Bioartificial Myocardium: Dream or Reality
Department of Cardiovascular Surgery and Laboratory of Biosurgical Research,
European Hospital Georges Pompidou (HEGP), University of Paris V., Paris, France
Ischemic myocardial disease, the main cause of heart failure, is a major public health and economic problem. Given the aging population, heart failure is becoming a bigger clinical issue and bigger financial burden [1, 2]. Thus, research in heart failure is of relevant interest and importance, involving specialities as cellular and molecular biology, tissue engineering, genetics, biophysics and electrophysiology.
The recent progress in cellular and molecular biology allows the development of new therapies for heart failure. One of the most innovative consists in the transplantation of stem cells into the myocardium for heart muscle regeneration. This approach is called “cellular cardiomyoplasty” [3,4].Adult myocardium cannot effectively repair after infarction due to the limited number of stem cells. Thus, most of the injury is irreversible . For this reason, cell transplantation strategies for heart failure have been designed to replace damaged cells with cells that can perform cardiac work, either in ischemic or non-ischemic cardiomyopathy.
Grafting of healthy cells into the diseased myocardium holds enormous potential as an approach to cardiovascular pathology. The goal of cell transplantation is to grow of new muscle fibers (myogenesis) and/or to develop angiogenesis in the damaged myocardium that potentially may contribute to improve systolic and diastolic ventricular functions, and to reverse the postischemic remodeling process of the ventricular chambers .
The encouraging results of experimental studies [6-10] have opened the way to the clinical application of cellular cardiomyoplasty in patients with akinetic and non-viable post-infarction scar and low ejection fraction and in patients presenting idiopathic and chagasic cardiomyopathies [11-14]. Cultured autologous cells do not raise immunological, ethical, tumorogenesis or donor availability problems. Thus, the development of cell therapy for heart failure is progressing according to a rigorous scientific methodology, from observation to experimentation to a careful evaluation of preliminary clinical results.
Current possibilities in cell therapy for myocardial regeneration are the transplantation into the damaged myocardium of different types of stem cells as: autologous myoblasts [originating from a skeletal muscle biopsy) , bone marrow stem cells , peripheral blood stem cells , vascular endothelial cells , mesothelial cells [removed from a biopsy of the omentum) , adipose tissue stem cells , and embryonic pluripotent cells .
Tissue engineering using biological and synthetic matrix is now associated with cell therapy, the goal is to develop a bioartificial myocardium [22-27]. The MAGNUM Clinical Trial (Myocardial Assistance by Grafting a New Upgraded bioartificial Myocardium) was initiated by our group .
I. Ischemic Cardiomyopathy
Clinical application for cell transplantation should be in patients presenting a cardiac dysfunction due to an extensive myocardial infarction. The cells are generally implanted during catheter-based or surgical revascularization procedures. The objective of cellular cardiomyoplasty (CMP) is to limit infarct expansion and cardiac remodelling, and regenerate the myocardium. Patients with right ventricular myocardial infarction and with ischemic mitral valve regurgitation can also be treated with stem cells [4, 29].
II. Non-ischemic cardiomyopathies
Non ischemic dilated cardiomyopathies and Chagas disease are also major causes of heart failure, with high mortality rates [2, 13]. Cell transplantation could offer new hopes in this disease by restoring impaired heart function, since the grafted cells appear to better survive in the host myocardium because myocardial irrigation in these pathologies are not significantly impaired. Stem cells are injected after catheterization of the coronary arteries.
Mechanisms of Action
The many proposed mechanisms of action of cellular cardiomyoplasty are: reduction of the size and fibrosis of infarct scars, limitation of postischemic ventricular remodeling, improvement of ventricular wall thickening and compliance, and increase of regional myocardial contractility. When skeletal myoblasts are used for cellular CMP the sequence of actions seems to be the following: cells transplanted into the myocardium first impact on diastolic dysfunction, and subsequently when sufficiently organized in myotubes and myofibres, systolic performance improves. Bone marrow cells principally induce angiogenesis and vasculogenesis. Mesenchymal bone marrow stromal cells are of great interest, since these cells can differentiate in cardiac cells .
The technical approach used to implant the cells should influence on the efficacy of cellular CMP. Cell mortality after transplantation seems to be important when they are grafted in the center of high-fibrotic ischemic scars, since there are limitations of oxygen and nutrients supply to the chronic ischemic myocardium. Implanting the cells mainly in the peri-infarct areas may improve the rate of surviving cells, thus the size of the infarct scar undergo a centripetal reduction .
It is possible that periodically repeated cell injections should be necessary to progressively reduce the infarct scars in ischemic cardiomyopathies or to gradually improve the diseased myocardium in non-ischemic cardiomyopathies. This approach should be facilitate by the development of a new generation of specific catheters for percutaneous cell implantations .
Intracoronary and endoventricular catheter-based cell delivery procedures for therapeutic angiogenesis and myogenesis have been performed. Nevertheless, the quantity of the cells injected in the target infarcted area is unknown, despite the use of myocardial mapping to identify the pathologic myocardium. The success is largely dependent on many technical considerations namely the risk of cell « regurgitation » at the injection site and the precise localization of the post-ischemic scar and the peri-infarct areas .
A new diagnostic-therapeutic device for local myocardial treatment has been created by our group, called “CELL-FIX” catheter . This system includes a method and apparatus to identify by electrophysiology the infarcted area and to simultaneous deliver the cells, stabilizing by vacuum the scar at the moment of the cell injection. The Cell-Fix catheter includes a fixing “sucker” system to the endocardium, in the form of a suction cup. This “umbrella” may be retracted inside the exterior tube of the distal part of the catheter.
Development of Bioartificial Myocardium
The objective of cellular cardiomyoplasty is to regenerate the myocardium by the implantation of living cells. However, in ischemic disease the extracellular matrix is often disrupted or destroyed. Therefore it could be important to associate a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We are currently working to evaluate the potential of a biodegradable tridimensional matrix seeded with cells and grafted onto the infarcted ventricle .
Shortly after myocardial infarction, inflammatory cells such as neutrophils, monocytes and macrophages infiltrate the infarcted zone, and then the necrotic myocytes in the injured myocardium are replaced by collagen fibers. This process uniformly occurs in the whole infarcted area, and determines the degree of early infarct expansion. Prevention of the dilation, secondary to LV remodelling, can increase cardiac performance .
There are two types of collagen fibers in the normal adult heart, types I and III, produced by fibroblasts and myofibroblasts. The fiber type I represents 80% of collagen protein in the heart, and type III is near to 10%. These fibers provide structural support and give the heart properties that include stiffness and resistance to deformation, they have also shown an important role as a link between contractile elements of adjacent myocytes, carrying some information useful for cell function. In the infarcted zone the extracellular myocardial matrix is modified, collagen type I decreases from 80 to 40%. Experimental and clinical studies performed by our group in ischemic patients showed that bone marrow cell therapy associated with the surgical implantation onto the epicardium of a cell-seeded collagen type I matrix prevented myocardial wall thinning and limited postischemic remodelling [22, 28].
Follow up of congestive heart failure patients has mobilized a growing number of research teams over the past years. Medical treatment [particularly with ACE inhibitors combined to beta and aldosterona blockers) as well as electrophysiological procedures (multisite pacing for atrial-biventricular resynchronization) have proven to be effective, improving the prognosis of heart failure patient. However, these treatments remain palliative and a lot of cardiovascular diseases still evolve towards the deficiency of the cardiac muscle .
Cardiac transplantation remains the only curative treatment of congestive heart failure, but has remained limited in its application secondary to shortage of donated organs, age of recipients, and other strict selection criteria. Surgical alternatives for refractory heart failure such as left ventricular geometry/remodeling interventions and dynamic cardiomyoplasty also remain limited in their applicability as well [3, 32]. Cardiomyoplasty, in which the latissimus dorsi muscle is used to create a LV wrap, has been proposed by our group at the earliest 80’s, but nowadays it remains dedicated to patients with right ventricular dysfunction and relativly preserved LV function . Implantable cardiac assist devices are still in evolution, and xenotransplantation is in the early phase of research with no clinical applications as of yet [34, 35].
Historically, tissue regeneration techniques based in cell transplantation technology had been used for the treatment of hemopathies (chronic lymphocytic leukemia, aplastic anaemia, immunodeficiencies, myeloma), in ophthalmology (transplantation of limbal stem cells for corneal regeneration), and in orthopedics (implantation of chondrocytes for articular defects). Current clinical investigations concern the following specialities: endocrinology [transplantation of stem cells in diabetes mellitus], urology (myoblasts transplantation to create a neo-sphincter in women, and in men after prostatectomy for cancer), neurology (Alzheimer and Parkinson diseases, spinal cord regeneration), hepatology (implantation of hepatocytes as a bridge to liver transplantation), myology (transplantation of myoblasts in Duchenne dystrophy), in dermatology (implantation of cultured keratinocytes and fibroblasts in burned patients) and for peripheral vascular diseases (implantation of angiogenic stem cells in critical limb ischemia).
The prevalence of severe heart failure and the clear clinical limitations of conventional interventions have encouraged the development of new methods based on the regeneration of the pool of myocardial contractile cells. This approach is supported by recent advances in cellular and molecular biology. New technologies for cell implantation, derived from interventional cardiology procedures, are emerging. Intracoronary and endoventricular catheter-based cell delivery for therapeutic angiogenesis and myogenesis have been performed [14, 16, 17].
Cell transplantation is becoming recognized as a viable strategy to improve myocardial viability and limit infarct growth. The major challenges for future research programs are the pre-conditioning for pre-differentiation of stem cells before transplantation, the optimization of the rate of surviving cells after myocardial implantation associating angiogenic therapy (growth factors and/or bone marrow derived cells) [36, 37] with myogenic cells (skeletal muscle cells and bone marrow mesenchymal stem cells)  the improvement of host-cell interactions (mechanical and electrical coupling). The development of a bio-artificial myocardium is a new challenge, in this approach tissue engineered procedures are associated with cell therapy [25, 27, 39]. The MAGNUM Clinical Trial (Myocardial Assistance by Grafting a New Upgraded bioartificial Myocardium) is progressing with interesting preliminary results .
Cell-based regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction. This biological approach is particularly attractive due to the potential for myocardial regeneration with a variety of myogenic and angiogenic cell types: skeletal myoblasts, bone marrow mesenchymal stromal cells, circulating blood-derived progenitor cells, endothelial and mesothelial cells, adipose tissue stem cells, and potentially embryonic cells. Over 500 patients have been treated worldwide with cell-based procedures for myocardial regeneration. The number of surgical implantations was equivalent to those of percutaneous catheter-based procedures. There is a tendency to use bone marrow cells for myocardial regeneration since this approach avoids the 3-week cell-culture procedure and the risk of ventricular arrhythmias and sudden death observed after skeletal myoblast transplantation. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore myocardial viability .
- Jessup M, Brozena S. Heart failure. N Engl J Med. 2003; 348: 2007–2018.
- Bleumink GS, Knetsch AM, Sturkenboom MC, Straus SM, Hofman A, Deckers JW, Witteman JC, Stricker BH. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J. 2004; 25:1614-9.
- Chachques JC, Abdel Shafy AB, Duarte F, Cattadori B, Goussef N, Shen L, Carpentier A. From dynamic to cellular cardiomyoplasty. J Card Surg 2002; 17: 194-200.
- Chachques JC, Acar C, Herreros J, Trainini J, Prosper F, D’Attellis N, Fabiani JN, Carpentier A. Cellular cardiomyoplasty: clinical application. Ann Thorac Surg 2004; 77 : 1121-30.
- Pfeffer MA, Braunwald E. Ventricular remodelling after myocardial infarction. Experimental observations and clinical implications. Circulation. 1990; 81: 1161-72.
- Wang JS, Shum-Tim D, Galipeau J, Chedrawy E, Eliopoulos N, Chiu RC. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg 2000; 120: 999-1005.
- Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Nat Acad Sci USA. 2001; 98: 10344-9.
- Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, Glower DD, Kraus WE. Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation. Nat Med. 1998; 4: 929-933.
- Rajnoch C, Chachques JC, Berrebi A, Bruneval P, Benoit MO, Carpentier A. Cellular therapy reverses myocardial dysfunction. J Thorac Cardiovasc Surg. 2001; 121: 871-8.
- Verfaillie CM, Schwartz R, Reyes M, Jiang Y. Unexpected potential of adult stem cells. Ann N Y Acad Sci. 2003; 996: 231-4.
- Chachques JC, Cattadori B, Herreros J, Prosper F, Trainini JC, Blanchard D, Fabiani JN, Carpentier A. Treatment of heart failure with autologous skeletal myoblasts. Herz. 2002; 27: 570-8.
- Haider HK, Tan AC, Aziz S, Chachques JC, Sim EK. Myoblast transplantation for cardiac repair: a clinical perspective. Mol Ther. 2004; 9: 14-23.
- Vilas-Boas F, Feitosa GS, Soares MB, Pinho-Filho JA, Mota A, Almeida AJ, Carvalho C, de Carvalho HG, de Oliveira AD, dos Santos RR. Bone marrow cell transplantation to the myocardium of a patient with heart failure due to Chagas' disease. Arq Bras Cardiol. 2004; 82: 185-7.
- Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003; 107: 2294-302.
- Chachques JC, Herreros J, Trainini J, Juffe A, Rendal E, Prosper F, Genovese J. Autologous human serum for cell culture avoids the implantation of cardioverter-defibrillators in cellular cardiomyoplasty. Int J Cardiol 2004 ; 95 [Suppl 1] : S29-S33.
- Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 361: 45-6.
- Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol. 2004; 44: 1690-9.
- Narmoneva DA, Vukmirovic R, Davis ME, Kamm RD, Lee RT. Endothelial cells promote cardiac myocyte survival and spatial reorganization. Implications for cardiac regeneration. Circulation. 2004; 110: 962-968.
- Elmadbouh I, Chen Y, Louedec L, Silberman S, Pouzet B, Meilhac O, Michel JB. Mesothelial cell transplantation in the infarct scar induces neovascularization and improves heart function. Cardiovasc Res. 2005; 68: 307-17.
- Planat-Benard V, Menard C, Andre M, Puceat M, Perez A, Garcia-Verdugo JM, Penicaud L, Casteilla L. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res. 2004; 94:223–9.Ç
- Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, Huber I, Satin J, Itskovitz-Eldor J, Gepstein L. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol. 2004; 22: 1282-9.
- Cortes-Morichetti M, Frati G, Schussler O, Duong JP, Lauret E, Carpentier A, Chachques JC. Association of bioartificial myocardium and cellular cardiomyoplasty for myocardial support and regeneration. Circulation. 2005; 112 [Suppl II]: II-741.
- Kutchska I, Kofidis T, Chen IY, Arai T, Sheikh AY, Hendry SL, Pearl J, Hoyt G, Connolly A, Yang PC, Gambhir SS, Robbins RC. Collagen matrices enhance survival of embryonic cardiomyoblasts following transplantation into ischemic rat hearts. Circulation. 2005; 112 [Suppl II]: II-741.
- Rogge C, Didie M, Naito H, Hermans-Borgmeyer I, Wobus AM, Field LJ, Eschenhagen T, Zimmermann WH. Generation of engineered heart tissue from embryonic stem cell derived cardiomyocytes. Circulation. 2005; 112 [Suppl II]: II-14.
- Eschenhagen T, Zimmermann WH. Engineering myocardial tissue. Circ Res. 2005; 97: 1220-31.
- Kofidis T, Akhyari P, Boublik J, Theodorou P, Martin U, Ruhparwar A, Fischer S, Eschenhagen T, Kubis HP, Kraft T. In vitro engineering of heart muscle: artificial myocardial tissue. J Thorac Cardiovasc Surg. 2002; 124: 63-69.
- Leor J, Cohen S. Myocardial tissue engineering: creating a muscle patch for a wounded heart. Ann NY Acad Sci. 2004; 1015: 312-319.
- Chachques JC, Trainini JC, Lago N, Mouras J, Christen AI, Cortes Morichetti M, Frati G, Schussler O. Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium [MAGNUM Trial]: Preliminary Results. Presented at the 86th Annual Meeting, American Association for Thoracic Surgery. Philadelphia [USA], May 1-3, 2006.
- Trainini JC, Lago N, De Paz J, Cichero D, Giordano R, Mouras J, Barisani JL, Christen A, Chachques JC : Myoblast transplantation for myocardial repair. J Heart Lung Transpl 2004; 23: 503-5.
- Chachques JC, Salanson-Lajos C, Lajos P, Shafy A, Alshamry A, Carpentier A. Cellular cardiomyoplasty for myocardial regeneration. Asian Cardiovasc Thorac Ann. 2005; 13: 287-96.
- Chachques JC, El Serafi M, Azarine A, Mousseaux E, Cortes-Morichetti M, Ba M, Fabiani JN, Carpentier A. Ex-vivo MRI evaluation of local myocardial treatments : comparison between epicardial and endocardial [Cell-Fix catheter] injection. Circulation. 2005; 112 [Suppl II]: II-750.
- Carpentier A, Chachques JC, Grandjean P, Eds, : Cardiac Bioassist. Futura Publishing, New York : 1-632.
- Chachques JC, Argyriadis PG, Fontaine G, Hebert JL, Frank RA, D'Attellis N, Fabiani JN, Carpentier AF. Right ventricular cardiomyoplasty: 10-year follow-up. Ann Thorac Surg. 2003; 75:1464-8
- Stevenson LW, Miller LW, Desvigne-Nickens P, Ascheim DD, Parides MK, Renlund DG, Oren RM, Krueger SK, Costanzo MR, Wann LS, Levitan RG, Mancini D; REMATCH Investigators. Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy: a subset analysis from REMATCH [Randomised Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure]. Circulation. 2004; 110:975-81.
- Copeland JG, Smith RG, Arabia FA, PE Nolan, Sethi GK, Tsau PH. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004; 351:859–867.
- Chachques JC, Duarte F, Cattadori B, Shafy A, Lila N, Chatellier G, Fabiani JN, Carpentier A. Angiogenic growth factors and/or cellular therapy for myocardial regeneration: a comparative study. J Thorac Cardiovasc Surg. 2004; 128: 245–53.
- Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines. Circulation. 2004; 109: 2487-2491.
- Carvalho KA, Guarita-Souza LC, Rebelatto CL, Senegaglia AC, Hansen P, Mendonca JG, et al.: Could the coculture of skeletal myoblasts and mesenchymal stem cells be a solution for postinfarction myocardial scar?. Transplant Proc 2004; 36: 991-2.
- Kadner A, Zund G, Maurus C, Breymann C, Yakarisik S, Kadner G, Turina M, Hoerstrup SP. Human umbilical cord cells for cardiovascular tissue engineering: a comparative study. Eur J Cardiothorac Surg. 2004; 25:635-641.
- Chachques JC, Herreros J, Trainini JC [eds]: Libro “Regeneración Cardiaca”. Editorial Magister Eos, Buenos Aires [Argentina], 2005: 205 pages.
CV of the author
- Director of Cardiac Surgery Research at the University of Paris and the Alain Carpentier Foundation, and professor of Surgical Sciences at the HEGP.
- Graduated of MD at the Faculty of Medicine of Rosario, Argentine. He obtained MS and PhD at the University of Paris, France.
- Clinical and surgical cardiologic training in Broussais Hospital of Paris, he gained expertise in experimental and clinical procedures for the treatment of heart failure.
- Developed Cardiac Bioassist surgical techniques, e.g. latissimus dorsi dynamic cardiomyoplasty, dynamic aortomyoplasty, atriomyoplasty.
- More recently he developed stem cell-based and tissue engineered procedures for myocardial support and regeneration, i.e. cellular cardiomyoplasty and bioartificial myocardium.
- Received the following honors: Chevalier in the French National Order of the Legion of Honor, Prizes of the French Academy of Surgery, Academy of Sciences and Academy of Medicine, Life Member of the New York Academy of Sciences.
- Clinician and surgical scientist with expertise in myocardial diseases and valve repair procedures.
- Pursues his research interests in the integrative electrophysiology and cellular biology, the goal is to use in-vitro and in-vivo functional electrostimulation for cardiomyogenic stem-cell conditionning in order to create a dynamic cell based cardiac support.
- Founder and president of the Cardiac Bioassist Association. His further clinical research focuses on E-medecine and in the development of clinical trials for heart failure patients, e.g. the MAGNUM Trial: Myocardial Assistance by Grafting a New Upgraded bioartificial Myocardium.
Publication: September 2007
FORMULÁRIO DESACTIVADO DESDE
30 de Novembro de 2007
Your questions, contributions and commentaries will be answered
by the lecturer or experts on the subject in the Cardiovascular Surgery list.
Please fill in de form and Press the "Send" button.
Access to questions and answers