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Stefanie Dimmeler
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Early Reperfusion strategies have reduced early mortality significantly and improved long term prognosis for patients with acute myocardial infarction (AMI). However, the development of post infarction heart failure remains a major challenge, despite improved pharmacological therapy.
Initial studies indicated that bone marrow-derived mononuclear progenitor cells (BMCs) might contribute to the functional repair of infarcted myocardium and increase neovascularisation of ischaemic tissue. Various additional progenitor cells have been isolated (for example from peripheral blood – the endothelial progenitor cells), which preferentially, but not exclusively, improve neovascularisation. Fat tissue also contains a variety of cells useful for cell therapy. |
Recently, different surface markers (e.g. c-kit or Sca-1) were used to isolate tissue-resident stem cells from the heart, and experimental studies showed functional benefit from infusing the different progenitor cell populations.
Slide from Stefanie Dimmeler's presentation
Now, pilot trials are aiming to regenerate myocardial function preferentially by infusion of BMCs in AMI patients. Phase I studies started in 2001 (TOPCARE-AMI) followed by the small-scale randomised trial BOOST and a study by Avilez.
Overall, these studies showed an improvement of the ejection fraction in cell-treated patients. A randomised, controlled trial by Janssens did not reveal a significant effect on global ejection fraction, but showed a reduction of the infarct size in the BMC group. Only one study, the ASTAMI trial (unpublished), did not show any benefit.
The largest study so far, the multi-centre REPAIR-AMI trial, confirmed the beneficial effects. It also showed a significant improvement of global and regional ejection fraction in the BMC group and a significant reduction of a combined endpoint death, MI and re-hospitalisation for heart failure.
Overall, the clinical data available at present indicate that cell therapy is safe, feasible and associated with improved heart function. A recent study questioned whether the improvement seen during six months is maintained over time. However, careful evaluation of the 18 months follow-up data of the BOOST trial indicated that the ejection fraction of the cell therapy group was maintained during six to 18 months of follow-up.
The long-term, two-year follow-up data of the TOPCARE-AMI trial demonstrated that the ejection fraction was maintained and even augmented in treated patients and NT-proBNP serum levels, as an objective marker of left ventricular remodelling, were persistently reduced. Long-term follow-up in larger-scale trials is essential to monitor the maintenance of the functional benefit seen in patients treated with BMCs after AMI.
While these initial trials of intracoronary infusion of BMCs suggested that it appeared to be feasible and safe in AMI patients, there is a question regarding the mechanism by which cell therapy improves heart function.
BMCs are incorporated to a significant extent into the capillaries after ischaemia and, thereby, physically contribute to the formation of new capillaries in the ischaemic tissue. However, the varying numbers of incorporated cells with an endothelial phenotype may not explain entirely the strong therapeutic effect observed after cell therapy in experimental models.
The efficiency of cell therapy may be influenced also by the release of pro-angiogenic factors in a paracrine manner. Recent studies suggest that progenitor cells augment arteriogenesis via the release of angiogenic growth factors.
Functional regeneration of the heart, in its pure sense, requires the replacement of dead cardiac myocytes. Several stem and progenitor cells isolated from the bone marrow, from circulating blood, or from cardiac tissue were shown to acquire a cardiomyogenic phenotype after injection or infusion into the heart. However, conflicting studies failed to document a significant differentiation of BMCs to cardiac myocytes.
The reason for this discrepancy is unclear and might be due to technical variations of the experimental settings. Moreover, different progenitor cells may have distinct capacities for cardiac differentiation. Even studies showing no evidence of cardiac differentiation documented an improved recovery of heart function after cell infusion, highlighting the importance of additional mechanisms by which cell therapy may exert beneficial effects.
Cell fusion might be an alternative mechanism underlying the acquirement of a cardiac phenotype by progenitor cells. However, the rate of cell fusion events is rather small in most of the studies.
Further experiments discovered a novel form of communication between progenitor cells and cardiac myocytes, namely the formation of “nanotubular highways” that allow the transport of proteins and organelles such as mitochondria between the two distinct cell types.
The transport of mitochondria from mesenchymal stem cells to mitochondria-deficient cells was shown to rescue aerobic respiration in the acceptor cells. Although the in vivo relevance of these in vitro findings is unclear, the transport of proteins or organelles may affect the cell fate and function of progenitor cells, as well as the connected cardiac myocytes.
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Ketil Lunde writes:
THE INTRODUCTION of stem cell therapies for regeneration of solid organs has attracted enormous interest from scientists, patients, the media and the public alike.
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While embryonic stem cells have attracted the most heated debate, the stem cells most extensively studied in patients with cardiac diseases have been derived from the patients’ own bone marrow. In this way immunorejection is avoided and major ethical obstacles are reduced.
Numerous reports have claimed the ability of bone marrow stem cells to transdifferentiate, i.e. differentiate to cells other than their usual destiny. In 2001, Orlic et al published their landmark study in Nature, reporting that bone marrow stem cells had myocardium, and had also improved cardiac pump function after myocardial infarction in mice. Shortly thereafter, Strauer et al published the first clinical study of intracoronary injections of autologous bone marrow cells (BMCs) in ten patients with acute myocardial infarction (AMI). They reported the method to be feasible and safe, and the results indicated improved cardiac performance.
Several other laboratories were unable to reproduce Orlic`s results, and the ability of BMCs to transdifferentiate is currently questioned. While the mechanistic fundament for clinical studies has been weakened, results of randomised studies using intracoronary injections of unfractioned BMCs a few days after reperfused ST-elevation AMI have been presented. From these studies, I will comment on the changes in global left ventricular ejection fraction (LVEF), which typically has been the primary end-point.
In the German BOOST study with 60 patients, a statistically significant positive effect of BMC treatment was found after six months. LVEF improved by 6.7% in the BMC group and 0.7% in the control group.
However, after 18 months, the difference between groups had vanished. Janssens et al studied 60 patients with AMI, and found no effect on LVEF of BMC treatment after four months’ follow-up.
The two largest studies to date were presented at the AHA Scientific Sessions meeting in 2005. The German REPAIR-AMI study included 204 patients, and reported that the stem cell group improved LVEF by 5.5% compared to 3.0% in the control group. The difference was statistically significant, but interpretation of the results were hampered by their use of ventriculography instead of more robust techniques for assessment of LVEF in patients with a myocardial infarction.
The Norwegian ASTAMI study included 100 patients with anterior wall infarctions only, and found no significant differences between groups for the change in LVEF from baseline to six months follow-up, as measured by SPECT, echocardiography and MRI. Interestingly, there was a similar, pronounced improvement in LVEF in both groups: 8.1% in the BMC group and 7.0% in the control group.
This is probably about what should be expected for AMI patients reperfused with PCI in the acute phase and receiving proper medical treatment. A similar increase in LVEF after six months follow-up (8.5% in the treatment group and 8.0% in the control group) was found in the Danish STEMMI trial, reporting no effect of cytokine mobilisation of BMCs in the acute phase of AMI.
These trials confirmed the safety of BMC treatment and differences between them might be due to differences in cell numbers and cell preparation, the time of administration and other unresolved issues.
Nevertheless, several fundamental common limitations of the methodology exist. We know that only a small fraction of BMCs administered via the intracoronary route remain in the heart.
While the concept of transdifferentiation has been undermined, other mechanisms of action such as paracrine effects and immune modulation have been suggested, yet need to be confirmed.
However, unrelated to the possible mechanism of action, no consistent, long-term effect of BMC treatment in AMI patients has yet been demonstrated, indicating that if there is an effect of this highly invasive treatment, the effect is likely to be small.
This may be illustrated by the results of exercise testing in the ASTAMI study, which will be presented at this congress. We found that the BMC group improved exercise capacity compared to the control group as measured by exercise time; however, there were no differences between groups for improvement inpeak oxygen uptake.
As some researchers call for larger trials to test the effect of unfractioned BMCs with the currently used methodology, the search for more potent cell populations and techniques to ensure the permanent engraftment of a larger number of cells continues. Based on the available data, it is our opinion that more experimental evidence should be obtained to identify more efficient methods of cell therapy to be tested in patients.
Source:
ESC Congress News - 05/09/2006