Copyright © 2007, European Society of Cardiology
Working with what we have: Options for myocardial infarct repair?
Faculty of Medicine, Department of Physiology, Institute of Cardiovascular Physiology, Room 3038, SBGH Research Centre, 351 Tache Avenue, Winnipeg, Canada
*Tel.: +1 204 235 3419. idixon{at}sbrc.ca
See article by Brüel et al. [4] (pages 400–408) in this issue.
The classic mythological tale of the crimes of Prometheus in gifting mortal men with, among other things, the divine fire, serves to remind us never to anger anyone as powerful as Zeus. For his efforts, Prometheus was shackled to a mountain to be tormented daily by Zeus' pet eagle who, according to legend, preferred liver. Each subsequent evening, Prometheus' tissues regenerated, and the cycle of mechanical destruction and regeneration would repeat ad nauseum until finally Zeus regained a modicum of calm and released him. What is possibly more fascinating (and certainly much less gruesome) – the notion of rebuilding or regenerating the myocardium following either catastrophic myocyte loss (as in myocardial infarction or MI) or in progressive loss of contractile cells in various progressive cardiomyopathies – has long intrigued both clinical and basic investigators in cardiology and is currently stirring a considerable degree of interest and effort. In this vein a number of exciting developments have come to pass within the past 2years that deserve comment.
New myocytes in the heart: stem cells vs. stimulation of primordial cells. The putative "carrot" within the approach of cardiac regeneration includes the reversal of progressive cardiac remodeling, e.g., maladaptive cardiac hypertrophy and the indefinite postponing of decompensated heart failure. Anversa and colleagues were among the first to challenge the pre-established view that the heart is primarily a post-mitotic organ (reviewed in [1]). In this light, a considerable body of evidence exists to support the suggestion that the heart contains undifferentiated primordial cells that are able to then differentiate into several different phenotypes. The exploitation of these cardiac stem cells (CSCs) to be coaxed into differentiating to myocytes, smooth muscle and endothelial cells (to form coronary vasculature) in damaged areas of the heart has stirred the imagination of those interested in regeneration of compromised myocardium. Alternatively, exogenous implantation of functioning cardiac myocytes has been held up as one of the more direct alternatives to stimulation of primordial cells [2]. The recent explosion of interest in the methodology directed towards achieving cardiac regeneration has taken experimental cardiology by storm, and, understandably, this excitement has spilled over into the public media. The recent work by C.E. Murry and colleagues [2] has been described as "thrilling" and a major scientific advance, as its seems to have solved confounding issues of specific and robust induction of differentiation of embryonic stem cells into cardiac myocytes and of then keeping the cardiac myocytes alive once transplanted. Overcoming the negative effects of inflammation, e.g., the harsh environment of the newly damaged heart that is associated with the death of newly transplanted cells that occur immediately after MI, was also the focus of Murry's work. In this regard, these investigators developed a cocktail of pro-survival factors to enable consistent formation of myocardial grafts in the infarcted rat heart. This development comes on the heels of other major contributions to stem cell work. For example, a novel method for the generation of bona fide embryonic stem cells from normal mouse skin cells has recently been sorted out by a number of groups, and thus the possibility of generation of patient-derived stem cells without embryonic tissue greatly smoothes the development of embryonic stem cell work and further strengthens the argument for implantation of differentiated myocytes for cardiac repair (reviewed in [3]). Nevertheless, very little work has been done to test whether the elevation of cardiac myocyte numbers can be induced in mature experimental animals in vivo.
The growth hormone/insulin growth factor-1 cascade and cardiac myocyte mitosis. In the current issue of Cardiovascular Research, Brüel and colleagues [4] demonstrate that, in genetically unmodified rat hearts, application of growth hormone (GH) increases proliferation of (Ki-67 positive) cardiac myocytes in vivo with a subsequent increase in myocyte numbers and measurable increases in left ventricular mass from intact hearts. The implication of this study is that these cells appear to be generated de novo from an endogenous pool; regardless of their source, the logical extension of these results would favor an elevation of cardiac myocyte numbers for an extended period of time. This development would be especially useful after the sudden loss of a large numbers of myocytes in the face of a myocardial infarction. No less important is that this work and other relevant results from this lab emphasize i) the indirect role of insulin-like growth factor-1 (IGF-1) in mediation of GH effects, and ii) the lack of fibrosis in concentrically hypertrophied hearts in animals treated with GH [4,5]. The stimulatory effects of the GH/IGF-1 cascade on cardiac myocyte cell division in vivo may be useful in other ways. For example, the combination of techniques – using implantation of stem cell-derived differentiated myocytes "glued" into the damaged myocardium and then stimulated with GH/IGF-1 in combination with the pro-survival cocktail – may lend further efficacy to the procedure of Murry et al. Whether this supposition holds true is far from clear, but this notwithstanding, and even in its most conservative interpretation, the current work by Brüel et al. stands as a carefully executed model for further investigation of myocyte division in vivo. Further, the authors have previously addressed possible differences between the effects of growth hormones on the growth of myocytes, capillaries, and matrix and have observed their concomitant growth in treated adult rat heart [6]. While significant questions surrounding the current avenue of investigation remain unanswered, including i) whether primordial stem cells or existing adult cardiac myocytes (or both) are the main targets of GH/IGF-1 in vivo and ii) whether IGF-1 alone is sufficient for a GH-like effect in promotion of mitosis in adult cardiac myocytes, the current paper is of considerable interest. As is characteristic of all good work, the body of data presented by Brüel and colleagues raises more questions than it answers.
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Acknowledgements |
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IMCD is a scholar of the Myles Robinson Heart Health Foundation, and acknowledges the support of the St. Boniface Hospital and Research Foundation, the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Manitoba.
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References |
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 Top References |
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- Anversa P., Leri A., Kajstura J. Cardiac regeneration. J Am Coll Cardiol (2006) 47:1769–1776.
[Abstract/Free Full Text] - Laflamme M.A., Chen K.Y., Naumova A.V., Muskheli V., Fugate J.A., Dupras S.K., et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol (August 26 2007) 10.1038/nbt1327.
- Rossant J. The magic brew. Nature (2007) 448:260–262.[CrossRef][Medline]
- Brüel A., Christoffersen T.E.H., Nyengaard J.R. Growth hormone increases the proliferation of existing cardiac myocytes and the total number of cardiac myocytes in the rat heart. Cardiovasc Res (2007) 76:400–408.
[Abstract/Free Full Text] - Bruel A., Oxlund H. The effect of growth hormone on rat myocardial collagen. Growth Horm IGF Res (1999) 9:123–130.[CrossRef][Web of Science][Medline]
- Bruel A., Oxlund H., Nyengaard J.R. Growth hormone increases the total number of myocyte nuclei in the left ventricle of adult rats. Growth Horm IGF Res (2002) 12:106–115.[CrossRef][Medline]
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