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European Heart Journal Advance Access originally published online on November 29, 2006
European Heart Journal 2006 27(24):3057-3064; doi:10.1093/eurheartj/ehl401
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Reduction in infarct size, but no functional improvement after bone marrow cell administration in a porcine model of reperfused myocardial infarction

Amber D. Moelker1, Timo Baks1,2, E.J. van den Bos1, R.J. van Geuns1,2, P.J. de Feyter1,2, Dirk J. Duncker1 and W.J. van der Giessen1,3,*

1 Department of Cardiology, Thoraxcenter, Ba 587, Erasmus MC, University Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
2 Department of Radiology, Erasmus MC Rotterdam, The Netherlands
3 Interuniversity Cardiology Institute of The Netherlands, The Netherlands

Received 1 August 2006; revised 19 October 2006; accepted 7 November 2006; online publish-ahead-of-print 29 November 2006.

* Corresponding author. Tel: +31 10 4635245; fax: +31 10 4634320. E-mail address: w.j.vandergiessen{at}erasmusmc.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Aims Stem cell therapy after myocardial infarction (MI) has been studied in models of permanent coronary occlusion. We studied the effect of intracoronary administration of unselected bone marrow (BM) and mononuclear cells (MNC) in a porcine model of reperfused MI.

Methods and results In 34 swine, the left circumflex coronary artery was balloon-occluded for 2 h followed by reperfusion. Ten swine without MI served as controls. All swine underwent magnetic resonance imaging (MRI) 1 week post-MI. The next day, 10 of the 30 surviving MI swine received BM, 10 other MI swine received MNC, and the remaining MI swine received medium intracoronary. Four weeks later, all swine underwent a follow-up MRI. One week after MI, end-diastolic volume (92±16 mL) and left ventricular (LV) weight (78±12 g) were greater, whereas ejection fraction (40±8%) was lower than in controls (69±11 mL, 62±13 g, and 53±6%). Injection of BM or MNC had no effect on the MI-induced changes in global or regional LV-function. However, there was a significant reduction in infarct size 4 weeks after MNC injection (–6±3%) compared with the medium (–3±5%).

Conclusion Intracoronary injection of BM or MNC in swine does not improve regional or global LV-function 4 weeks after injection. However, a reduction in infarct-size was noted after MNC injection.

Key Words: Myocardial infarction • Bone marrow stem cells • Left ventricular function • Magnetic resonance imaging • Infarct size • Swine


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Regeneration of infarcted myocardium by transplanting bone marrow (BM)-derived stem cells into the infarct region has been proposed to prevent heart failure by angiogenesis and/or myogenesis.1,2 Early experimental studies in animals with a myocardial infarction (MI) reported improvements in left ventricular (LV) function following cell therapy with BM-derived mononuclear cells (MNC),3 or a cell sub-population selected from MNC.1 These highly promising initial observations sparked a large number of non-randomized clinical trials, reporting beneficial effects of MNC therapy on global LV function and myocardial viability.4–8 However, out of four recent randomized trials (BOOST-update,9 Leuven trial,10 REPAIR-AMI,11 ASTAMI12), three failed to show an improvement in global LV function,9,10,12 although one reported a reduction in infarct size.10

In contrast to the discordant results obtained in clinical trials to date, the majority of experimental studies reported positive effects of MNC therapy on global LV function,3,13–15 although one study reported no effect.16 However, the beneficial effects of MNC on infarct size, which have been observed clinically,4,6,10 have not been investigated in these studies. Furthermore, all studies used a permanent coronary artery ligation, while all but one15 (which injected the MNC cells in a coronary venous vessel) injected the MNC directly in the peri-infarct area. Hence, these experimental studies have a markedly different design compared with the clinical trials. Furthermore, most animal studies used more selected, enriched populations, such as the CD34+, c-kitpos, or lin- BM-derived cells or BM-derived mesenchymal stem cells.

Consequently, we designed an experimental study that matches the clinical trial protocols more closely, using a porcine reperfused MI model and intracoronary cell injections. For this purpose, we first established cell survival and efficacy of the method of cell delivery in several pilot experiments. Subsequently, we studied the effect of BM-derived cell injection on LV geometry, function, and infarct size. MI was induced by PTCA-balloon inflation followed by reperfusion. LV remodelling as well as global and regional LV function was assessed using cine-magnetic resonance imaging (cine-MRI). Contrast-enhanced MR Imaging (Ce-MRI) was used to assess infarct size and infarct remodelling over time.

Although the clinical trials suggest that intracoronary BM-derived cell delivery appears safe, recently Yoon et al.17 reported increased calcifications after unselected BM cell injection. Therefore, we compared the effects of MNC to those of unselected BM.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Experiments were performed in 2–3-month-old Yorkshire-Landrace pigs of either sex (n=49), in compliance with the ‘Guide for the Care and Use of Laboratory Animals’ (NIH publication 1996) and after approval of the Animal Care Committee of the Erasmus MC.

Myocardial infarction
Animals were sedated (ketamine 20 mg/kg im and midazolam 1 mg/kg im), anesthetized (thiopental, 12 mg/kg iv), intubated and mechanically ventilated with a mixture of oxygen and nitrogen (1 : 2 vol/vol). Anaesthesia was maintained with fentanyl (12.5 µg/kg/h) and isoflurane (0.6–0.8% started after onset of occlusion). Subsequently, animals received antibiotic prophylaxis (200 mg procainebenzylpenicillin and 250 mg dihydrostreptomycinesulfate im) and underwent coronary catheterization through a carotid artery guided by fluoroscopy, followed by balloon occlusion of the proximal left circumflex coronary artery (LCX), for 2 h followed by reperfusion. Heparin was administered every hour (5000 Units).

BM aspiration and preparation
One week after MI, animals were anesthetized as described above and anaesthesia was maintained with 1–1.5% isoflurane. Approximately 40 mL of BM was aspirated from the iliac crest, using the same BM aspiration/biopsy needles (Kendall monoject, Tyco Healthcare, Gosport, UK) that are routinely used for clinical purposes in our hospital. MNC were isolated by Ficoll Paque-plus (Amersham Biosciences Europe GmbH, Freiburg, Germany) density gradient separation (25 min at 400 g) and suspended in 10 mL Modified Eagle's Medium (MEM). Crude BM (40 mL) was prepared for injection by filtering through a 100 micron filter. MNC were counted using a cell counter (Sysmex CDA 500, Malvern Instruments Ltd, Malvern, UK). In view of the identical volume of BM that was aspirated, the amount of MNC administered in either group was considered to be similar. BM and MNC were injected within 1 h after aspiration.

Efficacy of cell delivery
To investigate the efficacy of cell delivery, we tested injection with a selective, non-flow-limiting injection catheter (Multifunctional probing, Boston Scientific Co., Boston, MA, USA). One week after MI, BM was aspirated and five swine received an intracoronary injection of ~50x106 PKH-labelled MNC (PKH 26, Sigma-Aldrich, Schnelldorf, Germany) suspended in 10 mL saline; 5 mL was injected into the LCX (infarct area). The other 5 mL was injected into the left anterior descending coronary artery (LAD; non-infarct area) to investigate if cell injections cause micro infarctions.18 MNC were injected slowly (1 mL/min) into the coronary artery perfusing the MI area using a probing catheter. The site of injection was identical to the position of the occlusion balloon during MI induction. Four days after cell injection, animals were sacrificed for histological and immunocytochemical analyses.

Functional assessment
A total of 34 swine underwent MI as described above and 10 swine without MI served as controls for normal cardiac growth and function.

One week after induction of MI, all swine were anaesthetized as described above and underwent MRI to assess global and regional LV function. Then, 20 of the 30 surviving MI swine were randomized to undergo a BM aspiration after which 10 MI swine received an intracoronary injection of ~40 mL unselected autologous BM and 10 swine received an intracoronary suspension of MNC, a total of ~5x108 cells in 10 mL MEM. The remaining 10 MI swine received an intracoronary injection of 10 mL of MEM. The site of injection was identical to the position of the occlusion balloon one week before, and cells were slowly injected into the coronary artery (1 mL/min). Investigators were not blinded to treatment.

Four weeks later, animals underwent follow-up MRI for assessment of LV function and infarct size, after which animals were sacrificed for histological analysis of the LCX perfused area and remote area of the left ventricle.

Magnetic resonance imaging
Data acquisition
A clinical 1.5 Tesla MRI with a dedicated cardiac four element phased-array receiver coil was used for imaging (Signa CV/i, GE Medical systems, Milwaukee, WI, USA).19 Repeated breath-holds and gating to the ECG were applied to minimize the influence of cardiac and respiratory motion on data collection. To cover the entire left ventricle, six to eight consecutive slices of 8 mm were planned in the short-axis view, perpendicular to the long-axis four-chamber view of the left ventricle (gap=0). DE imaging was performed to assess total myocardial infarct mass 10–20 min after administration of gadolinium-DTPA (0.5 mmol/kg, Magnevist®, Schering).19 We have previously shown an excellent correlation between histological (TTC staining) and MRI (delayed enhancement) assessment of infarct size.19

Image analysis
The MR images were analysed with dedicated cardiac software (Cine display application 3.0, General Electric medical systems, USA).19 End-diastolic volume (EDV), end-systolic volume (ESV) and LV weight (LVW) were measured and stroke volume (SV=EDV-ESV), ejection fraction [EF=(SV/EDV)x100%], and cardiac output [CO=SVxheart rate (HR)] were computed. End-diastolic wall thickness (EDT) and end-systolic wall thickness (EST) were measured in 18 sections per slice, and regional systolic wall thickening (SWT) was calculated as (EST–EDT)/EDTx100%. Baseline and endpoint scans were matched for location using anatomical landmarks like insertion of the right ventricle to the septum and the papillary muscles.19

Histology and immunohistochemistry
The hearts were excised and cut into 6–8 transverse slices similar to the MRI short-axis slices. From the basal plane the first, third, fifth, and seventh slices were fixed in 4% buffered formaldehyde and embedded in paraffin. The second, fourth, sixth, and eight slices were embedded in tissue tec OCT and frozen in liquid nitrogen. Sections (5 µm) were stained with haematoxylin eosin (H&E) and resorcin-fuchsin (collagen). Immunohistochemistry was performed in the infarct sections to determine the expression of the pan-leukocyte marker CD45 (MCA1447, Setotec, Oxford, UK), macrophage surface marker (MAC378, Setotec, Oxford, UK), vimentin (Clone DE-R-11, DakoCytomation, California, USA), and desmin (Clone V9, DakoCytomation, California, USA). Desmin is expressed by myocytes and smooth muscle cells; vimentin is expressed by fibroblasts and endothelial cells.

Sections were semi-quantitatively assessed as negative (0) or the degree (from 1 to 5) of calcium deposition, collagen deposition, and vascularization. The infarct sections were scored for surface area covered with collagen, calcifications, or vascularization. In each animal, one section was scored per LV slice (corresponding with each of the 5–6 MRI LV short-axis slices). For each section, the total infarct area was scored (power field 10x).

Statistical analysis
Data were analysed with SPSS 11.0. All data were analysed using a one-way ANOVA and post hoc analysis using unpaired t-testing with Bonferoni correction to test for significant intergroup differences at corresponding time points. Effect of BM and MNC therapy at the follow-up MRI was tested using analysis of co-variance (ANCOVA) with baseline values as covariate. Statistical significance was accepted when P<0.05 (two-tailed). All data are presented as mean±SD.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Acknowledgements
 References
 
Efficacy of cell delivery
In three additional in vitro experiments, trypan blue exclusion staining showed that 99.7% of the cells were viable after the aspiration procedure. Furthermore, following subsequent injection through the probing catheter, 99.5% of the aspirated cells were viable. These results indicate negligible cell loss due to the BM cell aspiration and handling.

PKH labelled cells could be detected in the infarcted LV lateral wall of five swine, 4 days after injection into the LCX, whereas only a few cells (<1 cell/cm2) could be detected in the healthy non-infarcted LV anterior wall following injection into the LAD (Figure 1). Systematic histological analysis did not reveal any myocardial damage in the normal LAD-perfused myocardium. Quantative analysis showed that an average of 248±136 PKH positive cells/cm2 could be detected in the infarct zone, 4 days after injection with a probing catheter, corresponding to ~6.5% of the injected cells.


Figure 4011
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  		Figure 1 PKH-labelled cells do not home to healthy myocardium (A), but PKH positive cells (in red) home in infarcted myocardium after injection with a probing catheter (B).

 
Functional assessment of cell therapy
Infarct-related mortality
A total of 44 swine entered the study. Out of 34 MI swine, three animals encountered ventricular fibrillation during the 2 h occlusion, for which they were treated successfully by DC shock. Four animals died prematurely, of which three died within 24 h after induction of MI, while one animal died shortly after the baseline MRI (i.e. prior to any therapeutic intervention). Consequently, 40 surviving animals completed the protocol.

Magnetic resonance imaging
MI swine had a transmural MI of the lateral LV wall encompassing 14.3±5% of the left ventricle. There were no differences in body weight (BW), SV, or CO between controls and MI-animals at baseline (Table 1). Due to normal growth, BW, SV, and CO increased in all four groups over the 4 week follow-up period. Consequently, there were no significant differences in BW or systemic haemodynamics during the endpoint scan (Table 1).


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  		Table 1 Systemic haemodynamics and infarct size measured by delayed enhancement

 
One week after MI, LVW, EDV, and ESV were greater, whereas EF was lower in MI compared with control swine (Figure 2). Changes in LV volumes and mass from baseline to 4 weeks after cell injection did not differ significantly between medium, BM, and MNC-treated MI-animals (Figure 2).


Figure 4012
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  		Figure 2 LV EDV, LVW, LV EF, and LV ESV at baseline (solid bars) and at endpoint (open bars) in control swine and MI swine receiving either medium, BM, or MNC. There were no significant differences (all variables P>0.20) between BM, MNC, and medium-treated MI animals in the response over the 4 week follow-up period.

 
One week after MI, there were no significant differences in diastolic wall thickness between the different groups (Figure 3). SWT in the LCX area was abolished in the MI animals compared with control, which was not affected by BM or MNC treatment.


Figure 4013
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  		Figure 3 EDT (upper panel), absolute SWT (middle panel), and percent SWT (lower panel) at baseline (solid bars) and at endpoint (open bars) in control swine and MI swine receiving either medium, BM, or MNC. There were no significant (all variables P>0.10) differences between BM, MNC, and medium-treated MI animals.

 
Infarct size measured with delayed enhancement revealed that MNC treatment resulted in a significant decrease in infarct mass from 10.8±5.5 to 8.7±4.2 g, compared with medium treatment (11.1±5.0 and 12.3±3.9 g; P=0.045 change from baseline MNC vs. medium), whereas BM treatment had no significant effect (Table 1). Similarly, there was a greater decrease in infarct size expressed as a percent of the LV in the MNC, but not in the BM-treated animals, compared with the medium-treated swine (Table 1, Figure 4).


Figure 4014
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  		Figure 4 Change in infarct size from baseline in percentage of the LV. Regression lines; *P<0.05 vs. medium-treated MI swine.

 
Histology
Histology confirmed that all MI animals had a transmural infarct in the LCX region with total loss of viable myocardium, which matched the delayed enhancement scans performed at 1 and 5 weeks after MI. All treatments resulted in extensive collagen deposition in the centre of the infarct (Figure 5). Semi-quantitative analysis showed that there were no significant differences in the degree of calcium or collagen deposition, or of vascularization (Table 2). Immunohistochemistry showed that most of the cells in the infarct area were desmin negative, vimentin positive, CD45 positive, and occasionally positive for macrophage surface marker (Figure 6), suggesting that the majority of cells were fibroblasts (vimentin), inflammatory cells (CD45 and macrophage surface marker), and endothelial cells (vimentin).


Figure 4015
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  		Figure 5 Infarct area of medium treated (A and B) compared with crude BM (C and D) and MNC (E and F) treated swine. HE staining (A,C, and E) showed many fibroblasts. RF staining showed a lot of collagen (B,D, and F).

 

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  		Table 2 Semi-quantative histology score

 

Figure 4016
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  		Figure 6: Immunohistochemistry showed that cells (brown) in the infarct are desmin negative (A; infarct border zone), but vimentin positive (B, infarct border zone in a consecutive section), CD45 positive (C; central infarct zone), and that macrophages are present (D; central infarct zone).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Acknowledgements
 References
 
The present study investigated the effect of intracoronary injection of MNC or BM on LV function and histology at 4 weeks in a porcine model of acute MI followed by reperfusion. Our study shows that in swine an intracoronary injection of both MNC and unselected BM 1 week after MI does not improve global or regional indices of LV function 4 weeks later. In addition, BM-derived MNC or unselected BM treatment did not reverse the remodelling of the left ventricle induced by the MI. However, MNC reduced infarct size 4 weeks after injection, a finding also reported in the clinical study by Janssens et al.10

Infarct size reduction
From the present study, we cannot determine the underlying mechanism for the infarct size reduction by MNC treatment. Although it has been shown that BM-derived cells can differentiate into cardiomyocytes in vitro, it remains unclear whether BM-derived stem cells are capable of differentiating into cardiomyocytes in vivo,20–22 especially in large mammals. Conversely, it has been shown that stem cells engraft in the myocardium and induce angiogenesis23 that could result in improved perfusion, particularly in the border zone. It could be speculated that this might aid in preventing further ischaemic damage, thereby rescuing viable tissue in the border zone; alternatively, the MNC-induced angiogenesis may enhance infarct healing.24

Although there was a reduction in infarct size after MNC treatment, this was not associated with an improvement in global or regional LV function. This is in apparent contrast to the majority of preclinical studies that reported significant increases in EF or fractional shortening (Table 3). However, it should be emphasized that the experimental protocols in these studies differed considerably from the present study. For example, all these studies performed intramyocardial or intravenous cell injection in an infarct model of permanent coronary artery occlusion. In contrast, we employed a model that more closely mimics the clinical setting, by using intracoronary cell injection in a reperfused MI model, making direct comparison to previous preclinical studies difficult.


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  		Table 3 Overview of preclinical studies on the effects of MNC on global LV function after MI

 
Several explanations can be forwarded why cardiac function failed to improve after intracoronary injection of MNC or BM in the MI zone.

Timing of cell administration
Inspection of Table 3 suggests that in permanent ligation MI models, the timing of MNC administration does not appear to be critically important. Thus, MNC injections either immediately or up to 2 weeks after MI were reported to improve global LV function. In contrast, the optimal timing of stem cell delivery in reperfused MI remains incompletely understood. However, the REPAIR-AMI trial showed that the optimal timing of cell injection appears to be at least 5 days after MI.25 Also Bartunek et al.26 suggest that 3 to 10 days post-MI is the optimal timing of cell therapy. We chose to inject cells 1 week after MI, with the underlying idea that the acute inflammatory response is most pronounced shortly after MI, whereas the inflammatory response is diminished 1 week later, thus creating a better environment for injected cells. Therefore, the lack of functional benefit of BM-derived cells in this study cannot be explained by the timing of cell administration. It is likely that a proximal 2 h during LCX occlusion, followed by reperfusion creates a transmural infarct that represents a too hostile environment for injected cells to contribute to LV function recovery.

Route of administration
In contrast to previous experimental studies, which either used intramyocardial or retrograde coronary venous injection (Table 3), clinical trials have invariably used intracoronary arterial injections of MNC. Intracoronary injected cells are thought to disappear from the coronary circulation into liver, lung, or kidney within a few hours.27 Therefore, in clinical trials the intracoronary cell delivery typically involves repeated proximal balloon occlusion during cell delivery in order to prevent wash-out of cells and facilitate attachment of the injected cells onto the vascular wall.28 We observed that only ~6.5% of the injected MNC were present in the infarcted area 4 days after injection, which could be interpreted to suggest that the injection via the probing catheter could have resulted in suboptimal cell delivery. Therefore, in 5 additional MI pigs, MNC were injected intracoronary via an over-the-wire balloon catheter during repetitive balloon occlusions and pigs were sacrificed 4 days later. These experiments yielded a similar number of PKH positive cells (252±144 cells/cm2) in the infarct area as with the probing catheter. These findings indicate that injection during balloon occlusion does not result in better cell engraftment, and that the low number of MNC present in the infarct area 4 days after injection is not the result of the probing catheter.

The cell delivery study showed that injection of MNC in healthy myocardium did not induce myocardial damage. In contrast, intracoronary injection of BM-derived mesenchymal stromal stem cells have been shown to cause microinfarctions18 in dogs. No PKH positive cells could be detected in the LAD area (in contrast to the MI area). It is important to note that the MNC are smaller in size (5–7 µm as measured with the Sysmex Cell Counter) than cultured mesenchymal stem cells (~20 µm18), and therefore MNC are less likely to occlude micro vessels after intracoronary injection.

Follow-up time
It could be argued that the lack of effect of MNC on global LV function, despite the reduction in infarct size, was due to the relatively short follow-up period of 4 weeks. However, inspection of Table 3 shows that previous studies3,13–15 in swine did report improvement in cardiac function 3 or 4 weeks after MNC injections, although these were performed in a model of permanent coronary artery occlusion. Furthermore, recent clinical trials such as the ASTAMI-trial,12 the BOOST-update,9 and the trial performed in Leuven10 do not suggest that a longer follow-up will lead to an improvement in LV function. Thus, the BOOST-update showed that 18 months after MNC administration, the intergroup comparison between MNC-treated group and placebo was no longer significant. The ASTAMI-trial as well as the Leuven trial also did not see a beneficial effect on EF or EDV after MNC injection after 6 and 4 months. The preclinical study by Dai et al.29 showed a similar trend as the BOOST-update, in that the initial positive effect observed at 4 weeks was lost after 6 months. Taken together, the weight of available evidence from experimental and clinical studies suggests that a longer follow-up period may not yield a significant improvement in LV function.

Infarct composition
There were no significant differences between the MI group receiving medium, and either BM or MNC with respect to the histology. In all MI swine, a transmural infarct was observed with transmural loss of viable myocytes. There were no signs of cardiomyocyte regeneration since immunohistochemistry showed that all cells in the infarct were inflammatory cells, fibroblasts, or capillaries. A transmural infarct seems a hostile environment for the undifferentiated stem cells in the mononuclear fraction. It is not unlikely that MNC will differentiate into fibroblasts in such an environment, and therewith contribute to infarct reduction by infarct remodelling, i.e. scar contracture, but do not contribute to contractility.

Yoon et al.17 reported that injection of unselected BM aggravated calcifications within the infarct zone. Similarly, we observed a trend towards increased calcifications following BM administration, but this failed to reach statistical significance (P=0.084). Together with the lack of effect of BM on infarct size in the present study, these observations support the concept that MNC should be favoured over unselected BM.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Acknowledgements
 References
 
In a porcine model of MI followed by reperfusion, we could not demonstrate improvements in global or regional LV-function by the injection of BM-derived MNC. However, we did observe a reduction in infarct size 4 weeks after MNC-injection, which is in accordance with recent clinical observations.10


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
References
 
The authors gratefully acknowledge Marcel de Jong from the Cardiology department of the Erasmus MC for the isolation of the MNC. Financial support by ESA ESTEC (AO-99-LSS-006) is gratefully acknowledged.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

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  4. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918.
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  6. Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM. (2004) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 44:1690–1699.[Abstract/Free Full Text]
  7. Dobert N, Britten M, Assmus B, Berner U, Menzel C, Lehmann R, Hamscho N, Schachinger V, Dimmeler S, Zeiher AM, Grunwald F. (2004) Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT. Eur J Nucl Med Mol Imaging 31:1146–1151.[ISI][Medline]
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  10. 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. (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367:113–121.[CrossRef][ISI][Medline]
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