Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Widimsky, P.
Right arrow Articles by Aschermann, M.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Widimsky, P.
Right arrow Articles by Aschermann, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Intracoronary transplantation of bone marrow stem cells: background, techniques, and limitations

Petr Widimsky*, Martin Penicka, Otto Lang, Tomas Kozak, Zuzana Motovska, Radovan Jirmar and Michael Aschermann

Charles University, Srobarova 50, 100 34 Praha 10, Prague, Czech Republic

* Corresponding author. E-mail address: widim{at}fnkv.cz


   Abstract
Top
 Abstract
Introduction
 Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
 Limitations
 Acknowledgements
 References
 
Experimental data on myocardial regeneration with the use of bone marrow stem cells in recent years promoted first pilot clinical trials. Currently used methodology in these pilot clinical trials is based on the aspiration of autologous bone blood, separation of cell fraction thought to contain multipotent stem cells and reinjection of this autologous cellular blood material to the patient's coronary artery during balloon occlusion of this artery. Our experience obtained during almost 3 years led us to stop prematurely one trial and to continue under strict rules another one. This new promising method could bring a true revolution in future prevention or treatment of ischaemic heart failure. However, it is today unclear, whether this is a fascinating new hope for heart failure patients or a dead end route.

Key Words: Stem cells • Intracoronary transplantation • Myocardial regeneration • Autologous bone marrow


   Introduction
Top
 Abstract
 Introduction
Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
 Limitations
 Acknowledgements
 References
 
Acute myocardial infarction with subsequent left ventricular (LV) remodelling is the leading cause of congestive heart failure and death in developed countries. The mechanisms linking myocardial infarction to poor prognosis are straightforward and well described:1,2 acute myocardial ischaemia->infarction->loss of contractile LV mass->LV dilation->heart failure->poor long-term clinical outcome. In the current era, up to 30% of patients treated by primary percutaneous coronary intervention (PCI) show ongoing LV remodelling despite sustained patency of the infarct-related artery.3 Hence, causal treatment combining both revascularization and replacement of the lost cardiac muscle cells is crucial to limit LV dilation with all its sequels.

Cardiac stem cell therapy is currently investigated as an adjunctive therapy to promote regeneration of infarcted myocardium.4 Stem cells represent specific population of cells characterized by self-renewal, multipotency (ability to differentiate into derivatives of all three germ layers when implanted into blastocyst), and clonogenicity (ability to spawn colonies of various differentiated somatic cell types).5 In adult organisms, stem cells reside in specific microenvironmental compartments (or ‘niches’) such as bone marrow.6 Human bone marrow comprises several different types of stem cells with the potential to repair experimental infarction: haematopoietic stem cells, mesenchymal (or stromal) stem cells, and progenitor cells. It is currently unknown which cell type is optimal for clinical application. Of note, in the majority of pilot clinical studies, the whole unfractionated population of bone-marrow-derived mononuclear cells (BMNCs) was used.

Transplantation of BMNCs into diseased human myocardium can be performed using either intracoronary or direct intramyocardial injection via surgical (open chest) or percutaneous (catheter-based) approach. Intracoronary approach resembles percutaneous coronary angioplasty with over-the-wire balloon. Intramyocardial approach can be either transepicardial (direct surgical injections or catheter-based via coronary venous route) or transendocardial (endoventricular). In the setting of acute myocardial infarction, the percutaneous catheter-based intracoronary injection of BMNCs is the preferred approach since it is simple, safe and thus, the most feasible in routine clinical practice. Furthermore, in pilot clinical studies, intracoronary stem cell injection was associated with improved perfusion in the infarcted area and with enhanced global LV ejection fraction, while the rate of complications did not exceed that expected in patients with acute myocardial infarction.7–10 Concept of intracoronary stem cell therapy is based on the assumption of cells engraftment at the infarction site during the transcoronary passage. Experimental as well as human studies demonstrated extravasation of BMNCs to infarcted areas after intracoronary administration.11,12 Trafficking of BMNCs to infarcted tissue is regulated by chemokines and adhesion molecules induced by ischaemic injury. Stromal cell-derived factor 1 (SDF-1) and ß2 integrins appear to be the key players for homing of stem and progenitor cells to the myocardium.13–15

The aim of the review is to summarize methodical issues and limitations of bone marrow harvesting, processing, and intracoronary transplantation, as well as the 3 year experience with this technique in our institution.


   Methodology: haematologist's view
Top
 Abstract
 Introduction
 Methodology: haematologist's...
Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
 Limitations
 Acknowledgements
 References
 
Autologous bone marrow is the rational source of stem (primitive) cells for myocardial regeneration in clinical trials at this point. The other sources rich for stem cells, including cord blood are being explored.16 Circulating blood-derived progenitor cells with ex vivo expansion or selected CD133+ cells were also used in pilot clinical trials, but there is still controversy in practical definition, isolation, and cultivation of the right bone-marrow-derived stem cell population in human setting.8,17 Therefore, use of simple suspension of nucleated (mononuclear) cells from bone marrow not to lose necessary primitive elements and/or producers of important humoral factors seems optimal at present. The other crucial question is what amount of primitive cells is enough for therapeutic use for myocardial regeneration in humans. So far, the empirical consensus for clinical studies seems to be in the range 107 to 109 mononuclear cells total.17,18

To obtain suggested amount of primitive cells, the targeted volume of 150 mL of autologous bone marrow for each patient has been chosen at our institution. Deep analgesia without need for endotracheal intubation and local anaesthesia with 20 mL 1% trimecain was used. Under aseptic conditions, the bone marrow was obtained by 10–15 aspirations at three levels from both posterior iliac crests. Two millilitres of bone marrow was obtained by each single aspiration and mixed with 1 mL heparinised normal saline in the syringe. The mixture was put to the bag of bone marrow collection kit with inline filters and then processed in closed system in the stem cell laboratory. Under the GMP, the bone marrow was mixed with Gelofusin (B.Braun, Melsungen AG, Germany) at 25% of the total bone marrow volume, underwent erythrocyte sedimentation, centrifugation, and mononuclear-cell-rich plasma extraction with cell concentration adjustment. The targeted cell concentration in the final product was 108/mL, the final volume was 24–30 mL. The cell count, immunophenotyping, and sterility control were done in each product.


   Methodology: the view of interventional cardiologist
Top
 Abstract
 Introduction
 Methodology: haematologist's...
 Methodology: the view of...
Prague pilot clinical experience
 Imaging after transplantation
 Limitations
 Acknowledgements
 References
 
Stem cells harvested from bone marrow can be transplanted into the myocardium by different modes of delivery. Direct intramyocardial injection of cells during cardiac surgery is a simple process that allows direct visualization of the target zones. However, this approach of stem cell therapy is associated with operative risk and needs open-heart surgery. Therefore, catheter-based percutaneous techniques of stem cells transplantation represent valuable alternative. Until now, three different percutaneous techniques have been successfully used.

(1) Intramyocardial transventricular injections guided by LV electromechanical mapping with NOGA system.19 This system includes a mapping catheter that implements a low-intensity, active magnetic field energy as well as sensors allowing three-dimensional real-time mapping. Areas exhibiting low voltages and linear local shortening on the NOGA map are considered as the target areas of treatment if these areas are geographically concordant with the scar areas assessed by the pre-procedural LV angiogram and magnetic resonance imaging (MRI). It is important to refrain from transendocardial injections into areas with a known wall thickness less than 5 mm by MRI. Cells may be injected directly into non-viable areas of myocardium with an 8F MYOSTAR injection catheter. The catheter has nitinol tubing that ends in a retractable needle. Depending on the average wall thickness of the target region, the needle length is set at 4.5–6 mm when catheter tip had a 90° curve. Injection catheter is pre-loaded with the cell solution and after establishing endomyocardial contact on the NOGA map and fluoroscopy, the needle is advanced manually that often cause ventricular extrasystoles. Injections of 0.3 mL are made, spacing between injection sites being approximately 1 cm, they are marked on the NOGA map and the transparent tabloids.20 After the procedure, a control LV angiogram is performed and the patient is continually ECG-monitored for 18–24 h, cardiac enzymes are checked twice in 6–8 h intervals.

(2) Intracoronary injections using over-the-wire balloon catheter represents safe mode of delivery of stem cells.10 Intracoronary administration into the infarct-related artery delivers the maximum concentration of cells to the site of infarct and peri-infarct tissue during first passage of bone blood. It allows the stem cells to home in and engraft to the areas bordering the infarct zone in a homogeneous manner. Until now, intracoronary technique has been usually used in patients with first ST-segment elevation acute myocardial infarction, treated successfully by PCI with stent implantation, and with LV dysfunction confirmed by angiography done immediately after PCI. Two to seven days after acute PCI, bone marrow is aspirated under general anaesthesia from the ilium of cell therapy patients. Bone marrow is processed according to current GMP regulations and 4–6 h after bone-marrow harvest, final suspension of bone-marrow cells is injected into the infarct-related artery. The procedure starts with LV angiography to obtain basal LV function, then using standard coronary angioplasty technique, the over-the-wire balloon catheter enters infarct-related artery and is placed above the border zone of the infarction—optimally inside the previously implanted stent. Then the balloon is inflated and cell suspension is infused under stop-flow conditions. In this way, cells are transplanted into the infarcted zone via the infarct-related vasculature. To allow bone marrow cells maximum contact time with the microcirculation of the infarct-related artery, the balloon remains inflated for 3–4 min period. The entire bone-marrow cell suspension is infused during four to six coronary occlusions, the coronary artery is reperfused after every dose of cells for 3 min, and therefore the total duration of procedure is about 45–60 min. After the procedure, a control LV angiogram is performed and the patient is continually ECG-monitored for 18–24 h, and cardiac enzymes are checked twice in 6–8 h intervals.7 According to our experience, patients do not suffer from chest pain during coronary occlusions and we did not observe arrhythmias during the cell transfer. All patients were followed at coronary care unit and till now no arrythmogenic events or haemodynamic impairments were recorded in our study group.

(3) Intramyocardial trans-coronary-vein injection (using coronary sinus and great cardiac vein) is another catheter mode of delivery. In contrast to the transendocardial approach where cells are injected perpendicular to the ventricular wall, here the composite catheter system delivers cells parallel to the ventricular wall and deep into the injured myocardium. However, positioning of the injection catheter in a specific coronary vein is very delicate in every patient.21

Theoretically, simple intravenous administration of stem cells is a practical mode of delivery—it does not require cathetarization or cardiac surgery. It is believed that microenvironmental factors, expression of adhesion molecules and cytokines, homing receptors, and other factors are involved in the process of stem cells homing in infarcted myocardium.22 However, homing of stem cells into myocardium after intravenous administration will be probably very low, due to possible homing of cells in other organs.


   Prague pilot clinical experience
Top
 Abstract
 Introduction
 Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
Imaging after transplantation
 Limitations
 Acknowledgements
 References
 
The percutaneous catheter-based intracoronary injection of bone-marrow-derived cells is by far the most frequently used clinical approach for cardiac cell-based therapies. We describe here briefly the methodology as based on our own experience.

Patients after primary PCI with stent placement in the left anterior descending coronary artery (LAD) in the acute phase of anterior ST-elevation myocardial infarction, who fulfill the inclusion and exclusion criteria to the clinical trial and give informed consent, undergo bone blood aspiration in the morning few days after the onset of infarction. Cell preparation in vitro is performed within next 3–4 h and then patients undergo left heart catheterization via femoral arterial access. Procedure usually begins with left ventriculography to evaluate the baseline LV function. Then a standard 6 French coronary angioplasty guiding catheter is placed to the ostium of the left coronary artery and a soft-tip intracoronary guide wire is introduced to the distal segment of the LAD. Antithrombotic treatment used (including the dose of periprocedural unfractionated heparin) is exactly the same as during any other PCI procedure. Until this point, the procedure is exactly same as any routine coronary angioplasty.

A short (9 mm long) over-the-wire (i.e. with central lumen) angioplasty balloon is positioned within the stent. The balloon diameter is the same as the stent diameter. During repeated (up to six) low-pressure balloon inflations (lasting up to 3 min), the autologous bone blood with stem cells is slowly (softly) injected through the central lumen of the balloon catheter in total volume up to 30 mL. Procedure is finished by control coronary angiography to show unchanged morphology and flow in the treated vessel.

The total duration of the procedure is somewhat longer as compared with routine PCI due to the need for repeated and prolonged balloon inflations with ‘recovery intervals’ between these inflations. In our study, the procedure takes around 45 min. Patients tolerate it usually in the same way as any other PCI. Periprocedural complications in coronary artery disease patients were not described yet.

The first patient in the Charles University Cardiocentre Vinohrady (and in the Czech Republic) was treated by this method in June 2003.23 This was an ‘ideal’ patient for this new method: the young man, presenting in advanced cardiogenic shock with 100% thrombotic occlusion of the left main coronary artery. After successful primary PCI with left main coronary artery stenting, he stabilized, but remained in heart failure. He slowly improved after intracoronary autologous bone marrow stem cells transplantation and he is currently 30 months after this infarction, clinically stable in functional class II (NYHA). This case triggered enthusiasm in our centre and three different trials were designed.

The pilot randomized trial in acute myocardial infarction is focused on patients presenting late (>3 h after symptom onset) with anterior wall ST-elevation acute myocardial infarction. The trial is still ongoing, the data safety monitoring board gave us recently a green light to continue after interim analysis of the first 26 patients. There were no periprocedural complications during the percutaneous intervention. One patient developed fatal stent thrombosis during the bone blood aspiration. The overall 30-day mortality is thus 3.8%, which is less than expected in this high-risk group.

The second trial was aimed on patients with idiopathic dilated cardiomyopathy. After difficult and complicated procedures in the first two patients (both survived without consequences), this trial was prematurely terminated by us. This experience was described elsewhere in detail.24


   Imaging after transplantation
Top
 Abstract
 Introduction
 Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
Limitations
 Acknowledgements
 References
 
Though being clinically appealing, data that would firmly established distribution and engraftment rates of BMNCs using intracoronary approach are limited. Three experimental studies monitored myocardial homing of BMNCs after injection in the LV cavity using immunohistochemical analysis at different time points.12,25,26 Toma et al.25 used murine model of intact heart and showed disperse engraftment of individual cells throughout the entire myocardium at 4 to 60 days. The estimated percentage of engrafted cells at 4 days after injection was 0.44%. Barbash et al.26 and Aicher et al.12 used rat model of acute myocardial infarction. The biodistribution of labelled cells was assessed by nuclear imaging and subsequent immunohistochemical analysis. In the former study, less than 1% of the infused cells resided in the infarcted heart 4 h after infusion in the LV cavity. In the latter one, approximately 3% of injected activity was detected in the heart at 96 h after intracavitary injection. Of note, in both studies, the myocardial homing was confined to the site of infarct and its border zone and in contrast to intact murine heart,25 there were no donor cells in the remote myocardium. Only one experimental study monitored myocardial homing after intracoronary injection27 using an ischaemic swine model. Six days after anterior infarction, 107 111indium-oxine-labelled human peripheral blood mononuclear cells were infused in the LAD. Animals were euthanized 1 h after delivery and the distribution of transplanted cells was assessed by {gamma}-emission counting of harvested organs. Mean myocardial uptake was 2.6±0.3% of injected activity. Delivered cells were localized to the infarcted anterolateral and apical regions of the left ventricle. Nevertheless, the majority of transplanted cells were entrapped in the lungs.

Two pilot clinical studies28,29 monitored biodistribution of BMNCs in patients with acute myocardial infarction using labelling with [18F]-fluoro-2-deoxy-D-glucose at positron emission tomography. Hofmann et al.28 showed that 1.3–5.3% of unselected BMNCs (n=6 patients) and 14–39% CD34+ selected cells (n=3 patients) homed to the myocardium 50–75 min after intracoronary injection. Corroborating findings of experimental studies, activity in the heart was localized only in the area of the culprit vessel both at the infarct centre and border zone. No cells were detected in the remote myocardium. Nevertheless, the majority of cells homed to spleen, liver, or lungs. This study suggested that CD34+-enriched cells have higher retention in infarcted myocardium than mixture of unselected BMNCs. However, this finding was not confirmed by Blocklet et al.,29 who showed only 5.5% myocardial retention of labelled CD34+-enriched cells 1 h after intracoronary injection.

Our group has investigated the 1-day kinetics of myocardial engraftment of 99mTc-d,l-hexamethylpropylene amine oxime (99mTc-HMPAO)-labelled BMNCs after intracoronary injection in patients with acute myocardial infarction and chronic ischaemic heart failure.30 Nuclear imaging was performed at 2 and 20 h after BMNCs were injected in the LAD (Figures 1 and 2). Thus, myocardial engraftment of BMNCs was monitored for the longest time period so far in human. Corroborating findings of Hofmann et al.,28 immediate myocardial retention of unselected BMNCs in our study ranged between 1.31 to 5.10% 2 h after injections. At 20 h, myocardial engraftment was noted only in three patients with acute myocardial infarction, whereas no activity remained in the myocardium in any patient with chronic heart failure. These findings indicate that engraftment of BMNCs after intracoronary injection is dynamic, already within first 24 h, resulting in only transient myocardial activity in subset of patients with acute myocardial infarction. In addition, in chronic ischaemic heart failure, the efficacy of intracoronary injection to deliver BMNCs into the diseased myocardium is controversial.


Figure 0671
View larger version (69K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Example of organ distribution of 99mTc-HMPAO-labelled BMNCs in patient with an acute anterior myocardial infarction and persistent myocardial engraftment. BMNCs were injected in the LAD. Left panel shows the whole body scan at 2 h and right panel at 20 h after BMNCs injection in anterior views. The amount of cells in the myocardium (arrow) decreased from 4.5% of injected activity at 2 h to 1.34% at 20 h. The majority of transplanted cells were located in liver and spleen.

 

Figure 0672
View larger version (78K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 2 Example of organ distribution of 99mTc-HMPAO-labelled BMNCs in patient with an acute anterior myocardial infarction and transient myocardial engraftment. BMNCs were injected in the LAD. Left panel shows the whole body scan at 2 h and right panel at 20 h after BMNCs injection in anterior views. Heart is indicated by arrow. The 2 h scan showed large pools of activity in spleen, liver, and lungs. Myocardial uptake was 3.0% of injected activity. At 20 h, significant activity remained in spleen, liver, and urinary bladder. However, no activity remained in the heart suggesting transient myocardial retention in this patient.

 

   Limitations
Top
 Abstract
 Introduction
 Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
 Limitations
Acknowledgements
 References
 
Quantity and quality of bone-marrow-derived stem cells
Bone marrow is a heterogeneous tissue, containing a mixed population of various stem and progenitor cells, stromal cells, and haematopoietic cells at various maturation stages. It is not yet clear which population of stem cells is optimal for intracoronary application to recover myocardial function. The proportion of stem cells is very small. It is difficult to obtain multipotent stem cells in sufficient quantities. No specific markers of the true stem cell have been identified. Quantity of cells that can be harvested from the patient is limited. Bone-marrow-derived stem cells are difficult to maintain and to generate in vitro. The poor survival of the transplanted stem cells is another limitation to the efficacy of therapy. The majority of injected cells undergo apoptosis within ischaemic heart tissue because of exposure to the hostile environment.31 Moreover, the optimal number of stem cells to be transplanted have not been determined. Dosing studies need to be performed.

Timing
It is unknown whether stem cell therapy would be most beneficial early after myocardial infarction, later in the remodelling phase, or late at the end stage of ischaemic cardiomyopathy. On one hand, microvascular obstruction and extensive myocardial inflammation may prevent effective cells homing and survival during the first couple of days after infarction.32 On the other hand, once infarct scar is formed, the benefits of cell transplantation may be reduced.

Delivery
A crucial determinant of stem cell homing to the site of injury is a mode of cell delivery. The optimal model of stem cell delivery (intramyocardial injection, intracoronary administration, or systemic delivery) is currently unknown. By using intracoronary injection, cells may either be trapped in small capillaries without reaching the myocardium, or be lost in the systemic circulation. Also, intracoronary delivery of mesenchymal stem cells caused microinfarcts in dogs.33 However, this observation has not been reported for humans. The optimal route of stem cell administration offers high cell concentration in the damaged myocardium and prevents side homing to other organs. Studies comparing the different delivery modalities are scarce. Hou et al.27 compared efficacy of intramyocardial, intracoronary, and interstitial retrograde coronary venous injection to deliver peripheral blood mononuclear cells in an ischaemic swine model. The highest cell retention in the myocardium was observed after intramyocardial injection (11±3%) as compared with intracoronary (2.6±0.3%) or interstitial coronary venous (3.2±1%) delivery.

Homing
Ischaemic myocardium constitutes a hostile environment for transplanted cell populations. Experimental studies demonstrated very low engraftment of transplanted bone marrow stem cells into myocardium or vessel wall.34 Corroborating experimental studies, in patients with acute myocardial infarction, only a small fraction (1.3–2.6%) of the transplanted cells are retained in the myocardium after intracoronary injection.29,30 This proportion is inadequate for a clinically relevant regeneration of the injured heart. In an effort to improve the homing of bone-marrow-derived stem cells, many strategies are being developed.

Plasticity
Several potential mechanisms have been proposed to account for the therapeutic effects of stem cell transplantation after myocardial infarction: transdifferentiation, neovascularization, fusion, and secretion of cytokines with paracrine effect. The data in support of transdifferentiation have not always been replicable. Recent studies indicate that haematopoietic stem cells do not transdifferentiate into cardiac myocytes.35 The functional improvement after transplantation could be explained by beneficial paracrine effects of transplanted stem cells on endogenous cells to promote angiogenesis, improve metabolism, or inhibit apoptosis. There is general agreement that the endothelial progenitor cells have the capacity to induce neo-angiogenesis improving LV remodelling and function.

Fate of stem cells in the myocardium
Conflicting data exist on the fate of bone-marrow-derived stem cells in the myocardium. The long-term viability of bone marrow stem cells, their integration in the myocardium, and their function are uncertain.

Detection of engrafted cells
An important issue in this research is to mark the cells in a proper way. Current failure to label the donor cells adequately and to follow them in vivo could lead to misinterpretation. Imaging techniques that allow a correlation between cell survival and clinical benefit are needed.

Adverse events
Risk of tumorigenesis after transplantation of undifferentiated bone marrow stem cells was one of the major concern in cell-based therapies.36 However, no angiogenic neoplasia has yet been reported in clinical trials with autologous adult stem cells. Transfer of bone marrow cells and endothelial progenitor cells may result in an increase in atherosclerotic lesion size. Endothelial progenitor cell transfer could also potentially influence plaque stability.37 Implanted stem cells may differentiate into fibroblasts rather than myocytes. The consequences of increased scar formation may be worsening ventricular function and formation of an arrhythmic substrate.38


   Acknowledgements
Top
 Abstract
 Introduction
 Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
 Limitations
 Acknowledgements
References
 
The financial support of the Charles University Research Project MSM0021620817 is acknowledged. The authors thank the personnel of Cardiocentre, University Hospital Kralovske Vinohrady, Prague, Czech Republic for their support.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methodology: haematologist's...
 Methodology: the view of...
 Prague pilot clinical experience
 Imaging after transplantation
 Limitations
 Acknowledgements
 References
 

  1. Pfeffer MA and Braunwald E. (1990) Ventricular remodelling after myocardial infarction: experimental observations and clinical implications. Circulation 81:1161–1172.[ISI][Medline]
  2. St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E. for the SAVE Investigators. (1994) Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. Circulation 89:68–75.[Medline]
  3. Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D. (2002) Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 106:2351–2357.
  4. 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. (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705.[CrossRef][Medline]
  5. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776.[CrossRef][ISI][Medline]
  6. Fuchs E, Tumbar T, Guasch G. (2004) Socializing with the neighbors: stem cells and their niche. Cell 116:769–778.[CrossRef][ISI][Medline]
  7. 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.
  8. 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. (2002) Transplantation of progenitor cells and regeneration enhancement in AMI (TOPCARE-AMI). Circulation 106:3009–3017.
  9. Bartunek J, Vanderheyden M, Vandekerckhove B, Mansour S, De Bruyne B, De Bondt P, Van Haute I, Lootens N, Heyndrickx G, Wijns W. (2005) Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety. Circulation 112:Suppl. 9, I178–I183.
  10. 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. (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomized controlled clinical trial. Lancet 364:141–148.[CrossRef][ISI][Medline]
  11. Saito T, Kuang JQ, Lin CC, Chiu RC. (2003) Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction. J Thorac Cardiovasc Surg 126:114–123.[Abstract/Free Full Text]
  12. Aicher A, Brenner W, Zuhayra M, Badorff C, Massoudi S, Assmus B, Eckey T, Henze E, Zeiher AM, Dimmeler S. (2003) Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling. Circulation 107:2134–2139.
  13. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC. (2004) Progenitor cell trafficking is regulated by hypoxic gradients through hif-1 induction of sdf-1. Nat Med 10:858–864.[CrossRef][ISI][Medline]
  14. Chavakis E, Aicher A, Heeschen C, Sasaki K, Kaiser R, El Makhfi N, Urbich C, Peters T, Scharffetter-Kochanek K, Zeiher AM, Chavakis T, Dimmeler S. (2005) Role of b2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 201:63–72.[Abstract/Free Full Text]
  15. De Falco E, Porcelli D, Torella AR, Straino S, Iachininoto MG, Orlandi A, Truffa S, Biglioli P, Napolitano M, Capogrossi MC, Pesce M. (2004) Sdf-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104:3472–3482.[Abstract/Free Full Text]
  16. Emanueli C, Lako M, Stojkovi M, Madeddu P. (2005) In search of the best candidate for regeneration of ischaemic tissues. Are embryonic/fetal stem cells more advantageous than adult counterparts? Thromb Haemost 94:738–749.[ISI][Medline]
  17. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schümichen C, Nienaber CA, Freund M, Steinhoff G. (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361:45–46.[CrossRef][ISI][Medline]
  18. Emerson CP, Geng YJ, Willerson JT. (2003) Adult stem cell therapy in perspective. Circulation 107:935–938.
  19. Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam G, Josephson ME. (1996) Nonfluoroscopic in vivo navigation and mapping technology. Nat Med 2:1393–1395.[CrossRef][ISI][Medline]
  20. Smits PC, van Geuns RJ, Poldermans D, Bountioukos M, Onderwater EE, Lee CH, Maat AP, Serruys PW. (2003) Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischaemic heart failure. Clinical experience with six month follow-up. J Am Coll Cardiol 42:2063–2069.[Abstract/Free Full Text]
  21. Thompson CA, Nasseri BA, Makower J, Houser S, McGarry M, Lamson T, Pomerantseva I, Chang JY, Gold HK, Vacanti JP, Oesterle SN. (2003) Percutaneous transvenous cellular cardiomyoplasty: a novel nonsurgical approach for myocardial cell transplantation. J Am Coll Cardiol 41:1964–1971.[Abstract/Free Full Text]
  22. Semsarian C. (2002) Stem cells in cardiovascular disease: from cell biology to clinical therapy. Intern Med J 32:259–265.[CrossRef][ISI][Medline]
  23. Penicka M, Widimsky P, Kobylka P, Kozák T, Dvorák J, Spacek R, Tousek P. (2003) Transplantace autologních kmenovych bunek kostní drene po akutním infarktu myokardu zpusobeném uzáverem kmene levé vencité tepny. Cor et Vasa 45:465–468.
  24. Widimsky P and Penicka M. Complications after intracoronary stem cell transplantation in idiopathic dilated cardiomyopathy. Int J Cardiol Published online ahead of print November 30, 2005.
  25. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98.
  26. Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J. (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, body distribution. Circulation 108:863–868.
  27. Hou D, Youssef EA, Brinton TJ, Zhang P, Rogers P, Price ET, Yeung AC, Johnstone BH, Yock PG, March KL. (2005) Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials. Circulation 112:Suppl. I, I-150–I-156.
  28. Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. (2005) Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation 111:2198–2202.
  29. Blocklet D, Toungouz M, Berkenboom G, Lambermont M, Unger P, Preumont N, Stoupel E, Egrise D, Degaute JP, Goldman M, Goldman S. Myocardial homing of non mobilized peripheral-blood CD34+ cells after intra-coronary injection. Stem Cells Published online ahead of print October 13, 2005.
  30. Penicka M, Lang O, Widimsky P, Kleisner I, Kobylka P, Kozak T, Vanek T, Trojanova H. (2005) Early tissue distribution of bone marrow mononuclear cells after transcoronary transplantation in human. (Abstract). Eur Heart J 26:Suppl, 1458.[Free Full Text]
  31. Geng YJ. (2003) Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischaemic heart failure. Ann N Y Acad Sci 1010:687–697.[Abstract/Free Full Text]
  32. Rochitte CE, Lima JA, Bluemke DA, Reeder SB, McVeigh ER, Furuta T, Becker LC, Melin JA. (1998) Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation 98:1006–1014.
  33. Murry CE, Field LJ, Menasche P. (2005) Cell-based cardiac repair: reflections at the 10-year point. Circulation 112:3174–3183.
  34. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. (2001) Regeneration of ischaemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107:1395–1402.[CrossRef][ISI][Medline]
  35. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ. (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428:664–668.[CrossRef][Medline]
  36. Davidoff AM, Ng CY, Brown P, Leary MA, Spurbeck WW, Zhou J, Horwitz E, Vanin EF, Nienhuis AW. (2001) Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice. Clin Cancer Res 7:2870–2879.[Abstract/Free Full Text]
  37. George J, Afek A, Abashidze A, Shmilovich H, Deutsch V, Kopolovich J, Miller H, Keren G. (2005) Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 25:2636–2641.[Abstract/Free Full Text]
  38. Zhang YM, Hartzell C, Narlow M, Dudley SC Jr. (2002) Stem cell-derived cardiomyocytes demonstrate arrhythmic potential. Circulation 106:1294–1299.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Widimsky, P.
Right arrow Articles by Aschermann, M.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Widimsky, P.
Right arrow Articles by Aschermann, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?