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From the first success in cultivation of cells in vitro, it became clear that developing cell and/or tissue specific cultures would open a myriad of new opportunities for medical research. Expertise in various in vitro models has been developing over decades, so nowadays we benefit from highly specific in vitro systems imitating every organ of the human body. Moreover, obtaining sufficient number of standardized cells allows for cell transplantation approach with the goal of improving the regeneration of injured/disease affected tissue. However, different cell types bring different needs and place various types of hurdles on the path of regenerative neurology and regenerative cardiology. In this review, written by European experts gathered in Cost European action dedicated to neurology and cardiology-Bioneca, we present the experience acquired by working on two rather different organs: the brain and the heart. When taken into account that diseases of these two organs, mostly ischemic in their nature (stroke and heart infarction), bring by far the largest burden of the medical systems around Europe, it is not surprising that in vitro models of nervous and heart muscle tissue were in the focus of biomedical research in the last decades. In this review we describe and discuss hurdles which still impair further progress of regenerative neurology and cardiology and we detect those ones which are common to both fields and some, which are field-specific. With the goal to elucidate strategies which might be shared between regenerative neurology and cardiology we discuss methodological solutions which can help each of the fields to accelerate their development.

Currently, the clinical impact of cell therapy after a myocardial infarction (MI) is limited by low cell engraftment due to significant cell death, including apoptosis, in an infarcted, inflammatory, poor angiogenic environment, low cell retention and secondary migration. Cells interact with their environment through integrin mechanoreceptors that control their survival/apoptosis/differentiation/migration/proliferation. Optimizing these interactions may be a way of improving outcomes. The association of free cells with a 3D-scaffold may be a way to target their integrins. Collagen is the most abundant structural component of the extracellular matrix (ECM) and the best contractility levels are achieved with cellular preparations containing collagen, fibrin, or Matrigel (i.e. tumor extract). In the interactions between cells and ECM, 3 main proteins are recognised: collagen, laminin and RGD (Arg-Gly-Asp) peptide. The RGD plays a key role in heart development, after MI, and on cardiac cells. Cardiomyocytes secrete their own laminin on collagen. The collagen has a non-functional cryptic RGD and is thus suboptimal for interactions with associated cells. The use of a collagen functionalized with RGD may help to improve collagen biofunctionality. It may help in the delivery of paracrine cells, whether or not they are contractile, and in assisting tissue engineering a safe contractile tissue.

Prevention of postischaemic ventricular dilatation progressing towards pathological remodelling is necessary to decrease ventricular wall deterioration. Myocardial tissue engineering may play a therapeutic role due to its capacity to replace the extracellular matrix, thereby creating niches for cell homing. In this experimental animal study, a biomimetic cardiopatch was created with elastomeric scaffolds and nanotechnologies.

Background . Seven patients with acute tricuspid endocarditis underwent partial replacement of the tricuspid valve using mitral homograft tissue. Valve function was evaluated at midterm. Methods . Operative indications were uncontrolled sepsis in all cases associated with heart failure symptoms in 3 patients and septic pulmonary emboli in 2 patients. These patients were referred to our institution after a course of antibiotic treatment ranging from 7 to 12 weeks. Lesions found at the level of the anterior leaflet of the tricuspid valve were vegetations and rupture of more than half of the marginal cords in all patients. Vegetations were also found on the posterior leaflet in 5 patients. In all instances the septal leaflet was free of lesions. The aortic valve was involved in 4 patients and the pulmonary valve in 1 patient. All patients underwent resection of the anterior and posterior leaflets of the tricuspid valve with their corresponding papillary muscles leaving the septal leaflet in place. Replacement of the tricuspid valve was performed through a right longitudinal atrial access, using the anterior leaflet of a mitral homograft alone in 3 patients and the anterior leaflet with part of posterior leaflet in 4 patients. Associated procedures included aortic valve replacement by a homograft (n = 4) and pulmonary valve reconstruction (n = 1). Results . No hospital deaths are reported. One late death, at 16 months, is reported after reoperation due to recurrent aortic valve endocarditis. At midterm (mean follow-up, 30 months) patients had excellent functional status and normal valvular function during echocardiographic studies. Conclusions . We conclude that when the degree of tricuspid valve destruction prevents repair, partial homograft replacement can be used as an extension of the already existing reconstructive techniques, with excellent functional results.

Objective: Although cardiac transplantation has been performed for complete removal of ventricular tumors, complete surgical resection with ventricular reconstruction is desirable. Thus patients with benign tumors would probably be cured, and those with malignant tumors would have a better prognosis. In this study extensive and complete surgical resection of ventricular tumors is followed by anatomic and functional ventricular reconstruction with a dynamic cardiomyoplasty procedure. Methods: Seven patients (mean age, 32.7 years) underwent complete resection of ventricular tumors. Histologic types were distributed as follows: fibroma in 2 patients and sarcoma, lymphosarcoma, hemangioma, lipoma, and metastatic angiosarcoma, respectively, in the remaining 5 patients. Six of the patients were considered candidates for heart transplantation because of the extent of tumor invasion. Surgery consisted of 4 steps: (1) tumor resection; (2) coronary artery resection (when invaded by the tumor) and coronary artery bypass grafting; (3) valvular reconstruction (when possible) or replacement; and (4) ventricular wall reconstruction with a pericardial patch for closure of the ventricular defect (neoendocardium) covered by the electrostimulated latissimus dorsi muscle flap (neomyocardium). Results: All patients survived surgical intervention, but 2 late postoperative deaths are reported. Among the surviving patients, early complications played a major role in their postoperative course and consisted of arrhythmias, atrioventricular block necessitating a dual-chamber pulse generator, respiratory insufficiency, and heart failure. Two patients were assisted postoperatively with an intra-aortic balloon pump. On postoperative follow-up (mean, 72.4 ± 8.5 months), an improvement in the patients' functional status was observed. Patients moved from a mean New York Heart Association functional class of 2.8 to a mean functional class of 1.2. Conclusions: The excellent long-term evolution without recurrence, ventricular dysfunction, and/or thromboembolic complications implies that cardiomyoplasty could be recommended as an alternative to heart transplantation for the therapy of large ventricular tumors. J Thorac Cardiovasc Surg 2002;123:889-94

Objectives: Cellular cardiomyoplasty refers to the implantation of autologous skeletal muscle cells into the myocardium to reinforce its structure and function. In this study a reproducible method for the creation of a myocardial lesion was developed. The functional benefit of cell implantation was evaluated by 2-dimensional echocardiography for global contraction and color kinesis echocardiography, which allows the precise assessment of the regional contraction. Methods: A left ventricular intramyocardial injection with snake cardiotoxin was carried out on a sheep model to induce a well-delineated transmural lesion. Three weeks later, the lesion was assessed by echocardiography. Thereafter, autologous skeletal muscle cells or culture media (control) were injected into the lesion. Two months after cell implantation, the myocardial contraction was again evaluated by echocardiography and the implanted cells were analyzed by a fast myosin heavy chain antibody. Results: 1. The snake cardiotoxin produced a well-delineated transmural lesion in all animals. 2. Echocardiographic studies showed a significant improvement in global and regional left ventricular function in cell-treated sheep. 3. Histologic analyses demonstrated satellite cell survival at the periphery of the lesions. Conclusion: Satellite cells implanted in a cardiotoxin-induced myocardial lesion survived for a 2-month period and were associated with a significant functional improvement of both local and global contraction. (J Thorac Cardiovasc Surg 2001;121:871-8)

Tracheal reconstruction after extensive resection remains an unsolved surgical problem. Numerous attempts have been made using tracheal grafts or prosthetic conduits with disappointing results. In this study, we propose a new alternative using an aortic autograft as tracheal substitute. In a first series of experiments, a half circumference of two rings was replaced with an autologous carotid artery patch. In a second series, a complete segment of trachea was replaced with an autologous aortic graft supported by an endoluminal tracheal stent. No dehiscence or stenosis was observed. Microscopic examinations at 3 and 6 months showed the replacement of the aortic tissue by tracheal tissue comprising neoformation of cartilage and mucociliary or non-keratinizing metaplastic polystratified squamous epithelium. Although these results need to be confirmed by a larger series of experiments, they showed that a vascular tissue placed in a different environment with a different function can be submitted to a metaplastic transformation which tends to restore a normal structure adapted to its new function. These remarkable findings offer new perspectives in tracheal reconstruction in human.

Methods: To analyze the long-term outcome of dynamic cardiomyoplasty, we retrospectively studied 127 consecutive patients who underwent this procedure in Paris, France (n = 76), São Paulo, Brazil (n = 37), and Portland, Oregon (n = 14). Preoperative data were collected for patients operated on between January 1985 and June 1994 and examined with respect to effect on long-term survival. Patients had a mean age of 50 ± 13 years and were predominantly male (82%). In 46% the cause of disease was ischemic. Concomitant operations were performed in 22 patients. Results: Operative mortality was 12% (15/127). Kaplan-Meier survival ± standard error at 1 through 5 years was 73% ± 4%, 57% ± 5%, 49% ± 6%, 44% ± 6%, and 40% ± 7%, respectively. There was a distinct improvement at 6 months in New York Heart Association functional class (3.2 ± 0.05 vs 1.7 ± 0.07, p < 0.0001) and a small but significant increase in left ventricular ejection fraction (20% ± 0.8% vs 23% ± 1.5%, p = 0.04). Ninety-day mortality was associated with low right ventricular ejection fraction, a blunted hemodynamic response to exercise testing, and requirement for an intraaortic balloon pump at the time of the operation. Using a stepwise Cox regression method of multivariable survival analysis (n = 101), we determined that atrial fibrillation, New York Heart Association class IV, high pulmonary capillary wedge pressure, and balloon pump use were independent variables simultaneously associated with poor overall survival. When metabolic testing variables were added to this model, peak oxygen consumption eliminated both pulmonary capillary wedge pressure and functional class from the model, albeit with fewer (n = 74) patients. Conclusion: Dynamic cardiomyoplasty is an evolving therapy for symptomatic congestive heart failure, the results of which may be enhanced by intelligent, risk-sensitive patient selection. (J Thorac Cardiovasc Surg 1996;112:1640-50)

Aortomyoplasty consists of wrapping the latissimus dorsi muscle (LDM) around the ascending aorta and electrostimulating it during diastole. The ascending aorta will act as an ectopic neo-ventricle compressed during diastole, thus reproducing the effects of longterm diastolic counterpulsation. In 5 goats, the right LDM was transferred to the thoracic cavity after removal of the second rib. The ascending aorta was enlarged by a pericardial patch and wrapped with the LDM. Postoperative electrostimulation was delivered in a counterpul-sating manner. Hemodynamic studies were performed at 12 and 24 months postoperatively. Percent increase in the subendocardial viability index (diastolic pressure-time index/systolic tension-time index) was calculated using unassisted and assisted cardiac cycles with the stimulator off versus the stimulator on at a 1:1 ratio in the basal state and after acute heart failure was induced by the administration of high doses of propranolol hydrochloride. Diastolic counterpulsation of the ascending aorta resulted in significant improvement in the subendocardial viability index long term, both in basal state conditions and after induced cardiac failure. During heart failure, aortomyoplasty increased the cardiac output and decreased systemic vascular resistance. Histopathologic studies up to 24 months showed preservation of the histologie structure of the aortic wall and no evidence of thromboembolism. Tight adhesions developed between the aortic wall (including the pericardial patch) and the LDM. The diameters of the enlarged aortas showed no significant differences compared with diameters immediately postoperatively. In conclusion, aortomyoplasty produces chronic diastolic augmentation with preservation of aortic structure. After induction of heart failure, aortomyoplasty offers efficient circulatory support.

We describe a technique for mechanical cardiac assistance in an acute model of severe cardiac failure. Cardiac dysfunction was induced by a high dose of halothane in 13 dogs. Seven served as controls. Following median sternotomy, a pneumatically driven device was implanted in the other six dogs in a para-aortic position, using a simple surgical technique without cardiopulmonary bypass. The aorta was cross-clamped during cardiac assistance. During hemodynamic studies, the seven control animals with induced cardiac failure showed high end-diastolic left ventricular and right atrial pressures with low cardiac index and systolic left ventricular and aortic pressures. All dogs in this group died within 30 minutes. Use of a monovalvular cardiac assist device in the experimental group of six dogs to pump blood from the aortic root to the descending aorta in a counterpulsation manner, confirmed good preservation of systemic hemodynamic parameters after induction of heart failure. All animals in this treated group survived more than 45 minutes. Hemodynamically, the device acts as a new ventricle and the impaired left ventricle functionally becomes a left atrium. This condition is clinically appropriate for recovery of left ventricular function in severe acute myocardial failure.

Preliminary experimental studies in our laboratory have shown that autologous pericardium treated with glutaraldehyde prevents late deterioration and calcification of the tissue. For this reason, glutaraldehyde-treated autologous pericardium has been used in a series of 64 patients who underwent operations for leaflet extension of the mitral valve between 1980 and 1989. Ages ranged from 2.5 to 60 years (mean 19 +/- 15). The causes of mitral valve insufficiency were rheumatic fever (69%), bacterial endocarditis (17%), congenital (8%), endomyocardial fibrosis (4.5%), and trauma (1.5%). The autologous tissue was fixed in a 0.62% glutaraldehyde solution for 15 minutes and rinsed in saline for an additional 15 minutes. Patching techniques varied depending on the site and the extent of the lesion. Associated mitral valve repair techniques (Carpentier's techniques) were mandatory in all patients. The period of follow-up extended from 6 months to 9 years (mean 3.1 +/- 2.5 years). There were no operative deaths in this series, and there was one late death (2%). In the six patients (12%) who underwent reoperation, there has been no case of calcification of the pericardial patch. Postoperative mitral valve function was assessed by bidimensional color Doppler echocardiographic techniques. Mitral valve insufficiency was trivial or absent in 80% of the patients. This experience permits us to conclude that leaflet extension is a simple and safe technique in valve reconstruction, allowing repair of mitral valves that otherwise would need to be replaced. It permits use of an adult-size prosthetic ring in children. Glutaraldehyde-treated autologous pericardium is the material of choice for this type of repair.

Mitral valve replacement, using a cryopreserved mitral homograft, was performed in a 49-year-old patient with calcified mitral stenosis. Postoperative course was uneventful. Transesophageal echocardiography performed 6 months later showed normal function of the mitral homograft.

Background. Presently the only clinical method of skeletal muscle augmentation of the heart is achieved by wrapping muscle around the cardiac ventricles and then stimulating the muscle to contract synchronously with cardiac systole. Intraaortic balloon counterpulsation provides diastolic counterpulsation in the short-term with the known benefits of increasing diastolic pressure and reducing ventricular afterload. Using protocols already in existence for dynamic cardiomyoplasty we have investigated the long-term use of extraaortic skeletal muscle-powered counterpulsation. Methods. In five alpine goats the right latissimus dorsi muscle (LDM) was used to achieve a wrap around the ascending aorta, which had been augmented with an elliptic pericardial patch. Electrostimulation protocols were commenced after 2 weeks and continued for 12 to 24 months. At this time baseline, hemodynamic measurements were made with and without stimulation of the LDM. Acute cardiac depression was induced and further measurements were made, again with and without stimulation of the LDM. Results. Results in the basal state demonstrated improvement in all parameters with stimulation and a 23% increase of the subendocardial viability index. After induction of cardiac depression there was a 52% increase in cardiac output, 39% decrease in systemic vascular resistance, and 27% increase in subendocardial viability index. Histologic studies demonstrated tight adhesion between the aortic wall and the LDM, no dilatation of the aortic wall, and no deleterious effects in the aortic wall of the chronic intermittent constriction. Histochemical staining demonstrated transformation of the muscle fibers of the LDM flap into type 1 oxidative muscle fibers. Conclusions. In conclusion, our present study demonstrates that in this animal model aortomyoplasty produces a chronic counterpulsation with preservation of aortic architecture. With induction of heart failure aortomyoplasty provided an effective means of cardiac assistance. The use of the ascending aorta to achieve diastolic counterpulsation may be an efficient use of skeletal muscle energy to augment the heart in selected clinical cases. Early clinical experience is described in this article.

Background. Intraaortic and pulmonary artery counterpulsation are useful techniques to support circulation during either left or right ventricular dysfunction. Electrically stimulated skeletal muscles wrapped around the aorta, used as means of cardiac failure treatment, have proved to be an effective method of handling experimental left ventricular failure. In this article we report an induced cardiac failure model in acute open chest dogs and describe the hemodynamic improvement of simultaneous aortic and pulmonary artery counterpulsation. Methods. This was achieved with a bilateral latissimus dorsi muscle flap, stimulated with a software written in C++ for Windows. Dynamic aortomyoplasty was performed using the left latissimus dorsi muscle flap around the descending aorta, and dynamic pulmonaromyoplasty was achieved wrapping the pulmonary trunk with the right latissimus dorsi muscle flap. In all animals blood pressures and cardiac output were measured after cardiac failure induced by a high-dose of propranolol hydrochloride (3 mg/kg intravenously) before and after latissimus dorsi muscle flap stimulation. Results. Aortopulmonary counterpulsation resulted in a significant increase in mean aortic pressure, mean pulmonary pressure, and cardiac output. In addition, a significant decrease was observed in end-diastolic left ventricular pressure, systemic vascular resistance, and pulmonary vascular resistance. Subendocardial viability index (diastolic pressure-time index/systolic tension-time index) in aortomyoplasty and tension time index in pulmonaromyoplasty showed significant improvement when cardiac assistance was performed by electrical stimulation of both muscles ( p = 0.037 and p = 0.001, respectively). Conclusions. Treatment of experimentally induced cardiac failure using aortopulmonary counterpulsation allows effective hemodynamic improvement in open-chest dogs.

J Thorac Cardiovasc Surg 2001;122:197-8

Two hundred fifty-three patients who underwent isolated mitral valve replacement with a porcine bioprosthesis had long-term evaluation. One hundred forty-seven patients received a Carpentier-Edwards porcine bioprosthesis and 106, a Hancock valve. There were no significant differences in preoperative clinical characteristics between the two groups. Cumulative follow-up was 1,375 patient-years. At 10 years, 93% +/- 2.5% of the patients in the Carpentier-Edwards group and 85% +/- 7.8% of those in the Hancock group were free from valve-related death (not significant), and 95% +/- 2% and 91% +/- 3.8%, respectively, were free from thromboembolism (not significant). At 10 years, 65% +/- 7.2% of the patients in the Carpentier-Edwards group and 66% +/- 7.2% of those in the Hancock group were free from structural valve deterioration (not significant), and 64% +/- 6% and 59% +/- 7.3%, respectively, were free from reoperation (not significant). We conclude that the first generation of Carpentier-Edwards and Hancock prostheses produce comparable long-term results in the mitral position.

Cardiomyoplasty is a new surgical technique that uses an electrostimulated skeletal muscle to reinforce or partially replace the heart muscle. Since the first clinical case performed in 1985, long-term beneficial cardiac effects of latissimus dorsi Cardiomyoplasty have been documented in patients with various myocardial diseases (ischemic, neoplastic, dilated cardiomyopathy). In this article we describe the surgical technique that we have developed to biomechanically assist severe and irreversible ventricular failure.