represents a new era in bio-inspired versatility.

The French multicenter experience (6 centers) of dynamic cardiomyoplasty was analyzed for long-term survival and functional outcome, the most important endpoints in congestive heart failure therapy. Cardiomyoplasty was performed in 212 patients with symptoms of chronic heart failure despite maximal pharmacological therapy. The etiology was ischemic (48%), idiopathic (45%) or other (7%). Cardiomyoplasty was performed using the latissimus dorsi muscle which was electrostimulated after surgery. During follow-up, 88% of patients improved clinically. Hospital death occurred in 29 (14%) patients and was related to the severity of preoperative heart failure symptoms. Late mortality occurred in 99 patients due to heart failure (44%), sudden death (37%), or noncardiac causes (18%). Combined dynamic cardiomyoplasty and implantation of a cardiac rhythm management system was safely achieved in 22 patients, and 26 underwent heart transplantation for recurrent heart failure. Long-term functional improvements were observed in most patients, and the best outcome was achieved in those with isolated right ventricular failure. Dynamic cardiomyoplasty can be considered as a destination therapy or a mid- to long-term biological bridge to heart transplantation.

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.

Cardiac assistance from skeletal muscle offers an attractive surgical solution to the problem of end-stage heart failure, yet it is widely regarded as a failed approach. I argue here that this is an outdated assessment. Systematic progress has been made over the last 25 years in understanding the relevant basic science. In the light of these advances we should be reconsidering the place of skeletal muscle assist in the surgical armamentarium.

The overall purpose of circulatory assistance utilizing skeletal muscle is the most efficient application of muscle power. From the histological viewpoint, hot-knife dissection of the latissimus dorsi muscle (LDM) is presented to preserve muscle tissue. The shaw hemostatic scalpel could be used similarly to standard surgical blades, and its hemostatic performance was efficient in sealing collateral vessels from the thoracic wall. Muscular and nervous twitching was never observed throughout dissecting the LDM. Histological findings revealed that muscle fibers could be preserved by hot-knife dissection rather than by electrocautery. This technique may reduce the inconvenience of the operators, and, therefore, shorten the operation time in dynamic cardiomyoplasty and other experiments.

During the past several years, there have been increasing experimental and early clinical observations indicating that allogeneic, and even xenogeneic, mesenchymal stem cells (MSCs) may be useful for cellular cardiomyoplasty. Although the immune tolerance of MSCs is well established in various in vitro studies, controversies on the in vivo immune tolerance of MSCs persist. Confirmation of the feasibility of allogeneic cellular cardiomyoplasty will have vast clinical implications, since it will provide convenient "off-the-shelf" donor cells, as a vehicle for gene therapy, and avoid the need to use dysfunctional autologous MSCs in senile and/or disabled patients.

Objective: Dynamic cardiomyoplasty (CMP) was proposed as a treatment for refractory heart failure; more than 2000 procedures have been performed worldwide. Heart transplantation was indicated afterwards in some CMP patients with recurrent heart failure symptoms. This study reviews the multicentric French experience with CMP followed by heart transplantation. Methods: From 1985 to 2007, 212 patients (mean age 53 ± 11 years) with refractory heart failure (LVEF = 22 ± 9%, mean NYHA 3.2) underwent CMP in France. Heart transplantation was performed in 26 patients (12.3%), mean age: 51 ± 11 years, within 2.3 ± 3 years after CMP. Transplantation was indicated for persistent heart failure, i.e. no immediate improvement after CMP (19%) and for recurring heart failure (81%). Results: The surgical technique of heart transplantation following cardiomyoplasty presents few particularities. Routine extracorporeal bypass was instituted between the vena cavas and the ascending aorta. As in most of these patients the CMP procedure had been performed without the need of extracorporeal circulation, hearts were free of previous cannulations for cardiopulmonary bypass. The latissimus dorsi muscle flap was divided as far as possible inside the left pleural cavity and its vascular pedicle was obturated. The proximal portion of the muscle as well as the muscular pacing electrodes were kept in place in the pleural cavity. The adhesions between the flap and the heart were not released so as to achieve an en bloc resection of the heart and the muscle flap. During removal of the recipient's heart, care was taken not to injure the left phrenic nerve that was frequently in tight relation with the latissimus dorsi muscle. Heart transplantation was then performed in a routine manner, the donor heart being anastomosed to remnant atria and great vessels. Mean follow-up was 5.5 years (longest 13.5 years). Survival at 10 years was 40% for early heart transplantation (done within 4 months of CMP) and 57% for transplantation performed at 3 ± 2.8 years after CMP. Conclusions: Heart transplantation after CMP is technically feasible. Hospital mortality was higher when urgent transplantation was required. Long-term survival results are similar to those for primary heart transplantation. Cardiomyoplasty, when it fails, does not preclude transplantation, and when indicated, CMP could be considered as a biological bridge to heart transplantation.

Purpose Currently, only a small fraction of patients are able to receive reperfusion therapy for myocardial infarctions. We hypothesize that myometrial cell patch transplantation could be an alternative approach for the treatment of myocardial infarction. Design We performed a preliminary study to determine the feasibility of this novel therapeutic approach in a rabbit model. Procedures Six adult female New Zealand rabbits were used. Myocardial infarction was induced by left anterior descending artery ligation. A segment of uterus was removed via a laparotomy incision, and this uterine segment was transplanted as an autologous graft over the infarcted myocardium, which was then reinforced by greater omentum. Statistical methods and outcome measures Hemodynamic measurements and histological studies. Main findings: All uterine myometrial patches survived in the test animals. Fluoroscopic hemodynamic measurements were made for ejection fractions at 8 weeks after the application of the uterine patch. Histological study demonstrated well-healed myometrial-myocardium junctions with minimum scar tissue. Angiogenesis occurred in the transplanted myometrium. Connexin 43 expression was demonstrated in the transplanted patches. Conclusion Our noncontrolled preliminary rabbit experiments indicate that patches of uterine myometrium reinforced by greater omentum can be used as autologous transplant therapy for infracted myocardium. This is an innovative technique that could lead to future treatment for individuals who may suffer from an infarcted myocardium and may not be eligible for traditional reperfusion therapy.

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 Efficacy of cellular cardiomyoplasty seems to occur in a dose-related manner. However, the safety of multiple transendomyocardial transplantation procedures to administer high cell dosages has not been previously reported. The aims of this study were to assess the short- and intermediate-term results of a repeated cell administration strategy and evaluate the safety of an "off-the-shelf" allogeneic mesenchymal stem cell (MSC) source. Methods Porcine bone marrow-derived MSCs were culture-expanded through three cycles in vitro before transplantation. Yorkshire swine weighing 30–40 kg were allocated to receive the total dose during 1 injection procedure or divided over 2 procedures separated by 14 days, as follows: (i) 400×10 6 allogeneic MSC ( n =5), (ii) 800×10 6 allogeneic MSC divided in 2 doses ( n =5), (iii) cryopreservant vehicle containing 10% DMSO, 5% porcine serum and 85% PlasmaLyte A, 14 days apart ( n =2), or (iv) sterile saline 14 days apart ( n =2). During each procedure, twenty 0.5 ml aliquots of the assigned injectant were administered using the Stiletto™ Endocardial Direct Injection Catheter System, targeting at the left ventricular anterior, septal and lateral walls under fluoroscopy. Vital signs and electrocardiograms were recorded during the procedure and at 24 h. The animals were examined daily and cardiac enzymes were measured immediately post-procedure, and on days 1, 15 and 90. Necropsy and histopathology were performed at day 90. Results Mean transendocardial injection procedure time was 40±10 min. All ventricular target areas were accessed by the Stiletto™ system. Ventricular ectopic beats and/or non-sustained ventricular tachycardia associated with catheter contact or endomyocardial injections were observed in all cases. However, no sustained ventricular arrhythmia, anaphylaxis, or significant cardiac enzyme release was seen. One mortality resulted from air embolism during the procedure. All other swine survived from the time of recovery until planned sacrifice at day 90 and had normal physical examination findings. The 3-month histopathology showed no evidence of rejection, calcification, teratoma or myocardial infarction. Conclusion Repeated endomyocardial transplantation of high dose, bone marrow-derived allogeneic cells appeared safe in a large animal, human surrogate model. Such cellular cardiomyoplasty strategy warrants further investigation.

Objective : Our aim was to evaluate sinus rhythm restoration and its failure predictors after one-stage application of surgical radiofrequency ablation, left atrial reduction and mitral valve correction. Methods : This is a prospective longitudinal cohort study with historical controls. Patients were divided into 2 groups according to the performed type of operation — the main group included patients undergone one-stage mitral valve correction, surgical radiofrequency ablation and left atrial atrioplasty (n =47); and the control group consisted of patients undergone only mitral valve correction (n =76). Surgical radiofrequency ablation was performed under the scheme Maze-IV. Left atrial atrioplasty procedure was performed according to echocardiography data: if in women LA antero-posterior dimensions were more than 4.7 cm and in men more than 5.2 cm. Results : The study included 123 patients. In the main group ( age of the patients 61.0±9.1 years , 55% male ) sinus rhythm restoration was observed in 32 (68%) patients during the early postoperative period, but at the time of discharge it reduced to 19 (40%), but in 6 months it increased up to 37 (78%), and in 36 months sinus rhythm already was detected in 40 (85%) patients. At the same time, during the early postoperative period in the control group ( patients aged 59.0±11.0 years, 61% male ) only 31 (40%) of patients had sinus rhythm, in 6 months it was detected in 11 (14%) cases, and in 36 months sinus rhythm – only in 28 (37%) patients. Predictors of atrial fibrillation recurrence were revealed: valve disease continuance

Objective: Cardiac cell replacement therapy (cellular cardiomyoplasty) aims at restoring contractile function following cardiac infarction or cardiac myopathy and may add a new option to conventional treatments of cardiac failure in the future. Currently, this approach is hampered by the minor rate of cell engraftment and optimal strategies and routes of cell delivery need to be identified. Delivery of cardiomyocytes immobilized on biodegradable microspheres could support cell transfer. Methods: Murine induced pluripotent stem cell derived cardiomyocytes (iPS-CMs) expressing puromycinacetyltransferase and enhanced green fluorescent protein (eGFP) under control of the Acta-2 promotor were used. Macroporous gelatine microspheres were loaded with single cell suspensions of purified iPS-CMs and transplanted into healthy murine myocardial tissue. Single cell suspensions were transplanted for control. Persisting cells were determined by quantitative real-time PCR with Y-chromosome specific primers and histological analysis. Results: Upon direct intramyocardial injection of iPS-CMs only 12.3 ± 4.4% of injected cells were detectable immediately after injection and this value further declined to 1.3 ± 0.5% at 24h. In contrast delivery of iPS-CMs on microspheres resulted in a persistence of 4.2 ± 1.2% at 24h (p

Background Dynamic training and maintaining muscle tension are important factors during skeletal muscle ventricle (SMV) conditioning that may improve SMV performance. This study sought to determine the effects of dynamic muscle training and progressive SMV resting pressure expansion on SMV pumping capability. Materials and methods SMVs were constructed in 14 goats using the left latissimus dorsi muscle. SMVs were conditioned with a 40 ml constant-volume isovolumetric implant (n = 5, IsoVol group) or a compliant, pneumatic system that allowed dynamic shortening and direct exposure to resting pressures. Dynamic SMV resting pressure was either progressively increased from 40 to 100 to 120 mmHg (n = 5, HiP group) or maintained at 40 mmHg (n = 4, LowP group) during conditioning. After 8 to 10 weeks of electrical stimulation conditioning, SMVs were connected to a counterpulsation mock circulation system and SMV pumping performance evaluated across a range of pressures and stimulation parameters. Results SMV pumping performance was similar in each group. Stroke works generally increased with pressure and reached a plateau in all groups above 80 mmHg (120 msec contraction ∼80 mJ/stroke; 480 msec contraction ∼180 mJ/stroke). Stroke volumes decreased with pressure except at high stimulation levels where loading effects were observed. Chronic changes in SMV volume significantly effected pumping performance. Conclusions These data suggest that acute pumping performance is not different between 8 to 10 weeks of dynamic or isovolumetric training if SMV volume is not constrained. A potentially improved SMV conditioning protocol is proposed that determines, positions, and maintains SMV volume near the initial volume for maximal isovolumetric pressure during conditioning.

Heart failure (HF) affects a rapidly growing population of patients. Despite improvements in the understanding and therapy of many stages of cardiovascular disease, there has been little progress in treating HF. In the late-stage disease, current options are cardiac transplantation and mechanical support--options that are limited to a small patient collective. The ischemically injured failing heart lacks contractile myocardium, functional vasculature, and electrical integrity, which has made treatment of the underlying injury untenable in the past. Restoring all of these components seems an overwhelming challenge. Yet, the concept of cell therapy--tissue repair by transplantation of stem and progenitor cells--has opened new potential options for patients with heart failure. Skeletal myoblasts, bone marrow, and blood-derived stem cells have all shown considerable myogenic and angiogenic potential in vitro and have rapidly moved from bench to bedside. A number of nonrandomized, non-placebo-controlled safety and feasibility studies have been reported and now double-blinded randomized controlled trials are underway. Despite this rapid clinical pace, the exact mechanisms underlying the functional benefits of different cell types are not well understood. Instead, multiple similar mechanism have been ascribed to virtually every cell type. Thus, while the field is exciting and offers unheralded promise to treat patients with CVD, we must proceed with due diligence and caution. Only a deep understanding of the benefits versus the risks, and the mechanisms involved in cell-mediated cardiac repair, will allow us to design clinically valuable tools and fulfill the potential of this exciting 21st century approach to treating cardiovascular disease.

Background- We propose a new surgical procedure for advanced heart failure - adaptive cardiac binding - which allows for a gradual increase in compression on the dilated heart with separate loads on the left and right ventricles. Method- A canine model of biventricular heart failure (arteriovenous anastomosis – AVA, and doxorubicin administration) was created. Twenty-four dogs were divided into four groups: control, adynamic cardiomyoplasty (CMP), usual plastic cardiac binding (PCB), and adaptive cardiac binding (ACB). Systolic and diastolic area and volume and LVEF were measured before creation of heart failure, six weeks after, immediately after main operation, and 4 weeks later. In the animal group with ACB, liquid was added incrementally (35ml, 15ml, and finally 10ml) to each side of the pouch at weeks 1, 2, and 3. Results- LVEF was 59±4 % before AVA and doxorubicin administration and dropped to 27±2% six weeks later. Immediately after the main operation, LVEF was 35±3% (CMP), 34±4% (PCB), and 35±4 (ACB) (p>0.05 between groups). Four weeks later, LVEF had not changed in the CMP (37±3%) and PCB (32±2%) groups but had significantly increased in the ACB group (48±5%, p

In the last 25 years, techniques utilising muscle flaps to perform mechanical work have become part of the reconstructive surgeon's repertoire. In this paper, these techniques and the particular physiological challenges faced by active flaps are discussed and a sub-classification of muscle flaps into passive and active is proposed. A series of experiments are described that were designed to compare local pO(2) and gaseous perfusion, at multiple sites in pedicled tibialis anterior muscle flaps and controls, using specially developed dual amperometric microelectrodes, in an in vivo rabbit model. No significant difference in perfusion was found comparing flaps and controls until the flap's vascular pedicles were divided and ligated, and then flap perfusion fell to zero. Flap and control oxygenation varied significantly only during mobilisation and again, after pedicle division and ligation (F[13,55] = 12.3; P < 0.001)]. This absence of functional ischaemia as a consequence of mobilisation in the model used suggests the practice of delaying electrical conditioning of muscle flaps in dynamic cardiomyoplasty and neoanal sphincteroplasty might be unnecessary if these data are reproduced in human latissimus dorsi muscle. The relevance of these findings to free flap oxygen consumption and to the delay phenomenon is discussed.

Successful hypothermic storage of primary cells is now recognized as a rate-limiting step in the development of clinical applications in regenerative medicine and in research-related settings. Heart transplantation and stem cell cardiomyoplasty require hypothermic storage for successful harvest/isolation and transport to the recipient. These processes are time constrained, thereby necessitating the need to recover fully functional bioproducts following prolonged hypothermia. Despite numerous attempts, extension of the cold storage interval for myocytes while maintaining viability and function has not been realized. In this study, investigation into several strategic approaches to hypothermic preservation was evaluated in the neonatal rat ventricular cardiomyocyte model (NRVCM). Samples were assessed for survival by a panel of indicators including cellular membrane integrity, metabolic activity and spontaneous contractile function. Cultured NRVCM were held at 4°C for 24–72 h in either standard culture medi...

Dynamic cardiomyoplasty has been performed in over 1000 patients worldwide but due to limited success the procedure was never been adopted as an alternative approach for the surgical therapy of heart failure. However, observations in these patients showed that the nonstimulated or fibrotic transformed latissimus dorsi by itself led to an improvement of heart failure symptoms. These findings stimulated animal experiments with so-called passive cardiomyoplasty devices. In several animal models, the progression of heart failure could be stopped, and even reversed remodeling could be demonstrated. Several different devices have been developed and tested in animal models. The Acorn CorCap has already passed a successful clinical feasibility study. However, the final evaluation of two multicenter trials has to be awaited to assess the future role of this device in the treatment of heart failure.

Background Myocardial infarction results in irreversible myocyte loss. In a murine model, we tested the feasibility of a novel repair technique combining bone marrow cell (BMC) transplantation and cardiomyoplasty. Methods Myocardial infarction was induced cryogenically in backcrossed ROSA 26 transgenic × C57BL/6J mice (n = 75). Thirty days later, surviving mice (n = 69) were randomized to sham treatment (rethoracotomy only; n=11), patch only treatment (n = 29), or patch + BMC treatment (n = 29). Abdominal muscle patches were harvested from donor littermates not expressing the β-galactosidase reporter gene and sutured on the epicardium directly above the infarct zone. Patch only–treated mice received uncoated patches. Patch + BMC–treated mice received patches coated with 5 × 10 6 β-galactosidase-expressing BMCs embedded in a collagen-rich three-dimensional matrix. Results Mortality rate was 52% after muscle patch implantation. Bone marrow cells were able to migrate from muscle patch into the infarct zone, as demonstrated by β-galactosidase immunostaining, and ultimately constituted 8% of all cells in scar tissue (mean ± standard deviation, 219 ± 111/mm 2 ). Angiogenesis and cell survival in the scar were improved by patch + BMC treatment. Left ventricular geometry and cardiac function were improved by patch treatment, with or without BMC, although the effects were stronger after patch + BMC treatment. Conclusions Epicardial deposition of a BMC-coated muscle patch is a promising approach to restoring cardiac function after myocardial infarction.

The death of highly vulnerable cardiomyocytes during ischemia leads to cardiac dysfunction, including heart failure. Due to limited proliferation of adult mammalian cardiomyocytes, the dead myocardium is replaced by noncontractile fibrotic tissue. Introducing exogenous cells to participate in the regeneration of infarcted myocardium has thus been proposed as a novel therapeutic approach. In view of the availability of various xenogeneic cells and fewer ethical and political concerns that surround human embryonic stem cells and fetal cardiomyocytes, cellular xenotransplantation may be a potential alternative approach for cardiac repair in humans. However, one of the most daunting challenges of xenotransplantation is immunorejection. This article summarizes the progress in cellular xenotransplantation for cardiac repair in experimental settings and the current understanding of possible immune responses following the engraftment of xenogeneic cells. The public attitude towards xenotransplantation is reportedly more favorable to receiving cells or tissues than a whole organ, but many scientific obstacles need to be overcome before the utilization of xenogeneic cells for cardiac repair in patients with heart disease becomes applicable to clinical practice.

Heart failure is still associated with a poor prognosis despite great advances in drug therapy, so that surgical procedures are necessary in patients with end-stage cardiac failure. Cardiac transplantation was the therapy of choice during the last decades, but due to its disadvantages and the increasing scarcity of donor organs other surgical procedures were developed. Multisite pacing improves quality of life, but a longterm survival benefit remains to be proved. Coronary artery bypass grafting and valve surgery demonstrated to improve quality of life and to increase long-term survival. Ventricular assist devices are effective in bridging up to 70% of patients to cardiac transplantation, but the number of complications must be reduced. Partial left ventriculectomy may be performed with results similar to those obtained of cardiac transplantation, but long-term results are not yet available. Dynamic cardiomyoplasty and Myosplint® implantation were not successful, but it must be awaited, if passive cardiomyoplasty leads to better results. Xenotransplantation is under intense investigation, but cannot be used clinically until now due to the hurdles of rejection and transfer of infectious diseases. This work provides a summary of today’s knowledge about surgical procedures for end-stage heart failure.

OBJECTIVES The study evaluated a nonsurgical means of intramyocardial cell introduction using the coronary venous system for direct myocardial access and cell delivery. BACKGROUND Direct myocardial cell repopulation has been proposed as a potential method to treat heart failure. METHODS We harvested bone marrow from Yorkshire swine (n = 6; 50 to 60 kg), selected culture-flask adherent cells, labeled them with the gene for green fluorescence protein, expanded them in culture, and resuspended them in a collagen hydrogel. Working through the coronary sinus, a specialized catheter system was easily delivered to the anterior interventricular coronary vein. The composite catheter system (TransAccess) incorporates a phased-array ultrasound tip for guidance and a sheathed, extendable nitinol needle for transvascular myocardial access. A microinfusion (IntraLume) catheter was advanced through the needle, deep into remote myocardium, and the autologous cell-hydrogel suspension was injected into normal heart. Animals were sacrificed at days 0 (n = 2), 14 (n = 1, + 1 control/collagen biogel only), and 28 (n = 2), and the hearts were excised and examined. RESULTS We gained widespread intramyocardial access to the anterior, lateral, septal, apical, and inferior walls from the anterior interventicular coronary vein. No death, cardiac tamponade, ventricular arrhythmia, or other procedural complications occurred. Gross inspection demonstrated no evidence of myocardial perforation, and biogel/black tissue dye was well localized to sites corresponding to fluoroscopic landmarks for delivery. Histologic analysis demonstrated needle and microcatheter tracts and accurate cell-biogel delivery. CONCLUSIONS Percutaneous intramyocardial access is safe and feasible by a transvenous approach through the coronary venous system. The swine offers an opportunity to refine approaches used for cellular cardiomyoplasty.