doi: 10.1161/CIRCULATIONAHA.106.623777
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2006;113:1926-1928.)
© 2006 American Heart Association, Inc.
Editorial |
The End of Granulocyte Colony-Stimulating Factor in Acute Myocardial Infarction?
Reaping the Benefits Beyond Cytokine Mobilization
From the Cardiovascular Division (J.M.H.), King’s College, London, United Kingdom, and Cardiovascular Center and Cardiovascular Research Center (J.B.), OLV Hospital, Aalst, Belgium.
Correspondence to Jonathan Hill, Clinical Senior Lecturer and Consultant Cardiologist, King’s College London, Cardiovascular Division, Bessemer Rd, London SE5 9PJ, United Kingdom. E-mail Jonathan.Hill{at}kcl.ac.uk
Key Words: Editorials • cells • myocardial infarction
"Perfect as the wing of a bird may be, it will never enable the bird to fly if unsupported by the air. Facts are the air of science. Without them a man of science can never rise."— —Ivan Pavlov
Facts must be sought from the rigorous application of scientific method. Indeed, the hardest questions sometimes require the hardest methods. Having a tool that can answer the questions with the minimum number of side effects in the minimum number of patients must be the desire of all clinical investigators who wish to generate new facts and contribute to the pool of knowledge. Progress in cell therapy for cardiovascular disease has been hindered at both the preclinical and clinical stages, perhaps because the appropriate tools to address the pertinent questions have not been used. In this context, magnetic resonance imaging (MRI) has, by necessity, rapidly evolved as the ideal tool for surrogate end-point measurements in early-phase clinical trials. In this issue of Circulation, Ripa and colleagues1 have elegantly demonstrated the utility and maturation of this technology in their study of granulocyte colony-stimulating factor (G-CSF) as an adjunctive therapy to mechanical reperfusion after myocardial infarction.
Article p 1983
Cardiovascular cell transplantation and cytokine mobilization originally began in clinical trials with the explicit goal of myocardial regeneration,2,3 but more recently, the emphasis has been focused on "remodeling attenuation" therapy, in which the presumed mechanism has shifted from the "replacement" capacity of transplanted cells to their "paracrine" effects.4 This thesis becomes more convincing given the lack of cardiomyogenic transdifferentiation demonstrated by adult hematopoietic stem cells.5 Despite the indistinct mechanism, the early-phase, nonrandomized clinical studies of G-CSF given after myocardial infarction demonstrated provocatively the potential efficacy of G-SCF administered as sole therapy.6,7
The study presented in this issue of Circulation is a randomized, double-blind, placebo-controlled trial of the effects of G-CSF given in the postinfarction period. This study demonstrated neither myocardial regeneration nor "remodeling attenuation" in G-CSF–treated patients; however, by application of cardiac MRI, the authors have used the "gold standard" method to assess the effects of cytokine mobilization on the regional wall-motion parameters of thickness and thickening. In so doing, they have generated a robust data set from the control group on which to base further studies. Despite the accepted accuracy and reproducibility of these MRI measures, they have seldom been used as a primary end point8,9 in cell therapy trials to date. The baseline and control measurements would suggest that if G-CSF induced a detectable change, it would have had to exceed the 17% improvement in left ventricular (LV) systolic wall thickening seen in the placebo group. In fact, no such difference was observed, and the systolic wall thickening improved by only 17% in the treatment group as well. Similarly, the global measurements of LV ejection fraction showed similar degrees of change, with no significant differences seen between the treatment and control arms.
Despite these findings, this study does have some limitations, but these are mostly related to the concept of using G-CSF as sole therapy rather than as an adjunct therapy for cell mobilization and subsequent harvesting. In addition, MRI, although the gold standard, is not the perfect imaging modality given that there are some difficulties in scanning every patient because of the presence of implantable pacemaker and defibrillator devices, as well as claustrophobia.
Interestingly, these data also correlate with another recent study that used G-CSF after myocardial infarction.10 In that study, G-CSF was used at the same dosing level but for 1 less day (10 µg/kg for 5 instead of 6 days), also to no effect. The primary end point in that study was reduction of LV size measured by 99mTc sestamibi scintigraphy. The secondary end point of LV ejection fraction assessment actually demonstrated a slightly greater (but nonsignificant) increase in the placebo group compared with the treatment group. Furthermore, in 2 previous studies using G-CSF in chronic myocardial ischemia, there actually appeared to be a deterioration in regional measures of LV function and perfusion in patients treated with G-CSF.11,12 The accumulated data from the 2 randomized, placebo-controlled studies of G-CSF in myocardial infarction are difficult to reconcile with a similar study reported by Ince et al.13 It could be speculated that this is attributable to differences in the study design, such as timing of G-CSF injection, and that the method of LV function assessment, namely, transthoracic echocardiography including use of dobutamine stress, is not equivalent to cardiac MRI in terms of either sensitivity or specificity.14
What are the lessons for cardiac cell transfer after acute myocardial infarction, and how may patients reap the benefits beyond cytokine mobilization? Will G-CSF simply join the vast selection of other experimental agents designed to aid myocardial infarction healing that did not live up to their preclinical and early-phase clinical hype? Perhaps it will find its true role as a means to harvest peripheral blood mononuclear cells for the purposes of ex vivo manipulation and direct delivery. At least when administered in the context of recent acute myocardial infarction, this approach would appear to be safe,1,10,13 although doubts were raised previously about its safety in both acute and chronic myocardial ischemia.11,12,15 Future cell mobilization research should be directed to alternative agents that can lead to targeted release of stem and progenitor cell populations, without the release of potentially proinflammatory cells such as neutrophils.16
In contrast to the concept of cytokine-mediated mobilization, the promise of autologous cell transfer to augment LV recovery has recently been supported by the results of the double-blind, randomized, placebo-controlled REPAIR-AMI trial (Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction).17 That study showed a significantly higher improvement in LV ejection fraction compared with placebo injection. Although the overall effect was moderate and MRI was not used for the measurement of the primary end point, that trial provides the most provocative evidence so far that intracoronary cell transfer may augment LV recovery beyond an optimal reperfusion strategy. This is clearly more optimistic than the neutral result of the present G-CSF study1; however, perhaps the margin of benefit should be interpreted cautiously, given the natural history of regional myocardial recovery demonstrated by these 2 recently reported G-CSF studies.1,10 No study has convincingly demonstrated any sustained benefit beyond the 4- to 6-month period, and in this regard, the randomized but not placebo-controlled BOOST trial (BOne marrOw transfer to enhance ST-elevation infarct regeneration) suggested only acceleration of LV recovery without long-term benefit on LV function after coronary cell transfer.18 If these data are later corroborated by long-term follow-up of REPAIR-AMI patients, several new hypotheses need to be addressed in future clinical research. Among these, the hypotheses of dose dependency, purification of a heterogeneous mononuclear cell fraction, enrichment for particular cell types such as CD34+ or CD133+ cells,19 and pharmacological modifications to enhance engraftment and functional effect are warranted. When these trials are designed, however, lessons from the studies on cytokine mobilization should be taken into account. First, the choice of a primary end point and imaging modality should be chosen with relevance to the potential clinical impact. Most trials use conventional change in global LV ejection fraction as a primary end point, but the effect of cell transfer on this end point may be clouded by later effects of ß-blockade or angiotensin-converting enzyme inhibitors on infarcted or remote segments. Instead, end points that reflect morphological changes such as infarct size20 or functional analysis of regional wall motion in the infarct area may be more appropriate. Cardiac MRI is the current state-of-the-art technique to address these issues in a repetitive manner with high spatial resolution that outmatches the power of conventional LV angiography or other noninvasive techniques by providing the needed information in 1 session.8,9
Optimal timing in relation to reperfusion and infarct healing also appears to be a common issue in G-CSF1,10,13 and coronary cell transfer trials.17,18,20 For instance, conflicting results of the REPAIR-AMI trial and the study by Janssens et al21 on LV recovery may relate to differences in timing of cell transfer. Thus, future cell therapy studies should apply cell transfer in a manner that is consistent with the time course of myocardial healing and homing signals. Conceptual risks for atherosclerosis should be addressed with direct imaging of the vascular wall in combination with observation of the physiological impact on epicardial segments downstream from cell transfer.22,23 Imaging modalities such as intravascular ultrasound or virtual histology24 should give more precise answers to this than quantitative coronary angiography.
The present study by Ripa et al1 answers previous critics of published cell therapy studies who have pointed out that the margin of change seen in the control groups did not match their experience in clinical practice. However, in so doing, this study also sets the bar considerably higher for future studies. To proceed with further clinical studies without the use of cardiac MRI will expose too many patients to potential side effects of these new biological therapies. As clinical investigators, we have a duty to use the best available means of measurement to generate the knowledge that will progress the field of cardiovascular cell therapy.
 |
Acknowledgments |
|---|
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
 Top References |
|---|
1. Ripa RS, Jørgensen E, Wang Y, Thune JJ, Nilsson JC, Søndergaard L, Johnsen HE, Køber L, Grande P, Kastrup J. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled Stem Cells in Myocardial Infarction (STEMMI) Trial. Circulation. 2006; 113: 1983–1992.
2. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410: 701–705.[CrossRef][Medline] [Order article via Infotrieve]
3. 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 Natl Acad Sci U S A. 2001; 98: 10344–10349.
4. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms [published erratum appears in Circ Res. 2005;97:e51]. Circ Res. 2004; 94: 678–685.
5. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004; 428: 668–673.[CrossRef][Medline] [Order article via Infotrieve]
6. Kuethe F, Figulla HR, Herzau M, Voth M, Fritzenwanger M, Opfermann T, Pachmann K, Krack A, Sayer HG, Gottschild D, Werner GS. Treatment with granulocyte colony-stimulating factor for mobilization of bone marrow cells in patients with acute myocardial infarction. Am Heart J. 2005; 150: 115.[CrossRef][Medline] [Order article via Infotrieve]
7. Valgimigli M, Rigolin GM, Cittanti C, Malagutti P, Curello S, Percoco G, Bugli AM, Della Porta M, Bragotti LZ, Ansani L, Mauro E, Lanfranchi A, Giganti M, Feggi L, Castoldi G, Ferrari R. Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J. 2005; 26: 1838–1845.
8. San Roman JA, Fernandez-Aviles F. The role of noninvasive imaging techniques in the assessment of stem cell therapy after acute myocardial infarction. Nat Clin Pract Cardiovasc Med. 2006; 3 (suppl): S38–S41.[CrossRef][Medline] [Order article via Infotrieve]
9. Fuster V, Sanz J, Villes-Gonzalez JF, Rajagopalan S The utility of cardiac magnetic resonance imaging in cardiac tissue regeneration trials. Nat Clin Pract Cardiovasc Med. 2006; 3 (suppl): S2–S7.[Medline] [Order article via Infotrieve]
10. Zohlnhofer D, Ott I, Mehilli J, Schomig K, Michalk F, Ibrahim T, Meisetschlager G, von Wedel J, Bollwein H, Seyfarth M, Dirschinger J, Schmitt C, Schwaiger M, Kastrati A, Schomig A; REVIVAL-2 Investigators. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA. 2006; 295: 1003–1010.
11. Hill JM, Syed MA, Arai AE, Powell TM, Paul JD, Zalos G, Read EJ, Khuu HM, Leitman SF, Horne M, Csako G, Dunbar CE, Waclawiw MA, Cannon RO III. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol. 2005; 46: 1643–1648.
12. Wang Y, Tagil K, Ripa RS, Nilsson JC, Carstensen S, Jorgensen E, Sondergaard L, Hesse B, Johnsen HE, Kastrup J. Effect of mobilization of bone marrow stem cells by granulocyte colony stimulating factor on clinical symptoms, left ventricular perfusion and function in patients with severe chronic ischemic heart disease. Int J Cardiol. 2005; 100: 477–483.[CrossRef][Medline] [Order article via Infotrieve]
13. Ince H, Petzsch M, Kleine HD, Schmidt H, Rehders T, Korber T, Schumichen C, Freund M, Nienaber CA. Preservation from left ventricular remodeling by front-integrated revascularization and stem cell liberation in evolving acute myocardial infarction by use of granulocyte-colony-stimulating factor (FIRSTLINE-AMI). Circulation. 2005; 112: 3097–3106.
14. Syed MA, Paterson DI, Ingkanisorn WP, Rhoads KL, Hill JM, Cannon RO III, Arai AE. Reproducibility and inter-observer variability of dobutamine stress CMR in patients with severe coronary disease: implications for clinical research. J Cardiovasc Magn Reson. 2005; 7: 763–768.[CrossRef][Medline] [Order article via Infotrieve]
15. Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, Kim YJ, Soo Lee D, Sohn DW, Han KS, Oh BH, Lee MM, Park YB. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet. 2004; 363: 751–756.[CrossRef][Medline] [Order article via Infotrieve]
16. Larochelle A, Krouse A, Metzger M, Orlic D, Donahue RE, Fricker S, Bridger G, Dunbar CE, Hematti P. AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in non-human primates. Blood. 2006;Jan 26. Epub ahead of print.
17. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holscherman H, Yu J, Cooti R, Mathey D, Hamm C, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher A. Intracoronary infusion of bone marrow-derived progenitor cells in acute myocardial infarction: a randomized, double-blind, placebo-controlled multicenter trial (REPAIR-AMI). Circulation. 2005; 112 (suppl II): II-3362. Abstract.
18. Meyer GP, Wollert KC, Lotz J, Steffens J, Lippolt P, Fichtner S, Hecker H, Schaefer A, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation. 2006; 113: 1287–1294.
19. Bartunek J, Vanderheyden M, Vandekerckhove B, Mansour S, De Bruyne B, De Bondt P, Van Haute I, Lootens N, Heyndrickx G, Wijns W. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation. 2005; 112 (suppl I): I-178–I-183.[Medline] [Order article via Infotrieve]
20. Van de Werf F. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006; 367: 113–121.[CrossRef][Medline] [Order article via Infotrieve]
21. Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Maertens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A, Mortelmans L, Boogaerts M, Van de Werf F. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet. 2006; 367: 113–121.[CrossRef][Medline] [Order article via Infotrieve]
22. Epstein SE, Stabile E, Kinnaird T, Lee CW, Clavijo L, Burnett MS. Janus phenomenon: the interrelated tradeoffs inherent in therapies designed to enhance collateral formation and those designed to inhibit atherogenesis. Circ Res. 2004; 109: 2826–2831.
23. Mansour S, Vanderheyden M, De Bruyne B, Vandekerckhove B, Delrue L, Van Haute I, Heyndrickx G, Carlier S, Granillo G, Wijns W, Bartunek J. Intracoronary delivery of hematopoietic bone marrow stem cells and luminal loss of the infarct-related artery in patients with recent myocardial infarction. J Am Coll Cardiol. In press.
24. Nair A, Kuban BD, Murat Tuzcu E, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002; 106: 2200–2206.
This article has been cited by other articles:
 |
|
 |
|
  W. Wojakowski, M. Kucia, K. Milewski, B. Machalinski, M. Halasa, P. Buszman, P. Klimeczek, M. Kazmierski, M. Pasowicz, M. Z. Ratajczak, et al. The role of CXCR4/SDF-1, CD117/SCF, and c-met/HGF chemokine signalling in the mobilization of progenitor cells and the parameters of the left ventricular function, remodelling, and myocardial perfusion following acute myocardial infarction Eur. Heart J. Suppl., December 1, 2008; 10(suppl_K): K16 - K23. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ndrepepa, J. Mehilli, S. Martinoff, M. Schwaiger, A. Schomig, and A. Kastrati Evolution of Left Ventricular Ejection Fraction and its Relationship to Infarct Size After Acute Myocardial Infarction J. Am. Coll. Cardiol., July 10, 2007; 50(2): 149 - 156. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||