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Ann Thorac Surg 2004;78:14-16
© 2004 The Society of Thoracic Surgeons
a Laboratory of Applied Myology, Department of Biomedical Sciences, University of Padua Medical School, Padova, Italy
* Address reprint requests to Dr Carraro, Laboratory of Applied Myology, Department of Biomedical Sciences, University of Padua Medical School, Viale G. Colombo 3, I-35121 Padova, Italy.
e-mail: ugo.carraro{at}unipd.it
In contrast to what is happening with other cardiac diseases, the incidence of congestive cardiac insufficiency is not decreasing despite significant progress in pharmacologic treatment, and that is likely due to the increased longevity of the population. Cardiac transplantation is the elective therapy, but the limit set by organ donors seems to have been reached all over the world. In the future, xenotransplants could offer a solution to the problem, even though such an approach would still carry the risk of zoonotic viral infections. Mechanical circulatory support has also been studied as a viable option, but many more studies are needed before considering it the final solution.
At present, the more promising alternatives come from biological approaches relying on autologous cell-based or tissue-based treatments (cardiac bioassistance). Although it is difficult to foresee which of the cardiac bioassists will have the highest impact on the existing clinical needs, in the future combined subsets of some of them will provide the long-awaited solutions.
When confronted with the problem of heart damage after infarction, cardiomyocyte replacement is the ideal scenario. In principle, such a goal could be achieved in two ways: by stimulating the proliferation of endogenous mature cardiomyocytes or stem cells, or by implanting exogenous donor cardiomyogenic cells.
See page 303
It should be emphasized that in order to be clinically effective (ie, the patient has to survive an acute insult that disrupts heart function through damage to the individual cardiac myocytes), the enhancement of cardiomyocyte proliferation after damage must be very rapid. In cases in which there is chronic damage to the heart muscle, proliferation would instead have to be sustained, so that it slowly but continuously replaces myocytes as necessary during the course of the disease. Whatever the source of the cells and the use to which they are put, concurrent revascularization must also keep pace with the repopulation of the infarct to ensure viability of the repaired region and prevent further scar tissue formation. Finally, the newly formed myocardium must integrate with the existing myocardial wall if it is to assume the function of the tissue it replaces. All of this must occur while the heart continues to beat and perform the essential work of supplying blood throughout the organism. Furthermore, even small areas of imperfectly integrated tissues are likely to severely alter the electrical conduction and syncytial contraction of the heart, with long-term life-threatening consequences. That is in marked contrast to the situation in skeletal muscle where the tissue can rest during repair [1–5]. Related to the absence of urgency, a less demanding application of cell cardiac bioassistance is in the treatment of congestive heart failure.
In postnatal muscle, skeletal muscle precursors (myoblasts) can be derived from satellite cells (reserve cells located beneath the basal lamina on the surface of mature myofibers) or from cells lying beyond the myofiber, ie, from interstitial connective tissue (in and out of blood vessels) or bone marrow. Both of these cell classes may have stem-like properties. In addition, the old idea that postmitotic myonuclei lying within mature myofibers might be able to reform myoblasts or stem cells is now being reexamined, in view of recent "heretical" observations for similar postmitotic cardiomyocytes. Indeed, in adult hearts (which previously were not considered capable of repair), the role of replicating endogenous cardiomyocytes and the recruitment of other (stem) cells into cardiomyocytes for new cardiac muscle formation has recently attracted much attention [2–6].
Although many endogenous cell types can be converted to skeletal muscle, the contribution of nonmyogenic cells to the formation of new postnatal skeletal muscle in vivo appears to be negligible. Whether specific inducers and appropriate microenvironments can significantly enhance the recruitment of such cells to the myogenic lineage is still being intensively investigated. Among the growing list of options, dermal fibroblasts appear promising as a realistic alternative source of exogenous myoblasts for transplantation purposes. With regard to heart muscle, the results of experiments showing the participation of bone marrow-derived stem cells and of endothelial cells in the repair of damaged cardiac muscle are encouraging [1–6].
Recently, it has been shown at autopsy 17.5 months after implantation of autologous skeletal myoblast in postinfarction scar, the derived myotube-like skeletal muscle fibers are viable, and longitudinally coaligned with the adjacent myocardium. The severely atrophic myofibers expressed either fast (35%) or slow (32%) myosin isoforms, or coexpressed both slow and fast (33%) myosin isoforms [7].
In addition to their role in regeneration, normal skeletal myoblasts have been isolated, cultured, and then transplanted in vivo in an attempt to treat inherited muscular dystrophies, such as Duchenne Muscular Dystrophy (DMD) [8]. The clinical possibilities of myoblast transfer therapy have stimulated much research, although many fundamental problems, such as immune response to allogenic cells, remain to be solved [9]. In the potential treatment of DMD patients, an ex vivo gene therapy approach based on the use of satellite or stem cells could be very effective, given that the use of autologous cells would avoid the problems related to immune rejection. Satellite cells from the skeletal muscle of DMD patients have limited capacity for replication, however, and therefore alternative source of autologous myogenic cells (eg, from dermal fibroblasts or bone marrow stem cells) would be better suited for genetic correction and reimplantation into the dystrophic muscles.
Transplantation of cultured myoblasts has also been used to replace defective muscles, eg, for urinary incontinence [10] and in acutely injured myocardium [11–13], and has been widely used to deliver genes into the bloodstream, brain, or joints [14]. Cultured myoblasts are also required for the rapidly emerging discipline of tissue engineering to construct ex vivo potential artificial muscles for transplantation purposes. Myoblast transplantation in skeletal muscle transferred around the heart for cardiac assistance may overcome the limitations of use of cardiomyocytes directly transplanted in the heart [15].
It is possible that during development circulating stem cells may give rise to many of the stem cells ascribed to specific tissues. In postnatal tissues, it is not clear whether bone marrow–derived stem cells contribute to the endothelial cells in the vasculature or whether they become resident in interstitial connective tissue. However, on the basis of data deriving from studies of the clearance of green fluorescent protein-labeled lineage-negative blood cells, it has been calculated that 20,000 to 100,000 hematopoietic stem cell (HSC)/progenitors enter the blood every day and are then rapidly sequestered (within minutes) into tissues [6]. These observations on circulating bone marrow–derived stem cells have attracted great interest because the delivery of muscle precursors through the bloodstream would represents an ideal route for their distribution to all skeletal muscles.
It should also be kept in mind that the use of umbilical cord blood might be an alternative, and possibly superior, source of pluripotent stem cells. The banking of such cord cells has been proposed for future clinical applications. Marrow stromal cells could also be a good source of therapeutic cells for transplantation purposes, thanks to the fact that, as opposed to HSC, adherent cardiomyogenic stem cells obtained from adult bone marrow can be expanded in culture.
At any rate, the critical point is the potential scale of contribution of such nonmuscle stem cells, especially those derived from adult tissues, to de novo myocardium formation in vivo. Successful transplantation of skeletal or fetal cardiac muscle cells into hearts has been done experimentally using different cell types [16–22].
Given the time constraints for repair after acute myocardial infarction, the delivery of predifferentiated cells (cardiomyocyte and vascular cells, possibly derived from stem cells) appears desirable. Local delivery of these cells results in direct seeding of the damaged zone, but we need to understand more about how the microenvironment promotes cell differentiation in order to exploit this possibility. Local delivery might be improved if such cells were engineered into three-dimensional grafts on appropriate matrix biomaterials.
Systemic delivery of stem cells is relatively noninvasive and remains an attractive option. This approach obviously relies on the capability of cells to home onto damaged tissue, but at present little is known about the factors responsible for such specific tissue targeting. Furthermore, the stem cell population would have to expand and differentiate into functional cardiomyocytes, and the local conditions that could direct such phenomena still need to be elucidated. We are still in the early days, and in the absence of solid in vivo data, it seems premature to extend such studies to the clinical setting.
Considering the present uncertainties of cell-based approaches, a surgical approach to cardiac assist based on a redeployment of the patient's own skeletal muscle remains an attractive prospect. Such an approach offers a biological solution that is free from the risks, debilitating side effects, and costs associated with long-term immunosuppression therapy. Moreover, it is not limited by donor availability, and it does not require the patient's own heart to be discarded but rather shares the workload, thereby offering some potential for myocardial recovery. The costs are mainly those associated with the surgical procedure itself, including the implantable stimulator used to activate the grafted muscle.
When compared with mechanical assist devices as a biological source of power, skeletal muscle has the great advantage of being more energy efficient. A small expenditure of energy (needed to stimulate the motor nerve) is enough to trigger the release of a potentially large amount of energy derived ultimately from the normal intake of food and oxygen. In other words, muscle converts that energy with great efficiency into mechanical work, which can, in principle, be harnessed in various ways to assist a failing circulation. The cardiomyostimulator, like a conventional pacemaker, would have to be renewed every 5 years or so, but no other energy source would be required. New options, such as active heart biogirdling without or with cell engineering, are also attractive [23–31].
Although it is difficult to foresee which of the cardiac bioassists will have the highest impact on the existing clinical problems, in the future, combined subsets of some of them will provide the long-awaited solutions.
Acknowledgments
This study was supported in part by institutional funds from the Italian National Research Council to the Unit for Neuromuscular Biology and Physiopathology of the Neuroscience Institute; and by the Italian Ministry of University and Scientific and Technologic Research (MURST Contract no. 9806192428), the Italian Trial of Demand Dynamic Cardiomyoplasty, and ex60% funds to Dr Carraro.
References
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