European Heart Journal Advance Access originally published online on May 23, 2008
European Heart Journal 2008 29(14):1772-1782; doi:10.1093/eurheartj/ehn216
Published by Oxford University Press on behalf of the European Society of Cardiology 2008
Intracoronary infusion of autologous mononuclear cells from bone marrow or granulocyte colony-stimulating factor-mobilized apheresis product may not improve remodelling, contractile function, perfusion, or infarct size in a swine model of large myocardial infarction
1 Cardiovascular Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA
2 Department of Nuclear Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
3 Haematology Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA
4 Pathology Core, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA
5 Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
Received 29 September 2007; revised 6 April 2008; accepted 6 May 2008; online publish-ahead-of-print 23 May 2008.
* Corresponding author: NHLI, Imperial College London, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, UK. Tel: +44 20 73518626, Fax: +44 20 73518629. Email: r.desilva{at}imperial.ac.uk
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Abstract |
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Aims: In a blinded, placebo-controlled study, we investigated whether intracoronary infusion of autologous mononuclear cells from granulocyte colony-stimulating factor (G-CSF)-mobilized apheresis product or bone marrow (BM) improved sensitive outcome measures in a swine model of large myocardial infarction (MI).
Methods and results: Four days after left anterior descending (LAD) occlusion and reperfusion, cells from BM or apheresis product of saline- (placebo) or G-CSF-injected animals were infused into the LAD. Large infarcts were created: baseline ejection fraction (EF) by magnetic resonance imaging (MRI) of 35.3 ± 8.5%, no difference between the placebo, G-CSF, and BM groups (P = 0.16 by ANOVA). At 6 weeks, EF fell to a similar degree in the placebo, G-CSF, and BM groups (–7.9 ± 6.0, –8.5 ± 8.8, and –10.9 ± 7.6%, P = 0.78 by ANOVA). Left ventricular volumes and infarct size by MRI deteriorated similarly in all three groups. Quantitative positron emission tomography (PET) demonstrated significant decline in fluorodeoxyglucose uptake rate in the LAD territory at follow-up, with no histological, angiographic, or PET perfusion evidence of functional neovascularization. Immunofluorescence failed to demonstrate transdifferentiation of infused cells.
Conclusion: Intracoronary infusion of mononuclear cells from either BM or G-CSF-mobilized apheresis product may not improve or limit deterioration in systolic function, adverse ventricular remodelling, infarct size, or perfusion in a swine model of large MI.
Key Words: Angiogenesis • Imaging • Myocardial infarction • Myogenesis • Stem cell
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Introduction |
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Pre-clinical investigations of bone marrow (BM)-derived progenitor cell therapy in large animal models of acute myocardial infarction (MI), with prognostically significant reductions of left ventricular function, have not been reported. This would appear valuable given the increasing clinical interest in cardiac regenerative strategies for such patients.1 We therefore performed a blinded, placebo-controlled study of intracoronary infusion of autologous mononuclear cells derived from either cytokine-mobilized apheresis product or BM in a swine model of large MI.
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Methods |
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Animal procedures
Animal procedures were approved by the NHLBI Animal Care and Use Committee. The experimental protocol is summarized in Figure 1. Twenty-four Yucatan miniswine (wt 37–52 kg) underwent 90 min balloon occlusion of the left anterior descending (LAD) artery as described previously.2
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In a blinded fashion, animals were alternately assigned to receive no injections or daily subcutaneous injections of either human recombinant granulocyte colony-stimulating factor (G-CSF, n = 8, 10 µg/kg, Neupogen, Amgen) or placebo (n = 7, equal volume of normal saline) for five days. The first injection was administered after LAD occlusion and daily thereafter. All injected animals underwent apheresis. Animals receiving no injections underwent BM aspiration (n = 7) without apheresis. Animals in the placebo group formed the cellular control against which the G-CSF and BM groups were compared.
Apheresis and bone marrow aspiration
Apheresis was performed using citrate anticoagulant in a 1:13 ratio to the whole blood flow rate. Aseptic BM aspiration from both iliac crests was performed under general anaesthesia.
Cell preparation
Immediately after apheresis or BM aspiration, the cellular product was prepared for infusion. The product was incubated with ammonium chloride (ACK, BioWhittaker), washed, labelled with CM-DiI (Molecular Probes) according to the manufacturer's instructions, and resuspended in plasmalyte A/2% human serum albumin which was heparinized (30 U/mL).
Colony-forming assays
Haematopoietic colony-forming assays were performed as an index of progenitor cell activity (Supplementary Methods). The combined number of myeloid [colony-forming unit (CFU) G/M] and erythroid (BFU E) colonies counted 2 weeks after plating determined the total number of CFUs. The number of colony-forming cells (CFCs) was calculated assuming one CFU per CFC. All procedures were performed by investigators blinded to treatment allocation and imaging results.
Intracoronary cell infusion
Intracoronary cell infusion was performed into the LAD as reported previously,3 by investigators blinded to the identity of the cell product, followed by coronary angiography to confirm vessel patency.
Positron emission tomography
Dynamic positron emission tomography (PET) was performed using a GE Advance scanner (GE Medical Systems). Myocardial blood flow was measured at rest and during adenosine infusion (140 µg/kg/min) using a bolus administration of 50 mCi of oxygen-15-labelled water (H215O).4 Myocardial fluorodeoxyglucose (FDG) uptake rate was measured after intravenous administration of fluorine-18 FDG (15 mCi) under a hyperinsulinaemic euglycaemic glucose clamp.5
Magnetic resonance imaging
Magnetic resonance imaging (MRI) was performed at 1.5 T (Sonata, Siemens Medical Systems) using an eight-channel phased array surface coil (Nova Medical Inc.). Breath-held, ECG-gated cine steady-state free precession (SSFP) MRI was acquired [TR/TE 3.6/1.8 ms; flip angle 65°; field of view (FOV) 300 x 244 mm; matrix 256x127 pixels; slice thickness 8 mm; bandwidth 1085 Hz/pixel]. Delayed enhancement (DE-MRI) images were acquired after intravenous Gd-DTPA (0.2 mmol/kg) using a phase-sensitive inversion recovery sequence (TR/TE 11/4.45 ms; flip angle 30°; inversion time 300 ms; FOV 350 x 241 mm; matrix 256 x 141 pixels; slice thickness 8 mm; bandwidth 140 Hz/pixel).
Follow-up
At 6 weeks, animals returned for cardiac catheterization, MRI, and PET after which they were euthanized. Tissues were prepared for histology (Supplementary data).
Data analysis
All analyses were performed by investigators blinded to treatment allocation after six animals in each group had completed the protocol.
Magnetic resonance imaging
All images were analysed on a Leonardo workstation (Siemens). Ejection fraction (EF), end-systolic volume (ESV), end-diastolic volume (EDV), and stroke volume (SV) were calculated. Regional wall thickening was determined using a 16-sector model. Sectors were categorized as either hypokinetic (wall thickening >0 and <1.5 mm) or akinetic (wall thickening 
0 mm). Infarct volumes were quantified from DE-MRI images using a previously validated tool which automatically windows, levels, and contours images of infarcted regions.6
Positron emission tomography
PET and MRI images were registered (Supplementary data). Manually segmented infarct, peri-infarct, and remote myocardial regions on MR images were transformed on to PET images for kinetic analysis. Myocardial blood flow values in the infarct, peri-infarct, and remote regions were calculated from the dynamic H215O data.4 The ratio of myocardial blood flow during adenosine infusion to resting myocardial blood flow was defined as the adenosine vasodilator response. Rate constants for net myocardial FDG uptake (Ki) were calculated using Patlak analysis. Parametric Ki images were generated on a pixel-by-pixel basis in each animal.7 Partial volume correction of the FDG data was based on the H215O data for corresponding regions.
Statistics
The primary endpoint was change in EF from baseline to 6 weeks. Secondary endpoints included EF, EDV, ESV, SV, and infarct volume at 6 weeks. Data were assessed for normality using the Kolmogorov–Smirnov method. Continuous parameters are shown as mean ± SD. Data were analysed using one-way ANOVA with specific intergroup comparisons made using unpaired Student's t-tests with Bonferroni correction for multiple comparisons. P < 0.05 was considered significant.
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Results |
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Six of 24 animals failed to complete or were excluded from the protocol due to death before intracoronary cell infusion (n = 4), severe biventricular failure due to extensive left and right ventricular infarction 7 days after cell delivery (n = 1, G-CSF), or baseline MRI scanner failure (n = 1, BM). Data are presented from 18 animals. G-CSF increased total leukocyte count and CFC concentration in peripheral blood (Supplementary data). The composition of infused cells is summarized in Table 1. Trypan blue viability for all cellular products was >90%. The weight-adjusted dose of CFCs administered by intracoronary infusion was similar in the G-CSF and BM groups (8.04 ± 4.13 x 103 vs. 7.27 ± 3.38 x 103 CFCs/kg) (Table 1).
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Apheresis was tolerated in all animals despite recent large MIs. Intracoronary cell infusion was performed successfully and without complication in 18/19 animals. In one G-CSF-treated animal, receiving the highest infused dose of total nucleated cells (1.57 x 109 cells/kg), no reflow occurred.
At 6 weeks, there was no haemodynamic improvement in any group. Cardiac output was maintained by increased heart rate, not improved SV (Supplementary data). Coronary angiography revealed no collateralization of the LAD territory.
Large infarcts were created as evidenced by baseline EF of 34.3 ± 9.7, 31.2 ± 7.8, and 40.4 ± 6.0% in the placebo (n = 6), G-CSF (n = 6), and BM (n = 6) groups, respectively (P = 0.16 by ANOVA) (Table 2). EF, ESV, and EDV deteriorated in all groups at 6 weeks. There was no significant difference in any parameter between treatment groups (Figure 2). At 6 weeks, the number of sectors with a wall motion abnormality increased to a similar degree in all three groups (Figure 3), with an increasing proportion of akinetic segments (Table 3). After completing blinded analyses, assuming the null hypothesis could be rejected, we estimated that n = 134 pigs per group would be required to achieve 80% power to detect a significant difference (P < 0.05) in change in EF from baseline to 6 weeks of follow-up. The study was therefore terminated on grounds of futility.
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Transmural-delayed enhancement was evident in the antero-septal wall in all animals at baseline (Figure 4). At 6 weeks, transmural-delayed enhancement persisted consistent with non-viable myocardium. These regions underwent significant thinning and expansion, and accordingly, the mass of tissue showing delayed enhancement at follow-up was reduced (Figure 4).
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Quantitative myocardial FDG uptake (Ki) images before intracoronary cell infusion demonstrated preserved or enhanced FDG uptake in sectors showing transmural-delayed enhancement (Figure 5). At follow-up, these regions thinned, and exhibited markedly reduced FDG uptake despite partial volume correction, suggesting non-viable infarcted myocardium (Figures 5 and 6). Ki calculated on remote, infarct, and peri-infarct regions reflected a similar trend.
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Adenosine vasodilator response, an index of coronary microcirculatory function, was measured in the infarcted and peri-infarct myocardium at baseline and at 6 weeks follow-up and was not different in any of the three groups in the peri-infarct regions (Figure 7).
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Haematoxylin and eosin and Masson's trichrome-stained sections from the border and infarct zones of the hearts in all three groups demonstrated equivalent degrees of myocyte hypertrophy, myocyte degeneration, oedema, fibrosis, inflammatory cell infiltrate, haemorrhage, and vascular density. These findings are inconsistent with myocyte regeneration or neovascularization in any group.
Confocal microscopy demonstrated persistent CM-DiI-labelled cells. There was no difference in the density of arterioles staining positive for alpha smooth muscle actin between the three groups (Supplementary data). There was no specific co-localization of CM-DiI-labelled cells with stains for CD31, desmin, or vimentin (Figure 8). There was evidence of co-localization of CM-DiI cells with CD45 staining, suggesting that some of the labelled cells retained a leukocyte lineage (Supplementary data). These observations do not support transdifferentiation of infused cells.
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Discussion |
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In this blinded study, intracoronary infusion of mononuclear cells from BM or G-CSF-mobilized apheresis product failed to improve adverse remodelling, global or regional contractile function, rest and stress perfusion, or viability in an animal model of large prognostically significant reperfused antero-septal MI. If cell treatment were efficacious, a noticeable treatment effect could be anticipated in this experimental model, given the combination of large infarct size and assessments using highly sensitive measurement tools capable of detecting subtle changes in global and regional parameters of myocardial function. In addition, there was no evidence of myocyte regeneration, or neovascularization in the G-CSF or BM groups. Although a treatment effect cannot be excluded, we thought this unlikely and hence were doubtful that submission of additional animals to this protocol would alter the result. Therefore, consistent with previously reported pilot studies,8 our investigation was terminated and unblinded.
Our observations were made in a model where mean baseline EF was 35.3 ± 8.5%. This is analogous to post-infarct patients at high risk of developing adverse ventricular remodelling and cardiac failure. Such patients would benefit considerably from safe and effective regenerative strategies and are the focus of a number of clinical trials of cellular therapy. Cardiac MRI is the modality of choice for quantifying ventricular remodelling as well as global and regional left ventricular functions. This technique is infrequently used in pre-clinical investigations of cellular therapies.9 Consistent with the findings of our study, recent clinical reports employing quantitative assessments of ventricular function by MRI failed to demonstrate early or long-term benefit of G-CSF therapy10–12 or intracoronary administration of BM-derived mononuclear cells13–15 in subjects with acute MI. In addition, we did not observe improvements in regional contractile function, with an increasing proportion of akinetic segments at follow-up.
We quantified infarct size from DE-MRI using a semi-automated tool that reduces potential bias introduced by manual windowing, levelling, and segmentation of images.6 Imaging performed before intracoronary cell infusion demonstrated extensive transmural-delayed enhancement in the antero-septal myocardium. The mass of tissue showing delayed enhancement was similar in all three groups (Figure 6). At follow-up, this measurement declined significantly, consistent with recent reports.3,9,13 This appears owing to tissue loss, wall thinning, and scar contracture rather than replacement of infarcted myocardium with viable tissue (Figure 6). These observations are characteristic of the natural history of DE-MRI in reperfused MI.16,17 The decrease in the mass of tissue showing delayed enhancement may therefore not represent evidence of myocardial regeneration as proposed by other investigators.3,13 Interestingly, FDG-PET imaging performed before intracoronary cell infusion demonstrated preserved and in many cases enhanced uptake in regions of myocardium showing transmural-delayed enhancement. We believe this is explained by FDG uptake by the intense inflammatory cell infiltration that occurs in reperfused myocardium18 rather than FDG being taken up by metabolically active viable cardiac myocytes. At follow-up, FDG uptake in the infarcted myocardium reduced (Figures 7 and 8), indicative of metabolically inactive non-viable myocardium. Histopathological examination demonstrated extensive transmural infarction with no evidence of transdifferentiation (Figure 8), cardiac regeneration, or neovascularization (Supplementary data).
Certain haematopoietic progenitor cell populations may be angiogenic.19 Histological assessment of the density of vascular structures in peri-infarct and infarcted regions was similar in all three groups (Supplementary data). Furthermore, the number of arterioles staining positive for anti-smooth muscle actin was similar in all three groups (Supplement data). Adenosine vasodilator response measured quantitatively in the peri-infarct regions with H215O-PET showed no improvement and was similar in all three groups (Figure 7). Selective coronary angiography failed to demonstrate collateral growth. These data do not support functional neovascularization in this model.
Clinical studies have reported few immediate procedural complications from infusion of mononuclear cells into infarct-related coronary arteries. The total nucleated cell dose in these studies has progressively increased from 9 x 106 to 24.6 ± 8.4 x 108.3,13,15,20,21 In one animal, no reflow was observed at the highest infused total nucleated cell dose. Pending results from further dose escalation studies, we would caution against exceeding this intracoronary cell dose in clinical studies.
Study limitations
We recognize the limitations of simulating human clinical disease using animal models. Unlike many clinical observations where EF improves after reperfusion in MI,22 we observed a consistent decrease in EF in all groups. This has been observed in clinical studies23 and may be due to the extensive MIs created in this study.24 The small number of animals reflects the pilot nature of this protocol and is consistent with sample sizes in previously published pre-clinical investigations using large animals.25,26 We estimated that approximately 400 animals should be studied to detect a significant difference (beneficial or otherwise) between the treatment groups. Although the sample size in this study is small, the measurement techniques were highly sensitive and reproducible and performed in a model of large infarction in which any benefits should have been easily discerned. Our results in part may be explained by the use of an unselected cell product. Currently, clinically relevant progenitor cell populations cannot be selected in swine owing to lack of appropriate antibodies. Furthermore, intramyocardial rather than intracoronary cell delivery may be more efficacious in this model system. The follow-up time point in the current study was chosen, as previous pre-clinical investigations have demonstrated functional improvements by this time which plateau thereafter.9,25–28 A cellular control (mononuclear cells from non-mobilized apheresis product) was chosen to maintain the study blind and help determine whether the test cell populations would exert any effect over and above simple interstitial reinforcement of the infarct region.29 We cannot exclude the possibility that all three cell populations administered in the current study conferred improvement relative to an acellular control, though this seems unlikely as previous studies have not shown benefit over intracoronary administration of medium on EF in reperfused MI.9
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsSupplementary materialFundingAcknowledgementsReferences |
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Intracoronary infusion of mononuclear cells from either BM or G-CSF-mobilized apheresis product may not improve or limit deterioration of left ventricular systolic function, rest or stress perfusion, and infarct size in a swine model of large prognostically significant reperfused antero-septal MI. These cell populations may not necessarily confer benefit to analogous patient populations. Studies in animal models of large reperfused MI which employ local delivery systems and endpoint assessments equivalent to those used in contemporary clinical studies may represent an essential step in selecting cellular products that ultimately demonstrate sustained therapeutic benefit in clinical trials.30
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Supplementary material |
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Supplementary material is available at European Heart Journal online.
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Funding |
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This work was supported by NIH Z01-HL005062-04 (R.J.L.).
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Acknowledgements |
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We thank Kathryn Hope, Katherine Lucas, and Joni Taylor for their expert animal care; William Schenke and Victor Wright for technical assistance; Cengizhan Ozturk and Ludovic Le Meunier for assistance with MRI and PET imaging; Peter Kellman for the phase-sensitive inversion recovery sequence; Li-Yueh Hsu for infarct volume analysis software. We are grateful to Dawson Smith of Gambro BCT for providing the Cobe Spectra system. Amgen provided Neupogen (recombinant human G-CSF) under a materials collaborative research and development agreement with NIH. Finally, we pay tribute to and posthumously thank Charles Carter for his invaluable contribution without which this study would not have been possible.
Conflict of interest: none declared.
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References |
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- Penn MS. Stem-cell therapy after acute myocardial infarction: the focus should be on those at risk. Lancet (2006) 367:87–88.[CrossRef][Web of Science][Medline]
- de Silva R, Gutierrez LF, Raval AN, McVeigh ER, Ozturk C, Lederman RJ. X-ray fused with magnetic resonance imaging (XFM) to target endomyocardial injections: validation in a swine model of myocardial infarction. Circulation (2006) 114:2342–2350.
[Abstract/Free Full Text] - Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet (2004) 364:141–148.[CrossRef][Web of Science][Medline]
- Bonow RO, Dilsizian V, Cuocolo A, Bacharach SL. Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction. Comparison of thallium scintigraphy with reinjection and PET imaging with 18F-fluorodeoxyglucose. Circulation (1991) 83:26–37.
[Abstract/Free Full Text] - Chareonthaitawee P, Schaefers K, Baker CS, Turkheimer F, Stegger L, Banner NR, Yacoub M, Bonser RS, Iozzo P, Camici PG, Rimoldi O. Assessment of infarct size by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose: a new absolute threshold technique. Eur J Nucl Med Mol Imaging (2002) 29:203–215.[CrossRef][Web of Science][Medline]
- Hsu LY, Natanzon A, Kellman P, Hirsch GA, Aletras AH, Arai AE. Quantitative myocardial infarction on delayed enhancement MRI. Part I. Animal validation of an automated feature analysis and combined thresholding infarct sizing algorithm. J Magn Reson Imaging (2006) 23:298–308.[CrossRef][Web of Science][Medline]
- Choi Y, Hawkins RA, Huang SC, Gambhir SS, Brunken RC, Phelps ME, Schelbert HR. Parametric images of myocardial metabolic rate of glucose generated from dynamic cardiac PET and 2-[18F]fluoro-2-deoxy-D-glucose studies. J Nucl Med (1991) 32:733–738.
[Abstract/Free Full Text] - Penicka M, Horak J, Kobylka P, Pytlik R, Kozak T, Belohlavek O, Lang O, Skalicka H, Simek S, Palecek T, Linhart A, Aschermann M, Widimsky P. Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction: a prematurely terminated randomized study. J Am Coll Cardiol (2007) 49:2373–2374.
[Free Full Text] - Moelker AD, Baks T, van den Bos EJ, van Geuns RJ, de Feyter PJ, Duncker DJ, van der Giessen WJ. Reduction in infarct size, but no functional improvement after bone marrow cell administration in a porcine model of reperfused myocardial infarction. Eur Heart J (2006) 27:3057–3064.
[Abstract/Free Full Text] - Ripa RS, Haack-Sorensen M, Wang Y, Jorgensen E, Mortensen S, Bindslev L, Friis T, Kastrup J. 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 (2007) 116(Suppl. 11):I24–I30.[Web of Science][Medline]
- Ripa RS, Jorgensen E, Wang Y, Thune JJ, Nilsson JC, Sondergaard L, Johnsen HE, Kober 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.
[Abstract/Free Full Text] - 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. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA (2006) 295:1003–1010.
[Abstract/Free Full Text] - 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][Web of Science][Medline]
- 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.
[Abstract/Free Full Text] - Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Muller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med (2006) 355:1199–1209.
[Abstract/Free Full Text] - Fieno DS, Hillenbrand HB, Rehwald WG, Harris KR, Decker RS, Parker MA, Klocke FJ, Kim RJ, Judd RM. Infarct resorption, compensatory hypertrophy, and differing patterns of ventricular remodeling following myocardial infarctions of varying size. J Am Coll Cardiol (2004) 43:2124–2131.
[Abstract/Free Full Text] - Baks T, van Geuns RJ, Biagini E, Wielopolski P, Mollet NR, Cademartiri F, van der Giessen WJ, Krestin GP, Serruys PW, Duncker DJ, de Feyter PJ. Effects of primary angioplasty for acute myocardial infarction on early and late infarct size and left ventricular wall characteristics. J Am Coll Cardiol (2006) 47:40–44.
[Abstract/Free Full Text] - Go LO, Murry CE, Richard VJ, Weischedel GR, Jennings RB, Reimer KA. Myocardial neutrophil accumulation during reperfusion after reversible or irreversible ischemic injury. Am J Physiol (1988) 255:H1188–H1198.[Web of Science][Medline]
- Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med (2003) 9:702–712.[CrossRef][Web of Science][Medline]
- Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med (2006) 355:1222–1232.
[Abstract/Free Full Text] - Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation (2002) 106:3009–3017.
[Abstract/Free Full Text] - Baks T, van Geuns RJ, Biagini E, Wielopolski P, Mollet NR, Cademartiri F, Boersma E, van der Giessen WJ, Krestin GP, Duncker DJ, Serruys PW, de Feyter PJ. Recovery of left ventricular function after primary angioplasty for acute myocardial infarction. Eur Heart J (2005) 26:1070–1077.
[Abstract/Free Full Text] - Tarantini G, Razzolini R, Cacciavillani L, Bilato C, Sarais C, Corbetti F, Marra MP, Napodano M, Ramondo A, Iliceto S. Influence of transmurality, infarct size, and severe microvascular obstruction on left ventricular remodeling and function after primary coronary angioplasty. Am J Cardiol (2006) 98:1033–1040.[CrossRef][Web of Science][Medline]
- Chareonthaitawee P, Christian TF, Hirose K, Gibbons RJ, Rumberger JA. Relation of initial infarct size to extent of left ventricular remodeling in the year after acute myocardial infarction. J Am Coll Cardiol (1995) 25:567–573.[Abstract]
- Fuchs S, Baffour R, Zhou YF, Shou M, Pierre A, Tio FO, Weissman NJ, Leon MB, Epstein SE, Kornowski R. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol (2001) 37:1726–1732.
[Abstract/Free Full Text] - Silva GV, Litovsky S, Assad JA, Sousa AL, Martin BJ, Vela D, Coulter SC, Lin J, Ober J, Vaughn WK, Branco RV, Oliveira EM, He R, Geng YJ, Willerson JT, Perin EC. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation (2005) 111:150–156.
[Abstract/Free Full Text] - Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med (2001) 7:430–436.[CrossRef][Web of Science][Medline]
- 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]
- Wall ST, Walker JC, Healy KE, Ratcliffe MB, Guccione JM. Theoretical impact of the injection of material into the myocardium: a finite element model simulation. Circulation (2006) 114:2627–2635.
[Abstract/Free Full Text] - Unger EF. All is not well in the world of translational research. J Am Coll Cardiol (2007) 50:738–740.
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