WHAT IS IMPORTANT IN BONE MARROW DERIVED STEM CELL TRANSPLANTATION

Coronary artery disease is one of the leading causes of mortality in western world. One of the most important factors in the progression of left ventricular dilatation, the process of ventricular remodelling, is the loss of cardiomyocytes after an acute myocardial infarction. After the injury, the endogenous repair mechanisms are inadequate and the injured tissue is replaced by a fibrous scar, promoting more dilatation, infarct expansion, hypertrophy and loss of ventricular function until the patient develop progressive heart failure and death. Although the old concept that the adult cardiomyocytes is terminally differentiated has been challenged by the recent evidence that myocytes have the potential capability to initiate cell cycle after myocardial infarction, the ratio of myocytes undergoing proliferation and differentiation is only 0.015-0.08%. Recently, bone marrow derived stem cell transplantation has become a realistic option of treatment to replace damaged cardiomyocytes. The bone marrow cells are a heterogeneous group of undifferentiated cells that have the capacity to self-renew, proliferate, as well as the ability to generated many differentiate cells. Since the original work published by Orlic and colleagues in PNAS in 2001, many different human trials has been published. After twelve months of the original work, Bodo Strawer et al published the first clinical experience with bone marrow derived cell transplantation in patients with acute myocardial infarction. After that, several clinical trials and metaanalysis are now reported with data from more than 800 patients demonstrating the safety, feasibility and beneficial effects of this kind of therapy.

But, why many investigators say: “Curb your enthusiasm?” like one article published in Circulation as an editorial? There are many unresolved questions about stem cell transplantation, for example: what type of cells is better to regenerate cardiomyocytes? What is the better way to implant these cells? What kind of patients benefits to this type of treatment? What disease we should treat? Acute or chronic ischemic heart disease? At what point of the disease we should treat our patients?
At this time, we do not have all answers, however is possible to explain some negative results in clinical trials. The first concern was about the results of the BOOST trial. This study originally published in Lancet in 2004 showed a change in left ventricular ejection fraction (LVEF) by 6.7 percent after 6 months of follow-up in the bone marrow cell (BMC) group, however in the long term follow-up at 18 months the difference between groups was no longer significant, 3.1% percent improvement in LVEF in the control group vs 5.9% in the BMC group. Is possible to expect a trend toward improvement in LVEF in the control group? And is possible to demonstrate any differences between two groups at 18 months in a trial planned for a 6 months follow-up? The sample size was calculated to achieve a power of at least 80% to detect a difference in global LVEF change of 5 percent points between study groups, with a two sided significance level of p<0.05,> and common standard deviation of 6.5 percentage points for the global LVEF change from baseline to 6 months follow-up. We should remember that many drugs approved to use in the setting of acute myocardial infarction produce only modest improvement in LVEF.
What happened with the Janssens trial? The answer was in the baseline characteristics of patients in this trial. The mean LVEF was 55-56% and the bone marrow cell transplantation was performing in the first 24 hours of index event. The recent REPAIR AMI trial showed that the differences between groups are statiscally significant when the procedure is performing after 5 days of infarction and in patients with ejection fraction less than 50 %.
REPAIR AMI Results

The last trial with negative results was the ASTAMI trial, published in the New England Journal of Medicine in 2006. In the same issue of the journal was published the REPAIR AMI trial and TOPCARE CHD. The trials used different protocols for cell isolation and storage. Cell isolation protocols have a major impact in functional capacity of stem cells. It affects significantly the recovery of cell numbers, hematopoietic and mesenchymal colony forming cells, and the functional activity.

Cell Isolation Protocol
ASTAMI

REPAIR AMI

Finally, in the field of stem cell transplantation for myocardial regeneration, we are agreeing with the phrase of Winston Churchill: “Now is not the end, it is not even the beginning of the end, but it is perhaps, the end of the beginning”.


References

1. Circulation. 2006; 113:1287-1294.
2. European Heart Journal 2007 28, 766–772.
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4. www.thelancet.com Published online January 5, 2006 DOI:10.1016/S0140-6736(05)67861-0
5. N Engl J Med 2006; 355:1199-209.
6. N Engl J Med 2006;355:1210-21
7. European Heart Journal (2006) 27, 2775–2783
8. N Engl J Med 2006; 355:1222-32.
9. J Am Coll Cardiol 2007;50:1761–7)