Editorial
The End of Granulocyte Colony-Stimulating Factor in Acute
Myocardial Infarction?
Reaping the Benefits Beyond Cytokine Mobilization
Jonathan M. Hill, MA, MBChB, MRCP; Jozef Bartunek, MD, PhD
“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
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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 ␮g/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
F
acts 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 opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
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 [email protected]
(Circulation. 2006;113:1926-1928.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.623777
1926
Hill and Bartunek
Granulocyte Colony-Stimulating Factor in Acute MI
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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 ␤-blockade or
1927
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.
Disclosures
None.
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.
3. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, NadalGinard 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.
6. Kuethe F, Figulla HR, Herzau M, Voth M, Fritzenwanger M, Opfermann
T, Pachmann K, Krack A, Sayer HG, Gottschild D, Werner GS.
1928
Circulation
April 25, 2006
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Treatment with granulocyte colony-stimulating factor for mobilization of
bone marrow cells in patients with acute myocardial infarction. Am
Heart J. 2005;150:115.
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.
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.
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 colonystimulating 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.
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 granulocytecolony-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.
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
16.
17.
18.
19.
20.
21.
22.
23.
24.
function and restenosis after coronary stenting in myocardial infarction:
the MAGIC cell randomised clinical trial. Lancet. 2004;363:751–756.
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.
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.
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.
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):I178 –I-183.
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.
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.
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.
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.
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.
KEY WORDS: Editorials
䡲
cells
䡲
myocardial infarction
The End of Granulocyte Colony-Stimulating Factor in Acute Myocardial Infarction?:
Reaping the Benefits Beyond Cytokine Mobilization
Jonathan M. Hill and Jozef Bartunek
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
Circulation. 2006;113:1926-1928
doi: 10.1161/CIRCULATIONAHA.106.623777
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