Published online before print November 7, 2005, doi: 10.1161/CIRCULATIONAHA.105.541433
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2005;112:3097-3106.)
© 2005 American Heart Association, Inc.
Heart Failure |
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)
From the Department of Internal Medicine, Divisions of Cardiology and Hematology (H.D.K., M.F.), and the Department of Nuclear Medicine (C.S.) at the University Hospital Rostock, Rostock School of Medicine, Rostock, Germany.
Correspondence to Christoph A. Nienaber, MD, FACC, FESC, Division of Cardiology, University Hospital Rostock, Rostock School of Medicine, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany. E-mail christoph.nienaber{at}med.uni-rostock.de
Received February 7, 2005; revision received July 22, 2005; accepted July 25, 2005.
Background— Considering experimental evidence that stem cells enhance myocardial regeneration and granulocyte colony–stimulating factor (G-CSF) mediates mobilization of CD34+ mononuclear blood stem cells (MNCCD34+), we tested the impact of G-CSF integrated into primary percutaneous coronary intervention (PCI) management of acute myocardial infarction in man.
Methods and Results— Fifty consecutive patients with ST-segment elevation myocardial infarction were subjected to primary PCI stenting with abciximab and followed up for 6 months; 89±35 minutes after successful PCI, 25 patients were randomly assigned in this pilot study (PROBE design) to receive subcutaneous G-CSF at 10 µg/kg body weight for 6 days in addition to standard care, including aspirin, clopidogrel, an ACE inhibitor, ß-blocking agents, and statins. By use of CellQuest software on peripheral blood samples incubated with CD45 and CD34, mobilized MNCCD34+ were quantified on a daily basis. With homogeneous demographics and clinical and infarct-related characteristics, G-CSF stimulation led to mobilization of MNCCD34+ to between 3.17±2.93 MNCCD34+/µL at baseline and 64.55±37.11 MNCCD34+/µL on day 6 (P<0.001 versus control); there was no indication of leukocytoclastic effects, significant pain, impaired rheology, inflammatory reactions, or accelerated restenosis at 6 months. Within 35 days, G-CSF and MNCCD34+ liberation led to enhanced resting wall thickening in the infarct zone of between 0.29±0.22 and 0.99±0.32 mm versus 0.49±0.29 mm in control subjects (P<0.001); under inotropic challenge with dobutamine (10 µg · kg–1 · min–1), wall motion score index showed improvement from 1.66±0.23 to 1.41±0.21 (P<0.004 versus control) and to 1.35±0.24 after 4 months (P<0.001 versus control), respectively, coupled with sustained recovery of wall thickening to 1.24±0.31 mm (P<0.001 versus control) at 4 months. Accordingly, resting wall motion score index improved with G-CSF to 1.41±0.25 (P<0.001 versus control), left ventricular end-diastolic diameter to 55±5 mm (P<0.002 versus control), and ejection fraction to 54±8% (P<0.001 versus control) after 4 months. Morphological and functional improvement with G-CSF was corroborated by enhanced metabolic activity and 18F-deoxyglucose uptake in the infarct zone (P<0.001 versus control).
Conclusions— G-CSF and mobilization of MNCCD34+ after reperfusion of infarcted myocardium may offer a pragmatic strategy for preservation of myocardium and prevention of remodeling without evidence of aggravated restenosis.
Key Words: myocardial infarction • remodeling • cells • angioplasty • glucose
This article has been cited by other articles:
 |
|
 |
|
  S-A Chang, H-K Kim, H-Y Lee, S-Y Choi, B-K Koo, Y-J Kim, D-W Sohn, B-H Oh, Y-B Park, Y-S Choi, et al. Restoration of left ventricular synchronous contraction after acute myocardial infarction by stem cell therapy: new insights into the therapeutic implication of stem cell therapy for acute myocardial infarction Heart, August 1, 2008; 94(8): 995 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H Ince, M Valgimigli, M Petzsch, J S. de Lezo, F Kuethe, S Dunkelmann, G Biondi-Zoccai, and C A Nienaber Cardiovascular events and re-stenosis following administration of G-CSF in acute myocardial infarction: systematic review and meta-analysis Heart, May 1, 2008; 94(5): 610 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Hinkel, C. El-Aouni, T. Olson, J. Horstkotte, S. Mayer, S. Muller;, M. Willhauck, C. Spitzweg, F.-J. Gildehaus, W. Munzing, et al. Thymosin {beta}4 Is an Essential Paracrine Factor of Embryonic Endothelial Progenitor Cell-Mediated Cardioprotection Circulation, April 29, 2008; 117(17): 2232 - 2240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zohlnhofer, A. Dibra, T. Koppara, A. de Waha, R. S. Ripa, J. Kastrup, M. Valgimigli, A. Schomig, and A. Kastrati Stem Cell Mobilization by Granulocyte Colony-Stimulating Factor for Myocardial Recovery After Acute Myocardial Infarction: A Meta-Analysis J. Am. Coll. Cardiol., April 15, 2008; 51(15): 1429 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Ripa, M. Haack-Sorensen, Y. Wang, E. Jorgensen, S. Mortensen, L. Bindslev, T. Friis, and J. Kastrup Bone Marrow Derived Mesenchymal Cell Mobilization by Granulocyte-Colony Stimulating Factor After Acute Myocardial Infarction: Results From the Stem Cells in Myocardial Infarction (STEMMI) Trial Circulation, September 11, 2007; 116(11_suppl): I-24 - I-30. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-F. Tse and C.-P. Lau Therapeutic Angiogenesis With Bone Marrow--Derived Stem Cells Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2007; 12(2): 89 - 97. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Sprigg, P. M. Bath, L. Zhao, M. R. Willmot, L. J. Gray, M. F. Walker, M. S. Dennis, and N. Russell Granulocyte-Colony-Stimulating Factor Mobilizes Bone Marrow Stem Cells in Patients With Subacute Ischemic Stroke: The Stem Cell Trial of Recovery EnhanceMent After Stroke (STEMS) Pilot Randomized, Controlled Trial (ISRCTN 16784092) Stroke, December 1, 2006; 37(12): 2979 - 2983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Engelmann, H. D. Theiss, C. Hennig-Theiss, A. Huber, B. J. Wintersperger, A.-E. Werle-Ruedinger, S. O. Schoenberg, G. Steinbeck, and W.-M. Franz Autologous Bone Marrow Stem Cell Mobilization Induced by Granulocyte Colony-Stimulating Factor After Subacute ST-Segment Elevation Myocardial Infarction Undergoing Late Revascularization: Final Results From the G-CSF-STEMI (Granulocyte Colony-Stimulating Factor ST-Segment Elevation Myocardial Infarction) Trial J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1712 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ben-Dor, S. Fuchs, and R. Kornowski Potential Hazards and Technical Considerations Associated With Myocardial Cell Transplantation Protocols for Ischemic Myocardial Syndrome J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1519 - 1526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lehrke, R. Mazhari, D. J. Durand, M. Zheng, D. Bedja, J. M. Zimmet, K. H. Schuleri, A. S. Chi, K. L. Gabrielson, and J. M. Hare Aging Impairs the Beneficial Effect of Granulocyte Colony-Stimulating Factor and Stem Cell Factor on Post-Myocardial Infarction Remodeling Circ. Res., September 1, 2006; 99(5): 553 - 560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pagliaro Post-infarct heart repair with granulocyte-colony stimulating factor: Is it a utopian goal? Cardiovasc Res, August 1, 2006; 71(3): 405 - 407. [Full Text] [PDF]
|
|
|
|
|
|
Y. Misao, G. Takemura, M. Arai, T. Ohno, H. Onogi, T. Takahashi, S. Minatoguchi, T. Fujiwara, and H. Fujiwara Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF Cardiovasc Res, August 1, 2006; 71(3): 455 - 465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Kang, H.-Y. Lee, S.-H. Na, S.-A Chang, K.-W. Park, H.-K. Kim, S.-Y. Kim, H.-J. Chang, W. Lee, W. J. Kang, et al. Differential Effect of Intracoronary Infusion of Mobilized Peripheral Blood Stem Cells by Granulocyte Colony-Stimulating Factor on Left Ventricular Function and Remodeling in Patients With Acute Myocardial Infarction Versus Old Myocardial Infarction: The MAGIC Cell-3-DES Randomized, Controlled Trial Circulation, July 4, 2006; 114(1_suppl): I-145 - I-151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. W. Serruys Fourth Annual American College of Cardiology International Lecture: A Journey in the Interventional Field J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1754 - 1768. [Full Text] [PDF]
|
|
|
|
 |
|
 P. S.M., M. T., S. A., Y. H.T., C. D., K. S.A., S. V.P., W. B., L. P.S., T. S.M., et al. Leaking Capillaries and White Lung in Sepsis--Is Angiopoietin 2 the Culprit?: Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans. PLoS Medicine 3: e46, 2006 J. Am. Soc. Nephrol., May 1, 2006; 17(5): 1207 - 1217. [Full Text] [PDF]
|
|
|
|
 |
|
 E. Deindl, M.-M. Zaruba, S. Brunner, B. Huber, U. Mehl, G. Assmann, I. E. Hoefer, J. Mueller-Hoecker, and W.-M. Franz G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis FASEB J, May 1, 2006; 20(7): 956 - 958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Hill and J. Bartunek The End of Granulocyte Colony-Stimulating Factor in Acute Myocardial Infarction?: Reaping the Benefits Beyond Cytokine Mobilization Circulation, April 25, 2006; 113(16): 1926 - 1928. [Full Text] [PDF]
|
|
|
|
|
|
R. S. Ripa, E. Jorgensen, Y. Wang, J. J. Thune, J. C. Nilsson, L. Sondergaard, H. E. Johnsen, L. Kober, P. Grande, and J. Kastrup 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, April 25, 2006; 113(16): 1983 - 1992. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill The Year in Interventional Cardiology J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1689 - 1706. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zohlnhofer, I. Ott, J. Mehilli, K. Schomig, F. Michalk, T. Ibrahim, G. Meisetschlager, J. von Wedel, H. Bollwein, M. Seyfarth, et al. Stem Cell Mobilization by Granulocyte Colony-Stimulating Factor in Patients With Acute Myocardial Infarction: A Randomized Controlled Trial JAMA, March 1, 2006; 295(9): 1003 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Kloner Attempts to Recruit Stem Cells for Repair of Acute Myocardial Infarction: A Dose of Reality JAMA, March 1, 2006; 295(9): 1058 - 1060. [Full Text] [PDF]
|
|
|
|
|
|
E. D. de Muinck and M. Simons Calling on Reserves: Granulocyte Colony Stimulating Growth Factor in Cardiac Repair Circulation, November 15, 2005; 112(20): 3033 - 3035. [Full Text] [PDF]
|
|