Letters to the editor

LETTERS TO THE EDITOR

Cell therapy plus transmyocardial laser revascularization: a proposed alternative procedure for refractory angina

Comments to the study "Cell therapy plus transmyocardial laser revascularization: a proposed alternative procedure for refractory angina", from the author PhD Luiz Dallan, presented at the 34th Congress of the Brazilian Society of Cardiovascular Surgery and published in the Brazilian Journal of Cardiovascular Surgery (2008;23[1])

Analyzing international literature on the topic of cell therapy, I noted the rarity of this association of techniques, and I found only two studies from the INCOR group, with the case report of the first patient of this series, from 2005 [1] - the same case presented in a study in which cell therapy was used together with conventional or transmyocardial laser revascularization from 2006 [2] - and one case by H.M. Klein from the University of Dusserdolf, Germany, 2004 [3], where the technique was used in two patients.

In all studies, improvement in left ventricular contractility was reported, proving to be another method of coronary revascularization, using either the antigen from CD 34⁺ hematopoietic progenitor cells, as in the INCOR'studies, or the CD 133⁺, as in the Klein' study [3], and concluded by Kobari [4] when he compared CD 133⁺ with CD 34⁺.

The technique of transmyocardial laser revascularization (TLMR) is already well established as an option for a cardiac procedure for coronary revascularization, showing an improvement in the angina functional class in most of the patients, according to the Canadian Cardiovascular Society [5]. The technique of using CD133⁺ stem cells is also already established as an alternative for patients for whom techniques of conventional coronary revascularization are not susceptible to indication, as proven by H.M. Klein in isolated uses [6].

The combined use of the two techniques performed by Klein in 2004 is now proven by this study. The study yielded excellent results from applying these techniques in nine patients: there was no mortality associated with the disease being studied. However, in the study, the authors do not offer any indirect measurements of improvement of the general situation (either through quality life questionnaires, or through measurement of the left ventricle ejection fraction,) but only to indirect data from angina classification and the ischemic index.

O uso conjunto das duas técnicas realizado por Klein, em 2004, está agora comprovado com este trabalho ao obter um excelente resultado quando de sua aplicação em nove pacientes, sem mortalidade associada á doença em estudo. No entanto, os autores não fazem referência no trabalho tanto a medidas indiretas mensuráveis de melhora do quadro geral, quer seja através de questionários de qualidade de vida, quer seja através da medida da fração de ejeção de ventrículo esquerdo e apenas a dados indiretos de classificação de angina e índice isquêmico.

However, some authors [7] highlight the fact that the use of these techniques should be performed only in patients in whom the clinical therapy already has been optimized, and some authors suggest that the ejection fraction should be higher than 40% to achieve the best results, due to the weight loss caused directly by the laser injury. This statement is supported by other groups [8] because the results present a lower quality of life and less survival after 18 months for patients with left ventricular dysfunction and heart failure.

Another point that must be clarified is the correct mechanism of action of TLMR, as there is currently no exact understanding of it, even despite study results that have shown a clinical improvement in the patients. However, in the same multicenter study by Samuels [9], it was proven that the performance of TLMR associated with another method (such as the simultaneous use of angiogenic growth factors or stem cells) may increase its effectiveness. In relation to the use of TLMR associated with the use of growth factor, Dr. Dallan's study may be the answer to the Samuels study, as was the case with the Horvath study [10].

I would like to ask the author the following questions, just for clarification:

1) Does the author believe that the use of this technique as a method of treatment is viable in the cases of patients with similar characteristics?

2) Does your service have an inclusion protocol for patients who receive this new technique?

3) If so, what is the minimum ejection fraction necessary for inclusion of patients in this protocol?

4) In relation to left ventricular function, although there were no doubts about the improvement of ejection fraction, what was the percent increase?

5) Was ventricular assistance (intra-aortic balloon) used in any of the cases presented herein?

I congratulate Prof. Dallan and his group for the excellent scientific contribution accomplished for our society. In the near future, with the continuation of this line of research, I hope to see the results of a more in-depth study with a larger number of patients; a study that is double-blind, randomized and placebo-controlled, as the author himself suggests.

Thank you very much.

Rui M. S. Almeida, Cascavel/PR - Brazil

Reply

We would like to thank Dr. Almeida and reaffirm our group's innovation in the field of cell therapy associated with transmyocardial revascularization with CO2-laser [1]. We have been working with transmyocardial laser revascularization since the 1990s [2.3], and with cell therapy since 2002 [4.5]. The successful outcomes that our group found using the CO₂ laser and the proof of safety with the use of cell therapy led to the study of the combination of these two techniques. After Phase I, which demonstrated the safety of the combination of cell therapy with transmyocardial laser revascularization [6.7], we are initiating Phase II, including a prospective randomized study in order to analyze the concrete benefits of the union of these two therapies.

Regarding your questions, we must say that the benefit of this union has not yet been proven. Because of this, in our circle, this procedure is not part of the cardiovascular surgery routine. The patients are indeed carefully selected, and meet specific criteria. To summarize, the inclusion criteria are: refractory angina in spite of maximally tolerated clinical therapy; myocardial ischemia (objectively recorded) by non-invasive methods; left ventricle ejection fraction of eˆ 50%; coronariography with multiarterial obstructive pattern that is not susceptible to percutaneous revascularization or classical surgery. After the procedure (and with an average of 6 months follow-up), there was no significant alteration in the left ventricle ejection fraction, which was 0.54 ± 0.09 to 0.59 ± 0.07, p=0.41. However, the study with magnetic resonance showed significant reduction of the ischemic index of the left ventricle, decreasing from 1.64 ± 0.10 (preoperative) to 0.88 ± 0.09 (6 months of postoperative), p = 0.01. Such a result may have occurred due to the synergic angiogenic potential of these two therapeutic modalities. We await the conclusion of Phase II of the study (prospective and randomized), with which we will be able to either confirm or negate our statement.

Luis Alberto de Oliveira Dallan - São Paulo/SP - Brazil

REFERÊNCIAS (Terapia celular associada à revascularização transmiocárdica a Laser: Uma nova proposta no tratamento da angina refratária aos métodos terapêuticos atuais) / REFERENCES (Cell therapy plus transmyocardial laser revascularization: a proposed alternative procedure for refractory angina)

REFERÊNCIAS (Resposta) / REFERENCES (Reply)

• 1. Gowdak LH, Schettert IT, Rochitte CE, Lisboa LA, Dallan LA, Cesar LA, Krieger JE, Ramires JA, Oliveira SA. Cell therapy plus transmyocardial laser revascularization for refractory angina. Ann Thorac Surg. 2005 Aug;80(2):712-4.
• 2. de Oliveira SA, Gowdak LH, Buckberg G, Krieger JE; RESTORE Group. Cell biology, MRI and geometry: insight into a microscopic/macroscopic marriage. Eur J Cardiothorac Surg. 2006 Apr;29 Suppl 1:S259-65.
• 3. Klein HM, Ghodsizad A, Borowski A, Saleh A, Draganov J, Poll L, Stoldt V, Feifel N, Piecharczek C, Burchardt ER, Stockschlader M, Gams E. Autologous bone marrow-derived stem cell therapy in combination with TMLR. A novel therapeutic option for endstage coronary heart disease: report on 2 cases. Heart Surg Forum. 2004;7(5):E416-9.
• 4. Kobari L, Giarratana MC, Pflumio F, Izac B, Coulombel L, Douay L. CD133+ cell selection is an alternative to CD34+ cell selection for ex vivo expansion of hematopoietic stem cells. J Hematother Stem Cell Res. 2001 Apr;10(2):273-81.
• 5. Frazier OH, March RJ, Horvath KA. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N Engl J Med. 1999 Sep 30;341(14):1021-8.
• 6. Klein HM, Ghodsizad A, Marktanner R, Poll L, Voelkel T, Mohammad Hasani MR, Piechaczek C, Feifel N, Stockschlaeder M, Burchardt ER, Kar BJ, Gregoric I, Gams E. Intramyocardial implantation of CD133+ stem cells improved cardiac function without bypass surgery. Heart Surg Forum. 2007;10(1):E66-9.
• 7. Nagele H, Stubbe HM, Nienaber C, Rodiger W. Results of transmyocardial laser revascularization in non-revascularizable coronary artery disease after 3 years follow-up. Eur Heart J. 1998 Oct;19(10):1525-30.
• 8. Guleserian KJ, Maniar HS, Camillo CJ, Bailey MS, Damiano RJ Jr, Moon MR. Quality of life and survival after transmyocardial laser revascularization with the holmium: YAG laser. Ann Thorac Surg. 2003 Jun;75(6):1842-7.
• 9. Samuels L, Emery R, Lattouf O, Grosso M, AlZeerah M, Schuch D, Wehberg K, Muehrcke D, Dowling R. Transmyocardial laser therapy: a strategic approach. Heart Surg Forum. 2004;7(3):E218-29.
• 10. Horvath KA, Lu CY, Robert E, Pierce GF, Greene R, Sosnowski BA, Doukas J. Improvement of myocardial contractility in a porcine model of chronic ischemia using a combined transmyocardial revascularization and gene therapy approach. J Thorac Cardiovasc Surg. 2005 May;129(5):1
• 1. Schettert I, Gowdak L, Rochitte C, Lisboa L, Dallan L, Cesar L, et al. Intramyocardial injection of autologous bone marrow cells combined to transmyocardial laser revascularization in a patient with refractory angina. Rev Bras Hematol Hemoter. 2004;26(supl 2):62.
• 2. de Oliveira SA, Dallan LA, Lisboa LA, Chavantes MC, Cesar LA, Pardi MJ, et al. Transmyocardial laser revascularization. Early clinical experience. Arq Bras Cardiol. 1999;72(4):441-50.
• 3. Dallan LAO, Oliveira SA. Cirurgia de revascularização transmiocárdica a laser de CO₂ Rev Bras Cir Cardiovasc. 2000;15(2):89-104.
• 4. de Oliveira SA, Gowdak LH, Buckberg G, Krieger JE; RESTORE Group. Cell biology, MRI and geometry: insight into a microscopic/macroscopic marriage. Eur J Cardiothorac Surg. 2006;29(Suppl 1):S259-65.
• 5. Gowdak LH, Schettert IT, Baptista E, Lopes NL, Rochitte CE, Vieira ML, et al. Intramyocardial injection of autologous bone marrow cells as an adjunctive therapy to incomplete myocardial revascularization: safety issues. Clinics. 2008;63(2):207-14.
• 6. Gowdak LH, Schettert IT, Rochitte CE, Rienzo M, Lisboa LA, Dallan LA, et al.. Transmyocardial laser revascularization plus cell therapy for refractory angina. Int J Cardiol. 2008;127(2):295-7.
• 7. Dallan LAO, Gowdak LH, Lisboa LAF, Schettert I, Krieger JE, Cesar LAM, et al. Terapia celular associada à revascularização transmiocárdica a laser como proposta no tratamento da angina refratária. Rev Bras Cir Cardiovasc. 2008;23(1):46-52.

Publication Dates

• Publication in this collection
  23 Sept 2008
• Date of issue
  June 2008