EDITORIAL
Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ - Brazil
Mailing address
Keywords: Stem cells; therapeutics/trends; bone marrow.
The use of autologous bone marrow cells in humans is celebrating ten years now, in an area where Brazilian cardiology has international recognition because of its pioneering initiative1. One decade ago the first cases were treated in patients with terminal chronic ischemic heart disease, which were published two years later2. The article by Vilas Boas et al3, published in this issue of the Archives, represents another pioneering effort in the field of cardiology in Brazil: the application in Chagas disease (CD). In this issue, the authors present a case series of 28 patients with heart failure due to CD with NYHA functional class III and IV who underwent transplantation of bone marrow-derived mononuclear cells (BMC) by coronary injection.
Like all scientific evidence, the articles on cellular therapy must undergo a process of critical evaluation. For this purpose, besides the general criteria for a therapy-related article4, we have learned through these ten years that some specific considerations must be made about BMC articles.
Firstly, it should demonstrate which cells were injected (and their subtypes), viability and degree of functionality. Especially when a study is negative5. In 2006, the same issue of the NEJM was presented in two studies with similar methodologies in the setting of acute myocardial infarction: a study suggesting benefit and another not suggesting benefit, which generated much controversy at that time6,7. The authors have devoted to understand why there was such a difference and today we know that the negative study had used cells with depressed functional capacity. Thus, the main questions to be asked are: which cells were injected? What functionality and viability tests were made and what is the experience of the group that accomplished it?
Another key point for the study on BMC relates to adverse events. We are usually interested in the risk-benefit of a new therapy. In the case of cell therapy, there has not been so far major adverse events established8. If that fact is proven, the criteria for clinical decision making changes to the extent that the risk-benefit ratio becomes favorable.
In the study by Vilas Boas et al3, 240 million cells were injected intracoronarily. Although there is no functional or cell typing test, viability was high (96%) and the testing center has extensive experience in this area. There were no adverse events related to cell harvesting or implantation. In a six-month follow-up, four deaths were reported, with improvement in clinical parameters (NYHA, quality of life, 6-minute walk test) and echocardiographic parameters (LVEF).
When we consider the evidence available, a systematic review of BMC in the setting of chronic ischemic benefits EF in these patients8. Interestingly, there is a disproportion between the improvement in EF and marked clinical improvement. Data from five years of our group showed a higher than expected survival and quality of life assessment by SF-36 and Minnesota in the general population in the same age group9. It could be argued that quality of life data are subjective and reflect a positive psychological influence. This fact is mischaracterized by the performance of patients in exercise testing, also disproportionately better than EF gains sustainable in the long term (psychological influences do not usually have five-year effects). The more serious the condition of patients, the more these have benefited from the performance of EF9.
One possible explanation could be a complex multi-dimensional mechanism of action, unlike chemical agents (working in a specific point in the pathophysiological cascade). Although BMC have their ability to transdifferentiate into cardiomyocytes discussed to these days, they have demonstrated angiogenic capacity, and capacity to restore the intrinsic nervous system of the heart and heart supporting tissue rearranging the cardiac collagen that modulates inflammation10.
After ten years, why do we still not have any definitive evidence in cell therapy? Simply because the BMC are not patentable; they do not generate any funding interest. This shows how important is the role of the industry in developing new cardiovascular technologies. In the case of CD, a more robust evidence sponsored by the Ministry of Health has demonstrated no benefits for patients11. Unfortunately, the study provides data on the functionality of cells administered, which will always keep us wondering: BMC therapy does not benefit CD, or the injected cells were not appropriate?
References
- 1. McMahon DS, Singer PA, Daar AS, Thorsteinsdottir H. Regenerative medicine in Brazil: small but innovative. Regen Med. 2010;5(6):863-76.
- 2. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107(18):2294-302.
- 3. Vilas Boas F, Feitosa GS, Soares MBP, Pinho-Filho JA, Mota ACA, Almeida AJA, et al. Transplante de células da medula óssea na insuficiência cardíaca chagásica: relato da primeira experiência humana. Arq Bras Cardiol. 2011;96(4):325-31.
- 4. Guyatt GH, Rennie D. Users' guides to the medical literature. JAMA. 1993;270(17):2096-7.
- 5. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J. 2007;28(6):766-72.
- 6. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med. 2006;355(12):1199-209.
- 7. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355(12):1210-21.
- 8. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, et al. Adult bone marrow-derived cells for cardiac repair: a systematic review and meta-analysis. Arch Intern Med. 2007;167(10):989-97.
- 9. Dohmann HFR. Terapias celulares na doença arterial coronariana: resultados clínicos e morfofuncionais [Doutorado]. Rio de Janeiro: Universidade Federal do Rio de Janeiro; 2008.
- 10. Guo J, Lin GS, Bao CY, Hu ZM, Hu MY. Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction. Inflammation. 2007;30(3-4):97-104.
- 11. Carvalho ACC. Terapia celular no Brasil. In: IV Simpósio Internacional Terapias Avançadas & Células-Tronco. Recife; 2009.
One decade of stem cell therapy for bone marrow: what is missing?
Publication Dates
-
Publication in this collection
30 Aug 2011 -
Date of issue
July 2011
