| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 2002;123:584-585
© 2002 The American Association for Thoracic Surgery
Letters to the Editor |
Division of Cardiac Surgery
University of Toronto
Toronto General Hospital
200 Elizabeth St, EN 14-215
Toronto, Ontario M5G 2C4, Canada
Reply to the Editor:
We appreciate the interest expressed by Gorman and Gorman with respect to cell transplantation. They have raised an important issue about the mechanism of the beneficial effects achieved in animal studies and clinical trials. In our editorial "Cell Transplantation Comes of Age," we suggested that cell transplantation stabilizes the infarct region, induces angiogenesis, and modifies the response of the remaining myocardium to the infarct. The beneficial effects of cell transplantation are the result of a profound biologic response to cell engraftment that influences both regional and global remodeling of the heart. Therefore, we believe cell transplantation is a targeted therapy for myocardial remodeling, not a haphazard replacement of lost cells. A biologic approach to patients at risk of congestive heart failure may be more effective than mechanical restraint in preventing infarct expansion and ventricular dilatation. However, the combination of a biologic and mechanical intervention may prove to be the most effective approach to prevent heart failure. We will review our evolving understanding of the possible mechanisms of cell transplantation on both regional and global left ventricular remodeling.
As suggested in our editorial, cells that engraft in the infarct region alter the elastic properties of the transplant site, stimulate angiogenesis, limit infarct thinning, and prevent ventricular dilatation and congestive heart failure. Some of these effects may be the result of a reorganization of the structural elements surrounding the engrafted cells. Extracellular matrix (ECM) remodeling plays a critical role in the progression of heart failure.
1-3 The structural support provided by the fibrillar collagen matrix determines myocyte shape, alignment, and the transduction of myocyte shortening into an overall ejection. Impaired structural support resulting from adverse left ventricular matrix remodeling leads to ventricular dilatation, increased wall stress, and both systolic and diastolic dysfunction. Both in human beings and in animal models of heart failure, left ventricular matrix remodeling results in functionally significant alterations in the amount, type, organization, and stability of fibrillar collagen. Therapeutic strategies that limit adverse matrix remodeling in heart failure, such as cell transplantation, may prevent ventricular dilatation and maintain the structural support necessary for effective cardiomyocyte contraction. 4 For example, mechanical unloading by left ventricular assist device support can reverse left ventricular remodeling and improve functional recovery by reorganizing ECM components. 5 We are investigating the effects of cell transplantation on the fibrillar collagen network. Our preliminary data suggest that cell transplantation influences global fibrillar collagen content and organization, limiting ventricular dilatation and preserving cardiac function.
The site of transplantation must undergo remodeling to accommodate cell engraftment. First, the transplanted cells reorganize the degraded matrix of the host myocardium and secrete and incorporate new matrix elements within deficient areas. New fibrillar collagen matrix may improve structural support for native myocytes. Infarct expansion would be attenuated and regional function improved by a tethering effect to the hypercontractile border zone cardiomyocytes. This physical link between the donor cells and the ECM by integrin proteins could explain how muscle cell transplantation, even in the absence of synchronous contraction with the host myocardium, can improve cardiac function. 6 As well, the reorganized matrix maintains the elasticity of the infarct region. The collagen network stores elastic strain energy during the cardiac cycle only when correctly oriented with respect to adjacent myocytes. 7,8 Second, donor cells inhibit host matrix degradation, stimulate hypertrophy and local angiogenesis, and prevent further cell death by the release of growth factors (ie, insulin-like growth factor-I, vascular endothelial growth factor, fibroblast growth factor), cytokines, and other cell-signaling peptides. Angiogenesis induced by transplanted cells improves perfusion to the infarct region and modifies the remodeling of both the injured region and the remaining myocardium. 9 Increasing perfusion may salvage hibernating native cardiomyocytes and/or restore damaged cells. Increased perfusion may also aid in the restoration of injured matrix, which in turn may facilitate donor cell incorporation, donor to host cell communications, and increased structural support and stability. This cascade of events prevents or delays adverse myocardial remodeling.
Animal and clinical studies have demonstrated that cell transplantation attenuates wall thinning and ventricular dilatation and delays or prevents the development of congestive heart failure. This surprising finding can be explained only by a modification of the remodeling process at a distance from the transplanted region. Cell engraftment has profound effects on the entire myocardium in addition to local effects in the transplant region. In a hamster model of global cardiomyopathy, muscle cell transplantation (heart cells, smooth muscle cells, or skeletal myoblasts) into the anterior left ventricle consistently prevented left ventricular dilatation and improved global cardiac function. 10,11 Beneficial effects on limiting fibrosis and dilatation were found in areas remote from the site of transplantation (unpublished observations). These results suggest that the benefit of the transplanted cells on left ventricular ECM remodeling extends beyond the site of cell engraftment.
Many novel surgical approaches have been proposed to prevent adverse remodeling and ventricular dilatation. Cell transplantation may have the greatest promise as a directed biologic tool to remodel the failing myocardium. The clinical results of cell transplantation have been encouraging. 12 The goal of cell transplantation remains the replacement of cells lost to injury with equivalent contractile elements. In addition, engrafted cells induce angiogenesis and reorganize the ECM, improving the prognosis of patients with heart failure. We are investigating the effects of cell transplantation on myocardial remodeling to fully understand the problem that we are trying to solve and, importantly, to provide a biologic solution.
12/8/120723
References
This article has been cited by other articles:
|
|
 |
|
  P. W.M. Fedak, P. E. Szmitko, R. D. Weisel, S. M. Altamentova, N. Nili, N. Ohno, S. Verma, S. Fazel, B. H. Strauss, and R.-K. Li Cell transplantation preserves matrix homeostasis: A novel paracrine mechanism J. Thorac. Cardiovasc. Surg., November 1, 2005; 130(5): 1430 - 1439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Chachques, C. Acar, J. Herreros, J. C. Trainini, F. Prosper, N. D'Attellis, J.-N. Fabiani, and A. F. Carpentier Cellular cardiomyoplasty: clinical application Ann. Thorac. Surg., March 1, 2004; 77(3): 1121 - 1130. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
