Association between a cell-seeded collagen matrix and cellular cardiomyoplasty for myocardial support and regeneration.

The objective of cellular cardiomyoplasty is to regenerate the myocardium using implantation of living cells. Because the extracellular myocardial matrix is deeply altered in ischemic cardiomyopathies, it could be important to create a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We evaluated the potential of a collagen matrix seeded with cells and grafted onto infarcted ventricles. A myocardial infarction was created in 45 mice using coronary artery ligation. Animals were randomly assigned to 4 local myocardial treatment groups. Group I underwent sham treatment (injection of cell culture medium). Group II underwent injection of human umbilical cord blood mononuclear cells (HUCBCs). Group III underwent injection of HUCBCs and fixation onto the epicardium of a collagen matrix seeded with HUCBCs. Group IV underwent fixation of collagen matrix (without cells) onto the infarct. Echocardiography was performed on postoperative days 7 and 45, followed by histological studies. Echocardiography showed that the association between the cell-loaded matrix and the intrainfarct cell implants was the most efficient approach to limiting postischemic ventricular dilation and remodeling. Ejection fraction improved in both cell-treated groups. The collagen matrix alone did not improve left ventricular (LV) function and remodeling. Histology in Group III showed fragments of the collagen matrix thickening and protecting the infarct scars. Segments of the matrix were consistently aligned along the LV wall, and cells were assembled within the collagen fibers in large populations. Intramyocardial injection of HUCBCs preserves LV function following infarction. The use of a cell-seeded matrix combined with cell injections prevents ventricular wall thinning and limits postischemic remodeling. This tissue engineering approach seems to improve the efficiency of cellular cardiomyoplasty and could emerge as a new therapeutic tool for the prevention of adverse remodeling and progressive heart failure.

Vien Tim Institut du Coeur: Success of a Congenital Heart Disease Center in a Developing Country.

OBJECTIVE: The goal of the Vien Tim Institute du Coeur is to provide high quality cardiac surgical care to the Vietnamese population with 25% of care allocated to the indigent. This article discusses the history; functional and financial implementation of creating a long-term fully sustainable adult and pediatric cardiac surgery center in Southeast Asia in a developing country. METHODS: The Institut du Coeur in Ho Chi Minh City, Vietnam is a fully functional and financially solvent cardiac surgery center that was formed 28 years ago. It was borne from the Alain Carpentier Foundation which oversees its activity and the Centre Médical International which is an outpatient clinic in Ho Chi Minh City and continues to financially support and oversee the development and future of the Institute. This article details many of the key components to the development of this sustainable program and its evolution. RESULTS: Since 1996, over 25,000 patients with complicated adult and congenital cardiac disease have been treated at the infirmary with support from the Alain Carpentier Foundation since it was established in 1992. The hospital has also performed surgery and treatment to poor patients across Vietnam with over 6,700 impoverished patients having had free operations with an estimated cost of VND230 billion (US$10.2 million). In addition, 96 surgeons and nearly 500 medical staff have carried out charitable health checks on 12,000 patients in many provinces and cities throughout Vietnam. Through profit sharing with the Centre Médical International and corporate and personal donations, proceeds are given to the Institute to help perform roughly 25% of all cardiac surgery free of charge to indigent patients in need of congenital heart surgery. CONCLUSION: The Vien Tim Institute du Coeur has stayed true to its goal of offering high quality cardiac surgical care including congenital heart surgery to a large patient population with one quarter directed to the medically indigent. It also continues to empower and train the health care professionals locally and throughout the country. Creation and growth through this model may help provide a fully functional and financially self-sustaining institution in a developing nation.

Cardiomyoplasty: ventricular reconstruction after tumor resection.

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.

Angiogenic growth factors and/or cellular therapy for myocardial regeneration: a comparative study.

BACKGROUND: Locally delivered angiogenic growth factors and cell implantation have been proposed for patients with myocardial infarcts without a possibility of percutaneous or surgical revascularization. The goal of this study was to compare the effects of these techniques in an experimental model of myocardial infarct. METHODS: Left ventricular myocardial infarction was created in 27 sheep by ligation of 2 coronary arteries. Three weeks after creation of the infarct, animals were randomized into 4 groups. In group 1, sheep received a culture medium injection to the infarct area (control group); group 2 underwent autologous myoblast implantation; group 3 received vascular endothelial growth factor; and group 4 received injection of both vascular endothelial growth factor and myoblasts. Evaluation included serum troponin IC levels, echocardiography (2-dimensional and color kinesis), and immunohistologic studies for quantitative analysis of capillaries (3 months after surgery). RESULTS: Four animals died of refractory ventricular fibrillation during myocardial infarction; 2 died after surgery because of stroke and 2 because of infections. Serum troponin increased to 45.6 +/- 4.7 ng/mL at postinfarction day 2. Echocardiography at 3 months showed a significant limitation of left ventricular dilation in the cell group (57 +/- 11.1 mL) and in the cell plus vascular endothelial growth factor group (58.6 +/- 6.6 mL: control group, 74.4 +/- 11.2 mL; vascular endothelial growth factor group, 68.1 +/- 3.4 mL). Color kinesis echography showed important improvements of regional fractional area change in the cell group (from 13.6% +/- 0.8% to 21.1% +/- 1.5%) and in the cell plus vascular endothelial growth factor group (from 12.8% +/- 0.9% to 18.7% +/- 2.3%). The number of capillaries increased in the peri-infarct region of the vascular endothelial growth factor group (1036 +/- 75: control group, 785 +/- 31; cell group, 830 +/- 75; cell plus vascular endothelial growth factor group, 831 +/- 83). CONCLUSIONS: In the cell therapy groups, regional ventricular contractility improved and heart dilatation was limited compared with either vascular endothelial growth factor or control; thus, postischemic remodeling was reduced. Angiogenesis was demonstrated in the vascular endothelial growth factor group, without improvement of ventricular function and remodeling. To improve local conditions for cell survival, further studies are warranted on prevascularization of myocardial scars with angiogenic therapy.

Growth factors improve latissimus dorsi muscle vascularization and trophicity after cardiomyoplasty.

BACKGROUND: Dynamic cardiomyoplasty consists of wrapping the electrostimulated latissimus dorsi muscle (LDM) around the failed heart. Partial ischemia followed by atrophy of the middle and distal part of the LDM were observed in 30% of clinical cases after LDM flap elevation from its origin. In the current study, we hypothesized that local administration of growth factors at the LDM/epicardial interface could improve muscle vascularization and trophicity. METHODS: In 24 sheep, dynamic cardiomyoplasty was performed using the left LDM. A multiperforated catheter was positioned at the LDM/epicardial interface for a weekly administration, during a 1-month period, of the following factors: basic fibroblast growth factor (bFGF, n = 6), vascular endothelial growth factor (VEGF, n = 6), and regenerating agent (RGTA, n = 6). Six sheep injected with phosphate-buffered saline (used for dilution of the growth factors) were used as a control group. At 3 months, angiographic, histologic, and histomorphometric studies were performed. RESULTS: Angiographic studies of the animals treated with growth factors demonstrated hypervascularization due to the development of new vessels. Histomorphometric and histologic studies showed a significant increase in the number of capillaries and arterioles (100 fields/muscle) in the groups treated with bFGF (443.0 +/- 101.2, p < 0.01), RGTA (293.2 +/- 29.3, p < 0.05), and VEGF (246.5 +/- 45.9, p < 0.05), as compared with the control group (81.5 +/- 11.4). A significantly lower atrophy score was observed in the groups treated with bFGF (1.4 +/- 0.18, p < 0.05), RGTA (1.59 +/- 0.17, p < 0.05), and VEGF (1.96 +/- 0.14, NS), as compared with the control group (2.48 +/- 0.16). CONCLUSIONS: Local administration at the heart/muscle interface of growth factors increases muscle vascularization and avoids muscle atrophy in an experimental cardiomyoplasty model, both of which are advantageous to the contracting LDM. The local growth factors delivery system used in this study appears efficient, easy to implant, and manipulate and safe.

Long-term evaluation of the replacement of the trachea with an autologous aortic graft.

BACKGROUND: Tracheal reconstruction after extensive resection remains a challenge in thoracic surgery. The goal of this experimental study was to analyze the long-term evolution of tracheal replacement using an autologous aortic graft. METHODS: In 21 sheep, a 5-cm segment of the cervical trachea was replaced by a segment of the descending thoracic aorta that was reconstructed to a prosthetic graft. Because of the airway collapse reported in a previous series, a permanent (n = 13) or temporary (n = 8) stent was systematically placed in the lumen of the graft. Clinical, bronchoscopic, and histologic examinations were performed up to 3 years after implantation. RESULTS: All animals survived the operation with no paraplegia. In the group with a permanent stent, three complications occurred: one stent displacement, one laryngeal edema, and one infection. Stent removal was tolerated after 6 months in the group with a temporary stent. Histologic examination showed a progressive transformation of the arterial segment into first extensive inflammatory tissue with a squamous epithelium, and after 6 to 36 months well-differentiated tracheal tissue including a continuous mucociliary epithelium and regular rings of newly formed cartilage. CONCLUSIONS: An autologous aortic graft used as a substitute for extensive tracheal replacement in sheep remained functional for periods up to 3 years. The progressive transformation of the graft into a structure resembling tracheal tissue seems to be a key factor in long-term patency. The mechanism of this regenerative process and the possibility of using arterial homografts, which would make clinical application easier, remain to be evaluated.

Cellular cardiomyoplasty: clinical application.

Myocardial regeneration can be induced with the implantation of a variety of myogenic and angiogenic cell types. More than 150 patients have been treated with cellular cardiomyoplasty worldwide, 18 patients have been treated by our group. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility. Techniques for skeletal myoblasts culture and ex vivo expansion using autologous patient serum (obtained from plasmapheresis) have been developed by our group. In this article we propose (1) a total autologous cell culture technique and procedures for cell delivery and (2) a clinical trial with appropriate endpoints structured to determine the efficacy of cellular cardiomyoplasty.

Right ventricular cardiomyoplasty: 10-year follow-up.

BACKGROUND: Chronically depressed right ventricular (RV) function presents an unsolved therapeutic challenge in cardiac surgery. Despite recent advances in medical and surgical therapies, prognosis remains poor and patient's quality of life and mortality are frequently unacceptable. The aim of this study is to present the first clinical report and long-term results of RV dynamic cardiomyoplasty applied in patients with RV failure caused by isolated RV cardiomyopathies. METHODS: Seven consecutive patients (5 males, 2 females; mean age, 40 +/- 9 years; range, 15 to 63 years) from a series of 113 cardiomyoplasty procedures performed at Broussais and Pompidou Hospitals were evaluated. The mean duration of follow-up was 10 +/- 3.5 years. All patients had predominant RV dysfunction, associated with tricuspid regurgitation in 6 patients. The cause of RV failure was arrhythmogenic cardiomyopathy (4 patients), ischemic (2 patients), and Uhl's disease (1 patient), and endomyocardial fibrosis (1 patient). Six patients were in preoperative New York Heart Association functional class III and 1 was in intermittent class III/IV. The mean preoperative ejection fraction (measured by isotopic technique) was 18% +/- 5.7% for the right ventricle and 40% +/- 13% for the left ventricle. Right ventricular dynamic cardiomyoplasty consists of wrapping the RV free walls with the left latissimus dorsi muscle flap. The distal part of the latissimus dorsi muscle is fixed to the diaphragm and then electrostimulated. Six patients required associated tricuspid valve surgery. RESULTS: There were no perioperative deaths. The mean duration of follow-up was 10 +/- 3.5 years. Six patients are alive with a remarkable quality of life, 4 are in New York Heart Association functional class I and 2 are in class II. One patient who was in New York Heart Association functional class II died in postoperative year 7 caused by stroke. At last follow-up, mean RV ejection fraction was 33% +/- 11.8% and left ventricular ejection fraction was 52% +/- 12.6%. CONCLUSIONS: The results of this long-term study demonstrate hemodynamic and functional improvements after RV cardiomyoplasty without perioperative mortality, no long-term malignant arrhythmias, and RV dysfunction related deaths. We believe that RV cardiomyoplasty, associated with tricuspid valve surgery when required, could be an effective treatment for severe RV failure.

Partial replacement of the tricuspid valve by mitral homografts in acute endocarditis.

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.

Aortic cusp extension valvuloplasty for rheumatic aortic valve disease: midterm results.

BACKGROUND: The surgical management of rheumatic aortic insufficiency in the young remains problematic owing to the drawbacks of prosthetic valve replacement at this age. In young foreign patients, for whom long-term anticoagulation therapy is unavailable, we have used a glutaraldehyde preserved autologous pericardium cusp extension technique to repair rheumatic aortic valve insufficiencies resulting from cusp retractions. METHODS: From September 1992 to December 2000, 89 consecutive patients with a mean age of 16 +/- 5 years underwent triple pericardial aortic cusp extension valvuloplasty. Eighty patients had pure aortic insufficiency, 9 had mixed aortic disease. Twenty-nine patients (33%) had isolated aortic valve disease and 60 patients (69%) had combined aortic and mitral valve disease with significant tricuspid valve disease in 21 (24%). Aortic repair consisted of free edge aortic cusp extension using three rectangular strips of glutaraldehyde stabilized autologous pericardium. Twenty-nine patients (33%) underwent an isolated aortic repair, 39 patients (44%) underwent combined aortic and mitral procedures (34 mitral repairs, 3 mitral homografts, and 2 prosthesis replacements), and 21 patients (23%) underwent a triple valve repair. RESULTS: The hospital mortality was 2.2%. Primary failure of the aortic repair requiring immediate reoperation occurred in 2 patients. During follow-up (mean of 62 +/- 22 months) 1 patient died and 7 underwent redo valvular surgery. At 5 years the actuarial survival rate was 96.4%, and 92.1% of the patients were free from redo valvular surgery. At 7 years 90% of the patients were free from valve-related complications. Among the 76 patients free from redo valvular surgery at follow-up, 6 had deterioration of the repair resulting in grade II aortic and mitral insufficiencies. CONCLUSIONS: Our midterm results of glutaraldehyde stabilized autologous pericardial aortic cusp extension are encouraging and suggest that this technique should be considered as a viable alternative palliative procedure in a young rheumatic population, allowing for growth of the annulus and delaying to a less critical period the need for the lifelong anticoagulation therapy required for a prosthetic mechanical valve.

Prosthetic valve selection for middle-aged patients with aortic stenosis.

Choosing the optimal aortic valve prosthesis for middle-aged patients (late 40s to early 60s) with aortic stenosis presents a challenge. The available options all have substantial drawbacks that must be considered in the decision-making process. Current data indicate that there is little or no difference in survival between mechanical and bioprosthetic aortic valve replacement in middle-aged patients at 10-15 years after surgery. Patients who receive a mechanical valve replacement have an annual risk of major hemorrhagic or embolic events of 2-4% per year for life compared with about 1% per year for patients who have a bioprosthetic valve. However, bioprostheses are associated with an increasing risk of structural valve degeneration from 10 years postimplantation, and most patients will require reoperation if they survive much longer than a decade. The mortality risk associated with reoperation is similar to that of primary surgery for most patients, and does not seem to impact on the 15-year survival in this patient group. The Ross procedure, in which the aortic valve is replaced with a pulmonary autograft, can provide improved freedom from morbidity, but operative mortality is probably double that of isolated aortic valve replacement and most patients will require reoperation. Informed patient choice is the most important factor in deciding which valve to use, with biological valves increasingly favored over mechanical valves in middle-aged patients.

Cardiac bioassist: results of the French multicenter cardiomyoplasty study.

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.

Results and predictors of early and late outcome of coronary artery bypass graft surgery in patients with ejection fraction less than 20%.

BACKGROUND: Severely depressed left ventricular ejection fraction (EF9%) was significantly greater in the group with EF less or equal to 20% (49%) than in the group with EF above 20% (20%). EF less or equal to 20% was not shown by multivariable logistic regression analysis to be an independent predictor of operative mortality. Survival rates at one year were 85+/-2.8%, 93+/-0.9%, and 98%+/-0.3% for patients with EF less or equal to 20%, over 20-40% and greater than 40% respectively; and at five years: 72+/-0.4%, 81+/-0.2% and 89+/-0.1%, respectively (p<0.001). CONCLUSION: We demonstrate acceptable mortality rates in patients with an EF less or equal to 20%, and show that EF less or equal to 20% does not appear to be an independent predictor of hospital mortality in our practice. Incremental changes in practice including improved patient selection and peroperative management may have reduced the impact of EF less or equal to 20% on mortality following CABG.

MRI evaluation of local myocardial treatments: epicardial versus endocardial (Cell-Fix catheter) injections.

AIMS: We compared two procedures for local myocardial treatment: transepicardial versus transendocardial catheter injection. Transepicardial injections were performed under direct surgical visualization whereas transendocardial injections were performed using electrophysiological guidance. METHODS: A left ventricle (LV) myocardial infarction (MI) was surgically created in 14 sheep. At 3 months, gadolinium was injected IV followed by the injection of super paramagnetic iron oxide (SPIO) into MI. Animals were divided in two groups: transepicardial injection (Group I) versus transendocardial (Group II) using "Cell-Fix" catheter injection. This catheter was developed to identify by electrophysiology the infarcted area and to stabilize injections suctioning the device to the endocardium. Postgadolinium delayed-enhancement magnetic resonance imaging (MRI) was performed to stain the infarct size. SPIO injections were used to assess the magnitude of the treated area. The ratio between SPIO black stained treatment areas and white gadolinium stained infarcted areas was calculated using MRI. RESULTS: The electrophysiological recordings by the catheter for the MI versus normal LV wall were: R wave amplitude 4.16 versus 12.08 mV (P = 0.003), slew rate (slope of the signal) 0.36 V/s versus 1.04 V/s (P = 0.008). The ratio of the SPIO diffusion into the MI was 41.2 +/- 8.1% for surgical and 63.7 +/- 8.2% for percutaneous endocardial injections (P = 0.0132). CONCLUSION: MRI allows evaluation of the extent of local myocardial treatments. The differences shown between epicardial and endocardial injections concerning the distribution of SPIO can be justified by the methodology of injection and by a more precise MI detection by electrophysiology. In conclusion, electrophysiological recordings to guide injections is superior to direct surgical visualization in terms of injecting into infarcted tissue.

Tracheal regeneration following tracheal replacement with an allogenic aorta.

BACKGROUND: Tracheal replacement remains an unsolved surgical problem. Attempts to use tracheal substitutes have failed to achieve reliable results. In this study, tracheal regeneration was obtained after tracheal replacement with an allogenic aorta. METHODS: Twenty female sheep underwent a 8-cm tracheal replacement with a fresh aortic allograft. In the six last animals, aortic grafts came from male sheep. A stent prevented airway collapse. No immunosuppressive therapy was used. Aortic segments were retrieved at regular intervals up to 16 months. A polymerase chain reaction for the SRY gene was performed in specimens with aortic grafts from male sheep. RESULTS: All animals but one survived the operation without complications. Clearly identified between the suture lines, the aortic segments were completely transformed into a tracheal structure. Histology showed initially an inflammatory reaction with proliferation of a squamous epithelium followed by mucociliary epithelium and newly formed cartilage rings. SRY gene was not found in newly formed cartilage rings showing that the regeneration originated from recipient cells. CONCLUSIONS: This study presents a new type of tissue regeneration and brings hopes to the treatment of extensive tracheal lesions.