The arrythmogenic potential of post-myocardial infarction cytokine treatment

Abstract

EDITORIAL FOCUSThe arrythmogenic potential of post-myocardial infarction cytokine treatmentD. J. McKitrickD. J. McKitrickPublished Online:01 Aug 2009https://doi.org/10.1152/ajpheart.00544.2009This is the final version - click for previous versionMoreSectionsPDF (43 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations a front page story in The New York Times (22) at the end of March 2001 reported that “the basis of a possible revolution in treating heart attack patients has been laid by three reports of using stem cells from bone marrow to repair heart tissue in animals.” Those three reports (11, 16, 24) reported that the delivery of stem cells to the hearts of animals with experimental myocardial infarction (MI) improved the functional profile of the infarcted heart. To make the treatment viable, there are a number of ways in which stem cells can be provided. Broadly, they fall into three categories: human embryonic stem cells, autologous progenitor cells, and implants of xenografts (13). But how many cells, and which type, remained the question.One of the three reports above (11) and a subsequent report by another (17) suggested that the use of cytokines, specifically granulocyte colony-stimulating factor (G-CSF), could recruit bone marrow stem cells (20) or resident cardiac progenitor cells (4) to rescue damaged myocardium after MI. The great advantage of this was that it mobilized the body's own resources to repair damage, thus how many and which type were not so relevant. The stage was set for the exciting possibility that “it may even prove possible, though this concept has not been tested, to do no more than inject a heart attack patient with a cytokine, a natural protein that stimulates the bone marrow's stem cells to proliferate. The cells would home in on damaged heart tissue, and repair it.”(22). Indeed, G-CSF-mediated stem cell recruitment was reported following myocardial injury (1) and was shown to support neovascularization (11, 15), reduce cardiomyocyte apoptosis (11), repair the heart, improve function and survival (8, 17), prevent remodeling (9, 11, 15), and even suppress ventricular arrhythmias (3). In addition, cytokine-mediated stem cell mobilization is less invasive than surgical grafting or a percutaneous delivery of stem cells via the coronary arteries.G-CSF is a hematopoietic cytokine that works within bone marrow to regulate the production of neutrophils (2). It is involved in granulocyte proliferation and the mobilization of stem (14) and cardiac progenitor cells (4). G-CSF receptor is also expressed on cardiomyocytes, and the binding of G-CSF activates signaling molecules that reduce cardiomyocyte apoptosis (9). The G-CSF-mediated mobilization of stem cells causes an upregulation of CXCR-4 receptors on CD34+ cells that, in turn, guides the homing interaction with stromal cell-derived factor 1 expressed on injured myocardium (1). The recruitment of CD34+ cells supported the idea that, in addition to its beneficial effects on myocardium, G-CSF would promote the revascularization of the infarct zone in the damaged heart (18).But a problem appeared. It was known that sympathetic innervation and nerve activity had a role in ventricular arrhythmogenesis and sudden cardiac death (5, 6). It was shown that a relationship existed between ventricular arrhythmia and increased regional sympathetic innervation of the left ventricle in heart failure patients (6) and that increased nerve growth factor synthesis had a causal role in ventricular hyperinnervation by sympathetic fibers following MI (10). In stem cell therapy, it was demonstrated that autologous skeletal myoblast transplantation was associated with serious ventricular arrhythmias (12) and that mesenchymal stem cell injection into the infarct region in the left ventricle of swine induced cardiac sympathetic nerve sprouting (19). In vitro studies showed that mesenchymal stem cells in coculture with rat ventricular myocytes produced an arrhythmic substrate likely based on the heterogeneity of electrically coupled stem cells and native myocytes (7). Thus, in stem cell transplantation, arrhythmogenesis could arise in two ways: 1) from conduction abnormalities resulting from electrical pathways between heterogenous cell types that give rise to reentrant arrhythmias (7) or 2) from a direct effect of introduced stem cells on cardiac sympathetic nerve hyperinnervation (17). There is little evidence that G-CSF-recruited stem cells contribute to conduction abnormalities, but is sympathetic hyperinnervation and arrhythmogenesis a consideration with G-CSF therapy?In the American Journal of Physiology-Heart and Circulatory Physiology, Lee et al. (11a) report on the effects of the administration of G-CSF on the sympathetic reinnervation and arrhythmogenic response of the rat myocardium after MI. The anterior descending artery was ligated, and 5 days of G-CSF treatment (50 μg/kg sc) was given 24 h post-MI. Control groups included rats with MI + subcutaneous vehicle, sham-operated MI + G-CSF, and sham-operated MI alone. Cardiac function was assessed by echocardiography before and 56 days after MI, and the hemodynamic parameters and infarct size were assessed 56 days after MI. To investigate the characteristics of sympathetic reinnervation of the myocardium, nestin and nerve growth factor mRNA and protein were quantified at days 5 and 56, respectively, and the immunohistochemical detection of CD34+, nestin, glial fibrillary protein, tyrosine hydroxylase growth-associated protein 43, and neurofilament was done at days 5 and 56 post-MI. Finally, to assess the arrhythmogenic potential, a programmed electrical stimulation of the right ventricular outflow tract was done. Laboratory measurements of circulating G-CSF were done at 0, 5, 28, and 56 days post-MI, and left ventricular norepinephrine levels were measured at the infarct border zone at day 56. Rats with an infarct scar >30% of the left ventricular free wall were studied.Consistent with the effects of G-CSF, the neutrophil counts were significantly increased in both G-CSF-treated groups. However, infiltrating CD34+ cells were only seen in the MI + G-CSF and MI groups, not in the sham-operated animals. This corresponds to the report of Abbott et al. (1) who reported that recruited stem cell homing does not occur in the absence of injury. The increase in CD34+ cells in the infarct border zone was paralleled by increased nestin mRNA, protein, and nestin+/glial fibrillary protein+ cells at day 5. This is significant because the intermediate filament protein nestin is known to be a marker migrating and proliferating cells (23) and drives neurogenesis (21). Nerve growth factor protein and mRNA were increased in MI + G-CSF rats at day 56, underlying the sympathetic reinnervation seen, and a functional role was suggested by an increased norepinephrine content in the border zone at day 56. Finally, pacing-induced arrhythmias were increased in severity in the MI + G-CSF group.Overall G-CSF administration produced a modest improvement in cardiac function but also showed clear effects on excessive functional sympathetic reinnervation that was associated with an enhanced arrhythmogenic potential. Several issues influence the interpretation of the results. The authors have provided evidence to suggest that the nestin-containing stem cells differentiate into neural tissue, but whether this represents an increase in functional neurons is unknown. The differences in study designs and species used may account for some of the differences between this and previous animal studies. This permanent occlusion study also does not address the effects of the more usual clinical situation of reperfusion or account for the important issues of the optimal start of treatment, the length of administration, and the safe and effective doses of G-CSF. 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Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodelling. Circulation 115: 1866–1875, 2007.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. J. McKitrick, Cardiology Research, Level 4, South Block, Royal Perth Hospital, Wellington St., Perth, WA 6000, Australia (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation More from this issue > Volume 297Issue 2August 2009Pages H508-H509 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00544.2009PubMed19542486History Published online 1 August 2009 Published in print 1 August 2009 Metrics