Acute myocardial infarction is a leading cause of mortality worldwide. In those that survive an attack, damage to the heart muscle can lead to heart failure. In an effort to repair this damage, researchers have investigated the potential of cellular therapies to help restore cardiac function. Following a myocardial infarct, an inflammatory response is triggered that stimulates a variety of progenitor and stem cells to mobilise, including cells from the bone marrow. These cells are thought to aid the body’s attempt to repair the damaged heart tissue, although precisely how is still unclear. This observation led to the development of autologous bone marrow cell (BMC) therapy, whereby an individual’s own bone marrow cells are harvested and directed at the site of damage. More than a decade since this therapy was first tested, the benefits of this treatment have shown to be less efficacious than expected in some cases. Patricia Lemarchand from the University of Nantes, France, and colleagues investigated one possible cause for the variability in treatment outcomes, as part of the BONAMI trial, by looking at the mobilization of bone marrow cells in smoking versus non-smoking patients. Lemarchand discusses discrepancies in clinical trial results for BMC therapy and what their findings published in Stem Cell Research & Therapy revealed on the effect of smoking.
What is autologous bone marrow cell (BMC) therapy? How is it relevant to acute myocardial infarction?
Autologous bone marrow cell (BMC) therapy has been used for more than 50 years to treat hematological diseases. In the setting of cardiac diseases, autologous BMC therapy consists of delivering cells obtained from the patient’s bone marrow to its diseased heart to restore, at least partially, cardiac function. This therapeutic strategy is now being investigated in patients who have suffered an acute myocardial infarction or have been affected by post-myocardial infarction heart failure. Cell therapy products can be composed of all bone marrow mononuclear cells or a specific BMC population such as CD34+ cells or mesenchymal stem cells. Cells can be delivered through different methods such as intracoronary infusion or direct intramyocardial injection. Some observations in humans show mobilization of bone marrow after acute myocardial infarction and others suggest that bone marrow cells engraft in cardiac tissue. In the last 15 years, BMC therapy has been tested in animal models of acute myocardial infarction and heart failure with promising results. Injected cells can enhance angiogenesis, stimulate cardiac progenitor cells or act through secretion of paracrine factors. Whether some bone marrow cells can directly transdifferentiate in vivo into cardiomyocyte or endothelial cell is still debated.
What problems have been observed in clinical trials of bone marrow cells (BMCs) in patients with acute myocardial infarction?
In the past decade, more than 1800 patients with acute myocardial infarction have been enrolled in about 25 phase II randomized BMC clinical trials, some of them double-blinded. In most of these trials the primary endpoint was the improvement in cardiac contractility and function, measured by left ventricular ejection fraction (LVEF) and/or cardiac viability quantification. Results from these clinical trials have supported the safety and feasibility of intracoronary delivery of bone marrow and circulating stem cells. However, despite encouraging results in animal models, the efficacy of bone marrow cell transplantation in patients has been modest overall and inconsistent between studies. Several meta-analyses of randomized trials, including a recent meta-analysis on individual data from 1640 subjects, have shown that intracoronary BMC therapy leads to a modest but significant improvement of LVEF in patients after acute myocardial infarction. Patients of younger age and with a more severely depressed LVEF showed the largest benefit.
What could be the reasons for these discrepancies?
First, the variability in reported treatment effects may be related to differences in cell type and quantity of transplanted cells, timing and approach of cell transplantation and patient selection. Second, the use of autologous BMCs for clinical application may affect the potency of the cellular product, because it is known that age and risk factors for coronary artery disease impair both the functional capacity and the paracrine activity of bone marrow-derived and circulating progenitor cells.
Your current study uses data from the BONAMI trial. What is this trial and what did it find?
The BOMAMI trial was a randomized clinical trial, in which 101 patients with severe acute myocardial infarction received intracoronary autologous BMC infusion or state-of-the-art therapy. The primary endpoint of the study was improvement of myocardial viability three months after acute myocardial infarction. We observed a trend in favor of the BMC transplantation group.
What effect does smoking have on myocardial viability recovery after acute myocardial infarction?
In the BONAMI trial, we showed that active smokers had reduced myocardial viability recovery after acute myocardial infarction. This effect was independent of the effect of bone marrow cell therapy on myocardial viability.
What differences did you observe in the bone marrow and blood samples of smoking and non-smoking patients?
Our study focused on the effect of active smoking on bone marrow and notably circulating progenitor cell number after acute myocardial infarction. In this context, we observed in bone marrow, but not in blood, cell activation with a higher absolute number of white cells and haematopoietic progenitor cells in active smokers. Also, the major difference between smoking and non-smoking patients was on circulating endothelial progenitor cells (EPCs), with decreased EPC number in active smokers in both bone marrow and blood samples.
In summary, we observed a greater overall bone marrow activation post-acute myocardial infarction in active smokers, but with a lack of specific activation of the endothelial cell lineage in either bone marrow and blood samples. This result is important since active smoking-associated EPC alteration may impact the capacity of cardiac function recovery in smokers after acute myocardial infarction.
What are the clinical implications of your findings?
Our findings show that active smoking through its effects on endothelial progenitor cells is not only a risk factor for coronary artery disease progression but also impairs cardiac function recovery after acute ischemic events, reinforcing the need to promote smoking cessation in these patients.
Regarding bone marrow cell therapy, our findings suggest that both non-smokers, former smokers and active smokers can receive BMC therapy after acute myocardial infarction, and that this therapy may override the role of endothelial progenitor cells on cardiac function recovery, irrespective of their smoking status.
What further research is needed?
For the time being, it is important to establish whether the simple BMC approach has clinical benefit. There is now a need to perform a large scale clinical trial using clinical hard end-points such as mortality, to establish whether the positive effects seen on surrogate end-points can indeed translate to meaningful clinical benefits. The effect of intracoronary reinfusion of BMCs on all-cause mortality in acute myocardial infarction (BAMI) is a phase III outcome study being conducted in European countries. This and other future large-scale studies will cut through the current number of small trials involving multiple variables that at present constrain our ability to readily determine the optimal stem cell approach to cardiac repair.
The exact mechanism of the therapeutic beneficial effects of cell transplantation treatment also remains to be determined.
Difference in mobilization of progenitor cells after myocardial infarction in smoking versus non-smoking patients: insights from the BONAMI trial
Stem Cell Research & Therapy 2013, 4:152
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