Brazilian Journal of Cardiovascular Surgery 27.4 - 2012

27.4 outubro/dezemBRO 2012

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY/ REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

VOL. 27 Nยบ 4 OUTUBRO/DEZEMBRO 2012

20 13

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EDITOR/EDITOR Prof. Dr. Domingo M. Braile - PhD São José do Rio Preto - SP - Brasil domingo@braile.com.br

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

EDITORES ANTERIORES/FORMER EDITORS • Prof. Dr. Adib D. Jatene PhD - São Paulo (BRA) [1986-1996] • Prof. Dr. Fábio B. Jatene PhD - São Paulo (BRA) [1996-2002]

EDITOR EXECUTIVO EXECUTIVE EDITOR Ricardo Brandau Pós-graduado em Jornalismo Científico - S. José do Rio Preto (BRA) brandau@sbccv.org.br

ASSESSORA EDITORIAL/EDITORIAL ASSISTANT Rosangela Monteiro PhD - São Paulo (BRA) rosangela.monteiro@incor.usp.br

EDITORES ASSOCIADOS/ASSOCIATE EDITORS • Antônio Sérgio Martins • Gilberto Venossi Barbosa • José Dario Frota Filho • José Teles de Mendonça • Luciano Cabral Albuquerque • Luis Alberto Oliveira Dallan • Luiz Felipe Pinho Moreira

Botucatu (BRA) Porto Alegre (BRA) Porto Alegre (BRA) Aracaju (BRA) Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA)

• Manuel Antunes • Mario Osvaldo P. Vrandecic • Michel Pompeu B. Oliveira Sá • Paulo Roberto Slud Brofman • Ricardo C. Lima • Ulisses A. Croti • Walter José Gomes

Coimbra (POR) Belo Horizonte (BRA) Recife (BRA) Curitiba (BRA) Recife (BRA) S.J. Rio Preto (BRA) São Paulo (BRA)

EDITOR DE ESTATÍSTICA/STATISTICS EDITOR • Orlando Petrucci Jr.

Campinas (BRA)

CONSELHO EDITORIAL/EDITORIAL BOARD • Adib D. Jatene • Adolfo Leirner • Adolfo Saadia • Alan Menkis • Alexandre V. Brick • Antônio Carlos G. Penna Jr. • Bayard Gontijo Filho • Borut Gersak • Carlos Roberto Moraes • Christian Schreiber • Cláudio Azevedo Salles • Djair Brindeiro Filho • Eduardo Keller Saadi • Eduardo Sérgio Bastos • Enio Buffolo • Fábio B. Jatene • Fernando Antônio Lucchese • Gianni D. Angelini • Gilles D. Dreyfus • Ivo A. Nesralla • Jarbas J. Dinkhuysen • José Antônio F. Ramires • José Ernesto Succi • José Pedro da Silva • Joseph A. Dearani

São Paulo (BRA) São Paulo (BRA) Buenos Aires (ARG) Winnipeg (CAN) Brasília (BRA) Marília (BRA) Belo Horizonte (BRA) Ljubljana (SLO) Recife (BRA) Munique (GER) Belo Horizonte (BRA) Recife (BRA) Porto Alegre (BRA) Rio de Janeiro (BRA) São Paulo (BRA) São Paulo (BRA) Porto Alegre (BRA) Bristol (UK) Harefield (UK) Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) Rochester (USA)

VERSÃO PARA O INGLÊS/ENGLISH VERSION • Alexandre Werneck • Fernando Pires Buosi • Marcelo Almeida • Pablo Sebastian Maluf

• Joseph S. Coselli • Luiz Carlos Bento de Souza • Luiz Fernando Kubrusly • Mauro Paes Leme de Sá • Miguel Barbero Marcial • Milton Ary Meier • Nilzo A. Mendes Ribeiro • Noedir A. G. Stolf • Olivio Souza Neto • Otoni Moreira Gomes • Pablo M. A. Pomerantzeff • Paulo Manuel Pêgo Fernandes • Paulo P. Paulista • Paulo Roberto B. Évora • Pirooz Eghtesady • Protásio Lemos da Luz • Reinaldo Wilson Vieira • Renato Abdala Karam Kalil • Renato Samy Assad • Roberto Costa • Rodolfo Neirotti • Rui M. S. Almeida • Sérgio Almeida de Oliveira • Tomas A. Salerno

Houston (USA) São Paulo (BRA) Curitiba (BRA) Rio de Janeiro (BRA) São Paulo (BRA) Rio de Janeiro (BRA) Salvador (BRA) São Paulo (BRA) Rio de Janeiro (BRA) Belo Horizonte (BRA) São Paulo (BRA) São Paulo (BRA) São Paulo (BRA) Ribeirão Preto (BRA) Cincinatti (USA) São Paulo (BRA) Campinas (BRA) Porto Alegre (BRA) São Paulo (BRA) São Paulo (BRA) Cambridge (USA) Cascavel (BRA) São Paulo (BRA) Miami (USA)

ÓRGÃO OFICIAL DA SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR DESDE 1986 OFFICIAL ORGAN OF THE BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY SINCE 1986

ENDEREÇO/ADDRESS

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Rua Beira Rio, 45 • 7º andar - Cj. 72 • Vila Olímpia • Fone: 11 3849-0341. Fax: 11 5096-0079.

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Publicação trimestral/Quarterly publication Edição Impressa - Tiragem: 200 exemplares (*)

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR (Sociedade Brasileira de Cirurgia Cardiovascular) São Paulo, SP - Brasil. v. 119861986, 1: 1,2 1987, 2: 1,2,3 1988, 3: 1,2,3 1989, 4: 1,2,3 1990, 5: 1,2,3 1991, 6: 1,2,3 1992, 7: 1,2,3,4 1993, 8: 1,2,3,4 1994, 9: 1,2,3,4

1995, 10: 1,2,3,4 1996, 11: 1,2,3,4 1997, 12: 1,2,3,4 1998, 13: 1,2,3,4 1999, 14: 1,2,3,4 2000, 15: 1,2,3,4 2001, 16: 1,2,3,4 2002, 17: 1,2,3,4 2003, 18: 1,2,3,4

2004, 19: 1,2,3,4 2005, 20: 1,2,3,4 2006, 21: 1 [supl] 2006, 21: 1,2,3,4 2007, 22: 1 [supl] 2007, 22: 1,2,3,4 2008, 23: 1 [supl] 2008, 23: 1,2,3,4 2009, 24: 1 [supl]

2009, 24: 1,2,3,4 2009, 24: 2 [supl] 2010, 25: 1,2,3,4 2010, 25: 1 [supl] 2011, 26: 1,2,3,4 2011, 26: 1 [supl] 2012, 27: 1,2,3,4 2012, 27: 1 [supl]

ISSN 1678-9741 - Publicação online ISSN 0102-7638 - Publicação impressa RBCCV 44205

CDD 617.4105 NLM18 WG 168

(*) ASSOCIAÇÃO PAULISTA DE BIBLIOTECÁRIOS. Grupo de Bibliotecários Biomédicos.

Normas para catalogação de publicações seriadas nas bibliotecas especializadas.

São Paulo, Ed. Polígono, 1972

INDEXADA EM • Thomson Scientific (ISI) http://science.thomsonreuters.com • PubMed/Medline www.ncbi.nlm.nih.gov/sites/entrez • SciELO - Scientific Library Online www.scielo.br • Scopus www.info.scopus.com

• ADSAUDE - Sistema Especializado de Informação em Administração de Saúde www.bibcir.fsp.usp.br/html/p/pesquisa_em_ bases_de_dados/programa_rede_adsaude • Index Copernicus www.indexcopernicus.com • Google scholar http://scholar.google.com.br/scholar

• LILACS - Literatura Latino-Americana e do Caribe em Ciências da Saúde. www.bireme.org • LATINDEX -Sistema Regional de Información en Línea para Revistas Cientificas de America Latina, el Caribe, España y Portugal www.latindex.uam.mx

Distribuída gratuitamente a todos os sócios da Sociedade Brasileira de Cirurgia Cardiovascular

SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY DEPARTAMENTO DE CIRURGIA DA SOCIEDADE BRASILEIRA DE CARDIOLOGIA DEPARTMENT OF SURGERY OF THE BRAZILIAN SOCIETY OF CARDIOLOGY

“Valorizando o profissional em prol do paciente” DIRETORIA 2011 - 2013 Presidente: Vice-Presidente: Secretário Geral: Tesoureiro: Diretor Científico:

Walter José Gomes (SP) João Alberto Roso (RS) Marcelo Matos Cascudo (RN) Eduardo Augusto Victor Rocha (MG) Fábio Biscegli Jatene (SP)

Conselho Deliberativo:

Bruno Botelho Pinheiro (GO) Henrique Barsanulfo Furtado (TO) José Glauco Lobo Filho (CE) Rui M.S. Almeida (PR) Henrique Murad (RJ)

Editor da Revista: Editor do Site: Editores do Jornal:

Domingo Marcolino Braile (SP) Vinicius José da Silva Nina (MA) Walter José Gomes (SP) Fabricio Gaburro Teixeira (ES) Josalmir José Melo do Amaral (RN) Luciana da Fonseca (SP)

Presidentes das Regionais Afiliadas Norte-nordeste: Rio de Janeiro: São Paulo: Minas Gerais: Centro-Oeste: Rio Grande do Sul: Paraná: Santa Catarina:

Maurílio Onofre Deininger (PB) Marcelo Sávio da Silva Martins Carlos Manuel de Almeida Brandão AntonioAugusto Miana Luiz Carlos Schimin (DF) Marcela da Cunha Sales Rodrigo Mussi Milani Lourival Bonatelli Filho

Departamentos DCCVPED: DECAM: DECA: DECEN: DEPEX: DECARDIO:

Marcelo B. Jatene (SP) Alfredo Inácio Fiorelli (SP) Luiz Paulo Rangel Gomes da Silva (PA) Rui M. S. Almeida (PR) Melchior Luiz Lima (ES) Miguel Angel Maluf (SP)

SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY E-mail: revista@sbccv.org.br Sites: www.scielo.br/rbccv www.rbccv.org.br

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

ISSN 1678-9741 - Publicação online ISSN 0102-7638 - Publicação impressa RBCCV 44205

Impact Factor: 1.239

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brasil) oct/dec - 2012;27(4) 503-660

CONTENTS/ SUMÁRIO EDITORIALS/EDITORIAIS Renewal: ongoing process in BJCVS Domingo M. Braile...............................................................................................................................................................................I Risk scores: coronary artery bypass grafting with and without cardiopulmonary bypass Enio Buffolo....................................................................................................................................................................................... III The mitral valve and endothelin-1 in cardiovascular homeostasis Edmilson Moura.................................................................................................................................................................................VI Cardiac Surgery, the Brazilian Archives of Cardiology and the Brazilian Journal of Cardiovascular Surgery Paulo Roberto B. Evora................................................................................................................................................................... VIII Lessons from the clinical trials FREEDOM and SYNTAX 5-years: new evidence or evidence only noticed now?

Luciano Cabral Albuquerque........................................................................................................................................................... XII The evidence-based medicine and coronariopathy Eduardo Augusto Victor Rocha........................................................................................................................................................ XV ORIGINAL ARTICLES/ARTIGOS ORIGINAIS 1416 On-Pump or Off-Pump? Impact of risk scores in coronary artery bypass surgery Com ou sem CEC? Impacto dos escores de risco na cirurgia de revascularização miocárdica Omar Asdrúbal Vilca Mejía, Luiz Augusto Ferreira Lisboa, Luiz Boro Puig, Luiz Felipe Pinho Moreira, Luis Alberto Oliveira Dallan, Fabio Biscegli Jatene........................................................................................................................................................................ 503 1417 Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves Expressão gênica de receptores de endotelina em valvas mitrais reumáticas estenóticas substituídas Sydney Correia Leão, Fernanda Maria Silveira Souto, Ricardo Vieira da Costa, Thaisa de Fatima Almeida Rocha, Yolanda Galindo Pacheco, Tania Maria de Andrade Rodrigues................................................................................................................................... 512 1418 Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery Fatores preditores independentes de ventilação mecânica prolongada em pacientes submetidos à cirurgia de revascularização miocárdica Raquel Ferrari Piotto, Fabricio Beltrame Ferreira, Flávia Cortez Colósimo, Gilmara Silveira da Silva, Alexandre Gonçalves de Sousa, Domingo Marcolino Braile................................................................................................................................................... 520 1419 Adults with congenital heart disease undergoing first surgery: prevalence and outcomes at a tertiary hospital Adultos com cardiopatia congênita submetidos à primeira cirurgia: prevalência e resultados em um hospital terciário Gustavo Alves de Mello, Jehorvan Lisboa Carvalho, José Augusto Baucia, José Magalhaes Filho............................................... 529 1420 Hemolysis in extracorporeal circulation: relationship between time and procedures Hemólise na circulação extracorpórea: correlação com tempo e procedimentos realizados Francisco Ubaldo Vieira Junior, Nilson Antunes, Reinaldo Wilson Vieira, Lúcia Madalena Paulo Álvares, Eduardo Tavares Costa................................................................................................................................................................................................ 535

1421 Effect of exercise associated with stem cell transplantation on ventricular function in rats after acute myocardial infarction Efeito do exercício associado ao transplante de células-tronco sobre a função ventricular de ratos pós-infarto agudo do miocárdio Simone Cosmo, Julio César Francisco, Ricardo Correa da Cunha, Rafael Michel de Macedo, José Rocha Faria Neto, Katherine Athayde Teixeira de Carvalho, Nelson Itiro Miyague, Luiz César Guarita-Souza.......................................................................... 542 1422 Cavo-pulmonary anastomosis associated with left ventricular in comparison with biventricular circulatory support in acute heart failure Anastomose cavo-pulmonar associada ao suporte circulatório esquerdo comparada à assistência biventricular na falência cardíaca aguda Luis Alberto Saraiva Santos, Anderson Benício, Ewaldo de Mattos Júnior, Luiz Alberto Benvenutti, Idágene Aparecida Cestari, Noedir Antonio Groppo Stolf , Luiz Felipe Pinho Moreira............................................................................................................. 552 1423 Clinical and functional capacity of patients with dilated cardiomyopathy after four years of transplantation Evolução clínica e capacidade funcional de pacientes com cardiomiopatia dilatada após quatro anos do transplante Daniela Gardano Bucharles Mont’Alverne, Lara Maia Galdino, Marcela Cunha Pinheiro, Cíntia Souto Levy, Glauber Gean de Vasconcelos, João David de Souza Neto, Juan Alberto Cosquillo Mejía........................................................................................ 562 1424 Minimally invasive aortic valve replacement: an alternative to the conventional technique Troca valvar aórtica minimamente invasiva: uma alternativa à técnica convencional Jeronimo Antonio Fortunato Júnior, Alexandre Gabelha Fernandes, Jeferson Roberto Sesca, Rogério Paludo, Maria Evangelista Paz, Luciana Paludo, Marcelo Luiz Pereira, Amélia Araujo................................................................................................................... 570 1425 Risk factors for hospital mortality in valve replacement with porcine bioprosthesis at an universitary institution Fatores de risco hospitalar para pacientes submetidos à substituição valvar com a bioprótese porcina em instituição universitária Ana Carolina Tieppo Fornari, Luís Henrique Tieppo Fornari, Juan Victor Piccoli Soto Paiva, Pauline Elias Josende, João Ricardo Michelin Sant’Anna, Paulo Roberto Prates, Renato A. K. Kalil, Ivo A. Nesralla........................................................................... 583 1426 In vivo study of lyophilized bioprostheses: 3 month follow-up in young sheep Estudo in vivo do comportamento de bioprótese liofilizada: seguimento de 3 meses em carneiros jovens Fábio Papa Taniguchi, Marina Junko Shiotsu Maizato, Rafael Fávero Ambar, Ronaldo Nogueira de Moraes Pitomb, Noedir Antônio Groppo Stolf..................................................................................................................................................................................... 592 1427 Does diabetes mellitus increase immediate surgical risk in octogenarian patients submitted to coronary artery bypass graft surgery?

Diabetes mellitus aumenta risco cirúrgico imediato em pacientes octogenários submetidos à cirurgia de revascularização miocárdica?

Fernando Pivatto Júnior, Edemar M. C. Pereira, Felipe H. Valle, Guaracy F. Teixeira Filho, Ivo A. Nesralla, João R. M. Sant’Anna, Paulo R. Prates, Renato A. K. Kalil................................................................................................................................................. 600 1428 Evaluation of maximal inspiratory and sniff nasal inspiratory pressures in pre- and postoperative myocardial revascularization Avaliação das pressões inspiratória máxima e inspiratória nasal sniff no pré e pós-operatório de revascularização do miocárdio Juliana Paula Graetz, Antonio Roberto Zamunér, Marlene Aparecida Moreno............................................................................... 607 SPECIAL ARTICLE/ARTIGO ESPECIAL 1429 Cardiac Surgery: the infinite quest Cirurgia cardiaca: a busca infinita Rodolfo A. Neirotti........................................................................................................................................................................... 614 EXPERIMENTAL WORK/TRABALHO EXPERIMENTAL 1430 Sanguineous normothermic, intermittent cardioplegia, effects on hypertrophic myocardium. Morphometric, metabolic and ultrastructural studies in rabbits hearts Efeitos da cardioplegia sanguínea normotérmica intermitente, em miocárdio hipertrófico. Estudos morfométricos, metabólicos e ultraestruturais em corações de coelhos Clovis Carbone Junior, José Eduardo de Salles Roselino, Valder Rodrigues Mello, Paulo Roberto Barbosa Evora, Albert Amin Sader.................................................................................................................................................................. 621

REVIEW ARTICLE/ARTIGO DE REVISÃO 1431 Off-pump versus on-pump coronary artery bypass surgery: meta-analysis and meta-regression of 13,524 patients from randomized trials Cirurgia de revascularização miocárdica com CEC versus sem CEC: meta-análise e meta-regressão de 13.524 pacientes de estudos randomizados Michel Pompeu Barros de Oliveira Sá, Paulo Ernando Ferraz, Rodrigo Renda Escobar, Wendell Nunes Martins, Pablo César Lustosa, Eliobas de Oliveira Nunes, Frederico Pires Vasconcelos, Ricardo Carvalho Lima......................................................................... 631 SHORT COMMUNICATIONS/COMUNICAÇÕES BREVES 1432 Hybrid treatment for correction of pseudoaneurysm after surgical treatment of aortic coarctation Tratamento híbrido para correção de pseudoaneurisma após tratamento cirúrgico de coarctação aórtica João Carlos Ferreira Leal, Victor Rodrigues Ribeiro Ferreira, Valéria B. Braile Sternieri, Rodolfo Wichtendahl, Achilles Abelaira Filho, Luis Ermesto Avanci, Domingo Marcolino Braile................................................................................................................ 642 1433 Endovascular correction of abdominal aortic aneurysm as a late complication of type A aortic dissection Correção endovascular de aneurisma de aorta abdominal em complicação tardia de dissecção de aorta tipo A José Carlos Dorsa Vieira Pontes, João Jackson Duarte, Augusto Daige da Silva, Amaury Mont’Serrat Ávila Souza Dias........... 645 1434 The positioning of the internal thoracic artery extra-pleural and perihilar in coronary artery bypass grafting Trajeto extrapleural, pari-hilar da artéria torácica interna esquerda pediculada nos enxertos coronarianos Hermes de Souza Felippe, Marco Cunha, Eduardo Sérgio Bastos, Marcos Floripes da Silva, Marco Cunha................................648 LETTERS/CARTAS 1435 Letter to the Editor Cartas ao Editor .............................................................................................................................................................................. 652 Reviewers RBCCV 27.4................................................................................................................................................................... 653

Projeto Gráfico: Heber Janes Ferreira

SOCIEDADE BRASILEIRA DE CIRURGIA CARDIOVASCULAR BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY E-mail: revista@sbccv.org.br Sites: www.scielo.br/rbccv www.rbccv.org.br

Editorial

Renewal: ongoing process in BJCVS Domingo M. Braile* DOI: 10.5935/1678-9741.20120085

T

he Brazilian Journal of Cardiovascular Surgery (BJCVS) closes the year 2012 with many achievements, a result of hard work of the Editorial Board, the Board of the Brazilian Society of Cardiovascular Surgery and reviewers, who always are fundamental to the scientific level of our journal is growing.

An example is the number of citations, always growing, reflecting the Impact Factor (IF), which rose from 0.963 in 2011 to 1.239 in that year. As I emphasized in the Editorial from Issue 2.27 [1], the goal for 2013 is to overcome 1.599 in order that we may be classified as boundless“B1� according to CAPES criteria in Medicine I, II and III. To continue our ascent, because in Scimago (the Scopus database) our index is 1.281, as described in the graph below (Fig. 1), it is necessary to continue to be cited, in addition to maintain our renewal process. One is to increase the visibility of BJCVS. For this, we are finalizing preparations for the journal is available in PubMed Central (PMC), an online repository of open access publications in the area of Health Sciences. Currently, there are 2.5 million articles, published in over 3000 journals [2].

Fig. 1 - Graph showing the citation index from BJCVS at Scimago (the Scopus database)

But to be part of the PMC, some requirements are needed. The files must be converted to XML format and the images must be of high quality (Table 1). Thus, BJCVS will increase the requirement in respect of the details of the figures and graphs.

Table 1. PubMed Central specifications for images and graphics Type LineArt (images with linear lines, usually graphics with text)

Format TIF or JPEG

Resolution 900 to 1200dpi Width: 2700px

Halftone (images, usually photographs)

TIF or JPEG

300dpi Width: 900px

Combo (mixture of graphic and image)

TIF or JPEG

500 to 900dpi Width: 2700px

We ask that authors pay attention to submit their studies, as if the images are not within standards, the system will not allow the process to move forward. If there are doubts, the BJCVS Editorial Board and GN1, the company responsible for managing the journal's website (www.rbccv.org.br), will be available for the necessary assistance.

The new picture standard will be clear in the Journal's Rules, which will be updated to fit the new reality of the journal, available in several databases, as demanding quality standards, as quoted above, in addition to be available in multiple formats (HTML, PDF, e-pub and flip), beyond the printed edition. Each of these databases has its own characteristics, for which the journal must be appropriate, at the risk of jeopardizing the quality of the product.

We also emphasize ethics. It is useless to have a modern look, be at the edge of technological advances, if we treat this aspect as secondary. I have always been concerned about this issue and therefore we are providing a link to the I

COPE (Committee On Publication Ethics) website, so that everyone can clearly understand the requirements to avoid unpleasant problems. I suggest the authors and reviewers who access the site (http://publicationethics.org/), which has a vast amount of material that will certainly be of much use.

Concurrently, we are adopting the Crossref, which operates a system of link cross-reference, which allows a researcher to click on a reference cited in a publication by the editor A and be taken directly to the cited content on a publishing from editor B. The link cross-reference system is based on the consensus around the DOI - digital object identifier - as identifier to their collections [3].

This system minimizes the risk of plagiarism, which unfortunately is still a serious problem in the scientific community. The concept of plagiarism is widespread. The Caldas Aulete Dictionary, in its online version, defines as “Presentation of imitation or copy of intellectual or artistic work of others as of their own authorship” [4]. However, if passages of others study are not cited it is considered plagiarism. All the care is not enough to not take risks and be subject to the penalties imposed by the law, among other sanctions.

Within this topic, I suggest reading the presentation I made, along with Prof. Dr. Décio dos Santos Pinto Jr., at the Health Forum, during the Workshop of Scientific Publishing promoted by the Brazilian Association of Science Editors (ABEC), in November, in Florianópolis.

The PowerPoint file is available here (http://rbccv.org. br/imageBank/download/20121116_215024_forum_de_ saude.ppsx ).

Parallel to this, we took an important step towards reducing the time between the completion of each issue and the availability of articles in Thomson (ISI). As each volume is ready, Thomson will be informed and will download data directly from our site. Before, the data were “captured” page of BJCVS in SciELO, which by internal issues, takes longer to deliver the journal.

We also acquired a cutting-edge software for desktop publishing, which will increase the quality of the journal in both print edition and in the online version, in addition to streamline the production. I appreciate the support of the Board of BSCVS, which has always met our demands.

In 2013, the BSCVS hold its 40th Congress, on 18th to th 20 April, in Florianópolis, Florianópolis, SC, which once housed the Congress in 2007. It is an extremely pleasant, with adequate infrastructure for such events. The BSCVS Board and the Executive Local Committee, coordinated by Dr. Lourival Bonatelli Filho, are already working to ensure that the success of previous years is repeated, providing scientific enrichment and socialization among cardiovascular surgeons and other health professionals in Brazil and abroad. In the next issue we will return to the theme.

II

The articles available for testing by the Continuing Medical Education (CME) in this issue are: “On-Pump or Off-Pump? Impact of risk scores in coronary artery bypass surgery” (p. 503), “Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery” (p. 520), "Does diabetes mellitus increase immediate surgical risk in octogenarian patients submitted to coronary artery bypass graft surgery?" (p. 600), "Offpump versus on-pump coronary artery bypass surgery: meta-analysis and meta-regression of 13,524 patients from randomized trials" (p. 631).

In addition to the articles in this issue, with important contributions to the practice of cardiovascular surgery, I recommend reading the following editorials, which bring out issues that serve for reflection and discussion. The authors present their arguments with data and discuss with mastery. This is one of the tasks of a scientific publication: promoting understanding, promoting discussion among peers, so that knowledge can advance, becoming the benefit of the community.

I also highlight the special article “Cardiac surgery: the infinite quest”, written by Dr. Rodolfo Neirotti (p. 614), divided into three parts, to be published until the edition 28.2, in which he outlines some theories and provocative points of view (using his own words) on cardiac surgery, demonstrating how the specialty has to gain if their “actors” are willing to break some paradigms.

I conclude by wishing all those who collaborate with BJCVS this year a 2013 full of success!

My warmest regards,

Domingo Braile Editor-in-Chief BJCVS

REFERENCES

1. Braile DM. Novo fator de impacto: 1,239. Meta é passar de 1,5 em 2013. Rev Bras Cir Cardiovasc. 2012;27(2):I-IV. 2. PubMed Central. Disponível em: http://www.ncbi.nlm.nih. gov/pmc/ Acesso em: 29/11/2012.

3. Brasil. Seer/Ibict. Disponível em: http://seer.ibict.br/index. php?option=com_content&task=view&id=301&Itemid=74 Acesso em: 30/11/2012.

4. Dicionário Caldas Aulete. Versão Digital. Disponível em: http://aulete.uol.com.br/ Acesso em 30/11/2012

Editorial

Risk scores: coronary artery bypass grafting with and without cardiopulmonary bypass Enio Buffolo1 DOI: 10.5935/1678-9741.20120086

The work "With or without CPB? Impact of risk scores in CABG surgery" [1], published in this issue, brings about great contribution of still controversial aspects of the benefit of avoiding the use of cardiopulmonary bypass in CABG (coronary artery bypass graft).

After 30 years of its description and initial results in systematic series of cases [2,3], only years later, in 1995, with the description of even less invasive technique known as "MIDCABG" (Minimally Invasive Coronary Artery Bypass Graft) [4,5], the alternative off-pump coronary artery bypass received special consideration and international focus, occupying the main topic of discussion at specialty congresses.

The contribution of Brazilian heart surgery in this field was extensive and internationally recognized, demonstrating the feasibility of the technique, its benefits and, subsequently, extension of the procedure through creative maneuvers to a large group of patients [6-8]. It should be noted that these contributions were demonstrated at the time when stabilizers were not yet available, and the facilitation of the procedure was obtained by pharmacological stabilization, surgical maneuvers and perfusates [9].

Despite the intuitive advantages to avoid revascularization without cardiopulmonary bypass, turning the procedure into a thoracotomy, there are controversial opinions regarding the indication of this technique in various clinical scenarios, with respect to patient selection, results, patency of the grafts, benefits and disadvantages [10-14].

In reality, these controversies are fueled by biases in patient selection, inadequate training and longer learning curve.

In the literature, the data are compared in retrospective non-randomized single or multicenter studies and the 1. Full Professor at Paulista School of Medicine, UNIFESP, S達o Paulo, SP, Brazil.

results reported as an advantage for either method. There are few prospective and randomized studies, often with sample sizes that do not allow conclusions about which often bring more confusion than clarification.

The approach of this work is original and creative for it uses comparisons among alternative revascularization considering known and approved risk scores as the Bernstein-Parsonnet and EuroSCORE (European System for Cardiac Operative Risk Evaluation).

Based on a ROC curve (Receiver Operating Characteristic) of predicted and observed risk, the study identifies the benefits of revascularization without cardiopulmonary bypass in high risk patients: 17.75 in Parsonnet (OR 7.4 for a P <0.0001) and> 4.5 in EuroSCORE (OR 5.4 for a P <0.0001).

The results are very impressive and give the off-pump revascularization an indisputable advantage for high risk patients and did not detect significant differences in patients without comorbidities [15].

In recent guidelines of the European Society of Cardiology (ESC) and European Association for Cardiothoracic Surgery (EACTS), 2010, we noticed the recognition of the procedure without cardiopulmonary bypass with special technique and preferred in patients with relevant comorbidities, especially chronic renal failure [16,17].

The authors study is the first to demonstrate in expressive sample that in order to detect differences, we have to add to the selection criteria predicted risk, which will have great impact in the planning and selection of alternative revascularization, with effect on real world strategies. The limitations consist in the fact that this is a retrospective, non-randomized unicenter study, but the sample with significant sampling allows both groups to admit that the conclusions are valid as institutional truth; however not allowing to extrapolate to other centers in which the conditions of structure and training teams may not be the same.

III

Abbreviations, acronyms and symbols EACTS European Association for Cardiothoracic Surgery ESC European Society of Cardiology EuroSCORE European System for Cardiac Operative Risk

Evaluation MIDCABG Minimally Invasive Coronary Artery Bypass

Graft ROC Receiver Operating Characteristic STS Society of Thoracic Surgeons

Another important observation concerns the use of not updated risk scores: Bernstein-Parsonnet and EuroSCORE logistic I 2000 - 1999, being that, currently, the most used are the STS and EuroSCORE II. This observation, however, does not invalidate the study proposal, which highlights a finding in a lot of quality information into the real world. What could possibly change if they used the Society of Thoracic Surgeons (STS) risk calculator or EuroSCORE II it would be the cut-off level and not contestation of the results.

SEE ALSO ORIGINAL ARTICLE ON PAGES 503-511 Moreover, the work gives way to the introduction of a specific risk for myocardial revascularization without cardiopulmonary bypass, which in our opinion it would be different from the risks available, which do not distinguish between technical situations that are not similar.

I would like to congratulate the authors that offer a valuable complement to their previous contributions [18,19] and introduce a systematic assessment of procedures from deviations of ROC curves, based on previously known risks.

REFERENCES

3. Benetti FJ. Direct coronary surgery with saphenous vein bypass without either cardiopulmonary bypass or cardiac arrest. J Cardiovasc Surg. (Torino). 1985;26(3):217-22.

4. Benetti FJ, Ballester C, Guido S, Doonstra P, Grandjean J. Video assisted coronary bypass surgery. J Card Surg.

1995;10(6):620-5.

5. Calafiore AM, Giammarco GD, Teodori G, Bosco G, D’Annunzio E, Barsotti A, et al. Left anterior descending coronary grafting via left anterior small thoracotomy without cardiopulmonary bypass. Ann Thorac Surg.

1996;61(6):1658-63.

6. Buffolo E, Andrade CS, Branco JN, Teles CA, Aguiar LF, Gomes WJ. Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg. 1996;61(1):63-6.

7. Lima RC, Escobar MAS, Lobo Filho JG, Diniz R, Saraiva A, Cesio A, et al. Resultados cirúrgicos na revascularização do miocárdio sem circulação extracorpórea: análise de 3410 pacientes. Rev Bras Cir Cardiovasc. 2003;18(3):261-7.

8. Lobo Filho JG, Dantas MCBR, Rolim JGV, Rocha JA, Oliveira FM, Ciarline C, et al. Cirurgia de revascularização completa do miocárdio sem circulação extracorpórea: uma realidade.

Rev Bras Cir Cardiovasc. 1997;12(2):115-21.

9. Rivetti LA, Gandra SM. Initial experience using an intraluminal shunt during revascularization of the beating heart. Ann Thorac Surg. 1997;63(6):1742-7.

10. Sellke FW, DiMaio JM, Caplan RL, Ferguson TB, Gardner TJ, Hiratzka LF; American Heart Association, et al. Comparing onpump and off-pump coronary artery bypass grafting: numerous studies but few conclusions: a scientific statement from the American Heart Association council on cardiovascular surgery and anesthesia in collaboration with the interdisciplinary working group on quality of care and outcomes research.

Circulation. 2005;111(21):2858-64.

11. Puskas JD, Williams WH, Duke PG, Staples JR, Glass KE, Marshall JJ, et al. Off-pump coronary artery bypass grafting provides complete revascularization with reduced myocardial injury, transfusion requirements, and length of stay: a prospective randomized comparison of two hundred unselected patients undergoing off-pump versus conventional coronary artery bypass grafting. J Thorac Cardiovasc Surg.

2003;125(4):797-808.

1. Mejía OAV, Lisboa LAF, Puig LB, Moreira LFP, Dallan LAO, Jatene FB. Com ou sem CEC? Impacto dos escores de risco na cirurgia de revascularização miocárdica. Rev Bras Cir Cardiovasc. 2012;27(4):503-11.

12. Buffolo E, Lima RC, Salerno TA. Myocardial revascularization without cardiopulmonary bypass: historical background and thirty-year experience. Rev Bras Cir Cardiovasc.

2011;26(3):III-VII.

2. Buffolo E, Andrade JC, Succi JE, Leão LE, Cueva C, Branco JN, et al. Revascularização direta do miocárdio sem circulação extracorpórea: descrição da técnica e resultados iniciais. Arq Bras Cardiol. 1982;38(5):365-73.

13. Chu D, Bakaeen FG, Dao TK, LeMaire SA, Coselli JS, Huh J. On-pump versus off-pump coronary artery bypass grafting in a cohort of 63,000 patients. Ann Thorac Surg.

2009;87(6):1820-6.

IV

14. Shroyer AL, Grover FL, Hattler B, Collins JF, McDonald GO, Kozora E, et al. On-pump versus off-pump coronary-artery bypass surgery. N Engl J Med. 2009;361(19):1827-37.

15. Gerola LR, Buffolo E, Jasbik W, Botelho B, Bosco J, Brasil LA, et al. Off-pump versus on-pump myocardial revascularization in low-risk patients with one or two vessels disease: perioperative results in a multicenter randomized controlled trial. Ann Thorac Surg. 2004;77(2):569-73.

16. Sajja LR, Mannam G, Chakravarthi RM, Sompalli S, Naidu SK, Somaraju B, et al. Coronary artery bypass grafting with or without cardiopulmonary bypass in patients with preoperative non-dialysis dependent renal insufficiency: a randomized study. J Thorac Cardiovasc Surg. 2007;133(2):378-88.

17. Caputi GM, Palma JH, Gaia DF, Buffolo E. Off-pump coronary artery bypass surgery in selected patients is superior to the conventional approach for patients with severely depressed left ventricular function. Clinics (Sao Paulo).

2011;66(12):2049-53.

18. Mejía OA, Lisboa LA, Puig LB, Dias RR, Dallan LA, Pomerantzeff PM, et al. The 2000 Bernstein-Parsonnet score and EuroSCORE are similar in predicting mortality at the Heart Institute, USP. Rev Bras Cir Cardiovasc. 2011;26(1):1-6.

19. Mejia OAV, Lisboa LAF, Dallan LAO, Pomerantzeff PMA, Moreira LFP, Jatene FB, et al. Validação do 2000 BernsteinParsonnet e EuroSCORE no Instituto do Coração – USP. Rev Bras Cir Cardiovasc. 2012;27(2):187-94.

V

Editorial

The mitral valve and endothelin-1 in cardiovascular homeostasis Edmilson Moura1 DOI: 10.5935/1678-9741.20120087

The mitral valve, once considered an inert structure with a mechanical response to the demands of intracardiac flow, has been the aim of research that may reveal different functions from those we are used to assign.

The action of substances with autocrine or paracrine effect may be co-responsible for constant adjustments in their morphology and function. The use of techniques of biology and molecular pharmacology to elucidate these issues offers a fertile field for research.

The observation of receptors in valve tissue reveals that this tissue may be subject to change. It is noteworthy that, in addition to being a site capable of morphogenetic changes, the mitral valve appears as a source of substances with cardiovascular effects. In this scenario, endothelin-1 (predominant isoform in the endothelium) seems to be a good example: its complexity is shown by pharmacological diversity of actions in the cardiovascular system [1,2]. After its identification in 1988, huge interest in its functions led scientists to write more than 20 000 scientific papers about the subject [3,4].

However, many questions still remain enigmatic. Among them, we highlight the mitral valve involvement in certain diseases, sometimes suffering morphofunctional adaptations, sometimes enhancing and perpetuating these pathological conditions.

Through its receptor, endothelin-1 has one of the most potent vasoconstrictors effect known by Science.

It affects the inotropism and chronotropism, and is an adjunct in diseases such as pulmonary hypertension [5], systemic hypertension [6] and atherosclerosis [7].

It is a mediator of hypertrophy and cardiac remodeling in congestive heart failure [2]. But what is the real participation of the mitral valve in the pathophysiology of these diseases as a possible source of endothelin-1 in

1. Cardiovascular Surgeon. Intensivist physician, BrasĂ­lia Base Hospital, BrasĂ­lia. BrasĂ­lia, DF, Brazil.

VI

adjacent cardiomyocytes and to its own structure? And what is the action of these diseases over the mitral valve morphogenesis, taking into consideration that this valve is site for endothelin receptor-1?

Such pathophysiological dilemmas hide potential therapeutic responses to highly prevalent diseases that victimize millions of people. The use of receptor antagonists (A and B) of endothelin-1 is already a reality in medical practice [8]. Logically, the affinity of the antagonist for the receptor type resonates with its pharmacological action. Mapping these receptors in different tissue sites, typifying its action, establishing the selectivity and the effects of its chemical block, we will be able to act more accurately in the treatment of these diseases.

ALSO SEE ORIGINAL ARTICLE PAGES 512-519 However, there is still much doubt about the approach to this issue, taking into account the difficulty in obtaining normal and viable tissue valve for comparative quantitative study. This research would allow us to determine whether there is more or less density of endothelin-1 and its receptors in normal mitral valves.

This is due to two main reasons: the rapid degeneration of messenger RNA by RNases, only allowing its extraction in vivo (as the chosen technique) and the importance of the valve structure in healthy individuals, preventing the removal of endothelin-1 genes quantification sample and its receptors in valves free from pathological changes.

One option would be derived tissue of organ donation, however, the acquisition of samples from this source lacks specific legislation [9].

Therefore, the mitral valve is no longer the same, nor should be the approach of their duties. Its ultrastructure certainly still hides many unknown molecules. The answer to their interference in pathological situations

may lie in these molecules, and possible modulatory effects on homeostasis. Such responses will mark the left atrioventricular valve in an indelible way.

REFERENCES

1. Masaki T. Endothelins: homeostatic and compensatory actions in the circulatory and endocrine systems. Endocr Rev. 1993;14(3):256-68.

2. Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851-76.

3. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411-5.

4. Barton M, Yanagisawa M. Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol. 2008;86(8):485-98.

5. Cacoub P, Dorent R, Nataf P, Carayon A. Endothelin-1 in pulmonary hypertension. N Engl J Med. 1993;329(26):1967-8.

6. Kaasjager KA, Koomans HA, Rabelink TJ. Endothelin-1induced vasopressor responses in essential hypertension.

Hypertension. 1997;30(1 Pt 1):15-21.

7. Fan J, Unoki H, Iwasa S, Watanabe T. Role of endothelin-1 in atherosclerosis. Ann N Y Acad Sci. 2000;902:84-93.

8. Dobrek L, Thor P. Endothelin antagonists and their role in pharmacotherapy. Pol Merkur Lekarski. 2010;28(167):404-6.

9. Brasil. Legislação brasileira sobre doação de órgãos humanos: Lei nº 9.434, de 4 de fevereiro de 1997, que dispõe sobre a remoção de órgãos, tecidos e partes do corpo humano para fins de transplante e tratamento, e legislação correlata. Brasília: Câmara dos Deputados, Coordenação de Publicações;2001.

VII

Editorial

Cardiac Surgery, the Brazilian Archives of Cardiology and the Brazilian Journal of Cardiovascular Surgery Paulo Roberto B. Evora1

DOI: 10.5935/1678-9741.20120088

In the last Brazilian Congress of Cardiology, there was a round table dedicated to the Brazilian Archives of Cardiology (BAC). The interesting initiative of the Editor, Professor. Luiz Felipe Pinho Moreira, was addressing the varied lines of articles published in the triennium 2010-2013 in its co-editors' view. The idea was that the presentations gave rise to editorials that, in analytical style, provide the reader with a sectoral analysis of co-auditorships. In the case of our presentation, we adopted a strategy based on three topics: 1) Establishing a parallel between the BAC editorial and two journals devoted to cardiology clinics, 2) assessing the content based on published articles, and 3) searching possible evidence of impact of the creation of the Brazilian Journal of Cardiovascular Surgery (BJCVS) on the publication of articles in cardiac surgery at the Brazilian Archives of Cardiology.

Editorial parallel between the BAC and two famous clinical cardiology journals The journals chosen for editorial comparisons were the Journal of the American College of Cardiology (JACC) and the European Heart Journal (EHJ). The source of information was the MEDLINE. In the period in question, there were published a significant number of studies: 2286 (JACC), 3299 (EHJ) and 689 (BAC). Of this total, 473/20,7% (JACC), 569/29,6 (EHJ) and 79/11,6 (BAC) are articles related to cardiac surgery and among these items were separated the articles according to the three groups of more common surgical heart diseases: coronary artery disease, valvular and congenital heart disease (Figure 1).

1. Cardiovascular Surgeon. Full Professor, Department of Surgery and Anatomy, Faculty of Medicine of Ribeir達o Preto, University of S達o Paulo. Associate Editor of the Arquivos Brasileiros de Cardiologia.

Member of the Editorial Board of the Brazilian Journal of Cardiovascular Surgery.

VIII

Fig. 1 - Number of articles published in journals JACC, EHJ and BAC related to cardiac surgery according to the three groups of more common surgical heart diseases: coronary artery disease, valvular and congenital heart disease

Thus, the numbers calculated were: 1) Coronary Disease: 140/29% (JACC), 126/29, 6% (EHJ) and 12/15,2% (BAC) 2) Valve Disease: 93/19,7% (JACC), 93/32,2% (EHJ) and 7/8,9% (BAC), and 3) Congenital heart defects: 11/2,33% (JACC), 18/13,6% (EHJ) and 6/7, 6% (BAC).

Content analysis based on articles published in BAC For this assessment we adopted a systematic similarly based on the three most common cardiac surgery and heart transplantation. But regardless of any editorial strategy, with large margin of certainty, the publication of greatest impact was the publication of analytical evolution of cardiovascular surgery at the Heart Institute based on impressive institutional experience and 71,305 surgeries

Abbreviations, acronyms and symbols BAC CVA CPB IAC IVC EHJ JACC BJCVS

Brazilian Archives of Cardiology Stroke Cardiopulmonary bypass Interatrial communication Interventricular communication European Heart Journal Journal of the American College of Cardiology Brazilian Journal of Cardiovascular Surgery

between 1984 and 2007, considering the trend of the main procedures and mortality rates. The study shows the following results: 1) The number of CABG surgeries, which in the 1980s had an average of 856/year increased to about 1.106/year, 2) heart valve procedures increased from 400 to 597 operations/year, an increase of 36.7% compared to the 1990s, and 3) the correction of congenital heart disease also had a significant increase of 50.8% over the last decade. The average overall mortality, which at the beginning was 7.5%, decreased to 7%, and 4.9% among elective procedures [1]. This article deserved a brilliant editorial, which highlights the numbers presented, but above all draws a parallel with the historical evolution of Brazilian heart surgery. The title of the editorial speaks for itself: “Evolution of Cardiovascular Surgery. The Brazilian Saga. A History of Work, Success and Pioneering”[2].

CABG Surgery In relation to coronary artery bypass grafting, two aspects were addressed: surgery in octogenarians and prospecting results between surgery with and without cardiopulmonary bypass (CPB).

We studied 140 consecutive cases between January 2002 and December 2007. Patients were on average 82.5 ± 2.2 years (80-89), and 55.7% were male. In the sample, 72.9% were hypertensive, 26.4% had diabetes, 65.7% had severe lesions in three or more vessels and 28.6% in the left main coronary artery. Associated surgery was present in 35.7% of patients, and aortic valve in 26.4% and mitral in 5.6%. These results led to the conclusion that bypass surgery in octogenarians is associated with greater morbidity and mortality than in younger patients, which, however, does not preclude intervention if indicated by the clinical condition [3].

A meta-analysis of available randomized trials demonstrated that off-pump CABG is associated with lower mortality rates and lower risk of cerebrovascular accident (CVA). However, this apparent clinical superiority compared to CPB in CABG surgery still needs to be demonstrated in particular clinical contexts.

Both techniques are evolving and have advantages and disadvantages in certain subgroups of patients in whom

the risks and benefits of both approaches need to be considered, so that the choice of strategy to allow the patient to maximize the long-term benefit and minimize risks in the short-term [4].

Since the review published in BAC was quite cautious, we opted for the inclusion of the concepts derived from recent meta-analysis published by the Cochrane Database Systematic Review. This systematic review did not observe any significant benefit of OPCAB surgery compared to surgery with CPB, considering the operative mortality.

In contrast, we observed better survival in the group undergoing surgery with CPB. Based on this evidence, the CABG with CPB should be the standard procedure.

The surgery without CPB should be used when there is contraindication to aortic cannulation [5].

Cardiac Valve Disease A text of my own illustrates a view of the carcinoid valvulopathy as a puzzle and a challenge of modern cardiology. Why puzzle and challenge? Some data would be still enigmatic: 1) the unknown role of serotonin in valvular disease, 2) against the hypothesis of the presence of IAC, as a condition for left valvulopathies, there are cases approaching left valvulopathy without the presence of such communication, 3) the natural history of the disease is still unclear and the disease could be underestimated.

Some highlights “challenges” would be: 1) early diagnosis based on imaging examination and more accurate biomarkers, 2) what is the optimal surgical timing? 3) although there is a preference for bioprostheses, would possible treatments that reversed the binomial term graft/ patient survival arise? 4) does the association between repair and valve exchanges make sense? It is noteworthy that the increasing number of publications on carcinoid heart disease can provide it characteristic of emerging disease, deserving more attention to basic researchers, clinicians and surgeons [6].

Congenital heart defects A study aimed to assess the feasibility and effects of anatomic repair of Ebstein's anomaly with the cone technique in the clinical evolution of patients, the function of the tricuspid valve and right ventricular morphology.

This is an original surgical technique, proposed by the authors in 1989, called cone reconstruction of the tricuspid valve, aimed at rebuilding valve like normal. We compared the clinical, radiological and echocardiographic data obtained in the preoperative, immediate postoperative and long-term of 52 consecutive patients with a mean age of 18.5 ± 13.8 years, who underwent cone technique. The cone technique showed low hospital mortality, correcting tricuspid insufficiency effectively and in a lasting way, with the restoration of the right ventricle functional IX

area, allowing the heart reverse remodeling and clinical improvement in most patients in the long-term [7]. The relevance of this issue prompted an editorial which highlights three important points: 1) the introduction of the cone technique, as it is called, immediately becomes an important technical advance of considerable magnitude and breath in the general management of Ebstein's anomaly, 2) the difficulty with this cone technique is still expressed in its non-reproducibility and use in other medical centers, thus it is believed that hereafter it may be performed more, stimulated by the good results demonstrated already in sufficient period of long-term outcome, and 3) one aspect that should be further emphasized is that the technique could be performed on younger patients than that currently performed (18.5 Âą 13.8 years), in order to prevent unfavorable evolutionary adverse aspects, as the marked right ventricular dilatation and subsequent ventricular dysfunction [8].

It is worth mentioning a study proposed to identify the risk factors associated with dysfunction and pulmonary homograft failure in children undergoing expansion of the right ventricular outflow tract.

The final sample of 75 patients with a median age at surgery of 22 months, ranging from 1 to 157 months, showed 13 (17%) patients who developed homograft dysfunction, characterized by severe pulmonary stenosis or insufficiency. The authors concluded that the pulmonary homograft of size smaller than 21 mm and the pulmonary valve inadequate for the patient's age and weight are factors for graft dysfunction [9].

Still in the field of congenital heart disease, deserves special mention the growing individualized interest in adult congenital heart disease, and who should be responsible for operating them: the pediatric surgeon or adults' surgeon? Two articles were published on the subject. One aimed to describe the profile of patients who had undergone surgery over the age of 16 years and assessing the risk factors predictive of hospital mortality.

One thousand five hundred and twenty patients (mean age 27 Âą 13 years) underwent surgery between January 1986 and December 2010. We performed descriptive analysis of the epidemiological profile of the population studied and analysis of risk factors for hospital mortality, considering the complexity score, the year in which the surgery was performed, a procedure performed by pediatric surgeon or not and the presence of reoperation. It was also observed an increasing number of patients aged over 16 years and that, despite the large number of simple cases, the most complex were referred to pediatric surgeons, who had lower mortality, especially in recent years [10].

The other study aimed to describe the basic clinical profile of adults with congenital heart disease receiving care at a tertiary center. In the study, the most patients were X

treated invasively, residents in the region and most aged below 40 years. Defects such as atrial septal defect (ASD), ventricular septal defect (VSD) and pulmonary stenosis predominated in the untreated group, while in the treated, most had undergone surgical correction of ASD, tetralogy of Fallot, aortic coarctation and VSD. Hypertension and arrhythmias were significant in both groups, and large variety of other comorbidities was also recorded [11].

Heart Transplant A study aimed to compare the effects of sildenafil and sodium nitroprusside on hemodynamic, echocardiographic, and neurohormonal variables during lung reactivity test.

Sildenafil and nitroprusside are vasodilators that reduce, significantly, pulmonary hypertension and cardiac geometry, besides improving biventricular function.

Nitroprusside, unlike sildenafil, was associated with systemic hypotension and worsening of venous oxygen saturation [12].

A well-designed meta-analysis concludes that the bicaval and total orthotopic heart transplants are better in terms of prognosis than the biatrial. Therefore, the indication of biatrial technique for transplantation should be the exception and not the rule [13].

Impact of the creation of BJCVS approaching heart surgery articles publishing on BAC After the arbitrary evidence above described emerged the curiosity if the publication of BJCVS caused some impact on the profile of publications with respect to cardiac surgery issues in BAC. Querying MEDLINE in the triennium 1983-1985 (before BJCVS), the following numbers were calculated: a total of 615 studies, 58 (9.43%) were about the heart surgery.

Fig. 2 - Number of articles published in journals BJCVS and BAC related to cardiac surgery according to the three groups of more common surgical heart diseases: coronary artery disease, valvular and congenital heart disease

Among these, 9 (13.9%) were related to coronary surgery, 3 (4.9%) with valvular heart disease, and were not published articles on congenital heart defects. If there is a gross bias, Figure 2 shows it is favorable to BAC in relation to publications related to valvular and congenital heart disease. Emphasizing that presentations of case reports were not considered, it is curious to note the almost nonexistent publications of studies on congenital heart diseases in BJCVS. As a final comment, the studies published in BAC may be considered compatible with the orientation of disseminating information that are of mutual interest among clinicians and surgeons.

4. Godinho AS, Alves AS, Pereira AJ, Pereira TS. On-pump versus off-pump coronary-artery bypass surgery: a metaanalysis. Arq Bras Cardiol. 2012;98(1):87-94.

5. Møller CH, Penninga L, Wetterslev J, Steinbrüchel DA, Gluud C. Off-pump versus on-pump coronary artery bypass grafting for ischaemic heart disease. Cochrane Database Syst Rev. 2012;3:CD007224.

6. Evora PR, Bassetto S, Augusto VS, Vicente WV. Carcinoid heart valve disease: still a puzzle and a challenge. Arq Bras Cardiol. 2011;97(5):e111-2.

7. Silva JP, Silva LF, Moreira LF, Lopez LM, Franchi SM, Lianza AC, et al. Cone reconstruction in Ebstein's anomaly repair: early and long-term results. Arq Bras Cardiol. 2011;97(3):199-208.

8. Atik E. Ebstein's anomaly. Arq Bras Cardiol. 2011;97(5):363-4.

9. Lenzi AW, Olandoski M, Ferreira WS, Sallum FS, Miyague NI. Dysfunction of the pulmonary homograft used in the reconstruction of the right ventricle exit tract. Arq Bras Cardiol.

2011;96(1):2-7.

REFERENCES

1. Lisboa LA, Moreira LF, Mejia OV, Dallan LA, Pomerantzeff PM, Costa R, et al. Evolution of cardiovascular surgery at the Instituto do Coração: analysis of 71,305 surgeries. Arq Bras Cardiol. 2010;94(2):162-8.

2. Braile DM, Gomes WJ. Evolution of cardiovascular surgery: the Brazilian saga. A history of work, pioneering experience and success. Arq Bras Cardiol. 2010;94(2):141-2.

3. Pivatto Júnior F, Kalil RA, Costa AR, Pereira EM, Santos EZ, Valle FH, et al. Morbimortality in octogenarian patients submitted to coronary artery bypass graft surgery. Arq Bras Cardiol. 2010;95(1):41-6.

10. Caneo LF, Jatene MB, Riso AA, Tanamati C, Penha J, Moreira LF, et al. Evaluation of surgical treatment of congenital heart disease in patients aged above 16 years. Arq Bras Cardiol.

2012;98(5):390-7.

11. Amaral F, Manso PH, Granzotti JA, Vicente WV, Schmidt A. Congenital heart disease in adults: outpatient clinic profile at the Hospital das Clínicas of Ribeirão Preto. Arq Bras Cardiol.

2010;94(6):707-13.

12. Freitas Jr AF, Bacal F, Oliveira Júnior JD, Fiorelli AI, Santos RH, Moreira LF, et al. Sildenafil vs. sodium before nitroprusside for the pulmonary hypertension reversibility test before cardiac transplantation. Arq Bras Cardiol.

2012;99(3):848-56.

13. Locali RF, Matsuoka PK, Cherbo T, Gabriel EA, Buffolo E. Should biatrial heart transplantation still be performed? A meta-analysis. Arq Bras Cardiol. 2010;94(6):829-40.

XI

Editorial

Lessons from the clinical trials FREEDOM and SYNTAX 5-years: new evidence or evidence only noticed now?

Luciano Cabral Albuquerque1 “There are many hypotheses in science which are wrong. That’s perfectly all right: it’s the aperture to finding out what’s right” Carl Sagan “There is nothing new under the sun - nihil novi sub sole” Eclesiastes 1:9

DOI: 10.5935/1678-9741.20120089

In recent weeks, the two most important and awaited scientific evidence in the treatment of multivessel coronary disease after eluting stents were released: the results from the FREEDOM study [1] and the 5-year analysis of the SYNTAX trial [2]. In a current scenario, in which the roles of intervention, surgery and medical treatment are increasingly discussed, and in which it is increasingly spread the need for therapeutic decision by multidisciplinary heart teams, the critical analysis of methodologically well-designed studies that bring a broader clinical applicability than previously published trials comparing angioplasty and coronary artery bypass surgery, becomes widely needed.

However, if the main findings of both studies are not surprising, reasserting the role of revascularization surgery as preferred in patients with multivessel disease, a more detailed assessment of the body of evidence previously available will show that the information is already in the literature.

The final analysis of 5-year follow-up of the SYNTAX trial, presented at the European Congress of Cardiothoracic Surgery in October, confirmed the strategy of revascularization, as more beneficial than the implantation of drug-eluting stents for patients with lesions of left main 1. Member of SBCCV and Associate Editor of BJCVS. Doctor in Cardiology at the Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.

XII

coronary artery or multivessel coronary heart disease and additionally separation was observed in the curves of some outcomes in relation to the previously published analyzes of 1 to 3 years of follow up. The rates of cardiovascular death and myocardial infarction, which previously did not reach statistical significance, were significantly higher in the PCI group (9.2% vs. 4.0% and 10.6% vs. 3.3%, respectively - P <0.001). Moreover, the rate of cerebral vascular accident (CVA), higher in the surgical previous analyzes, proved to be similar between groups after 5 years (3.0% vs. 3.4% - P = 0.66).

Before this evidence, in April of this year, the record ASCERT [3] already signaled with similar results.

Evaluating a robust sample of nearly 200,000 patients who underwent CABG (n = 86.244) or angioplasty with stents (n = 103.549), a study funded by the National Heart, Lung, and Blood Institute revealed on 4 years of follow up, mortality 20% lower in operated cases compared to cases intervened by catheter (16.4% vs. 20.8%, CR 0.79 - 95% CI 0.76 to 0.82 - P = 0.002), which was effective similar evaluation of other variables, and in comparison between subgroups.

Even more remotely, this information was already available in the publication of results from the registry of the Department of Health of the State of New York [4].

Evaluating all cases of coronary artery bypass grafting (n = 7437) and implantation of pharmacological stents (n = 9963) conducted in that state between 2003 and 2005,

Abbreviations, acronyms and symbols ASCERT

American College of Cardiology Foundation-The Society of Thoracic Surgeons collaboration on the Comparative Effectiveness of revascularization sTrategies CVA Cerebrovascular accident BARI Bypass Angioplasty Revascularization Investigation EVASTENT EVAluation of active STENT EXCEL Evaluation of XIENCE PRIME™ Everolimus Eluting Stent System (EECSS) or XIENCE V® EECSS Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization FREEDOM Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal Management of multivessel disease MACCE major adverse cardiovascular and cerebrovascular event SYNTAX SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery

this portrait of the real world revealed differences in the outcomes of interest, in 18 months of follow-up hitherto not revealed by clinical trials. In patients with lesions in three or more vessels, the survival rate favored the surgical group (94% vs. 92% - P = 0.03), and the rate of survival free of myocardial infarction (92% vs. 89th % - P <0.001). Also, in the group with lesions in two vessels, the same analysis of outcomes showed benefit with revascularization strategy (96% vs. 94% - P = 0.003 and 94.5% vs. 92.5% - P < 0.001). And, as expected, the rate of subsequent revascularization was much higher in the group undergoing angioplasty.

Another alleged "gap" of evidence in the treatment of coronary artery disease concerned what type of intervention should be preferred in patients with multivessel disease with diabetes mellitus.

In the FREEDOM trial, coronary surgery was compared to angioplasty with drug-eluting stents, in 1,900 diabetic patients with multivessel disease were randomized into 140 different institutions, in which all patients received optimal therapy to control cholesterol, blood pressure and glycosylated hemoglobin. The primary endpoint was previously defined as death from any cause, non-fatal myocardial infarction and / or stroke, and occurred more frequently in the PCI group (27% vs. 19%, P = 0.005), after 5 years of follow up. A more detailed analysis of outcomes so-called "hard" also demonstrated the benefit of surgery on the lower occurrence of myocardial infarction (P <0.001) or death from any cause (P = 0.049). On the other hand, stroke was the most frequent in the surgery group (5.2% vs. 2.4%, P = 0.03). The authors concluded that "in diabetic patients with advanced coronary disease, bypass surgery is superior to angioplasty, by significantly

reducing the rates of death and myocardial infarction, although with higher rates of stroke."

In fact, in the subgroup of diabetic patients, information that CABG offers more benefit than PCI, and that, in particular, among the types of stents, those coated with drugs have worse outcomes in this population, was already included in the results of some other important studies.

In the final analysis of the BARI study [5], which compared the performance of surgical and percutaneous revascularization in multivessel coronary disease, there was no difference in late survival when evaluated the total sample (n = 1,829). However, following 5 and 10 years of diabetic subgroup (n = 353), there was a lower mortality from all causes, lower cardiovascular mortality and lower rate of myocardial infarction in patients who underwent CABG, and not the percutaneous angioplasty (P = 0.002).

Moreover, in the French multicenter registry EVASTENT [6], 1,731 patients with multivessel coronary artery disease, revascularization exclusively with sirolimus stents had their outcomes measured in the 1 year follow-up, although overall survival free of major cardiovascular events (MACCE) has been excellent (98%), assessment of diabetic patients showed mixed results. While at one extreme 99% of non-diabetic patients with univascular disease were free of MACCE, amongst diabetic patients with multivessel disease only 87% showed no severe outcomes at 1 year. And an even more important finding: when analyzed only allcause mortality, independent of the patient be uni, bi, or multiarterial, the condition of being diabetic increased by 3.1 times the chance of death - P <0.001 (Figure 1 ).

Fig. 1 – EVASTENT study [6]: late survival in diabetic and nondiabetic patients after stenting with sirolimus

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Another important revelation, but not surprising, arises when evaluated outcomes so-called "hard" of implantation of bare-metal stents versus drug-eluting stents, as in the combined analysis of four randomized trials in patients with multivessel disease [7]. In the population of 428 diabetic patients, the survival rate at 4 years was significantly lower in those who received sirolimus-eluting stents (87.8%) compared to bare-metal stents (95.6%). In other words, the condition of the pharmacological stent be increased by 2.9 to an odds ratio of death from any cause, in diabetic patients, due to the higher incidence of late thrombosis (95% CI: 1.38 to 6.10 - Figure 2).

those relating to the controversy vs. angioplasty, is not exactly new, and always within reach of our eyes; it was only a matter of willingness to see them.

REFERENCES

1. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012. DOI: 10.1056/ NEJMoa1211585.

2. Taggart D. Surgery is best for most patients, final SYNTAX data confirm. Disponível em: http://www.theheart.org/ article/1466345.do.

3. Weintraub WS, Grau-Sepulveda MV, Weiss JM, O'Brien SM, Peterson ED, Kolm P, et al. The ASCERT Study Investigators.

Comparative effectiveness of revascularization strategies. N Engl J Med. 2012;366(16):1467-76.

4. Hannan EL, Wu C, Walford G, Culliford AT, Gold JP, Smith CR, et al. The Registry of New York State Department of Health. Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease. N Engl J Med. 2008;358(4):331-41.

5. BARI Investigators. The final 10-year follow-up results from the BARI randomized trial. J Am Coll Cardiol.

2007;49(15):1600-6.

Fig. 2 - Analysis of long-term survival of diabetic patients after implantation of sirolimus-eluting stents or bare-metal stents [7]

Finally, while the results are awaited for further studies in progress, as the EXCEL trial [8], which evaluates the performance of the everolimus eluting stent vs. revascularization surgery in patients with lesions of left main coronary artery, a careful reading of the body of evidence available for some time in the literature may reveal "truths" that seemingly emerge only now, in the light of the findings of large multicenter clinical trials.

As the millennial initial quote "There is nothing new under the sun - nihil novi sub sole", most "new" evidence in the treatment of ischemic heart disease, in particular

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6. Machecourt J, Danchin N, Lablanche JM, Fauvel JM, Bonnet JL, Marliere S et al. Risk factors for stent thrombosis after implantation of sirolimus-eluting stents in diabetic and nondiabetic patients: the EVASTENT Matched-Cohort Registry. J Am Coll Cardiol. 2007;50(6):501-8.

7. Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med. 2007;356(10):989-97.

8. The EXCEL Trial Investigators. Evaluation of Xience Prime™ Everolimus Eluting Stent System (EECSS) or Xience V® EECSS versus coronary artery bypass surgery for effectiveness of left main revascularization. Disponível em: http://www. clinicaltrials.gov/ct2/show/NCT01205776.

Editorial

The evidence-based medicine and coronariopathy Eduardo Augusto Victor Rocha1

DOI: 10.5935/1678-9741.20120090

In November, we had two important works presented that will change the course of the treatment of coronary artery disease. The presentation of the fifth follow-up year of SYNTAX study [1] and the results of the FREEDOM [2] demonstrated a clear advantage on the results of coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) with drug-eluting stents in triple vascular diabetic patients with trunk injuries of left main coronary artery.

In its fifth year, the SYNTAX shows that mortality from cardiac causes was 9% for PCI and 5.3% for CABG, myocardial infarction (MI) in 5 years: 3.8% for CABG and 9.7% for PCI. The need for another revascularization was 25.9% for PCI and 13.7% for CABG. The FREEDOM, study sponsored by the stent manufacturing industry, also demonstrates a clear advantage of the results of CABG compared to PCI. The all-cause mortality in 5 years was 18.7% in the CABG and 26.6% in PCI (P = 0.005), AMI 6% for CABG and 13.9% for PCI (P <0.001). However, patients undergoing CABG had more cerebrovascular accidents (5.2% versus 2.4%).

The evidence-based medicine will change the reality, with several medical and financial implications. Health plans and SUS (Unified Health System) will limit the indications of inappropriate practices, for their own survival. We, as doctors, have to specify the procedures well, avoiding unnecessary costs for payers, in order to achieve adequate remuneration.

The PCI solution seemed modern and suitable for coronary insufficiency. In 2007, the COURAGE study 1. Master in Surgery, Cardiovascular Surgery at Vera Cruz Hospital and Sao JosĂŠ University Hospital, both in Belo Horizonte, Minas Gerais, Brazil, and at the Ibiapaba Hospital, Barbacena, Minas Gerais, Brazil.

Professor of Surgery from College of Health and Human Ecology (FASEH), Vespasiano, Minas Gerais, Brazil. Full Member of BSCVS.

began to change that impression, demonstrating that clinical treatment is better than PCI for treatment of stable angina [3]. However, despite always hearing that the prosthesis would develop continually, after seeing the results of the FREEDOM and SYNTAX made us disbelievers. Some multinationals are discouraging their production or closing line of stents and devices due to the fear of legal issues and also a fall in the profitability of this market.

In the United States, some doctors are being prosecuted and jailed for indication of inadequate therapeutic procedures. Moreover, ethical issues should be raised.

No procedure is risk-free, if the indication is not precise, certain patients will certainly perish or suffer serious complications, which is unacceptable.

We have observed speeches totally unfounded used in our day-to-day activities who have influenced on the indication of procedures, such as the culprit lesion. It is not easy to understand what a culprit lesion is; we know that there are patients with severe injuries in one, two or three major coronary arteries. The clinical presentation, characteristics and anatomy, besides the severity of coronary lesions, are the factors that determine the indication for revascularization procedures.

A very interesting article was published this year, about the real world in the United States for the treatment of coronary artery disease. The study shows that 91% of patients undergoing PCI had lesions in one or two vessels, without involvement of the proximal left anterior descending artery or were under clinical treatment which was considered insufficient [4].

A principle must exist even before angiography: a decision about the treatment should be discussed, with a clinical cardiologist, an interventionist and a surgeon [5]. This decision divided among the professionals who are involved in the treatment of coronary artery disease XV

Abbreviations, acronyms and symbols

REFERENCES

CABG Coronary Artery Bypass Grafting COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation FREEDOM Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal Management of multivessel disease AMI Acute Myocardial Infarction PCI Percutaneous Coronary Intervention SUS Unified Health System SYNTAX SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery

1. Mohr F, Redwood S, Venn G, Colombo A, Mack M, Kappetein P, et al. Final five-year follow-up of the syntax trial: optimal revascularization strategy in patients with three-vessel disease. J Am Coll Cardiol. 2012;60(17S). Doi:10.1016/j. jacc.2012.08.052

prevents conflicts of interest and can provide the best treatment for the population.

The structuring cardiology and cardiovascular surgery services with well-equipped hospitals and adequate training of surgeons, intensivists, cardiologists and nursing is essential. We need to know our results and evaluate them using international risk criteria, offering excellent services to our patients.

We can no longer accept impressions, pressures from the industries or rhetoric as reasons to indicate any medical treatment. There is no other way unless the evidence-based medicine, with its best argument, the scientific truth.

3. Boden WE, O'Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, et al Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):150316.

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2. Farkouh ME, Domanski M, Sleep LA, Siami FS, Dangas G, Mack M, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012. DOI:10.1056/ NEJMoa1211585.

4. Hannan EL, Cozzens K, Samadashvili Z, Walford G, Jacobs AK, Holmes DR Jr, Stamato NJ, et al. Appropriateness of coronary revascularization for patients without acute coronary syndromes. J Am Coll Cardiol. 2012;59(21):1870-6.

5. Hlatky MA. Compelling evidence for coronary-bypass surgery in patients with diabetes. N Engl J Med. 2012. DOI: 10.1056/ NEJMe1212278

ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):503-11

On-pump or off-pump? Impact of risk scores in coronary artery bypass surgery Com ou sem CEC? Impacto dos escores de risco na cirurgia de revascularização miocárdica

Omar Asdrúbal Vilca Mejía1, Luiz Augusto Ferreira Lisboa2, Luiz Boro Puig3, Luiz Felipe Pinho Moreira4, Luis Alberto Oliveira Dallan5, Fabio Biscegli Jatene6

DOI: 10.5935/1678-9741.20120091

RBCCV 44205-1416

Abstract Objective: Remain controversies about the use of cardiopulmonary bypass (CPB) in coronary artery bypass grafting (CABG). The aim of this study was to evaluate the impact of the 2000 Bernstein Parsonnet (2000BP) and EuroSCORE (EU) for choice CPB in CABG. Methods: 1551 consecutive patients underwent CABG. CPB was used in 1,121 (72.3%) patients. The performance of 2000BP and EU was assessed by calibration, discrimination and correlation tests. For both risk scores, increasing the value of the score and presence of CPB were directly related to a higher risk of death (P <0.05). Therefore with these two variables was constructed a logistic regression model for each risk score, in order to determine in which value of score the presence of CPB increases significantly the risk of death.

Results: The calibration, like the area under the ROC curve for the group with CPB [2000BP=0.80; EU=0.78] and without CPB [2000BP=0.81; EU=0.85] were appropriate.

The Spearman correlation for groups with and without CPB was 0.66 (P<0.001) and 0.62 (P<0.001), respectively.

Using the 2000BP, for a value>17.75 the presence of CPB increased the chance of death to 7.4 [CI 95% (4.4-12.3), P<0.0001]. With the EU, for a value >4.5 the presence of CPB increased the chance of death to 5.4 [CI 95% (3.3-9), P<0.0001].

Conclusion: In decision making, the 2000BP>17.75 or the EU>4.5 guide to identify patients who underwent CABG with CPB increases significantly the chance of death.

1. Doctor of Science (Cardiovascular Surgery) USP, Specialist Surgery Thoracic Aorta / Incor-HCFMUSP, physician assistant Charitable Portuguesa de São Paulo, São Paulo, SP, Brazil. Author.

2. Professor, Physician Assistant Surgical Unit Cardiac Coronary InCor / HCFMUSP, São Paulo, SP, Brazil. Coauthor.

3. Professor, Associate Professor FMUSP, Physician Assistant Surgical Unit Cardiac Coronary InCor / HCFMUSP, São Paulo, SP, Brazil. Coauthor.

4. Professor, Associate Professor FMUSP, Director of Surgical Research Unit InCor / HCFMUSP, São Paulo, SP, Brazil. Coauthor.

5. Professor, Associate Professor FMUSP, Director of the Surgical Unit of Cardiac Coronary InCor / HCFMUSP, São Paulo, SP, Brazil. Coauthor.

6. Professor of Cardiovascular Surgery FMUSP, São Paulo, SP, Brazil.

Coauthor.

Work performed at the Heart Institute of the Clinical Hospital of the Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.

Descriptors: Risk Factors. Cardiopulmonary Bypass.

Coronary Artery Bypass. Hospital Mortality.

Correspondence address: Omar Asdrúbal Vilca Mejía Av. Dr. Enéas de Carvalho Aguiar, 44 – São Paulo, SP, Brazil – Zip code: 05403-000.

E-mail: omarvmejia@sbccv.org.br Article received on July 2nd, 2012 Approved on November 13th, 2012

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Mejía OAV, et al. - On-pump or off-pump? Impact of risk scores in coronary artery bypass surgery

Abbreviations, acronyms and symbols 2000BP 2000 Bernstein Parsonnet escore CAPPesq Ethics Committee for Analysis of Research Projects CPB Cardiopulmonary bypass CABG Coronary Artery Bypass Grafting EU EuroSCORE InCor-HCFMUSP Heart Institute of the Clinical Hospital of the

School of Medicine, University of São Paulo ROC Receiver operating characteristic SI3 Electronic medical records system InCor- HCFMUSP SPSS Statistical Package for the Social Sciences STSscore Society of Thoracic Surgeons escore

Resumo Objetivo: Permanecem as controvérsias sobre a utilização de circulação extracorpórea (CEC) na cirurgia de revascularização miocárdica (CRM). O objetivo deste estudo foi avaliar o impacto do 2000 Bernstein Parsonnet (2000BP) e EuroSCORE (EU) para escolha de CEC na CRM. Métodos: Foram submetidos à CRM 1551 pacientes consecutivos. CEC foi utilizada em 1.121 (72,3%) pacientes.

INTRODUCTION Coronary artery bypass grafting (CABG) remains the most cardiovascular procedure performed worldwide [1], therefore the most studied. Over the years, cardiopulmonary bypass (CPB) has allowed to establish CABG as a safe and effective treatment. However, there has always been concern about the influence of CPB in increased morbidity [2,3]. The pioneering spirit made from the 1980s, some groups began to perform Off-Pump Coronary Artery Bypass Grafting (OPCAB) in selected patients [4,5]. Then came controversy regarding the indication of CPB in CABG. In literature, retrospective studies on large populations [6,7] reported a decrease in mortality when CABG was performed without CPB. However, in randomized studies with small populations, the difference in favor of OPCAB was not significant [8,9]. Thus, although there are welldefined criteria for the CABG indication in the treatment of obstructive coronary artery disease, the choice of CPB remains based on the clinical profile of the patient and the surgeon's experience.

Moreover, the risk scores are the best way to transfer scientific knowledge into clinical practice 504

O desempenho do 2000BP e EU para a amostra foi avaliado mediante testes de calibração, discriminação e correlação. Para ambos os escores de risco, o aumento do valor do escore e a presença de CEC tiveram relação direta com maior chance de óbito (P<0,05). Portanto, com essas duas variáveis foi construído um modelo de regressão logística para cada escore de risco, com a finalidade de determinar em que valor do escore a presença de CEC aumenta significativamente a chance de óbito.

Resultados: A calibração, ao igual que a área abaixo da curva ROC para o grupo com CEC [2000BP=0,80; EU=0,78] e sem CEC [2000BP=0,81; EU=0,85] foram adequadas. A correlação de Spearman para os grupos com e sem CEC foi de 0,66 (P<0,001) e 0,62 (P<0,001), respectivamente. No 2000BP, para um valor>17,75, a presença de CEC aumentou a chance de óbito para 7,4 [IC95% (4,4-12,3), P<0,0001].

No EU, para um valor>4,5, a presença de CEC aumentou a chance de óbito para 5,4 [IC95% (3,3-9), P<0,0001].

Conclusão: Na tomada de decisões, o 2000BP>17,75 ou o EU>4,5 orientam a identificar pacientes que quando submetidos a CRM com CEC têm chance de óbito aumentada significativamente.

Descritores: Fatores de Risco. Circulação Extracorpórea.

Ponte de Artéria Coronária. Mortalidade Hospitalar.

and its applicability in CABG is already certified as a recommendation IIA with level of evidence C [10]. Among these scores, the 2000 Bernstein Parsonnet (2000BP) [11] was adequate in patients undergoing CABG with and without CPB [12], similar to the EuroSCORE (EU) [13], which was also validated for both techniques [14,15].

In Brazil, both scores were also accurate for predicting mortality in CABG, including groups with and without cardiopulmonary bypass [16]. However, other scores, such as the Society of Thoracic Surgeons (STSscore), and more recently, the EuroSCORE II, were not used in this study because they have not yet been validated in our reality.

In theory, scores that predict mortality for both techniques used to treat the same disease can compare and choose preoperatively the best strategy to be applied in specific patients. The objective of the study was to evaluate the impact of EU and 2000BP choice for CPB in CABG. METHODS Sample size, inclusion and exclusion criteria This prospective, observational study was conducted at the Division of Cardiovascular Surgery, Department

Mejía OAV, et al. - On-pump or off-pump? Impact of risk scores in coronary artery bypass surgery

Rev Bras Cir Cardiovasc 2012;27(4):503-11

of Cardiology, Heart Institute of the Clinical Hospital of the School of Medicine, University of São Paulo (IncorHCFMUSP). In the sample, 1551 patients underwent CABG sequentially in both modality elective, urgent and emergency care, from May 2008 to July 2010.

We excluded from the study: reoperations associated surgeries (including valve, and other thoracic aorta) and coronary insufficiency alternative procedures (laser, injection of stem cells and other).

curve (ROC). Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 16.0 for Windows (IBM Corporation Armonk, New York). Abnormal distribution of continuous variables were described as medians. The standard deviation and categorical variables were described by absolute number and percentage. The comparison of categorical variables was performed by chi-square test. The value of P <0.05 was considered significant.

Gathering, defining and organizing the data Data were collected preoperatively and clinical evaluation system for electronic medical records InCorHCFMUSP (SI3) and stored in a single spreadsheet.

This worksheet was adapted to include all the variables described by the model 2000BP and the EU for each patient. Patients were sorted according to risk groups established by the scores and placed in the database made on Excel for this purpose. All patients were followed until hospital discharge. No patient was excluded from analysis due to missing data.

The outcome of interest was in-hospital mortality, defined as death occurring in the time interval between surgery and discharge.

Ethics and consent This study was approved by the Ethics Committee for Analysis of Research Projects (CAPPesq), Hospital das Clinicas, School of Medicine, University of São Paulo with the number 1575, which exempted the need for informed consent and informed by the type of design applied.

Surgical Technique After median sternotomy, the patients were operated with or without the use of CPB, this option by the surgeon in charge of the case. When operated using CPB, this was performed at normothermia or mild hypothermia and arterial cannulation had made in the ascending aorta and the right atrium vein. Cardiac arrest was induced by blood cardioplegia or crystalloid, always using the anterograde.

Off-pump patients needed the Octopus device (Medtronic).

Statistical Analysis For plausibility of the study was initially assessed the applicability of scores (2000BP and EU) in patients with and without CPB sample studied by testing calibration and discrimination. The correlation between both scores in patients with and without CPB was analyzed by the Spearman test and the presence of outliers via box plots.

From the directly proportional relationship between the score and the presence of in-hospital death (P <0.001) and there is more on-pump CABG group died (P <0.05) was built a logistic regression model with two variables (score value + presence / absence of CPB) for each risk score. The purpose of the study was to examine whether the same score value (total value represented by the sum of the weights assigned to each variable) the presence of CPB would alter the estimated probability of death.

To better prognostic accuracy cutoff points were obtained by means of receiver operating characteristic

RESULTS Mean age was 63 ± 10 years, and 27% of female patients. Overall mortality was 5%. In Figure 1, so informative and not comparative, is shown the prevalence of variables in patients with and without CPB. The pump CABG was performed in 1.122 (72.3%) patients and OPCAB in 429 patients, with a mortality of 5.7% and

Fig. 1 - Prevalence of variables in patients with and without cardiopulmonary bypass for patients undergoing coronary artery bypass grafting

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3.2%, respectively. In the calibration of the models in the on-pump group, the Hosmer-Lemeshow test showed a P = 0.864 (χ2 = 3.926, df = 8) to 2000BP and P = 0.442 (χ2 = 5.836, df = 6) for the EU. In the calibration of the models in the off-pump group, the Hosmer-Lemeshow test showed a P = 0.199 (χ2 = 11.046, df = 8) to 2000BP and P = 0.728 (χ2 = 3.623, df = 6) for the EU. Discrimination (Figure 2), the area under the ROC curve for the group with CPB was 0.799 [95% CI (0.741 to 0.856), P <0.001] for 2000BP and 0.775 [95% CI (0.711 to 0.838), P <0.001] for the EU. The area under the ROC curve for the off-pump group was 0.807 [95% CI (0.677 to 0.936), P <0.001] for 2000BP and 0.845 [95% CI (0.743 to 0.947), P <0.001] for EU. Therefore, the applicability of the models in the overall sample and by groups was adequate. From this analysis were prepared curves of observed mortality for the groups with and without cardiopulmonary bypass and its relation to expected mortality by EU and 2000BP (Figure 3).

The Spearman correlation between 2000BP and EU was good in both groups, showing a coefficient of 0.657 (P <0.001) in the on-pump group and 0.620 (P <0.001) in the group without CPB. However, the presence of outliers was observed in the group with and without cardiopulmonary bypass when estimated values for both risk scores were very high (Figure 4).

In Table 1, the association was demonstrated CPB with in-hospital death (P <0.05) and directly proportional relationship between the score and the presence of death (P <0.0001). To study the 2000BP and the presence of CPB as predictors of mortality, we adjusted the logistic regression model presented in Table 2. In this table, we observe that, for a given value of 2000BP, patients operated with CPB have chance of death twice that without CPB [95% CI (1.1 - 3.8), P <0.02] and each unit increase in score patients have increased risk of death of 1.1 [95% CI (1.09 to 1.14), P <0.0001].

Fig. 2 - ROC curve (Receiver Operating Characteristic) of the 2000 Bernstein Parsonnet (2000BP) and EuroSCORE (EU) for the groups with and without cardiopulmonary bypass for patients undergoing coronary artery bypass grafting

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Fig. 3 - Observed and expected mortality by 2000 Bernstein Parsonnet (2000BP) and EuroSCORE (EU) for the groups with and without cardiopulmonary bypass for patients undergoing coronary artery bypass grafting

Fig. 4 - Diagram showing the presence of outliers after application of the 2000 Bernstein Parsonnet (2000BP) and EuroSCORE (EU) in patients with and without cardiopulmonary bypass for patients undergoing coronary artery bypass grafting

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Table 1. Association of CPB and the value of the score with in-hospital deaths.

2000BP EU CPB

Yes (n = 78) 24.80 ± 10.67 7.46 ± 3.95 64 (82.1%)

Death

P <0.001 (1) <0.001 (1) 0.049 (2)

No (n = 1473) 13.77 ± 8.16 3.53 ± 2.94 1058 (71.8%)

Odds ratio 1.80

Power > 90%

1. Descriptive level of probability of Student's t test 2. Descriptive level of probability of the chi-square 2000BP-2000 Bernstein Parsonnet, EU-EuroSCORE, CPB-cardiopulmonary bypass P-probability

Table 2. Logistic regression model showing values Odds ratio for the presence of 2000BP and CPB. Odds ratio BP 2000 1.118 CPB 2.025

LL 1.093 1.080

95% CI

UL 1.143 3.796

P <0.001 0.028

Table 3. Logistic regression model showing odds ratio values for the EU and the presence of CPB

EU CPB

Odds ratio 1.350 2.011

LL 1.269 1.078

95% CI

UL 1.436 3.752

P <0.001 0.028

2000BP-2000 Bernstein Parsonnet; CPB-cardiopulmonary bypass LL-lower limit, UL upper limit, P-probability

EU-EuroSCORE, CPB-cardiopulmonary bypass LL-lower limit, UL - upper limit, P-probability

Fig. 5 - Model for the 2000 Bernstein logistic Parsonnet (2000BP) showing the probability of death overall, and for each of the groups with and without cardiopulmonary bypass for patients undergoing coronary artery bypass grafting

Fig. 6 - Model for logistic EuroSCORE (EU) showing the probability of death overall, and for each of the groups with and without cardiopulmonary bypass for patients undergoing coronary artery bypass grafting

For the study of the EU and the presence of CPB as predictors of mortality, we adjusted the logistic regression model presented in Table 3. In this table, we observe that, for a given value of the EU, patients operated with CPB have chance of death twice that without CPB [95% CI (1.1 - 3.8), P <0.03] and each unit increase in score patients have increased risk of death 1.4 times [95% CI (1.3 - 1.4), P <0.0001].

Thus, through these logistic models, made using 2000BP (Figure 5) and EU (Figure 6), one can calculate the probability of death for an overall score value, and for

each of the situations with and without cardiopulmonary bypass.

In the search for better prognostic accuracy 2000BP and the EU were obtained cutoff points (balance between sensitivity and specificity) by the ROC curve. Thus, in 2000BP, which have the value 73% sensitivity and specificity also is 17.75 and the EU, where we have the value 71% sensitivity and 69% specificity is 4.5. For both models, the calculation of the power of the sample as a function of proportion was> 90% (α = 0.05). From this, we have, with 2000BP, the chance of death in patients operated

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with CPB compared to off-pump increases from 1.9 to 7.4 times when the value of 2000BP stay above 17.75 [OR 7, 4, 95% CI (4.40 to 12.31), P <0.0001]. Likewise, the EU, the chance of death in patients operated with CPB compared to off-pump increases from 1.8 to 5.4 times when the value of the EU stay above 4.5 [OR 5.4, CI 95 % (3.3 - 9), P <0.0001].

stable patients at low risk and do not reflect the reality of the current profile of patients referred for CABG. In this sense, the last work of the greatest impact was published by Lamy et al. [23], in which 4752 patients from 79 centers in 19 countries were randomized. In the results, no significant difference, up to 30 days between CABG with and without CPB, on death, myocardial infarction, stroke and renal dysfunction requiring dialysis. However, OPCAB resulted in lower rates of transfusion, reoperation for bleeding, respiratory complications and acute renal failure, although the increased risk of early revascularization. Nationally, a randomized, multicenter published by Gerola et al. [24] almost a decade ago, had no significant difference was found within 30 days, between CABG with and without CPB in morbidity and mortality in low-risk patients.

As we can see, these studies were not considered highrisk patients with significant comorbidities and, unlike the patients included in our sample (the real world).

Recently, in non-randomized study, Cantero et al.

[25] reported a hospital mortality of 4.3% and 4.7%, respectively, in the group without CPB and CPB (P = 0.92).

However, the off-pump patients had fewer complications compared to perioperative infarction (P = 0.02) and the use of intra-aortic balloon (P = 0.01).

Moreover, the risk scores are predictive tools that can help patients and health professionals in decision making by informing about the likely risk of complications or death. In this setting, two of the most commonly performed procedures in the interventional cardiology world are influenced by risk scores. The Syntax score was developed from database to examine how best revascularization (CABG or PCI), based on the angiographic characteristics [26]. Moreover, the score Wilkins was created to orient the cases of mitral stenosis which would be better handled by conventional surgery as compared to balloon valvuloplasty [27].

Thus, in InCor-HCFMUSP, held after the statistical validation of models 2000BP and EU [28], even in patients with acute myocardial infarction [29], was of clinical interest and practical know the score (cutoff) that would have better prognostic accuracy to define which patients would benefit most from OPCAB those who could be safely treated using CPB. To do so, he had to be confirmed the good performance of risk scores for both patients with and without CPB (Figure 2), and good correlation between both models for each patient sample. However, as is expected for samples in the real world, outliers are described for scores 2000BP and EU in our study, confirming a truth about the stability of risk scores: the loss of calibration in the evaluation of high-risk patients (Figure 4).

Importantly, even though the subjective choice of the current CPB in CABG, it is supported in patients with low

DISCUSSION Several studies [2,3] confirm that significant reduction of the inflammatory response leads to reduced organ dysfunction in OPCAB. The results of observational studies based on wellstructured database (real world) do not overestimate the magnitude of treatment effects compared with randomized trials in the same clinical setting [17,18]. In CABG, retrospective analyzes in large populations describe a significant reduction in morbidity and mortality, especially in-hospital, when performed without CPB [6,7]. In this approach, a multicenter study of the four major EU centers showed benefit in the immediate postoperative period with OPCAB, especially in patients considered at high risk [12]. Furthermore, the use of CPB was an independent predictor of mortality in centers with significant experience in OPCAB. As in this study, without the artifice of randomization, found higher chance of death when patients underwent surgery with CPB compared to surgery without CPB, especially in considered high risk by the scores used. Similarly, a study odd authored by Buffolo et al. [19], revealing the experience of 30 years of OPCAB, demonstrated a significant reduction in hospital mortality outcomes, stroke, severe postoperative complications, length of hospital stay and decreased costs.

Also, was described biggest difference in mortality among high-risk patients when operated with or without CPB. This corroborates our analysis, where as the score values increase (worsening of the risk profile of the patient), also increases the risk of death among patients who underwent surgery with or without CPB (Figures 5 and 6).

A demonstration that this technique is reproducible was published by Lima et al. [20], in which 95% of patients undergoing CABG surgery without CPB were. Thus, it is revealed that virtually all patients with indication for CABG are potential candidates for OPCAB. In the study, the authors demonstrate that low-risk patients and patients without comorbidities also benefit from OPCAB, which was confirmed in our analysis, although to a lesser extent (Figure 5 and 6).

On the international scene, recent randomized studies that found differences in favor of OPCAB with regard to in-hospital mortality did not show statistical significance [21,22]. Unfortunately, randomized trials are composed of

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ejection fraction and should be avoided in patients with severe renal impairment. These data are consistent with that observed in our study (Figure 1).

Surely, this analysis is more objective evidence and practice, from the look of the risk scores, which justifies the preference for not using CPB in CABG in patients considered high risk by the scores 2000BP and EU. Limitations of this study were: 1. is a study in a single center, where there was lack of randomization between both groups, 2. although hospital mortality (up to 30 days after surgery) appears to be more complete than the inhospital mortality (until discharge), the current definitions suggest that both have equivalent accuracy, and in-hospital mortality was more practical and easy to use [30].

In summary, randomized controlled trials have found in the short term, statistically significant reductions in morbidity and mortality demonstrated in observational studies. These discrepancies may be due to differences in patient selection and study methodology. Future studies should focus on improving research methodology, recruiting high-risk patients and data collection in the long term.

Finally, it is important to reiterate that the current medical treatment must be integrated into individual clinical experience and the best available external evidence, therefore, risk scores cannot continue to be neglected [31].

3. Cleveland JC Jr, Shroyer AL, Chen AY, Peterson E, Grover FL. Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. Ann Thorac Surg.

2001;72(4):1282-9.

CONCLUSION The scores 2000BP and EU showed good performance in the evaluation of patients undergoing CABG with and without CPB. In the real world, patients with 2000BP> 17.75 and EU > 4.5 show, respectively, 7.4 and 5.4 times greater chance of death when operated with CPB regarding OPCAB.

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23. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Paolasso E, et al. Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med. 2012;366(16):1489-97.

15. Parolari A, Pesce LL, Trezzi M, Loardi C, Kassem S, Brambillasca C, et al. Performance of EuroSCORE in CABG and off-pump coronary artery bypass grafting: single institution experience and meta-analysis. Eur Heart J. 2009;30(3):297-304.

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16. Mejía OA, Lisboa LA, Puig LB, Dias RR, Dallan LA, Pomerantzeff PM, et al. The 2000 Bernstein-Parsonnet score and EuroSCORE are similar in predicting mortality at the Heart Institute, USP. Rev Bras Cir Cardiovasc. 2011;26(1):1-6.

25. Cantero MA, Almeida RM, Galhardo R. Analysis of immediate results of on-pump versus off-pump coronary artery bypass grafting surgery. Rev Bras Cir Cardiovasc. 2012;27(1):38-44.

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18. Hannan EL. Randomized clinical trials and observational studies: guidelines for assessing respective strengths and limitations. JACC Cardiovasc Interv. 2008;1(3):211-7.

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20. Lima RC, Escobar MAS, Lobo Filho JG, Diniz R, Saraiva A, Césio A, et al. Resultados cirúrgicos na revascularização do miocárdio sem circulação extracorpórea: análise de 3.410 pacientes. Rev Bras Cir Cardiovasc. 2003;18(3):261-7.

21. Moller CH, Penninga L, Wetterslev J, Steinbruchel DA, Gluud C. Clinical outcomes in randomized trials of off- vs. on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses. Eur Heart J. 2008;29(21):2601-16.

22. Shroyer AL, Grover FL, Hattler B, Collins JF, McDonald GO, Kozora E, et al. Veterans Affairs Randomized On/Off Bypass (ROOBY) Study Group. On-pump versus off-pump coronaryartery bypass surgery. N Engl J Med. 2009;361(19):1827-37.

26. Sianos G, Morel MA, Kappetein AP, Morice MC, Colombo A, Dawkins K, et al. The SYNTAX score: an angiographic tool grading the complexity of coronary artery disease.

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27. Wilkins GT, Weyman AE, Abascal VM, Block PC, Palacios IF. Percutaneous dilatation of the mitral valve: an analysis of echocardiographic variables related to outcome and the mechanism of dilatation. Br Heart J. 1988;60(4):299-308.

28. Mejía OAV, Lisboa LAF, Dallan LAO, Pomerantzeff PMA, Moreira LFP, Jatene FB, et al. Validação do 2000 BernsteinParsonnet e EuroSCORE no Instituto do Coração - USP. Rev Bras Cir Cardiovasc. 2012;27(2):187-94.

29. Mejía OAV, Lisboa LAF, Tiveron MG, Santiago JAD, Tineli RA, Dallan LAO, et al. Cirurgia de revascularização miocárdica na fase aguda do infarto: análise dos fatores preditores de mortalidade intra-hospitalar. Rev Bras Cir Cardiovasc. 2012;27(1):66-74.

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31. Kolh P, Wijns W. Essential messages from the ESC/EACTS guidelines on myocardial revascularization. Eur J Cardiothorac Surg. 2012;41(5):983-5.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):512-9

Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves Expressão gênica de receptores de endotelina em valvas mitrais reumáticas estenóticas substituídas

Sydney Correia Leão1, Fernanda Maria Silveira Souto2, Ricardo Vieira da Costa3, Thaisa de Fatima Almeida Rocha4, Yolanda Galindo Pacheco5, Tania Maria de Andrade Rodrigues6

DOI: 10.5935/1678-9741.20120092

RBCCV 44205-1417

Abstract Objectives: Rheumatic fever is a highly prevalent disease in Brazil, and it poses a major public health problem. It is the leading cause of acquired heart disease in childhood and adolescence. The aim of this study was to evaluate the gene expression of ET-3 and its receptors, in replaced rheumatic mitral valves.

Methods: We studied the gene expression of endothelin-3 (ET-3) and its receptors, endothelin receptor A and endothelin receptor B (ETr-A and ETr-B), in the rheumatic mitral valves of 17 patients who underwent valve replacement surgery. The samples also underwent a histological analysis.

Results: Our data showed that almost all patients, regardless of individual characteristics such as gender or age, expressed the endothelin receptor genes, but did not express the genes for ET-3. In quantitative analysis, the

ETr-A/GAPDH mean ratio was 33.04 ± 18.09%; while the ETr-B/GAPDH mean ratio was 114.58 ± 42.30%. Regarding histopathological individual features, the frequency of fibrosis is 100%, 88.23% of mononuclear infiltrate, 52.94% of neovascularization, 58.82% of calcification and absence of ossification.

Conclusion: The presence of receptors ETr-A and ETr-B in rheumatic mitral valves suggests its interaction with the system of circulating endothelins, particularly ETr-B (known for acting in the removal of excess endothelin) detected in a greater proportion, which could explain the lack of expression of endothelin in rheumatic mitral valve, process to be elucidated.

1. Medical student. Laboratory of Molecular Anatomy, Department of Morphology, Biological and Health Science Center, Sergipe Federal University, UFS, São Cristóvão, SE, Brazil (Bolsista PICVOL). Editing and proofreading of the manuscript.

2. Medical student. Laboratory of Molecular Anatomy, Department of Morphology, Biological and Health Science Center, Sergipe Federal University, UFS, São Cristóvão, SE, Brazil. Data collection, translation and revision of the manuscript.

3. Fellow of PROBP Master graduate program, Department of Medicine, Biological and Health Science Center, Sergipe Federal University, UFS, Aracaju, SE, Brazil. Data collection and editing of the manuscript.

4. Medical student. Laboratory of Molecular Anatomy, Department of Morphology, Biological and Health Science Center, Sergipe Federal University, UFS, São Cristóvão, SE, Brazil. Translation and revision of the manuscript.

5. Titular professor, Anatomy Department, Medicine Faculty, Brasília University, Brasília, DF, Brazil. Data collection, review of the final manuscript.

6. Adjunct professor, Department of Morphology, Biological and Health

Science Center, Sergipe Federal University, UFS, São Cristóvão, SE, Brazil. Data collection and editing of the manuscript.

512

Descriptors: Rheumatic fever. Mitral valve stenosis.

Endothelins.

Work carried out at Laboratory of Molecular Anatomy, Department of Morphology, Biological and Health Science Center, Sergipe Federal University, UFS, São Cristóvão, SE, Brazil.

Correspondence address Sydney Correia Leão Marechal Rondon Avenue – Jardim Rosa Elze – Professor José Aloísio de Campos University City – São Cristovão, SE, Brazil.

E-mail: sydneyleao@hotmail.com Financial support: National Consoling of Research (CNPq) [Universal Announcement MCT/CNPq grant number 14/2008; Universal, Process grant number 472808/2008-7, TMAR].

Article received on June 24th, 2012 Article accepted on November 12th, 2012

Leão SC, et al. - Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves

Abbreviations, Acronyms & Symbols bFGF Basic fibroblast growth factor ET-3 Endothelin type 3 ETr-A Endothelins receptors type A ETr-B Endothelins receptors type B ETr-C Endothelins receptors type C ETrs Endothelins receptors ETs Endothelins LAM Laboratory of Molecular Anatomy NO Nitric oxide PASP Pulmonary artery systolic pressure RF Rheumatic fever RT-PCR Reverse transcription polymerase chain reaction UFS Universidade Federal de Sergipe VEGF Vascular endothelial growth factor

Resumo Objetivos: A febre reumática é uma doença altamente prevalente no Brasil, e representa um importante problema de saúde pública. É a principal causa de cardiopatia adquirida na infância e adolescência. O objetivo deste estudo foi avaliar a expressão gênica de ET-3 e seus receptores, em valvas mitrais reumáticas substituídas. Métodos: Estudamos a expressão gênica de endotelina-3 (ET-3) e de seus receptores,

INTRODUCTION Rheumatic fever (RF) is a serious public health problem and a strong indicator of poverty and poor health services in developing countries. It is a rheumatic and inflammatory disease with an autoimmune origin. It recurs in response to Streptococcus pyogenes (Group A betahemolytic Strep, GAS) infection. This agent is responsible for approximately 15.6 million cases of rheumatic heart disease annually across the globe, with 282,000 new cases and 233,000 deaths each year. As a result, health systems incur high costs, paying for the tests, surgeries and hospitalizations required to treat the complications of this condition. For instance, approximately 3 million patients per year are hospitalized due to congestive heart failure [1-4].We can divide the manifestations of rheumatic fever in acute and chronic. Acute rheumatic fever affects several sites such as the skin (erythema marginatum), the basal ganglia (chorea of Syndeham) and heart (rheumatic carditis). The involvement of cardiac valves (especially mitral valve) is extremely common in chronic rheumatic heart disease.

There are two types of valve dysfunction on rheumatic disease: stenosis and insufficiency. These two types of

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receptor da endotelina A e receptor da endotelina B (ETr-A e ETr-B), nas valvas mitrais reumáticas de 17 pacientes que se submeteram à cirurgia de troca valvar. As amostras também foram submetidas à análise histológica.

Resultados: Nossos dados mostraram que praticamente todos os pacientes, independentemente de características individuais, como sexo ou idade, expressaram os genes de receptores de endotelina, porém não expressaram os genes para ET-3. Na análise quantitativa, a média da proporção ETr-A/GAPDH foi de 33,04 ± 18,09%; enquanto que a média da proporção ETr-B/GAPDH foi de 114,58 ± 42,30%. Em relação às características histopatológicas individuais, a frequência de fibrose foi de 100%, infiltrado mononuclear de 88,23%, neovascularização de 52,94%, calcificação de 58,82% e houve ausência de ossificação.

Conclusão: A presença de receptores ETr-A e ETr-B em valvas mitrais reumáticas sugere sua interação com o sistema de endotelinas circulantes, particularmente ETr-B (reconhecido por atuar na remoção do excesso de endotelina), detectado em maior proporção, o que poderia explicar a ausência da expressão de endotelina em valva mitral reumática, processo a ser elucidado.

Descritores: Febre reumática. Estenose da valva mitral.

Endotelinas.

dysfunction are not mutually exclusive. A patient with mitral stenosis may remain asymptomatic for long periods of time despite the gradual decrease in cardiac output and increase in pulmonary vascular resistance, which may eventually lead to a vascular morphofunctional change [57]. The symptoms usually depend on the effective valve area involved and the tissue damage level (obtained via a regular echocardiogram), although this correlation is not always reliable. In advanced disease, all of these events result from inflammatory damage to the tissue that is accompanied by neovascularization and the calcification of the mitral apparatus, which was formerly an avascular structure [8].

Increased peripheral vascular resistance is a key event in the development of heart failure, and endothelin is one of the most potent vasoconstrictors involved in this disease [9], and stimulates the secretion also of inflammatory cytokines [10]. The endothelins (ETs) are potent peptides formed by a chain of 21 amino acids. Some of their properties are well known, such as vascular tone control in both vascular and non-vascular tissues. Currently, there are three identified isopeptides encoded by three different genes: ET-1, ET-2 and ET-3. The pharmacological effects of ETs indicate the existence of three subtypes of receptors 513

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Leão SC, et al. - Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves

(ETrs): type A (ETr-A), type B (ETr-B) and type C (ETr-C) [11]. ETs and ETrs exhibit different affinities, and ETr-A acts as a vasoconstrictor in the smooth muscle layer (tunica media) of the arterial wall [12].

The importance of ETs and its receptors for the pathogenesis of many diseases has been the subject of intense research since its discovery [13-15]. Those diseases that involve excessive vasoconstriction and cell proliferation have been an especial focus. Over the last decade, a growing volume of research has been conducted on the actions of endothelin and its receptors, exploring its unique pharmacological response and its possible correlation with cardiovascular disease [16]. The correlation between the role of endothelin in the cardiovascular system and its proinflammatory activity has made it important to determine whether ETs participates in the pathophysiology of heart injury. However, severe pulmonary hypertension, either as a final outcome of those diseases that involve excessive vasoconstriction and cell proliferation or as perpetuating them, may also affect the influence of ETs [17].

Therefore, in this study we evaluated the expression of ET-3 and its receptors, ETr-A and ETr-B, in the rheumatic mitral valves of patients who underwent valve replacement surgery. Moreover, histological analysis in the valves was performed.

METHODS The University Hospital Ethics and Human Research Committee of the Federal University of Sergipe approved this project, which was assigned the number 0105.0.107.000-09. In addition, all experimental protocols were conducted according to Declaration of Helsinki and had signed the Informed Consent form. A histological analysis of the mitral valves was performed. The study group comprised seventeen patients (mean age 37.7 ± 13.7 years) with serious rheumatic mitral stenosis (mean valve area of 1.0 ± 0.28 cm2 and mean pulmonary artery systolic pressure (PASP) of 45.82 ± 6.45 mmHg) (Table 1) who underwent surgical treatment between the months of June 2009 and March 2010. These patients were six male and eleven female adults. The most common clinical manifestations of them were dyspnea (94.11%), chest pain (35.29%), and tachypnea (47.05%) (Table 1).

Seventeen valves were collected from the Cardiothoracic Surgery Service at Cirurgia Hospital in Aracaju, Sergipe, Brazil. After the valves had been collected, samples were sent to the Laboratory of Molecular Anatomy (LAM) at the Morphology Department, Sergipe Federal University (Universidade Federal de Sergipe, UFS), where they were stored and subjected to a molecular and histological analysis.

Table 1. Echocardiographic data of patients.

LAM01 LAM02 LAM03 LAM04 LAM05 LAM06 LAM07 LAM08 LAM09 LAM10 LAM11 LAM12 LAM13 LAM14 LAM15 LAM16 LAM17 Mean Std Dev

Gender F M F F F F F M M M F M F F F F M

Age 32 64 22 59 20 45 42 43 56 40 24 41 22 45 24 26 36 37.70588 13.70112

Dyspnea x x x x x x x x 0 x x x x x x x x

Chest Pain 0 x 0 x 0 0 0 x 0 x 0 0 0 x 0 0 x

Tachypnea x 0 x 0 x 0 0 x 0 0 x 0 x 0 x 0 x

Mitral Valve Area 0.8 1.5 0.6 1.3 0.9 0.7 0.6 1 0.9 1.4 0.9 0.8 1.2 0.8 1.4 1 1.2 1 0.285043856

F = female; M = male; PASP = Pulmonary Artery Systolic Pressure; Std Dev = standard deviation.

X represents presence of characteristic and 0 represents absence of it

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PASP 47 35 54 39 47 50 54 46 49 38 52 50 42 55 36 44 41 45.82353 6.454023

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Molecular analysis Immediately after removal, valve tissue obtained was fragmented into three roughly equal segments (named M1, M2 and M3), the first near the mitral annulus, second in the intermediate region and the third at the end in contact with the chordae tendineae. This division intended differentiation in regions that are macroscopically distinct as to their involvement by rheumatic disease. After that, each sample valve was submerged in RNAlater® stabilizer solution (Applied Biosystems/Ambion, Austin, Texas, USA) for 24 hours at room temperature (25°C). Next, the excess solution was discarded, and the samples were stored at -80°C. The mitral fragments (100 mg) were submitted to a total RNA extraction protocol using the SV RNA Purification Kit (Promega®, Madison, Wisconsin, USA). Then, each sample of total RNA was quantified by spectrophotometry (UV-1601-UV® Spectrophotometer Shimadzu Corporation). For this purpose, it was performed dilution of 4 μL de RNA in 196 μL of Milli-Q water totalizing 200 μL of solution. The samples were placed in an appropriate cuvette and then analyzed on the spectrophotometer. The absorbance values obtained were analyzed using the following formula: [RNA (µg/mL)] = 40 x A260 x dilution / 1000 [18]. A purity assessment was performed using the ratio of the absorbance values obtained at 260 nm and 280 nm (A260/A280); only values between 1.6 and 2.6 were considered viable.

The total cDNA was obtained from each analyzed sample via reverse transcription polymerase chain reaction (RT-PCR) analysis. We used the protocol provided by the manufacturer of the Reverse Transcriptase IMPROMII™ Kit (Promega®, Madison, Wisconsin, USA). From the cDNAs obtained, we amplified the target fragment using PCR [19,20]. The primers used in this technique

were ET-3 (Endothelin 3), ETr-A (receptor type A) and ETr-B (Receptor Type B) (Table 2). The constitutive gene GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) was analyzed as a sample control (Table 2). The programs used for amplification were optimized using different annealing temperature combinations in accordance with mean temperature data supplied by Promega®. The amplification products were analyzed via electrophoresis on 2% agarose gel stained with ethidium bromide (1 mg/ ml) and sample buffer (bromophenol blue) 6x. They were viewed using the photo documentation system (Kodak Gel Logic 100® Imaging System, Eastman Kodak Corporation, Rochester, NY, USA). Quantitative analysis of each sample was performed with software ImageJ (National Institute of Health, Bethesda, MD, USA). Quantification was performed by counting the average number of pixels of each sample (including GAPDH sample). Thereafter, it was performed a ratio between the average number of pixels in each sample by the amount found in GAPDH sample (ETr-A/GAPDH and ETr-B/GAPDH ratio).

Table 2. List of primers prepared for molecular analysis.

Name of Oligonucleotide ET-3 Sense

Sequency 5’ CCA AAC TCT GGA CGT CAG CAG 3’ ET-3 Antisense 5’ ATT TCC TGC ATG AAA CCG GAG 3’ ETr-A Sense 5’ TTC AGA CTT CGC CAG ACA GA 3’ ETr-A Antisense 5’ CAA GCA ACT GGA ACC TGA TGT 3’ ETr-B Sense 5’ AGA CAG GAC GGC AGG ATC T 3’ ETr-B Antisense 5’ GAA CAC AAG GCA GGA CAC AA 3’ GAPDH HUMAN Sense 5’ GCT CTC TGC TCC TCC TGT TC 3’ GAPDH HUMAN Antisense 5’ GTT GAC TCC GAC CTT CAC CT 3’

Histological analysis All of the excised, fragmented valves were formalin fixed in a neutral 10% solution (pH 7.0). They were then submitted to decalcification, embedded in paraffin and cut using a microtome (Hacker Edge SL-200® Microtome, Winnsboro, USA) at a 4 µm thickness. Hematoxylin and eosin staining was then performed. Each segment was examined for the presence of fibrosis, calcification, ossification, angiogenesis and mononuclear cells.

Statistical analysis For statistical analysis, it was perfomed measures of central tendency and variance. We also examined the correlation between the results obtained for the mean ratio ETr-A/GAPDH and ETr-B/GAPDH. For correlation analysis, we used Pearson’s correlation, with the significance level of 5% (P value< 0.05).

RESULTS Regarding RNA extraction of mitral valves, the average concentration of nucleic acid was 7.20 ± 5.60 ng/μl. The absorbance value obtained at 260 nm was 0.18 ± 0.14 and absorbance at 280 nm was 0.09±0.06. Ratio between A260 and A280 (A260/280) was 1.81 ± 0.16 (Table 3).

The expression of endothelin and its receptors in the mitral valves using the PCR of the cDNA is showed in the Figure 1. As shown in the Figure 1A, there was amplification of the 480 bp fragment corresponding with the expected ET-3 amplicon in only one sample. Figures 1B and 1C show the results for the ETr-A and ETr-B primers, respectively.

Interestingly, we observed that for ETr-A and ETr-B, 515

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Leão SC, et al. - Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves

Table 3. Quantification of total RNA and spectophotometry from mitral valves.

Sample LAM01 LAM02 LAM03 LAM04 LAM05 LAM06 LAM07 LAM08 LAM09 LAM10 LAM11 LAM12 LAM13 LAM14 LAM15 LAM16 LAM17 Mean Std. Dev

Nucleic Acid Conc. (ng/μl) 3.9 7 10.2 2.9 17.3 13.6 4.5 14.4 4 1.2 1.9 10.1 7.3 17.4 1.9 1.6 3.3 7.205882353 5.601168471

A260 0.099 0.175 0.254 0.073 0.434 0.339 0.112 0.359 0.1 0.029 0.048 0.253 0.181 0.436 0.047 0.041 0.082 0.180117647 0.140106603

A280 0.061 0.094 0.138 0.04 0.207 0.162 0.067 0.172 0.058 0.016 0.026 0.141 0.101 0.217 0.029 0.024 0.052 0.094412 0.066344

A260/280 1.61 1.86 1.84 1.8 2.09 2.08 1.66 2.09 1.72 1.78 1.85 1.79 1.8 2.01 1.62 1.67 1.57 1.814118 0.169524

Std Dev = standard deviation

Fig. 1 - Amplification of the ET-3, ETR-A and ETR-B encoding genes - Total RNA from 17 valve samples was reverse-transcribed to obtain cDNA and subsequent PCR using our primers for amplification of the genes analyzed.

Figure 1A: ET-3; 1B: ETR-A; 1C: ETR-B

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Table 4. Densitometric analysis of the amounts of the amplified ETr-A and ETr-B genes after normalization with the GAPDH gene (ETr-A/GAPDH and ETr-B/GAPDH ratio).

the amplicons were present in 94.11% and 100% of the reactions, respectively, with different degrees of intensity.

All experiments were performed in duplicate to confirm the reliability of the data obtained using this technique.

In quantitative analysis, the ETr-A/GAPDH mean ratio is 33.04 ± 18.09%; while the ETr-B/GAPDH mean ratio is 114.58 ± 42.30% (Table 4). Pearson’s correlation (R) between ETr-A/GAPDH and ETr-B/GAPDH of each sample is 0.73 (P= 0.0004), which is strongly positive.

In histological analysis on mitral valves, there were enormous amounts of fibrocytes, dense connective tissue, type I collagen (eosinophilic) and extracellular ground substance. The inflammatory process exhibited high cellularity, tissue vascularization with permeating capillaries, and transformed or neoformed collagen (Figure 2). It was also possible to observe fibroblasts, lymphocytes, and dystrophic calcification areas (tissue necrosis with deposits). Regarding histopathological individual features, fibrosis is found in all of the 17 samples (100%), mononuclear infiltrate in 15 samples (88.23%), neovascularization in nine samples (52.94%), calcification in ten samples (58.82%) and ossification in any sample (Table 5).

Number LAM01 LAM02 LAM03 LAM04 LAM05 LAM06 LAM07 LAM08 LAM09 LAM10 LAM11 LAM12 LAM13 LAM14 LAM15 LAM16 LAM17 Mean Std. Dev

ETr-A/GAPDH 44.94% 69.83% 18.90% 28.57% 36.06% 0.00% 24.93% 19.80% 38.89% 19.91% 61.05% 21.34% 63.41% 27.54% 32.67% 23.36% 30.47% 33.04% 18.09%

Std Dev = standard deviation

ETr-B/GAPDH 136.47% 200.24% 113.79% 107.22% 116.40% 98.45% 72.11% 59.86% 109.75% 115.43% 113.94% 83.15% 219.42% 77.93% 98.89% 80.09% 144.82% 114.58% 42.30%

Fig. 2 - Rheumatic mitral valves present neovascularization and an increase of mononuclear infiltrates Longitudinal cuts were done and then fixed and stained with hematoxylin and eosin (HE) and analyzed by optical microscopy (40x). A: The arrows indicate neovascularization and tissue breakdown of collagen fibers. B and C: The arrows indicate the presence of fibroblasts. D: Photomicrograph showing inflammatory infiltrate, fibrosis and some neoformed vessels.

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Table 5. Histopathological individual features of 17 rheumatic mitral valves.

LAM01 LAM02 LAM03 LAM04 LAM05 LAM06 LAM07 LAM08 LAM09 LAM10 LAM11 LAM12 LAM13 LAM14 LAM15 LAM16 LAM17

Fibrosis x x x x x x x x x x x x x x x x x

Infiltrate x x x 0 x x x x x x x x x 0 x x x

Neovascularization x 0 x 0 x x x x 0 x 0 0 x 0 0 x 0

Calcification x x 0 x 0 x 0 x x x x 0 0 0 x 0 x

Ossification 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

X represents presence of characteristic and 0 represents absence of it

DISCUSSION Our data suggest that the expression of ET-3 has no significant relation to rheumatic mitral valve disease in situ, because the amplification of the corresponding fragment was not visible in the gel. We also visualized the amplification of the ETr-A and ETr-B gene fragments in almost 100% of the samples. Moura et al. [21], studying 37 mitral valves, demonstrated that endothelin receptors (ETr-A and ETr-B) were present in this type of human tissue. However there were differences in the intensity of the amplified bands, which suggests that the receptors displayed different expression levels. The presence of ETr-A in the samples is interesting result but expected because in addition to being the predominant receptor in cardiac myocytes, this receptor is involved in inflammatory processes, mitogenesis and pathological vasoconstriction which are exuberant in rheumatic disease during the exudative and proliferative stages [16,21].

On the other hand, the presence of ETr-B in the samples in a higher proportion than ETr-A (114.58 ± 42.30% vs. 33.04 ± 18.09%) is not expected, because this receptor presents vasodilating properties, mediated by the release of nitric oxide (NO) and prostacyclin, which inhibits production of endothelin [16]. Beside vasodilator function, ETr-B, has an important role in removing excess of endothelin, being responsible for the maintenance of normal plasma levels of this peptide [22,23]. This paradoxical behavior of endothelin receptors is also found in some pathological conditions, such as chronic heart failure and myocardial ischemia [22].

Endothelin has some influence on histopathological 518

features encountered in our seventeen mitral valves, such as neoangiogenesis (through the expression of ETR-A receptors that lead to increased vascular endothelial growth factor - VEGF) and calcification (by increasing the gene expression of osteocalcin and osteopontin) [24,25]. Regarding fibrosis, endothelin stimulates type I collagen production, inhibition of collagenase activity and abnormal production of extracellular matrix promoting a reactive fibrosis [25-27]. This mechanism can be mediated for basic fibroblast growth factor (bFGF), which upregulates the expression of ETr-A and perhaps of ETr-B [22]. Endothelin also actives neutrophils, mast cells and stimulates monocytes to release some cytokines, such as TGF-beta and TNF-alfa [22].

The present data are preliminary but may be of great value because they may form the foundation for further investigation in this area, especially given the scarcity of studies of endothelins and its receptors in the context of rheumatic valve disease. In this study, the different patients may have different levels of intensity of expression of these receptors because they were experiencing different stages of rheumatic valve disease. Histological data are important indicators of the degree of valve involvement and suggest an interaction between neovasculogenesis and inflammatory molecular events. The presence of receptors ETr-A and ETr-B in rheumatic mitral valve suggests their interaction with the system circulating endothelins, particularly ETr-B (known for acting in the removal of excess endothelin), detected in a greater proportion, which could explain the absence of expression of endothelin in rheumatic mitral valve, process to be elucidated.

Leão SC, et al. - Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves

REFERENCES 1. American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease); Society of Cardiovascular Anesthesiologists, Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2006;48(3):e1-148.

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N Engl J Med. 2007;357(5):439-41.

5. Marron K, Yacoub MH, Polak JM, Sheppard MN, Fagan D, Whitehead BF, et al. Innervation of human atrioventricular and arterial valves. Circulation. 1996;94(3):368-75.

6. Waller BF, Howard J, Fess S. Pathology of mitral valve stenosis and pure mitral regurgitation: part II. Clin Cardiol. 1994;17(7):395-402.

7. Schmitto JD, Lee LS, Mokashi SA, Bolman RM 3rd, Cohn LH, Chen FY. Functional mitral regurgitation. Cardiol Rev. 2010;18(6):285-91.

8. Veinot JP. Pathology of inflammatory native valvular heart disease. Card Pathol. 2006;15(5):243-51.

9. Spieker LE, Noll G, Ruschitzka FT, Lüscher TF. Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J Am Coll Cardiol. 2001;37(6):1493-505.

10. Sharma D, Singh A, Trivedi SS, Bhattacharjee J. Role of endothelin and inflammatory cytokines in pre-eclampsia.

A pilot North Indian study. Am J Reprod Immunol.

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11. Yanagisawa M, Kurihara H, Kimura S, Goto K, Masaki T. A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels. J Hypertens Suppl. 1988;6(4):S188-91.

12. Schneider MP, Boesen EI, Pollock DM. Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol. 2007;47:731-59.

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13. Rossi GP, Pitter G. Genetic variation in the endothelin system: do polymorphisms affect the therapeutic strategies? Ann N Y Acad Sci. 2006;1069:34-50.

14. Davenport AP. Endothelin converting enzyme in human tissues. Histochem J. 1998;30:359-74.

15. Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol. 2008;153(6):1105-19.

16. Masaki T. Historical review: endothelin. Trends Pharmacol Sci. 2004;25(4):219-24.

17. Russell FD, Molenaar P. The human heart endothelin system: ET-1 synthesis, storage, release and effect. Trends Pharmacol Sci. 2000;21(9):353-9.

18. Sambrook J, Russel DW. Extraction, purification and analysis of mRNA from eukaryotic cells. In Sambrook J, Russel DW, eds. Molecular cloning: a laboratory manual. 3rd ed. New York: Cold Spring Harbor Laboratory Press;2001. p.610-21.

19. Yuan SM, Wang J, Hu XN, Li DM, Jing H. Transforming growth factor-β/Smad signaling function in the aortopathies.

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20. Yuan SM, Wang J, Huang HR, Jing H. Osteopontin expression and its possible functions in the aortic disorders and coronary artery disease. Rev Bras Cir Cardiovasc. 2011;26(2):173-82.

21. Moura EB, Gomes MR, Corso RB, Faber CN, Carneiro FP, Pacheco YG. Amplification of the genes that codify endothelin-1 and its receptors in rheumatic mitral valves. Arq Bras Cardiol. 2010;95(1):122-30.

22. Mayes, MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum. 2003;48(5):1190-9.

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Increased circulating endothelin-1 in rheumatic mitral stenosis: irrelevance to left atrial and pulmonary artery pressures. Chest.

2004;125(2):390-6.

24. Shimojo N, Jesmin S, Zaedi S, Otsuki T, Maeda S, Yamaguchi N, et al. Contributory role of VEGF overexpression in endothelin-1-induced cardiomyocyte hypertrophy. Am J Physiol Heart Circ Physiol. 2007;293(1):H474-81.

25. Wu SY, Zhang BH, Pan CS, Jiang HF, Pang YZ, Tang CS, et al. Endothelin-1 is a potent regulator in vivo in vascular calcification and in vitro in calcification of vascular smooth muscle cells. Peptides. 2003;24(8):1149-56.

26. Brás-Silva C, Leite-Moreira AF. Efeitos miocárdicos da endotelina-1. Rev Port Cardiol. 2008;27(7-8):925-51.

27. Ramires FJ, Nunes VL, Fernandes F, Mady C, Ramires JA. Endothelins and myocardial fibrosis. J Card Fail.

2003;9(3):232-7.

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ORIGINAL ARTICLE

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Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery Fatores preditores independentes de ventilação mecânica prolongada em pacientes submetidos à cirurgia de revascularização miocárdica

Raquel Ferrari Piotto1, Fabricio Beltrame Ferreira2, Flávia Cortez Colósimo3, Gilmara Silveira da Silva4, Alexandre Gonçalves de Sousa5, Domingo Marcolino Braile6

DOI: 10.5935/1678-9741.20120093

RBCCV 44205-1418

Abstract Objective: To determine independent predictors of prolonged mechanical ventilation in patients undergoing coronary artery bypass graft surgery.

Methods: Data of patients undergoing coronary artery bypass graft surgery were included prospectively from July 2009 to July 2010. All data were input into an electronic database. The resulting cohort included a total of 2952 patients of which 77 remained more than 48 hours on mechanical ventilation. Patients were divided into two groups: 1) a prolonged ventilation group, needing mechanical ventilation for more than 48 hours and 2) not prolonged ventilation group, undergoing a successful extubation within 48 hours.

Results: After adjustment for confounding factors a multivariate analysis identified the following factors as

independent predictors of prolonged mechanical ventilation: age (OR 1.06 95% CI 1.03 -1.09; P <0.001), chronic renal failure (OR 3.52 95% CI 1.84 - 6.74; P <0.001), chronic obstructive pulmonary disease (OR 2.65 95% CI 1.38 -5.09; P = 0.004), coronary artery bypass graft associated with other procedures (OR 3.33 95 % CI 1.89 - 5.58; P <0.001) and clamping time (OR 1.01 95% CI 1.00 -1.02; P = 0.018).

Conclusion: The identification of these predictors allows the development of preventive strategies that could reduce invasive ventilation time, since patients on prolonged mechanical ventilation present greater morbidity and mortality rates.

1. Post-Doctoral - Supervision Center for Teaching and Research Portuguese Beneficent Hospital of São Paulo, São Paulo, SP, Brazil.

Principal Author.

2. Doctoral Assistant Physician at the Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil. Coauthor.

3. PhD, Research Nurse - Center for Teaching and Research - Portuguese Beneficent Hospital of São Paulo, São Paulo, SP, Brazil. Coauthor.

4. Specialist, Nurse Research-Centre for Research and Teaching Portuguese Beneficent Hospital of São Paulo, São Paulo, SP, Brazil.

Coauthor.

5. Specialist in Cardiology, Medical Researcher - Center for Education and Research - Portuguese Beneficent Hospital of São Paulo, São Paulo, SP, Brazil. Coauthor.

6. Dean of the Graduate School of Medicine Regional São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil. Editor-in-Chief of the Journal of Cardiovascular Surgery. Coauthor.

Work performed at Hospital Beneficência Portuguesa de São Paulo, São Paulo, SP, Brasil.

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Descriptors: Myocardial revascularization. Respiration, artificial. Intensive care units.

Correspondence address: Raquel Ferrari Piotto Rua Maestro Cardim, 769 – Bela Vista – São Paulo, SP Brazil – Zip code: 01323-900 E-mail: raquelfpiotto@yahoo.com.br Paper presented at the 67th Brazilian Congress of Cardiology - Recife, Brazil, from 14 to 17 September 2012.

Article submitted on August 31st, 2012 Article accepted on November 8th, 2012

Piotto RF, et al. - Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery

Abbreviations, acronyms and symbols CPB CABG COPD HF BMI CRF STS SUS ICU MV

Cardiopulmonary Bypass Coronary Artery Bypass Grafting Chronic obstructive pulmonary disease Heart Failure Body Mass Index Chronic renal failure Society for Thoracic Surgeons Unified Health System Intensive Care Unit Mechanical ventilation

Resumo Objetivo: Determinar os fatores preditores independentes de ventilação mecânica prolongada em pacientes submetidos à cirurgia de revascularização miocárdica.

Métodos: Foram incluídos prospectivamente em um banco de dados eletrônico informações de pacientes submetidos ao procedimento de cirurgia de revascularização miocárdica no Hospital Beneficência Portuguesa de São Paulo, no período de julho de 2009 a julho de 2010. O total da amostra do estudo foi de 2952 pacientes, dos quais 77 permaneceram

INTRODUCTION The aging population is a worldwide phenomenon. Estimates suggest that the number of elderly in Brazil exceeds 30 million people over the next 20 years, which represent almost 13% of the population [1]. Coronary artery disease increases their frequency with age and, nowadays, is a highly prevalent condition worldwide population [2]. According Beaglehole [3], ischemic heart disease is the leading cause of death in developed countries, accounting for 30% of deaths per year. The treatment of this condition by coronary artery bypass graft (CABG) has significantly increased survival [4]. Moreover, it has been increasingly performed in patients with advanced age, which have more extensive coronary involvement, tortuous arteries more rigid and calcified, among other factors [5].

Since its first description by Favaloro [6] and Garrett et al. [7], the CABG has revolutionized the treatment of coronary disease and has become the surgical procedure of large most studied and

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em ventilação mecânica por mais de 48 horas. Os pacientes foram divididos em dois grupos, baseados na duração da ventilação mecânica, o grupo com ventilação prolongada e o grupo sem ventilação prolongada.

Resultados: Após os ajustes dos fatores de confusão foi realizada análise multivariada, que identificou os seguintes fatores como preditores independentes de ventilação mecânica prolongada: idade (OR 1,06 IC 95% 1,03-1,09; P<0,001), insuficiência renal crônica (OR 3,52 IC 95% 1,846,74; P<0,001), doença pulmonar obstrutiva crônica (OR 2,65 IC 95% 1,38-5,09; P=0,004), cirurgia de revascularização miocárdica associada a outros procedimentos (OR 3,33 IC 95% 1,89-5,58; P<0,001) e tempo de pinçamento (OR 1,01 IC 95% 1,00-1,02; P=0,018).

Conclusão: A identificação desses fatores possibilita o desenvolvimento de estratégias preventivas que diminuam o tempo de ventilação invasiva, uma vez que os pacientes em ventilação mecânica prolongada apresentam maior morbidade e mortalidade.

Descritores: Revascularização miocárdica. Respiração artificial. Unidades de terapia intensiva.

performed the story. The development of research in this field gives great scientific foundations of CABG procedures, with the precise definition of its indications, intraoperative management and postoperative care, which optimizes their results too [8].

Continuous improvement and technological advancement as well as the high prevalence of coronary heart disease in the world, made the procedure took propulsion. Currently, they are made in Brazil, approximately 350 heart surgeries per million inhabitants per year, a figure that includes implants pacemakers and defibrillators. This rate is even lower than the United States, with 2,000 cardiac surgeries per million population per year, and the UK and Europe, with more than 900 heart surgeries per million inhabitants per year, which suggests the potential for future growth of these procedures in Brazil [8].

Despite major advances already achieved in CABGs, studies still show significant rates of postoperative complications, which increase the length of hospital stay, raise the costs and impact in higher mortality [9]. The identification of factors that may

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influence the clinical course of these patients can assist in surgical indication and prevent postoperative complications. In Brazil, the rate of mortality after cardiovascular surgery in hospitals affiliated to the Unified Health System (SUS) is approximately 8% [10]. In the United States of America, is around 4%, according to the Society for Thoracic Surgeons (STS) [11].

Pulmonary complications are the leading cause of morbidity and mortality in post-CABG. Factors such as anesthesia, surgical incision, cardiopulmonary bypass (CPB), ischemia time, surgical technique and drains may predispose the patient to the change in pulmonary function postoperatively. Furthermore, mechanical ventilation (MV) is a prolonged contributing factor to these complications [12].

Patients undergoing cardiac surgery are usually able to resume spontaneous ventilation as soon as they recover from anesthesia. However, about 2.6% to 22.7% of patients requiring prolonged MV [13]. Those who remain in MV postoperatively and unsuccessful removal of ventilatory support have more complications, such as respiratory infections, and increased mortality in the short and medium term, beyond the increased length of hospital stay and increased costs [14-16]. Therefore, knowledge of the predictors of prolonged MV in patients undergoing CABG is crucial to improve the management of these cases.

The aim of this study was to determine the independent predictors of prolonged MV in patients undergoing CABG.

the database: age, sex, length of hospital stay, body mass index (BMI), comorbidities, indication for surgery (elective or emergency), operative time, CPB time, length of stay in the intensive care unit (ICU) acquired comorbidities after surgery and operative complications and postoperative.

The study was approved by the Ethics Committee of the Portuguese Beneficent Hospital of S達o Paulo, in the opinion of number 657-10.

METHODS Were prospectively included in an electronic database, information for patients undergoing CABG in the Portuguese Beneficent Hospital of S達o Paulo, 18 years or older, from July 2009 to July 2010. This database contains data of 3010 patients undergoing CABG, which comprises 69.6% of the total surgeries performed in the period. This loss percentage inclusion of patients in the database occurred randomly, without preference for day, time, time, staff, surgeon or patient conditions.

The form of data collection presents 243 variables with data collected from all fourteen teams Institution of cardiac surgery.

The team showed that contributed 81.4% of their patients included, while the team that offered fewer patients had 59.5% of their patients included in the database. All information was kept confidential, and the identity of the patients.

For the purpose of this study, we performed a retrospective review of this database. Mechanical ventilation was defined as prolonged invasive ventilation for more than 48 hours. The patients were divided into two groups based on the length of the MV, the prolonged ventilation group and the group without prolonged ventilation. We excluded 58 patients of the total bank because they died in a period of less than 48 hours. Therefore, the total study sample of 2952 patients, of which 77 remained on MV for more than 48 hours.

In this study, the following variables were selected from

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Statistical considerations Initially, all variables were analyzed descriptively. For quantitative variables, this analysis was done by observing the minimum and maximum values, and the calculation of means and standard deviations. For qualitative variables were calculated absolute and relative frequencies.

The Student t test was used to compare means between two groups. When the assumption of normality of the data was rejected, we used the nonparametric Mann-Whitney [17].

To test the homogeneity between the proportions we used the chi-square test or Fisher's exact test (when expected frequencies were less than 5) [17].

The multivariate logistic regression model was used to obtain the prognostic factors for prolonged MV [18].

The significance level used for the tests was 5%.

RESULTS The average age of the patients was 62.2 years, with 69.9% of patients were male, 15.3% were smokers, 82.8% and 36.6% hypertensive diabetics.

The clinical characteristics preoperative are described in Table 1. Patients on prolonged MV when compared to other, older and had a higher prevalence of chronic obstructive pulmonary disease (COPD), heart failure (HF), cerebrovascular disease and chronic renal failure (CRF), in addition to longer hospital pre surgery.

Table 2 shows the characteristics intraoperative. Patients on prolonged MV group had a smaller proportion of cases with CABG and higher clamping time compared to the group extubated in less than 48 hours (P <0.001).

Table 3 presents a univariate analysis of preoperative and intraoperative considered clinically relevant as predictors of prolonged MV. We considered as predictors of prolonged MV: age, HF, prior cerebrovascular disease, CRF, creatinine, COPD, clamping time, and CABG combined with other procedures including valve.

Based on Tables 1 and 2, we take the variables with P <0.25 to compose a set of candidate variables to identify possible predictors of MV> 48 hours. Using the logistic regression model with variable selection process "stepwise", observed that: the age, CRF, COPD, CABG and other procedures associated with clamping time are predictors of MV 48> hours. Table 4 presents these results.

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Piotto RF, et al. - Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery

Table 1. Descriptive results of preoperative demographic variables and their distribution in groups.

Variable Age, mean + SD (years) BMI, mean + SD (kg/m2) Creatinine, mean + SD (mg/dL) Systolic BP, mean + SD (mmHg) Diastolic BP, mean ± SD Internment pre-op., mean + SD (days) CRF, n (%) Hypertension, n (%) COPD, n (%) DAC, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Arterial insufficiency, n (%) Cerebrovascular disease, n (%) HF, n (%) Angina, n (%) Arrhythmia, n (%) Valve surgery, n (%) Angioplasty, n (%) Smoking, n (%) Yes No Prior

VM Time ≤ 48h > 48h 62.0 + 9.5 67.3 + 9.1 27.0 + 4.1 26.0 + 4.3 1.3 + 0.7 1.6 + 1.4 132.4 + 20.1 136.5 + 20.6 80.4 + 11.7 81.6 + 12.4 2.7 + 3.3 3.4 + 3.5 146 (5.1) 16 (20.8) 2375 (82.6) 69 (89.6) 193 (6.7) 14 (18.2) 856 (29.8) 15 (19.5) 1048 (36.5) 30 (39) 1292 (44.9) 31 (40.3) 136 (4.7) 7 (9.1) 49 (1.7) 4 (5.2) 73 (2.5) 7 (9.1) 2138 (74.4) 54 (70.1) 152 (5.3) 7 (9.1) 7 (2.2) 1 (1.3) 255 (8.9) 4 (5) 1284 (44.7) 35 (45.5) 438 (15.2) 12 (15.6) 1153 (40.1) 30 (39)

P Value < 0.001(1) 0.036(1) 0.050(1) 0.104(1) (NS) 0.434(1) (NS) 0.033(2) < 0.001(4) 0.108(3) (NS) < 0.001(3) 0.051(3) (NS) 0.652(3) (NS) 0.415(3) (NS) 0.097(4) (NS) 0.048(4) 0.004(4) 0.402(3) (NS) 0.191(4) (NS) 0.183(4) (NS) 0.055(4) (NS) 0.980(3) (NS)

(1) descriptive level of probability of Student's t test, (2) descriptive level of probability of the nonparametric Mann-Whitney test, (3) descriptive level of probability of the chi-square (4) descriptive level of probability Fisher's exact test, BMI - body mass index, BP - blood pressure, CRF - chronic renal failure (creatinine> 2 mg / dL), COPD - chronic obstructive pulmonary disease, CAD - coronary artery disease HF - heart failure; MV - mechanical ventilation, NS - not significant, SD - standard deviation

Table 2. Descriptive results of the intraoperative variables and their distribution in groups.

Variable Type of surgery, Elective n (%) Urgency Using ATI, n (%) CABG, n (%) Valve associated, n (%) Support CEC, n (%) Clamping time, mean ± SD (min) Temperature Hypothermia (≤ 34°C) n (%) Normothermia (> 34°C)

≤ 48h 2849 (99.1) 26 (0.9) 2530 (88.0) 2596 (90.3) 116 (4.0) 2527 (87.9) 46.1+ 21.8 1697 (67.1) 830 (32.9)

MV Time

> 48h 75 (97.4) 2 (2.6) 65 (84.4) 51 (66.2) 15 (19.5) 70 (90.9) 60.2 +39.0 53 (75.7) 17 (24.3)

P Value 0.165(4) (NS) 0.341(3) (NS) < 0.001(3) < 0.001(4) 0.422(3) (NS) < 0.001(1) 0.136(3) (NS)

(1) descriptive level of probability of Student's t test, (2) descriptive level of probability of the nonparametric Mann-Whitney test, (3) descriptive level of probability of the chi-square (4) descriptive level of probability Fisher's exact test; ITA - internal thoracic artery CABG - coronary artery bypass grafting, CPB cardiopulmonary bypass; MV-mechanical ventilation, NS - not significant, SD - standard deviation.

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Piotto RF, et al. - Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery

Table 3. Univariate analysis of clinically relevant variables for prolonged MV. Variable Age BMI Creatinine Systolic BP Internment pre op.

CABG SH COPD CAD Arterial insufficiency Cerebrovascular disease HF Arrhythmia Valve surgery prior Angioplasty Surgical indication urgency CABG Valvular surgery associated Time clamping

OR 1.07 0.94 1.29 1.01 1.04 4.90 1.82 3.09 0.57 2.02 3.16 3.84 1.79 5.39 0.56 2.92 0.21 5.76 1.02

Lim Inf 1.04 0.88 1.11 1.00 1.00 2.76 0.87 1.70 0.32 0.91 1.11 1.71 0.81 0.66 0.20 0.68 0.13 3.18 1.01

95% CI

Sup Lim 1.09 1.00 1.50 1.02 1.09 8.71 3.80 5.61 1.01 4.46 8.99 8.64 3.96 44.36 1.55 12.54 0.34 10.42 1.03

P Value < 0.001 0.035 < 0.001 0.104 (NS) 0.074 (NS) < 0.001 0.113 (NS) < 0.001 0.054 (NS) 0.085 (NS) 0.031 0.001 0.150 (NS) 0.117 (NS) 0.267 (NS) 0.149 (NS) < 0.001 < 0.001 < 0.001

OR "Odds Ratio" - odds ratio, BMI - body mass index, BP - blood pressure, CRF - chronic renal failure (creatinine> 2 mg / dL), COPD - chronic obstructive pulmonary disease; DAC - coronary artery disease, HF - heart failure, CABG - coronary artery bypass grafting, NS - not significant, MV - mechanical ventilation, CI - confidence interval, Lim Inf - lower limit, Sup Lim - upper limit

Table 4. Multivariate analysis of variables associated with prolonged MV. Variable Age CRF COPD CABG associated with other procedures Clamping time

OR 1.06 3.52 2.65 3.33 1.01

Lim Inf 1.03 1.84 1.38 1.89 1.00

95% CI

Sup Lim 1.09 6.74 5.09 5.88 1.02

P Value < 0.001 < 0.001 0.004 < 0.001 0.018

OR "Odds Ratio" - odds ratio, CRF - chronic renal failure (creatinine> 2 mg / dL); COPD - chronic obstructive pulmonary disease, CABG - coronary artery bypass grafting, CI - confidence interval, Lim Inf - lower limit; Sup Lim - upper limit

Table 5 presents the distribution of postoperative complications cases arranged as divided in the MV 48h. It is observed that patients in prolonged MV higher proportion of complications when compared to extubated at least 48 hours.

DISCUSSION The implementation of CABG requires adequate organizational support [8]. The results depend on the clinical condition of the patient, surgeon expertise, intensive care and trained multidisciplinary team, as well as appropriate followup after surgery in order to be successful, with a short and uneventful [19].

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As reported by Vincent A. Gaudiani: "The goal of a cardiac surgery program is to encourage patients to safer and less threatening journey through the hospital" [20]. They are essential to the success of this procedure, the type of heart disease, careful selection of cases, the precise preoperative diagnosis, adequate preoperative preparation, anesthesia team specialized intensive care postoperative appropriate, specific equipment in good operation, trained multidisciplinary team, fast and accurate laboratory, blood bank and able to meet demands faster [8].

The prolonged MV after CABG is still common in ICUs, despite the great advances made in recent years. In the present study, prolonged MV was defined according to scientific evidence, such as invasive ventilation for more than 48 hours

Rev Bras Cir Cardiovasc 2012;27(4):520-8

Piotto RF, et al. - Independent predictors of prolonged mechanical ventilation after coronary artery bypass surgery

Table 5. Descriptive results of the complications and their distribution in groups.

Complications Reoperation, n (%) Perioperative MI, n (%) Neurological, n (%) AVE, n (%) Renal, n (%) Infectious, n (%) Lung, n (%) ARDS, n (%) Pulmonary embolism, n (%) Pneumonia, n (%) Other pulmonary, n (%) Vascular, n (%) Gastrointestinal, n (%) Cardiopulmonary, n (%) Arrhythmia, n (%) CI, n (%) Cardiogenic shock, n (%) Multiple organ failure, n (%) Other complications, n (%)

â&#x2030;¤ 48h 59 (2.1) 28 (1) 204 (7.1) 40 (1.4) 100 (3.5) 235 (8.2) 372 (12.9) 6 (0.2) 7 (0.2) 141 (4.9) 12 (0.4) 16 (0.6) 128 (4.5) 58 (2.0) 498 (17.3) 82 (2.9) 25 (0.9) 4 (0.1) 73 (2.5)

Time VM

> 48h 18 (23.4) 5 (6.5) 37 (48.1) 13 (16.9) 36 (46.8) 42 (54.6) 73 (94.8) 5 (6.5) 0 44 (57.1) 3 (3.9) 5 (6.5) 41 (53.3) 30 (39) 46 (59.7) 16 (20.8) 11 (14.3) 9 (11.7) 10 (13)

P Value < 0.001(2) < 0.001(2) < 0.001(2) < 0.001(2) < 0.001(2) < 0.001(1) < 0.001(1) < 0.001(2) 1.000(2) < 0.001(2) 0.006(2) < 0.001(2) < 0.001(2) < 0.001(2) < 0.001(1) < 0.001(2) < 0.001(2) < 0.001(2) < 0.001(2)

(1) descriptive level of probability of the chi-square (2) descriptive level of probability of the Fisher exact test, AMI - acute myocardial infarction, stroke - stroke; ARDS - acute respiratory distress syndrome in adults, CI - heart failure; VM - Mechanical Ventilation

[21-23]. Several studies show that the incidence of these cases prolonged MV varies from 3.0 to 9.9% [24]. Of the 2952 patients included in this study, only 77 (2.6%) remained on MV for more than 48 hours, the lowest rate in the literature.

The prolonged MV has great clinical relevance because it is correlated with increased morbidity and mortality, in addition to large economic impact, due to the increased length of stay and resultant increase in costs. The hospitalization of patients with prolonged MV exceed 2 to 3 weeks and his hospital mortality may exceed 40% for those extubated earlier [13]. In a study conducted in Germany, the effective cost of patients on MV for more than 4 days was 18 times higher than those taken from the MV earlier [25].

Therefore, the identification of predictors of prolonged MV is extremely important because it allows the optimization of those patients at higher risk even before the start of surgery and assists physicians in managing postoperative clinical, to minimize this complication [26].

With regard to preoperative characteristics, patients with prolonged MV were older. This group also had a longer preoperative hospitalization, due to his medical condition worse.

These patients had higher prevalence of COPD, heart failure, renal failure and cerebrovascular disease, as observed in other studies (Table 1) [13,21,24,27-32].

Univariate analysis demonstrated as predictors of prolonged MV age, HF, prior cerebrovascular disease, CRF, creatinine> 2 mg / dL, COPD, clamping and CABG combined with other procedures including valve. Other studies have also shown these factors as predictors of prolonged MV (Table 3) [13, 24,27,29,30-32].

Patients with a higher BMI were less likely to prolonged MV (OR 0.94 95% CI 0.88 to 1.00, P = 0.035), which is contrary to data from other studies. Jin et al. [33] observed that the chance of prolonged MV increases significantly with increasing BMI, and Wigfiel et al. [34] reported that obesity is a risk factor for prolonged MV [21]. Mean BMI of the patients studied when

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divided in groups according to the time of MV were 26 ± 4.3 kg/m2 for the group with prolonged MV, and 27 ± 4.1 kg/m2 for the group with MV ≤ 48h (P = 0.036). This difference, although statistically significant, is not clinically relevant, considering the great similarity of the mean BMI of the two groups.

After adjusting for confounding factors, multivariate analysis was performed which identified the following factors as independent predictors of prolonged MV: age, CRF, COPD, CABG and other procedures associated with clamping time (Table 4).

Aging is one of the most important factors of poor prognosis in CABG, generally associated with increased morbidity and mortality. As demonstrated in this study, age is a predictor of prolonged MV, with an odds ratio of 1.06. This result is in agreement with the majority of published studies in this area [21,27-30].

CRF was defined as serum creatinine> 2.0 mg / dL, regardless of patients are not dependent or dialysis. Its incidence was 20.8% in patients with prolonged MV, and only 5.1% of those taken from MV in less than 48 hours. It was the strongest predictor in this study (OR 3.52 95% CI 1.84 to 6.74, P <0.001). Other studies have also shown similar results [26,27,29,32].

COPD is cited in the literature as a strong predictor of prolonged MV [22,26,27,31] as well as in our study (OR 2.65 95% CI 1.38 to 5.09, P = 0.004). Studies show that patients with COPD have proportionally higher mortality rate [27]. These patients prothrombotic condition, due to increased blood viscosity and endothelial dysfunction. Moreover, often share comorbidities like atherosclerosis, smoking and systemic vascular disease, and are more prone to complications in the postoperative period [3537]. However, some studies do not point to COPD as a predictor of prolonged MV [24,28-30,32].

The procedure associated with other CABG was also a predictor of prolonged MV. As for the associated surgical procedures CABG, the group showed prolonged MV rate of 33.8%, since the other group, 9.7% (P <0.001). Among these associated procedures, valvular surgeries were the most frequent, accounting for 42.9% of them. Branca et al. [29] also found that CABG associated with other procedures increases the risk of prolonged MV. And Rajakaruna et al. [38] observed an increase of 8.5 times the risk of prolonged MV in patients undergoing aortic surgery associated with CABG. Patients with prolonged MV group showed significantly greater clamping time, averaging 60.2 ± 39.0 min, compared to the other group, with 46.1 ± 21.8 min (P <0.001). This was also a predictor of prolonged MV (OR 1.01 95% CI 1.00 to 1.02, P = 0.018). Several other studies confirm this association [22,24,29-32].

As demonstrated in the literature, patients who remain in prolonged MV have higher morbidity and mortality [22,24,26-32].

In this study, these patients had significantly higher reoperation rate and a higher incidence of complications. Among these, figure as the most relevant, pulmonary complications, arrhythmias, infectious, gastrointestinal, neurological and kidney. The length

of stay of these patients in the ICU was on average 14.1 ± 13.1 days, while patients who were removed from the MV in less than 48 hours were, on average, only 2.1 + 3.5 days (P <0.001). Also, mortality in these patients was significantly higher, with a rate of 58.44%, while the mortality of those with lower MV 48h was only 2.26% (P <0.001), representing a likelihood of death 25.5 times higher in patients with prolonged MV. Other studies also show high rates of mortality in patients with MV for over 48 hours, with values of 18.5% [27], 22.3% [29] and 36.3% [32].

Several previous publications have evaluated the predictors of prolonged MV. However, most of these studies are retrospective and include a period of extensive data collection (average 4-5 years) in order to obtain a representative sample. These characteristics can lead to accumulation of biases arising from changes in the profile of patients during the collection period, and variations of operation of the service itself. This study, in turn, had a significant sample of 3010 patients, in only one year of data collection, which minimizes these effects. As far as we know, there is no published study with those dimensions that evaluated predictors of prolonged MV in patients undergoing CABG in a period as short review (PubMed and LILACS).

The retrospective nature of this study may give limitations inherent to its design. In addition to possible selection bias, interpretation of results is not possible to determine the causality of the associations between variables. Although the percentage of loss of patient inclusion in the database occurred randomly, it also gives a limitation of the study; it may have contributed to a selection bias in the sample.

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CONCLUSION Are independent predictors of prolonged MV: age, COPD, CRF, CABG and clamping time associated with other procedures?

Identifying these factors enables the development of preventive strategies that reduce the time of invasive ventilation, since patients in prolonged MV have higher morbidity and mortality.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):529-34

Adults with congenital heart disease undergoing first surgery: prevalence and outcomes at a tertiary hospital Adultos com cardiopatia congênita submetidos à primeira cirurgia: prevalência e resultados em um hospital terciário

Gustavo Alves de Mello1, Jehorvan Lisboa Carvalho2, José Augusto Baucia3, José Magalhaes Filho4

DOI: 10.5935/1678-9741.20120094

RBCCV 44205-1419

Abstract Introduction: Surgical treatment of congenital heart disease in adults showed a significant growth in recent years.

But even so, the number of patients who reach adulthood without adequate surgical treatment remains high.

Objective: To demonstrate the results and hospital diagnoses of adult patients with congenital heart disease underwent the first surgery.

Methods: A retrospective analysis of records of patients operated for correction of congenital heart disease and age greater than or equal to 18 years. The exclusion criterium was surgery for reoperation. Period analyzed was from December 2007 to December 2010 with inclusion of 79 patients.

Results: The atrial septal defects were the most prevalent (53.1%), followed by VSD (15.2%), the coarctation (6.3%) and partial atrioventricular canal (6.3%). Thirteen (16.4%) patients had associated disease acquired and 14 (17.7%) congenital disease. Thirty-three (41.8%) patients had pulmonary hypertension. The average hospital stay in ICU and hospital were 3.9 and 14.5 days, respectively. Complications occurred in 18 (22.8%) patients, with infections being the most common. The hospital mortality was two (2.5%) patients.

Conclusion: The treatment of congenital heart disease in adults as first surgery has very favorable results. However, in

our series, there was an increased length of stay in ICU and hospital.

1 - Specialist Member - SBCCV. HAN Cardiovascular Surgeon, Professor substitute. Assistant surgeon. Author.

2 - Doctor of Medicine - UFBA. HAN Coordinator Cardiovascular Surgery. Coauthor.

3 - PhD in Nuclear Technology - USP. Associate professor of FAMEDUFBA. Cardiovascular Surgeon HAN. Coauthor.

4 - Master of Medicine - Faculty of Medicine Bahiana. HAN Coordinator pediatric cardiologist clinic congenital heart disease in adults - HAN. Coauthor.

Work performed at Hospital Ana Nery, Salvador, Bahia, Brazil.

Descriptors: Adult.

Heart defects, Cardiovascular surgical procedures.

congenital.

Resumo Introdução: O tratamento cirúrgico da cardiopatia congênita em adultos apresentou importante crescimento nos últimos anos. Contudo, ainda assim, o número de pacientes que atingem a idade adulta sem tratamento cirúrgico adequado permanece elevado.

Objetivo: Avaliar os resultados hospitalares e diagnósticos dos pacientes adultos com cardiopatia congênita submetidos à primeira operação.

Métodos: Estudo retrospectivo, que analisou prontuários de pacientes operados para correção de cardiopatia congênita com idade maior ou igual a 18 anos. O critério de exclusão foi cirurgia para reoperação. Foi analisado o período entre dezembro de 2007 e dezembro de 2010, com inclusão de 79 pacientes.

Resultados: Os defeitos do septo atrial foram os mais prevalentes (53,1%), seguidos de comunicação interventricular (15,2%), coarctação da aorta (6,3%) e

Correspondence address: Gustavo Alves de Mello Rua Hilton Rodrigues, 394/902-A – Pituba – Salvador, BA Brazil – Zip code: 41830-630.

E-mail: mellomd@ig.com.br Article received on August 24th, 2012 Article accepted on October 23rd, 2012

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Rev Bras Cir Cardiovasc 2012;27(4):529-34

Mello GA, et al. - Adults with congenital heart disease undergoing first surgery: prevalence and outcomes at a tertiary hospital

Abbreviations, acronyms and symbols AF ASD CAVB CHDA IAC ICU IVC POD SUS VSD

Atrial fibrilation Atrial septal defect Complete atrioventricular block Congenital heart diseases in adults Interatrial communication Intensive care unit Interventricular communication Postoperative day Unified Health System Ventricular septal defect

canal atrioventricular parcial (6,3%). Treze (16,4%)

INTRODUCTION The surgical treatment of congenital heart disease in adults (CHDA) showed significant growth in recent decades [1,2], with predictions that in a few years the number of patients alive adults and children with congenital heart disease will be matched [3]. This is due to advances in treatment and diagnosis reached, however, still remains a multifactorial problem: the existence of a significant portion of patients surgically treated in adulthood that should have been corrected in childhood or adolescence.

In our environment, socioeconomic factors are identified in a significant portion of the problem. But nations have overcome the financial barrier continue to show their results with a significant proportion of patients treated as first surgery in adulthood [4].

Another factor that interferes with the proper treatment of this group of patients is currently recognizes the need to monitor patients with CCA in centers specializing in this type of disease, which differs from the adult acquired heart disease and children with congenital heart disease [3].

The objective of this study is to evaluate the results and hospital diagnoses of patients surgically treated adults with congenital heart disease as initial surgery in a tertiary hospital with structuring latest in cardiology and cardiovascular surgery.

METHODS Retrospective study through analysis of medical 530

pacientes apresentavam doença associada adquirida e 14 pacientes (17,7%), congênita. Trinta e três (41,8%) pacientes apresentavam hipertensão pulmonar. O tempo médio de internamento em UTI e hospitalar foi de 3,9 e 14,5 dias, respectivamente. Complicações ocorreram em 18 (22,8%) pacientes, sendo as infecciosas as mais comuns. A mortalidade hospitalar foi de dois (2,5%) pacientes.

Conclusão: O tratamento da cardiopatia congênita em adultos como primeira cirurgia apresentou resultado bastante favorável. Contudo, em nossa série, houve maior tempo de internamento em UTI e hospitalar.

Descritores: Adulto.

Cardiopatias Procedimentos cirúrgicos cardiovasculares.

congênitas.

records of patients who underwent surgery as the first surgery and congenital heart disease aged greater than or equal to 18 years. Patients who underwent reoperation in the same hospital performed the first surgery as well as patients with acquired diseases associated with congenital heart disease were not excluded.

The exclusion criterion was the patient admitted for reoperation.

There were analyzed the patients operated for correction of bicuspid aortic valve, because the intraoperative echocardiographic diagnosis and were often not documented, leading to a figure that does not represent reality.

The diagnosis of pulmonary hypertension was considered when there was a mean pressure greater than 25 mmHg or systolic blood pressure greater than 30 mmHg [5].

The charts in the period between December 2007 and December 2010, 79 patients with inclusion in this study.

RESULTS There was a predominance of females with 49 (62%) patients. The mean age was 34 years (range 1863 years), with 23 (29.1%) patients above 40 years.

In Table 1, the diagnoses are being considered as the main congenital disease that prompted the surgery. As a secondary diagnosis was considered the associated disease (congenital or acquired), which was also treated at the same hospital.

Mello GA, et al. - Adults with congenital heart disease undergoing first surgery: prevalence and outcomes at a tertiary hospital

Table 1. Diagnostics.

Main diagnosis secundum ASD Sinus venosus Partial atrioventricular canal Atrioventricular canal intermediate Atrial septal aneurysm Interventricular communication Patent ductus arteriosus Aortic coarctatio Interrupted aortic arch I Subaortic membrane Supra-aortic stenosis Sinus of Valsalva aneurysm Cor triatriatum Tetralogy of Fallot Pulmonary stenosis

N (%) 40 (50.6) 2 (2.5) 5 (6.3) 1 (1.3) 1 (1.3) 12 (15.2) 1 (1.3) 5 (6.3) 1 (1.3) 2 (2.5) 1 (1.3) 2 (2.5) 1 (1.3) 4 (5.1) 1 (1.3)

Rev Bras Cir Cardiovasc 2012;27(4):529-34

Secondary diagnosis (N) MS (2) TR (5), PS (4), AoR (1) and CA (1) ASD (1) preoperatively CAVB (1) TR PS (5), AoR (2), MS (1), Endoc. (2) AoR (1) and CA (1) AoS IVC (1) Sd. Williams IVC (1) PS, Situs inversus -

ASD = atrial septal defect, MS = mitral stenosis, TR = tricuspid regurgitation, PS = pulmonary stenosis, AoR = aortic regurgitation, CA = coronary atherosclerosis, CAVB = complete atrioventricular block, Endoc. = Endocarditis, AoS = aortic stenosis, IVC = interventricular communication, Sd. = syndrome

The atrial septal defects were the most prevalent with 53.1% (42 patients). Two cases presented with unique physiological atrium, yet both still existed a remnant of the septal region of the tricuspid annulus and are not therefore classified as single anatomical atrium.

The association of atrial septal defect (ASD) with mitral stenosis was present in two (2.5%) patients, which characterizes the syndrome Lutembacher.

The second most prevalent disease was congenital ventricular septal defect (VSD), and in all cases classified as perimembranous. Only one patient had association with other defect perimembranous VSD muscular type. In two patients with small defects and hemodynamic repercussion, surgery was performed for the presence of endocarditis.

In one of them there was a significant involvement of the tricuspid valve, which required repair, persisting with moderate impairment postoperatively.

Tetralogy of Fallot was treated in four patients and transannular enlargement was employed in both cases.

One of the patients had VSD doubly related, featuring the Eastern Fallot.

The presence of associated disease occurred in 27 (34.2%) patients, pulmonary stenosis associated with congenital disease most frequent (10 patients, 12.6%). The tricuspid regurgitation was the most common acquired disease, occurring in 5 (6.3%) patients.

The involvement of the aortic valve was present in 5 patients, but only one diagnosed with bicuspid. In another patient with VSD, the mechanism was the collapse of the non-coronary leaflet. The others had no definite etiology.

Table 2. Hospital complications. complication Respiratory infection Reoperation* Atrial fibrillation Moderate-severe pericardial effusion Pleural effusion Postoperative bleeding CAVB provisional CAVB permanent mediastinitis Wound infection Urinary tract infection ICS pneumomediastinum

N 7 6 5 3 2 2 2 1 1 1 1 1 1

(*) = included bleeding and mediastinitis, CAVB = complete atrioventricular block, ICS = ischemic cerebral stroke

The mean hospital stay was 14.3 days, ranging from 5 to 99 days. The average length of stay in the intensive care unit (ICU) ranged from 2 to 29 days, with an average of 3.9 days.

In Table 2, are related complications hospital. These occurred in 18 (22.8%) patients, however with more than one event per patient in some cases. The most common were infections (nine cases - 11.4%). Six patients underwent 531

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reoperation, two for bleeding and one for mediastinitis. In two other patients, we needed a valve replacement plasties unsatisfactory (mitral and aortic) and one case of rupture of the patch VSD and hemodynamic instability on day 4 postoperatively (POD) in a patient corrected with Fallot, which until then, was quite favorable evolution. This was reoperated of urgency, showing excellent progress.

Complications related to cardiac rhythm occurred in 8 (10.1%) patients, atrial fibrillation (AF) the most common.

In two cases of complete atrioventricular block (CAVB) provisional, the first was reversed on ICU admission, in a patient who had undergone VSD correction. The second CAVB began on the 1st postoperative day in a patient subjected to correction of ostium secundum IAC, being reversed in the 3rd POD. In patients with pericardial effusion in two drainage was necessary. Among patients with pleural effusion, was necessary to perform a thoracentesis.

A patient who presented with neurological deficit ischemia diagnosis confirmed by CT. This patient had already submitted event preoperatively classified as transient ischemic attack, but postoperatively the new change persisted for more than 48 h. However, the patient was discharged with neurological symptoms resolved without deficit.

In 76 (96.2%) patients, the preoperative rhythm was sinus, two had AF and CAVB. At hospital discharge, the two patients with preoperative AF and one with postoperative AF remained arrhythmia. The CAVB patients with preoperative pacemaker implanted and one case of permanent CAVB died. Then, at hospital discharge, 94.9% of patients were in sinus rhythm (excluding the patient who died).

Cyanosis was present in only 5 (6.3%) patients in this series, presenting them with a significant and polycythemia hematocrit above 65%.

Pulmonary hypertension was diagnosed in 33 (41.8%) patients.

The catheter was used in 36 (45.6%) patients, in order to complement the diagnosis and / or coronary angiography.

In five (6.3%) patients, angiography was used.

Mortality was two (2.5%) patients. The first was a young patient with secundum ASD and mild pulmonary hypertension, which had an uneventful surgery, but evolved with lung respiratory distress syndrome of acute on the 1st POD and progressive worsening. Postoperative tests did not identify cardiovascular causes. The patient died on POD 23 due to respiratory failure. The second case was a patient with partial atrioventricular canal and cavity very serious increase of the four heart chambers. The patient was operated and closure of cleft mitral wide. The valve was insufficient, then was re done and return. CAVB presented to the 1st POD, followed by FA with adequate

response has not been indicated pacemaker. However, after a prolonged postoperative course, now in recovery, had severe bradycardia at 28 POD, not having access to a temporary pacemaker. This patient was the only case that would require a permanent pacemaker complication in this series (1.3%).

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DISCUSSION The surgical treatment of congenital heart disease in adults is increasing and with that there is the need for a multidisciplinary team to monitor these patients [3]. Our hospital is a tertiary unit with exclusive service to the Unified Health System (UHS), and started its activities in cardiology and cardiovascular surgery Cardiopediatrics in August 2006. As of December 2007, there was increased interest in the treatment of CCA. Then at the end of 2010, was created a specific clinic for these patients. Having an initial target of operating 4-8 patients per month since 2008, was achieved only an average of 2.4 cases / month in the last three years. Several factors are implicated in this deficit and this discussion is beyond the aim of this work. However, it is noteworthy that two large European series [4,6] were published recently, with an incidence of 69% and 75% of first surgeries in the treatment of CCA. Thus, it is clear that serious socioeconomic problems, such as occur in our environment, are not the only factors responsible for the large number of patients with CCA without initial surgical treatment.

In 2007, a European study was published with 2012 patients from 19 different centers [4]. Of these, in 1509 patients, treatment of the CCA was offered as the first surgery. However, this study analyzed the congenital aortic valve (10.7%), which did not occur in our series.

Thus, we performed a comparison of diagnoses found in our work and in the European study, however excluding the percentage of patients treated aortic valve in the latter.

There was a similarity in prevalence of diagnoses in general, and the ostium secundum IAC, septal defect and aortic coarctation partial atrioventricular were diseases most prevalent in both studies, and our share of them, respectively: 48.2% versus 50.6%, 7.2% versus 6.3% and 4% versus 6.3%.

The interventricular communications were also frequent, but differ in higher percentage (15.2% versus 7.3%), getting our group with a high percentage of this type of disease. Initially this difference is justified because it is a disease with early manifestation and therefore treated in childhood. But the reality in our country is still different, getting many patients without treatment. Another explanation lies in the associated diseases, which in our series have pulmonary stenosis diagnosed in almost half of patients with VSD. There were also two cases of small

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VSDs and mild rebound, treated for endocarditis. That is, of the 12 patients treated with VSD in our study, 7 there was the evolution of communications unusual large, which may be related to the possibility of treatment in adulthood.

The European study makes no reference to individualized presence of associated disease.

Work on the treatment of tetralogy of Fallot demonstrated, even in our country, the majority of patients are treated in adulthood presents good performance and favorable anatomy diseases [7,8]. However, in our series, the four patients operated on in two there was a need for transannular enlargement, increasing the proportion of patients with unfavorable anatomy, which may be due to the small number of patients in this analysis. We should then await future results with more patients to confirm whether or not this reality in our population. All recovered uneventfully.

The complication rate in our group was 22.8%, as being the most prevalent infections. Cardiac arrhythmias were also very frequent with 10.1% and 7.6% with reoperations.

These data are in accordance with the findings of the study of Padalino et al. [6] in a series of 628 patients undergoing primary surgery and CHDA. Only the incidence of infection was not reported by the group. However, the group of Putman et al. [9] in a 17-year experience with 830 patients with CHDA, reported hospital morbidity of 33.1%, with cardiac arrhythmia being the most frequent. This result is higher than ours, but the group Putman evaluated the mechanical ventilation as a complication and it was not done by us. Another factor to explain this difference was the presence of complex cases in the study by Putman et al. [9], which certainly are related to increased morbidity, although this inference was not reported in the study. The infection rate was 2.8% of them being below the presented in this study.

The rate of ICU stay in this series was higher when compared to the results of Padalino et al. [6] (1.3 versus 3.9 days) and European study [4] (2.4 versus 3.9 days).

The same happens with our rate of hospitalization (10.5 versus 14.4 days) [4]. The learning curve and the adequacy of an initial service are heavily involved in this difference, moreover, the incidence of infection in this series (11.4%) with increased need for antibiotics that may be associated with longer hospitalization.

A major concern in the treatment of patients with CHDA is the presence of pulmonary hypertension, since the increased pulmonary with possibility of developing hyper-fixed lung resistance occurs in these patients. Studies demonstrate that 10% to 15% of these patients develop pulmonary hypertension in various degrees [10,11]. In the present study, pulmonary hypertension was present in 33 (41.8%) patients. But even in these patients, there was no greater difficulty postoperatively. So, an interesting

reference is the work of Sachweh et al. [12] demonstrated that in a number of adults with IAC and pulmonary hypertension, that even patients with severe hypertension preoperatively, had a good postoperative course, and found no relationship between pulmonary pressure preoperative biopsy pulmonary and surgical morbidity.

This study brings to light a discussion of the methods and results of the evaluation of pulmonary hypertension, as well as the evolution of these patients in a specific type of disease. This is beyond the aim of our study, mainly by the heterogeneity of our group with pulmonary hypertension, but it is pertinent to note that our patients had good graft.

The preoperative diagnostic evaluation of congenital heart disease is made in large numbers of patients by echocardiography combined with Doppler mainly in the study of diseases of small to medium complexity.

However, when this occurs in CHDA, other factors such as the need for coronary angiography or evaluation of pulmonary hypertension, necessitate the use of cardiac catheterization. In our group, while not presenting complexes cases, the use of catheterization was 45.6% (36 patients), which corresponds to a percentage higher than found in other studies [4,6]. Even with 29.1% of our patients having age above 40 years, still considered high indication for catheterization. One explanation may lie in the lack of uniformity in our conduct with patients who were prepared by different doctors and some of them were referred from another hospital with preoperative study performed. However, with the specialized ambulatory outpatient surgical center, we hope to reduce this number or even confirm an increased need this method in our population.

Patients with CHDA, to be operated later, when structural changes are more pronounced cardiopulmonary should have higher mortality. However, several authors demonstrate low mortality rate, even in our country [1,4,6,9,13-16], even when excluding patients treated by ostium secundum IAC, for these represent a simpler disease and low mortality. In our group there were also low mortality (2.5%), emphasizing that it is a relatively new service. However, complex congenital heart disease were not treated or palliative surgeries performed in this series, configuring these, especially the hearts of univentricular physiology as risk factors for hospital mortality [6].

Limitations of the study The main limitation of this study is that it is retrospective, with all the biases of this type of research.

The lack of outpatient data also hampers further analysis of the results, but in our country, with a large proportion of patients coming from the state, the loss to follow-up is still very common. But, with the implementation of CCA clinic in our hospital, we are confident that this monitoring can be done more systematically.

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CONCLUSION The treatment of CCA as first surgery presents a very favorable outcome. However, in this series, there was a longer hospital and ICU.

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7. Moraes RC, Rodrigues JV, Gomes CA, Tenório EA, Neto FM, Santos CL, et al. Tratamento cirúrgico da Tetralogia de Fallot em Adultos. Rev Bras Cir Cardiovasc. 1991;6(2):80-4.

8. Beach PM Jr, Bowman FO Jr, Kaiser GA, Malm JR. Total correction of tetralogy of Fallot in adolescents and adults.

Circulation. 1971;43(5 Suppl):I37-43.

9. Putman LM, van Gameren M, Meijboom FJ, de Jong PL, RoosHesselink JW, Witsenburg M, et al. Seventeen years of adult congenital heart surgery: a single centre experience. Eur J Cardiothorac Surg. 2009;36(1):96-104.

10. Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with congenital heart disease. Circulation.

2007;115(8):1039-50.

REFERENCES

1. Moons P, Engelfriet P, Kaemmerer H, Meijboom FJ, Oechslin E, Mulder BJ; Expert Committee of Euro Heart Survey on Adult Congenital Heart Disease. Delivery of care for adult patients with congenital heart disease in Europe: results from the Euro Heart Survey. Eur Heart J. 2006;27(11):1324-30.

2. Hoffman JI, Kaplan S, Liberthson RR. Prevalence of congenital heart disease. Am Heart J. 2004;147(3):425-39.

11. Steele PM, Fuster V, Cohen M, Ritter DG, McGoon DC. Isolated atrial septal defect with pulmonary vascular obstructive disease: long-term follow-up and prediction of outcome after surgical correction. Circulation. 1987;76(5):1037-42.

12. Sachweh JS, Daebritz SH, Hermanns B, Fausten B, Jockenhoevel S, Handt S, et al. Hypertensive pulmonary vascular disease in adults with secundum or sinus venosus atrial septal defect. Ann Thorac Surg. 2006;81(1):207-13.

3. Webb GD. Care of adults with congenital heart disease: a challenge for the new millennium. Thorac Cardiovasc Surg.

2001;49(1):30-4.

13. Stellin G, Vida VL, Padalino MA, Rizzoli G; European Congenital Heart Surgeons Association. Surgical outcome for congenital heart malformations in the adult age: a multicentric European study. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2004;7:95-101.

4. Vida VL, Berggren H, Brawn WJ, Daenen W, Di Carlo D, Di Donato R, et al. Risk of surgery for congenital heart disease in the adult: a multicentered European study. Ann Thorac Surg.

2007;83(1):161-8.

14. Srinathan SK, Bonser RS, Sethia B, Thorne SA, Brawn WJ, Barron DJ. Changing practice of cardiac surgery in adult patients with congenital heart disease. Heart.

2004;91(2):207-12.

5. Carvalho ACC, Almeida RD, Lopes AA. Diagnóstico da hipertensão pulmonar. Diagnóstico, avaliação e terapêutica da hipertensão pulmonar. Diretrizes da Sociedade Brasileira de Cardiologia. 2005:20-8. Disponível em: http://publicacoes. cardiol.br/consenso/2005/039.pdf

15. Jatene MB, Abuchaim DCS, Junior JLO, Riso A, Tanamati C, Miura N, et al. Resultados do tratamento cirúrgico da coarctação de aorta em adultos. Rev Bras Cir Cardiovasc.

2009;24(3):346-53.

6. Padalino MA, Speggiorin S, Rizzoli, Crupi G, Vida VL, Bernabei M, et al. Midterm results of surgical intervention for congenital heart disease in adults: an Italian multicenter study. J Thorac Cardiovasc Surg. 2007;134(1):106-13.

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16. Lisboa LAF, Abreu Filho CAC, Dallan LAO, Rochitte CE, Souza JM, Oliveira SA. Tratamento cirúrgico da coarctação do arco aórtico em adulto: avaliação clínica e angiográfica tardia da técnica extra-anatômica. Rev Bras Cir Cardiovasc.

2001;16(3):187-94.

ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):535-41

Hemolysis in extracorporeal circulation: relationship between time and procedures Hemólise na circulação extracorpórea: correlação com tempo e procedimentos realizados

Francisco Ubaldo Vieira Junior1, Nilson Antunes2, Reinaldo Wilson Vieira2, Lúcia Madalena Paulo Álvares3, Eduardo Tavares Costa4

DOI: 10.5935/1678-9741.20120095

RBCCV 44205-1420

Abstract Introduction: Extracorporeal circulation (EC) is very important in cardiac surgery but causes significant damage to the blood, including hemolysis.

Objective: To quantify the rate of hemolysis at different times during EC in elective coronary artery bypass grafting.

Methods: We measured rates of hemolysis of 22 patients at 6 different times during myocardial revascularization during EC: T0 - before the start of EC, T1 - five minutes after of the EC initiation, T2 - 30 minutes of EC, T3 - immediately before the aortic unclamping, T4 - immediately before passage of the residual volume to the patient and T5 - five minutes after the passage of the residual volume to the patient. Rates of hemolysis were calculated between the intervals of time: T0T1; T1-T2; T2-T3; T3-T4 and T4-T5.

Results: The first 5 minutes after the EC showed the highest rate of hemolysis (P = 0.0003) compared to the others calculated rates, representing 29% of the total haemolysis

until T4 (Immediately before passage of the residual volume to the patient).

Conclusion: There were no significant changes in the rate of hemolysis during the suction in the aortic root (P > 0.38), nor with the procedure used for the passage of the residual volume of blood in the circuit to the patient.

1 – PhD; State University of Campinas (Professor) – All involved had the same constribution.

2 – PhD; State University of Campinas.

3 – Perfusionist Nurse.

4 – PhD; University of London.

Correspondence address: Francisco Ubaldo Vieira Jr Rua Alexander Fleming, 105 – Cidade Universitária Zeferino Vaz – Campinas, SP, Brasil – CEP 13083-970.

E-mail: fubaldo@terra.com.br

This study was carried out at State University of Campinas, Campinas, SP, Brazil.

Article received on May 29th, 2012 Article accepted on August 30th, 2012

Keywords: Extracorporeal circulation. Hemolysis. Blood.

Resumo Introdução: A circulação extracorpórea (CEC) é indispensável para a maioria das operações cardíacas, mas causa danos significantes ao sangue, dentre eles a hemólise.

Objetivo: Quantificar as taxas de hemólise em diferentes tempos nas operações para revascularização do miocárdio com uso de CEC.

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Vieira Junior FU, et al. - Hemolysis in extracorporeal circulation: relationship between time and procedures

Abbreviations, acronyms and symbols CPB Cardiopulmonary bypass HLp Free plasma hemoglobin Ht Hematocrit PVC Polyvinyl chloride RPM Rates per minute Tx Hemolysis rate TxG Overall hemolysis rate

Métodos: Foram medidas as taxas de hemólise de 22 pacientes em 6 tempos distintos durante a revascularização do miocárdio com uso de CEC: T0 - antes do início da CEC, T1 - 5 minutos após o início da CEC, T2 - com 30 minutos de CEC, T3 - imediatamente antes do despinçamento da aorta,

INTRODUCTION Cardiopulmonary bypass (CPB) is the technology that enabled the great advance in cardiac surgery. Although it is an indispensable technique for correction of most heart disease requiring surgical correction, still carries intrinsic features that promote damage to the body. Among these changes we highlight the damage to the blood cells, particularly hemolysis.

Hemolysis is found in all surgical procedures using extracorporeal circuits, as shown in several studies that identify increasing levels of free hemoglobin in plasma and decreased levels of haptoglobin during and after CPB [1].

Hemolysis can occur in three ways: by natural selection of the spleen, physico-chemical imbalance (usually pathological), or by exposing the cells to a nonphysiological mechanical stress [2].

In the case of CPB, hemolysis occurs mechanically, either by direct trauma effect of the passage of blood through the rollers or by exposure to different surfaces at different speeds.

The hemolytic aspects have been studied by several researchers in an attempt to isolate and understand the factors causing hemolysis [2-5]. Experimentally, the red blood cells can be damaged during the flow of two factors acting simultaneously: the level of shear stress and exposure time of the cell to such stress [2,6,7]. In flows with high shear stress and exposure time relatively low, it is expected low level of hemolysis. Moreover, we found 536

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T4 - imediatamente antes da passagem do volume residual para o paciente e T5 - 5 minutos após o término da passagem do volume residual para o paciente. Foram calculadas as taxas de hemólise entre os intervalos de tempo: T0-T1; T1T2; T2-T3; T3-T4 e T4-T5.

Resultados: Os primeiros 5 minutos após a CEC demonstraram maior taxa de hemólise (P = 0,0003) em comparação às outras taxas calculadas, representando 29% da hemólise total até T4 (imediatamente antes da passagem do volume residual para o paciente).

Conclusão: Não foram observadas variações significantes nas taxas de hemólise durante a aspiração na raiz da aorta (P > 0,38) nem com o procedimento utilizado para a passagem do volume residual de sangue no circuito para os pacientes.

Descritores: Circulação extracorpórea. Hemólise. Sangue.

high hemolysis rate when flow presenting low shear stress, but sufficiently long exposure time. Therefore, one of the basic requirements for developing heart pump is a great compromise between shear stress and exposure time.

In CPB pump two rollers rotate within a raceway (pocket) compressing a flexible tube to promote movement of fluid (blood). The adjustment of the roller pumps is an important factor in hemolysis rates. Calibration is the technique of adjusting the distance between the roller and raceway (occlusion) and is intended to determine the point where the roller only internally collapses the tube without compressing its walls.

The static method or measure of drop rate is the most used in Brazil [8] and consists of observing a falling liquid column, representing the resistance against which the pump will work. Conventionally, the occlusion is adjusted to allow a falling speed of 2.5 cm/min from a column of about 1.000 mm of saline solution. However, few professionals actually use the methodology recommended in the literature [6]. This technique also presents operational difficulties for use in the operating room combined with the lack of reproducibility when performed with silicone tubes [3,9].

Hemodilution is desirable in CPB and hematocrit between 20% and 30% are accepted as suitable for maintenance of oxygen supply to tissues and promote protective effect, preventing contact between erythrocyte and lysis when passing through the rollers.

Studies show that aspiration during procedures involving CPB is responsible for severe hemolysis [10,11]

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Rev Bras Cir Cardiovasc 2012;27(4):535-41

and that the negative pressure and blood exposure to the air, when acting alone, produced no hemolysis, but with the combination of the two factors [12].

The peculiarities of each service in CPB procedures may also influence the rates of hemolysis (suction on the aortic root to prevent air embolism and the passage of residual volume from the CPB system for the patient).

The aim of this study was to quantify the rates of hemolysis at different times associated with CPB procedures in CABG procedures.

phlebotomy of the saphenous vein, which was catheterized after its removal in the surgical field. For this, we used the cardioplegia circuit with prior ligation performed using the venous reservoir tubing outlet. Blood was aspirated from the venous reservoir and pumped by roller cardioplegia, through the cardioplegia reservoir until the patient's venous network. This infusion flow did not exceed 200 ml/min.

The roller pump was adjusted as follows: the pump circuit has been filled, performed removal of air, removal of volume and replacement in order to form prime. With the pump stopped, the arterial line and the cardioplegia line were clamped. It was maintained open only recirculation line which communicates the oxygenation chamber with the venous reservoir, which has a length of approximately 50 cm. The roller was positioned at the point of maximum occlusion, vertically to the center of the raceway. The adjustment is accomplished by permitting the liquid in drop speed of 15 cm/min through the recirculation line.

The procedure was repeated for roller B. During the procedure, 6 blood samples were collected of 3 ml each, at the following times: T0 - before the start of CPB, T1 - 5 minutes after the start of CPB, T2 - with 30 minutes of CPB, T3 - immediately before the aortic unclamping, T4 - immediately prior to passing the residual volume for the patient and T5 - 5 minutes after the passing of the residual volume to the patient.

During the collections were recorded values of hematocrit, hemoglobin, nasopharyngeal temperature, blood pressure and higher blood pump rotation.

Free hemoglobin in plasma (FHp) was calculated by the Drabkin & Austin method [13] with the aid of a spectrophotometer Bioplus 200F (Bioplus, São Paulo, Brazil).

The hematocrit (Ht) was measured simultaneously with the withdrawal of blood samples for blood gas analysis (Radiometer ABL3, Copenhagen) and data concerning the FHp measurement at time t have been “corrected” for hemodilution according to the formula:

METHODS This study measured the degree of hemolysis during CPB surgeries for CABG procedures in a public hospital in the state of Sao Paulo - Brazil. This study was previously submitted to the Ethics Committee of the Institution, and was approved under protocol 0749.0.146.000-08.

We assessed 22 adult patients from March to August 2010. The study included patients older than 18 years, irrespective of the gender, undergoing isolated CABG. We excluded patients with cognitive problems, pregnant patients and patients who refused to sign the informed consent.

Was used to drive the blood a “Bakey” type roller pump (an arterial pump module, two aspirator pump modules and a blood cardioplegia pump module) and oxygenation was performed with the aid of a membrane oxygenator, all manufactured by Braile Biomédica Ltda.

The tubing used in all surgery was polyvinyl chloride (PVC) with 3/8 inch arterial inner diameter and 1/2 inch inner diameter for venous drainage and 1/4 inch inner diameter for aspirators. Silicone tube with 1/2 inch inner diameter was used for moving the blood through the roller pumps. In the CPB circuit was used oxygenator venous reservoir filter with capable of filtering particles larger than 100 micrometers, and in the arterial line, a filter of 40 micrometers, manufactured by Braile Biomédica.

Washing of the extracorporeal circuit was performed using ringer lactate solution, which was discarded after the effective circulation, replaced by new volume of the same solution as standard technique.

The formation of prime took into account the prior patient's hematocrit value, calculating hemodilution between 25% and 30%. The prime consisted of ringer lactate with albumin or mixed (ringer lactate + albumin + red blood cells), when the calculations demonstrate hemodilution hematocrit less than desired.

At the end of CPB, the residual volume of the oxygenator and arterial circuit was transferred to the venous reservoir, by inversion of the raceway (pocket) tubing of the arterial roller pump and infused into the

Equation 1

The Htbasic value was considered the average hematocrit of all patients (27.8%).

Hemolysis (Tx) rates were calculated for the time intervals listed below: 537

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Vieira Junior FU, et al. - Hemolysis in extracorporeal circulation: relationship between time and procedures

Equation 2. First 5 minutes of CPB

Equation 3. 25 minutes after CPB

Equation 4. Elapsed time for procedures

Equation 5. Aspiration in the aortic root (intensive aspiration at the time of release of the aortic clamp)

Patients receiving concentrated red blood cells during surgical procedures were recorded, as well as the storage time of the concentrate in the blood bank.

Statistical analysis We used the Shapiro-Wilk test for normality of the data verification and analysis of variance was calculated using the Kruskal-Wallis test. The difference between groups was calculated by the Student-Newman-Keuls test. The MannWhitney test was used to compare means. In all assessments, a P value <0.05 was considered statistically significant.

RESULTS Table 1 shows the demographic data of 22 patients, mean CPB time, mean body temperature and hematocrit during surgery.

Table 2 lists the average of six times measured during CPB, the respective values of free hemoglobin in the plasma and the rates of hemolysis.

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Equation 6. Passing of residual volume (roller pump maneuver)

Equation 7. Global rate of hemolysis (CPB)

Equation 8. Global rate of hemolysis in patients receiving packed red blood cells (n = 8).

Equation 9. Global rate of hemolysis patients not receiving packed red blood cells (n = 14).

Eight patients received packed red blood cells during surgery with stay time in the blood bank before the use of 1.1 ± 0.4 days. Each patient received only a bag of concentrate with 338 ± 22 ml. The overall hemolysis rate of patients who received packed red cells (TxG1) was 0.6 ± 0.2 (mg/dl/min). In fourteen patients who had not received packed red blood cells, the overall rate of hemolysis (TxG2) was 0.6 ± 0.3 (mg/dl/min). There were no statistical differences between groups (P > 0.82).

Table 1. Demographic data of 22 patients and cardiopulmonary bypass time, mean body temperature and hematocrit.

Values are expressed as mean and standard deviation.

Age (years) Body area (m2) Gender (M/F) CPB time (min) Temperature(°C) Hematocrit (%)

60 ± 9 1.8 ± 0.2 11/11 83.5 ± 23.5 35.3 ± 0.4 27.8 ± 2.7

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Table 2. Times recorded during CPB with respective measures of plasma free hemoglobin and hemolysis rates.

Values listed as mean ± standard deviation.

Time(min) T0 T1 T2 T3 T4 T5 0±0 5.0 ± 0.3 30.5 ± 2.4 64.5 ± 24.3 86.0 ± 31.2 97.0 ± 20.9 HLp (mg/dl) HLp0 HLp1 HLp2 HLp3 HLp4 HLp5 8.2 ± 2.5 23.2 ± 7.2 32.8 ± 10.2 48.5 ± 20.4 58.4 ± 23.2 51.5 ± 19.2 Hemolysis rate (mg/dl/min) Tx1 Tx2 Tx3 Tx4 Tx5 TxG 2.9 ± 1.7 0.4 ± 0.4 0.4 ± 0.5 0.6 ± 0.8 – 0.7 ± 1.0 0.6 ± 0.2

Table 3 shows the comparison between the average rates of hemolysis (ANOVA) among groups with respective probability values (P-value). Data were not normally distributed (P <0.05).

Table 3. Comparisons hemolysis rates between groups: Tx1, Tx2, Tx3, Tx4 e Tx5.

P-value Groups < 0.0001 Tx1 and Tx2 < 0.0001 Tx1 and Tx3 0.0003 Tx1 and Tx4 < 0.0001 Tx1 and Tx5 0.78 Tx2 and Tx3 0.38 Tx2 and Tx4 0.0003 Tx2 and Tx5 0.55 Tx3 and Tx4 < 0.0001 Tx3 and Tx5 < 0.0001 Tx4 and Tx5

DISCUSSION It is well established that surgical procedures using CPB promote damage to the blood cells, especially red blood cells by identifying increasing levels of free hemoglobin in plasma and decreased levels of haptoglobin during and after CPB [1].

Cardiac surgeries using CPB exposes blood to a request physical importantly, promoting the destruction of blood cells, particularly hemolysis.

Hemolysis occurs by several factors, which may or may not be associated: roller pump on excessive occlusion [14], shear stress [2,6,7,15], blood-air interface and negative pressure [12] and artificial surfaces [14].

This study aims to identify the rates of hemolysis in surgeries for CABG with CPB using the static calibration

method adapted to the conditions of the service. This adaptation was performed by the operational limitation of its use in the operating room and because it is not a technique with repeatability when used with silicone tubes as demonstrated in recent studies [3,9]. We also tried to identify the influence of using the aspirator in a more intense manner (at the time of aortic unclamping, in order to remove air from the left ventricular chamber) and the passage of the residual volume of the CPB circuit, hemolysis rates.

The Tx1 rate of hemolysis was calculated considering the evolution of hemolysis during the first 5 minutes of CPB and was the highest rate among the measured intervals (Table 3).

During CPB, hemodilution is performed with the help of the venous reservoir where the prime is stored.

Simultaneously, the blood begins to be drained into the venous reservoir and prime is infused into the patient by the motion of arterial pump, until there is a complete mixture of prime and blood. This initial procedure provides a small fraction of time in which blood passes through the rollers without being diluted. This procedure favors the breaking of red blood cells. Another important consideration is that some erythrocytes, already weakened or aged and with less flexible membranes, when requested by the mechanical action of the rollers are broken, resulting in further increasing rates of hemolysis.

Several studies have demonstrated the great influence of the use of blood aspirators in hemolysis [10-12], being considered by some the greatest cause of destruction of red cells when performed simultaneously air-blood.

In an article published in 1958, McCaughan et al. [16] demonstrated that aspiration of air mixed with blood contributed to increased levels of hemolysis compared to intermittent suction blood without this interface. Pohlmann et al. [12] demonstrated in an in vitro study that hemolysis is not caused by exposure to air or negative pressure alone, but by combining these factors. The increased hemolysis is directly related with the increase of negative pressure applied to the gas-blood interface.

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Rev Bras Cir Cardiovasc 2012;27(4):535-41

Vieira Junior FU, et al. - Hemolysis in extracorporeal circulation: relationship between time and procedures

In a recent study, Vieira et al. [17] studying the wall thickness of the silicone tube used in the pocket of the rollers, found that greater wall thickness promotes greater suction force and consequently higher pressures of aspiration and tubes of smaller thickness had flow limitation from 60 revolutions per minute (RPM). In this case, hemolysis may occur in two situations described above. The first by over-rotation, allowing for greater mechanical trauma caused by higher rotation without increasing its flow. The second case is the high pressure levels provided by a greater wall thickness, which leads to more pronounced shear stresses.

Tx2, Tx3 and Tx4 rates showed no differences in the hemolysis rates. There was an expectation that Tx4 associated with the intensive use of aspirator, had a higher rate of hemolysis compared to the Tx2 Tx3 rates, but this was not observed.

One hypothesis for the equality of Tx4 rates compared to the Tx2 Tx3 rates was that measures of Tx4 were predominantly characterized by continuous suction of the aortic root. The tube was almost totally submerged during suction and air-blood interface was reduced.

This explanation is supported by the results obtained by Pohlmann et al. [12] however, independently the thickness of the tubes in the aspirator pockets was not were not controlled, we expected greater hemolysis by the intensity use of suction, which was not found.

Another point of interest of the study was to assess the influence of the passage of the residual volume of blood in hemolysis. The TX5 rate was calculated between the instants: immediately prior to passing the residual volume for the patient (T4) and 5 minutes after the passing of the residual volume for the patient (T5).

The TX5 rate measured was negative (- 0.7 ± 1.0) over the time interval between T4 and T5, in the mean calculated of the 23 patients of 16.3 ± 3.3 minutes (mean ± standard deviation). In between, there was recovery in rates of hemolysis performed by the body. The results indicated no increase in hemolysis rates as a consequence of the procedure for passing residual volume.

Some authors emphasize that transfusion of red cells stored for longer than 2 weeks is associated with increased postoperative complications and reduced short-term survival and long-term after heart surgery [18]. Other authors point out that the storage time of red blood cells is not a risk factor for early and late mortality in patients undergoing coronary artery bypass grafting [19].

In our study, the group receiving packed red blood cells between one and two days of storage in blood bank (n=8) and the group that received packed red blood cells (n=14) showed no differences (P> 0.70) in overall hemolysis rates (TXG).

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CONCLUSION The first 5 minutes of CPB demonstrated a higher rate of hemolysis (P = 0.0003) and accounted for 29% of total hemolysis measured until the passage of residual volume for patients.

The suction on the aortic root to prevent air embolism showed no significant variations in the rates of hemolysis (P > 0.38).

There were no differences in hemolysis rates with the procedure used for passing residual volume of blood in the circuit for patients.

REFERENCES 1. Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a review in search of a treatment algorithm. J Extra Corpor Technol. 2008;40(4):257-67.

2. Sutera SP, Mehrjardi MH. Deformation and fragmentation of human red blood cells in turbulent shear flow. Biophys J. 1975;15(1):1-10.

3. Vieira FU Jr, Costa ET, Vieira RW, Antunes N, Petrucci O Jr, Oliveira PP. The effect on hemolysis of the raceway profile of roller pumps used in cardiopulmonary bypass. ASAIO J. 2012;58(1):40-5.

4. Vieira Jr. FU, Vieira RW, Antunes N, Oliveira PPM, Petrucci Jr O, Carmo MR, et al. Considerações sobre calibração de bombas de roletes. Rev Bras Eng Biom. 2010;26(1):25-32.

5. Tamari Y, Lee-Sensiba K, Leonard EF, Tortolani AJ. A dynamic method for setting roller pumps nonocclusively reduces hemolysis and predicts retrograde flow. ASAIO J. 1997;43(1):39-52.

6. Leverett LB, Hellums JD, Alfrey CP, Linch EC. Red blood cell damage by shear stress. Biophys J. 1972;12(3):257-73.

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7. Blackshear PL, Blackshear GL. Mechanical hemolisis. In: Handbook of bioengineering. 2a ed. Vol. 1. New York:Mc Graw-Hill;1987.

derivatives in human, dog and rabbit blood. J Biol Chem.

1932;98:719-33.

8. Vieira Jr. FU, Antunes N, Medeiros Jr. JD, Vieira RW, et al.

Os Perfusionistas brasileiros e o ajuste do rolete arterial: Comparação entre a calibração estática e dinâmica. Rev Bras Cir Cardiovasc. 2011; 26(2): 205-212.

9. Vieira FU Jr, Vieira RW, Antunes N, Petrucci O Jr, Oliveira PP, Silveira Filho LM, et al. The influence of the residual stress in silicone tubes in the calibration methods of roller pumps used in cardiopulmonary bypass. ASAIO J. 2010;56(1):12-6.

10. Edmunds LH Jr, Saxena NC, Hillyer P, Wilson TJ. Relationship between platelet count and cardiotomy suction return. Ann Thorac Surg. 1978;25(4):306-10.

11. Claugue CT, Blackshear PL Jr. A low-hemolysis blood aspirator conserves blood during surgery. Biomed Instrum Technol. 1995;29(5):419-24.

12. Pohlmann JR, Toomasian JM, Hampton CE, Cook KE, Annich GM, Bartlett RH. The relationships between air exposure, negative pressure, and hemolysis. ASAIO J. 2009;55(5):469-73.

13. Drabkin DL, Austin JH. Spectrophotometric studies. I. Spectrophoto-metric constant for common hemoglobin

14. Hirose T, Burman SO, O’Connor RA. Reduction of perfusion hemolysis by use of atraumatic low-pressure suction. J Thorac Cardiovasc Surg. 1964;47:242-7.

15. Kameneva MV, Burgreen GW, Kono K, Repko B, Antaki JF, Umezu M. Effects of turbulent stresses upon mechanical hemolysis: experimental and computacional analysis. ASAIO J. 2004;50(5):418-23.

16. McCaughan JS Jr, McMichael H, Schuder JC, Kirby CK. An evaluation of various devices for intracardiac suction. ASAIO Trans. 1958;4:130-42.

17. Vieira Jr FU, Antunes N, Costa ET. Comparação entre aspiradores de sangue combinados com tubos de silicone usados em circulação extracorpórea. Rev Ciência Tecnologia.

2012;15(26):65-76.

18. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229-39.

19. van Straten AH, Soliman Hamad MA, van Zundert AA, Martens EJ, ter Woorst JF, de Wolf AM, et al. Effect of duration of red blood cell storage on early and late mortality after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2011;141(1):231-7.

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ORIGINAL ARTICLE

Effect of exercise associated with stem cell transplantation on ventricular function in rats after acute myocardial infarction Efeito do exercício associado ao transplante de células-tronco sobre a função ventricular de ratos pós-infarto agudo do miocárdio

Simone Cosmo1, Julio César Francisco2, Ricardo Correa da Cunha3, Rafael Michel de Macedo4, José Rocha Faria-Neto5, Rossana Simeoni6, Katherine Athayde Teixeira de Carvalho7, Marcia Olandoski8, Nelson Itiro Miyague9, Vivian Ferreira do Amaral10, Luiz César Guarita-Souza11

DOI: 10.5935/1678-9741.20120096

RBCCV 44205-1421

Abstract Objective: To assess the functional and anatomicalpathological effect of transplantation of bone marrow mononuclear cells associated to aquatic physical activity after myocardial infarction in rats.

Methods: Twenty-one rats were induced by myocardial infarction, through left coronary artery ligation. After a week, the animals were subjected to echocardiography for evaluation of left ventricle ejection fraction (LVEF, %) and dyastolic and end systolic volume of the left ventricle

(EDV, ESV, ml), randomized and the transplantation of mononuclear stem cells. The animals were divided into four groups: sedentary group without cells (n=5), sedentary with cells (n=5), trained without cells (n=5) and trained with cells (n=6). The physical training was started 30 days after infarction and held in swimming during 30 days. At the beginning and at the end of the physical training protocol were held assay of lactate. The animals have been subjected to new echocardiography after 60 days of myocardial infarction.

1. Biologist, Master's Degree student of Pontifical Catholic University of Paraná (PUCPR), Curitiba, PR, Brazil. Project design.

2. Biochemist at PUCPR. Project design, bone-marrow blood collection.

3. PhD, Positivo University, Curitiba, PR, Brazil. Guidance on methodology of swimming physical activity.

4. PhD, PUCPR, Curitiba, PR, Brazil. Development of methodology and discussion.

5. PhD, PUCPR, Curitiba, PR, Brazil. Review of the article, methodology and discussion.

6. MD, PhD; PUCPR, Curitiba, PR, Brazil. Isolation of mononuclear cells.

7. MD, PhD, Pequeno Príncipe Faculty Institute and Paraná Federal University, Curitiba, PR, Brasil. Aid in the methodology of cell isolation.

8. PhD, PUCPR, Curitiba, PR, Brazil. Statistical analysis.

9 MD, PhD, PUCPR, Curitiba, PR, Brazil. Performance of ecocardiographic exams.

10. PhD, PUCPR, Curitiba, PR, Brazil. Paper discussion.

11. PhD, Adjunct Professor, PUCPR, Curitiba, PR, Brazil. Guidance on the project.

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This study was carried out at Pontifical Catholic University of Paraná, Curitiba, PR, Brazil.

Correspondence address: Luiz César Guarita-Souza Rua Rosa Kaint Nadolny, 190 – 5º andar – Curitiba, PR Brazil – Zip code: 81200-525 E-mail: guaritasouzalc@hotmail.com Support: CNPq

Article received on May 8th, 2012 Article accepted on September 27th, 2012

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Results: Two months after the transplant, were observed decrease in FE in the control group (35.20 to 23.54 P=0.022) and addition of LVEF and stabilization of ventricular remodeling in the group trained with cells (29.85 to 33.43% P=0.062 and 0.71 to 0.73 ml, P=0.776, respectively). Identified the reduction of collagen fibers, myocardial fibrosis regions in the group trained with and without cells.

Conclusion: The group trained with cells improves ventricular function compared to the control group, suggesting the benefit of associated cell therapy will physical activity.

Resumo Objetivo: Avaliar o efeito da associação terapêutica entre o transplante autólogo de células-tronco e o exercício físico aquático, sobre a fração de ejeção do ventrículo esquerdo (FEVE) de ratos com disfunção ventricular pós-infarto agudo do miocárdio (IAM).

Métodos: Foram induzidos ao IAM, por ligadura da artéria coronária esquerda, 21 ratos Wistar. Os animais foram submetidos à ecocardiografia para avaliação da FEVE (%) e dos volumes diastólico e sistólico finais do ventrículo esquerdo (VDF, VSF, ml), randomizados e ao transplante das células-tronco mononucleares. Os animais foram divididos em quatro grupos: grupo sedentário sem células (n=5), sedentário com células (n=5), treinado sem células (n=5) e treinado com células (n=6). O treinamento físico foi iniciado 30 dias após o IAM e realizado em piscina adaptada durante 30 dias. No início e no final do protocolo de treinamento físico, foram realizadas dosagens de lactato. Os animais foram submetidos a nova ecocardiografia após 60 dias do IAM. Resultados: Comparação dos valores de FEVE 30 dias e 60 dias pós-IAM, respectivamente: sedentário sem (35,20 ± 7,64% vs. 22,39 ± 4,56% P=0,026), com células (25,18 ± 7,73% vs. 23,85 ± 9,51% P=0,860) e no treinado sem (21,49 ± 2,70% vs. 20,71 ± 7,14% P=0,792), treinado com células (28,86 ± 6,68 vs. 38,43 ±7,56% P=0,062). Identificou-se a diminuição de fibras colágenas, nas regiões de fibrose miocárdica no grupo treinado com e sem células.

Conclusão: A associação terapêutica entre exercício físico e o transplante autólogo de células-tronco foi benéfica contra as ações do remodelamento ventricular.

Descriptors: Myocardial transplantation. Exercise.

Descritores: Infarto do miocárdio. Transplante de célulastronco. Exercício.

Abbreviations, acronyms and symbols ANOVA Analysis of variance LVEF Left ventricular ejection fraction H&E Hematoxylin-eosin AMI Acute myocardial infarction IMDM Iscove’s Modified Dulbecco’s Media PUCPR Pontifical Catholic University of Paraná rpm Rotations per minute FBS Fetal bovine serum SD with Infarcted group without exercise, sedentary, with cells SD without Infarcted group without exercise, sedentary TR with Infarcted group, trained, with cells TR without Infarcted group, trained, without cells EDV End-diastolic volume LV Left ventricle ESV End-systolic volume

infarction.

Stem

cell

INTRODUCTION Cardiovascular disease, the leading cause of death worldwide, constitute the major causes of morbidity and mortality, and acute myocardial infarction (AMI) is among the most frequent ischemic heart disease. Technological advances in the diagnosis and treatment have greatly increased the survival of patients, but the available options for the treatment of AMI are still palliative and limited, highlighting the need to develop new therapeutic modalities [1,2].

Although some authors suggesting that there mitotic division of the heart, the vast majority of cardiomyocytes has no capacity for regeneration after AMI and, when this occurs, there is deterioration of contractile activity and,

with the extensive area of AMI, ventricular remodeling can occur and heart failure [3].

Experimental studies indicate the possibility of myocardial regeneration through stem cell transplantation as an alternative for the treatment of this disease. In experimental models of acute and chronic myocardial ischaemia, implantation of bone marrow mononuclear cells was capable of improving myocardial perfusion and contraction. These results have been replicated in recent clinical studies in humans [4,5].

Physical exercises performed systematically result in large part to changes in the body. The changes have their place at the level of cell structures, tissues and the body as a whole. The changes extend from the cellular metabolic processes with their molecular mechanisms to 543

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the functional capacity of the organs cellular structures and their systems. Pronounced changes have been observed in relation to the mechanisms of control of bodily functions and metabolic processes, including cellular self-regulation, neural and hormonal levels [6].

Therefore, we sought to assess whether aquatic physical activity associated with the transplantation of bone marrow mononuclear cells in AMI also offers this same benefit. The aim of this study is to assess the functional and pathological effect of transplantation of stem cells from the bone marrow associated with aquatic physical activity after MI with left ventricular dysfunction in rats.

we observed absence of ocular reflex eyelid. With the relaxation of the animal, we obtained a definitive airway by tracheal intubation with peripheral venous line number 14. After each surgery, the airway patency was checked by connecting the catheter to the mechanical ventilation system with volume of 2.5 ml (O2/min.) And frequency of 50 cycles per minute, observing the lungs expansion.

Then, there were chest antisepsis using topical povidone-iodine and left thoracotomy in the third intercostal space. After opening the left pleura, the animal was connected to the mechanical ventilation system. We used the volume respirators (Harvard®, Inc., model 683 respirator, Massachusetts, USA) for small animals, with 21% oxygen (room air). The pericardium was opened for dislocation and better visualization of the area to be approached. After exteriorization of the heart, the left atrium was removed and the left coronary artery ligated using polypropylene monofilament nonabsorbable blue 7.0 suture, between the outflow of the pulmonary artery and left atrium. The infarcted region was immediately visualized by differential staining of the affected area. Then the heart was repositioned to the chest, the hyperinflated lungs and the chest wall sutured in layers using monofilament nylon nonabsorbable monofilament 4.0 suture. After recovery from anesthesia, the animals were kept in cages and fed with standard commercial diet and had free access to water.

METHODS The research was performed at the Center for Surgery and Diagnosis of the Laboratory of Experimental Surgical Technique of the Pontifical Catholic University of Paraná (PUCPR), after having been approved by the Research Ethics Committee (registration at CEUA/PUCPR n°434), with animals from PUCPR vivarium, according to the principles of the Brazilian College of Animal Experimentation [7].

We used 30 male Wistar rats weighing between 260 and 300g. Rats were grouped and kept stored in polypropylene cages at ambient with controlled temperature (22ºC 24ºC) and light, under light/dark (12/12h) cycles, and water ad libitum. All animals underwent induction of MI. After seven days, they underwent echocardiography and animals that had ejection fraction (LVEF) below 35% were included in the study (n=21). The remaining nine animals died from extensive AMI. At this moment, the animals were randomly divided into four groups, listed below: • Group I: infarcted without exercise, sedentary (SD without). The animals were monitored for 60 days (n = 5); • Group II: infarcted without exercise, sedentary, cell (SD with). The animals were transplanted with bone marrow mononuclear cells and monitored for 60 days (n = 5); • Group III: infarcted, trained without cells (RT without).

The animals underwent physical activity for 15 minutes three times a week and monitored for 60 days (n = 5); • Group IV: infarcted, trained with cell (TR with). The animals were transplanted with bone marrow mononuclear cells and underwent physical activity for 15 minutes three times a week and monitored for 60 days (n = 6).

Physical activity was initiated 30 days after induction of MI, after a period of aquatic adaptation.

Description of the procedure All rats in the experiment underwent general anesthesia with a combination of ketamine and xylazine (50 mg/kg) intramuscularly. After induction of anesthesia, 544

Echocardiography The animals were assessed by two-dimensional echocardiography equipment Sonos 5500 (Hewlett Packard, USA), with S12 sectorial transducer (5-12 MHz) and 15L6 linear (7-15 mHz). All animals, regardless of the group they belonged to, were anesthetized with ketamine and xylazine at a dose of 25 mg/kg and 5 mg/kg intramuscularly for examination. All animals underwent echocardiography at 7, 30 and 60 days post-myocardial injury, in order to follow the evolution of AMI. All animals were monitored in peripheral leads with pediatric electrodes, resulting in heart rate with cardioscopic visualization. The transducer was placed in the left ventrolateral portion of the chest wall, the images were viewed in two dimensions, and ventricular chambers visualized in two sections, transverse and longitudinal. In longitudinal section, axial view of the left ventricle (LV) was obtained, including mitral valve, aortic valve, anterior, and posterior LV apex, whereas in cross-section, it was observed septal, anterior, lateral and posterior wall in the median basal and apical LV region. The parameters assessed were: LVEF (%), LV end-diastolic volume (EDV) and LV end-systolic volume (ESV). Measurements were obtained by Simpson's method, using the computer software in both systole and diastole. All measurements were performed three times by

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the same observer in a blinded method, with the final result the average of the three.

Cell transplantation Cells derived from bone marrow mononuclear fraction were suspended in IMDM containing 20% fetal bovine serum (FBS, Gibco BRL, Grand Island, NY) and 1% antibiotic (100 μ/ml penicillin and 100/μL streptomycin).

The cell transplantation was performed on the same day of bone marrow puncture, in the transition area between the AMI and the intact myocardium, in the anterior wall of the left ventricle. The infusion was 15 μl of cells at a concentration of 5 x 106, using Hamilton syringe (LT 1701, Hamilton Bonaduz AG).

Obtaining blood from bone marrow After 7 days of AMI, bone marrow blood was obtained.

For this purpose, we used the aspiration puncture method in the bone marrow of mice in autologous way, always preceded by anesthesia: ketamine (50 mg/kg) and xylazine (10 mg/kg). The animals were placed in the lateral position, with the lower leg bent and the upper straight. The punctureaspiration was performed in the posterior iliac crest of the femur with disposable syringe (BD Plastipak®-) 5 mL, with 0.2 mL of heparin (5000 IU/mL), using 21 mm needle 25x8 G1 (BD-Precision Glide®); approximately 1 mL of blood from bone marrow was collected from each rat, followed by identification of syringes[8].

Isolation of mononuclear bone marrow stem cells For the isolation of the mononuclear fraction we used density gradient (d=1.077 g/m3) (Ficoll-Hypaque Sigma, St. Louis, MO) according to Böyum, on modified-Dulbecco's Iscove's media (IMDM GIBCO-BRL) supplemented with 1% antibiotics (penicillin and streptomycin) and 20% buffer solution. The material collected from each rat was placed in plastic sterile centrifuge tube of 15 ml. Immediately after completed this tube up to 12 ml with IMDM culture media (Iscove's Modified Dulbecco's Media), it was supplemented with 4% buffer and 1% antibiotics (penicillin and streptomycin) and homogenated. In a plastic tube of 15 ml, 3 mL of density gradient separation (d= 1.077) (Ficoll-Hypaque) were placed and hence then added to the homogenate containing animal bone marrow and IMDM culture medium carefully so it does not mix [8,9].

This tube was taken and subjected to centrifuge at 1400 revolutions per minute (rpm) for 40 minutes at 22°C. Soon after, it was led to flow again, and removed the ring formed between the middle and gradient. This homogenate was withdrawn, which mononuclear stem cells were, and were placed into another plastic tube of 15 mL. It was completed with IMDM medium up to 15mL and centrifuged again by 1500 rpm for 10 minutes at 22°C. After removal of the centrifuge tube, it was performed quickly removal of discard from the supernatant. A precipitate was observed at the bottom of the bottle, which were mononuclear stem cells.

After repeating the previous step and placing 13 mL of medium in the tube, the precipitate was resuspended and centrifuged again at 1500 rpm for 10 minutes at 22°C. After this phase, the supernatant was discarded, placed 3 mL of medium in the tube and resuspended the cells to count them. This count was performed in a Neubauer chamber and examined under an optical microscope Olympus® CX31 in a 40X objective [8].

Exercise Adaptation Protocol Physical activity with swimming was performed in temperature-controlled environment at 30°C, using a pool of 85 cm long by 30 cm wide by 50 cm high. The animals were adapted before training for 10 minutes at three different levels of water column: 20 cm with the first day, second day with 30 cm and last day with 40 cm [10].

Training protocol Physical activity occurred with swimming for 30 days in trained groups. The animals were exercised for 15 minutes a day, three days a week. The onset of activity occurred after 30 days of AMI. The same time was observed for the group of control animals, or that is, without exercising [10].

Lactate blood assessment Blood samples (25 µl) were collected from the tail of the animal, to quantify the exercise. Samples were collected during two periods: the first day of physical activity, being considered baseline data and 30 days after physical activity. The rats which exercised were tested immediately before and after physical activity. Trained groups were assessed with and without cells. Lactate concentration was determined using the portable lactimeter (Accutrend). The sedentary groups with and without cells underwent lactate concentration assessment, aiming to expand the control sample.

Euthanasia All animals euthanized received the lethal dose (LD50) (148 mg/kg) of the anesthetic ketamine [11]. The samples were sent for histopathological analysis.

Pathological study Hearts were preserved in vials containing 10% formalin for 24 hours. After this period, the hearts were cleaved into four crossed equal parts in the microtome (Leica RM2145 model) with a thickness of 5 mm.

Dehydration of the cuts was performed, which 545

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underwent successive baths in 70%, 80% and 90% alcohol, three baths in 100% alcohol (Leica TP1020 model) for one hour. Thereupon, liquid paraffin was impregnated in the sections through three baths at 65°C in the same apparatus.

Then the sections were mounted on slides and stained with hematoxylin-eosin (H&E) and Picrosirius Red. Two blades from each fragment were performed with four cuts and the mentioned colorings.

7.73% vs. 23.85% P= 9.51 ± 0.860 and 21.49 ± 2.70% vs.

20.71 ± 7.14% P= 0.792, respectively). Regarding the group trained with cells, we identified increasing of this parameter vs. 29.85 ± 6.68%. 33.43 ± 7.56%, P=0.246 (Figure 1).

With respect to SV, we identified an increase in this parameter in the sedentary groups with and in the trained group without cells 60 days after AMI (0.39 ± 0.15 ml vs.

0.65 ± 0.12 ml P=0.020, 0.50 ± 0.07 ml vs. 0.98 ± 0.12 ml P=0.018, 0.50 ± 0.09 ml vs. 0.64 ± 0.05 ml P=0.014, respectively). Regarding the trained group with cells, we identified that this parameter decreased from 0.61 ± 0.14 ml vs. 0.59 ± 0.22 ml (P=0.872).

Regarding the EDV, we identified increase in this parameter in the four groups 60 days after acute myocardial infarction: sedentary with and without cells and trained with and without cells (0.59 ± 0.19 ml vs. 0.83 ± 0.13 P=0.117 ml, 0.89 ± 0.13 vs. ml. 1.25 ml ± 0.20 P=0.033 vs. 0.70 ± 0.14 ml. 0.82 ml ± 0.09 P=0.058; 0.71 ± 0.13 ml vs. 0.73 ml ± 0.06 P=0.776, respectively).

Morphometric analysis The morphometric analysis was performed on the 60th day after AMI, once the markers were directed at the chronic phase of healing. We performed analysis of collagen, coloring the histological cuts using H&E technique and examining under an optical microscope.

The slides were examined with knowledge of known identity in a light microscope (Olympus BX40), increase of 200 X, coupled to a Sony® camera and a computer.

We used the Image-Pro Plus® for Windows software for digital image analysis.

Slide images were captured for later analysis on a computer and, using the Image-Pro Plus® software, the selected areas of interest were measured.

With the dropper tool, we selected the objects of interest and the program automatically generated the measure. Since the total area of the exam was constant, we selected statistics of the program that provided the percentage of the area occupied by the object of study, or that is, the collagen.

Ten fields were measured in histologic sections of each blade in the area of AMI, obtaining then an average reading of those cuts.

Statistical Analysis To compare the pre- and post moments within each group, we used the Student's t test for paired samples.

To compare the groups with respect to the results of premoments, we used the analysis of variance model (ANOVA) with one factor. To compare the groups regarding the postassessment results and regarding the differences between pre and post was used analysis of covariance, considering the pre-measure and the result of lactate as covariates. P values <0.05 were considered statistically significant. Data were organized into an Excel spreadsheet and analyzed using the Statistica software v.8.0.

RESULTS Intragroup echocardiographic analysis Regarding LVEF, we identified a decrease in this parameter in the sedentary groups with and without cells and in the trained groups without cells 60 days after AMI (35.20 ± 7.64% vs. 22.39 ± 4.56% P= 0.026 and 25.18 ± 546

Intergroup echocardiographic analysis Comparing the four groups together, statistically significant difference in echocardiographic values 30 days after AMI was found in the LVEF and EDV parameters of the LV.

Fig. 1 - Left ventricular ejection fraction

Regarding LVEF 30 days after AMI, we identified that the groups were not homogeneous (P=0.022), so we used an analysis of covariance. When assessing the results in 60 days after AMI, we found statistically significant difference only when comparing sedentary groups without cells with trained with cells (P=0.031) and trained groups with and without cells (P=0.015).

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Table 1. Lactate Variable Basal lactate

30 days lactate

Group

n

Mean

SD without cell SD with cell TR without cell TR with cell SD without cell SD with cell TR without cell TR with cell

5 5 5 6 5 5 5 6

2.50 4.28 3.70 4.50 3.28 3.00 3.40 5.98

Table 2. Lactate Comparison of groups two by two SD without x SD with SD without x TR without SD without x TR with SD with x TR without SD with x TR with TR without x TR with

Pre 0.009 0.065 0.003 0.354 0.710 0.187

P value (Comparison of 4 groups)

0.016

0.019

Post 0.762 0.897 0.007 0.666 0.003 0.009

Regarding the EDV parameter 30 days after AMI, we identified that the groups were also not homogeneous (P=0.040), thus we used analysis of covariance. When assessing the results in 60 days we observed statistically significant differences between the sedentary groups with and without cells (P<0.001), sedentary with cells and trained without cells (P <0.001) and sedentary and trained with cells (P <0.001).

Regarding the ESV parameter 30 days after AMI, we identified that the groups were homogeneous (P=0.052).

After 60 days there were statistically significant differences between the sedentary groups with and without cells (P=0.008), sedentary with cells and trained without cells (P=0.007) and sedentary and trained with cells (P=0.002).

Table 3. Collagen Variable AMI area

Standard deviation 1.28 1.04 0.80 0.67 0.64 1.27 1.46 1.83

Group SD without cell SD with cell TR without cell TR with cell

Fig.2. Collagen

Lactate assessment The values obtained after lactate are shown in Tables 1 and 2.

Collagen assessment Regarding the assessment of collagen in the area of AMI, the results in 60 days revealed that there was statistically significant difference between the groups trained with and without cells (Table 3 and Figure 2).

n 5 5 5 6

Mean 4.2 4.2 9.7 3.8

Standard deviation 3.8 2.5 2.7 3.5

P value

<0.001

AMI= acute myocardial infarction

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Cosmo S, et al. - Effect of exercise associated with stem cell transplantation on ventricular function in rats after acute myocardial infarction

DISCUSSION Physical activity can produce changes in myocardial perfusion. Coronary flow is inversely proportional to vascular resistance exerted specially by the vessels situated in the microcirculation. The increase in cardiac metabolism produced by exercise promotes the reduction of vascular tone (microcirculation), consequently improving myocardial perfusion. This improvement can be considered significant, even when considered other components involved in the process, such as endothelial function, microcirculation, regression of coronary atherosclerotic lesions, increased collateral circulation, reduce blood viscosity and increased diastolic perfusion time [12,13].

The transplantation of bone marrow mononuclear stem cells in ischemic cardiomyopathy has been performed with results that suggest improved myocardial function, especially for the mechanism of angiogenesis at the site of transplantation [14].

Physical activity also has the potential of regional vasodilation in regions close to AMI, which enables improvement of infarcted myocardium perfusion and also overall recovery of LV function. These two treatment options have been applied in patients with associated heart failure. In this study, we used a similar experimental model because it included animals with established fibrosis and severe left ventricular dysfunction.

The association between the two therapies showed a trend of better control over the deleterious factors of ventricular remodeling, since there was no significant difference in LVEF values obtained before and 60 days post-training. There was also increase in absolute values.

With respect to functional analysis in the pre-transplant, the four groups had the LV LVEF and EDV parameters with statistical difference between them, hence, the LVEF and EDV were assessed as covariance, in an attempt to homogenize them.

The control group, or that is, sedentary without cells, showed significant deterioration of LVEF after 60 days of AMI, confirming the effect of muscle necrosis and, as a consequence, the development of heart failure, which was already expected. It was identified small drop of LVEF, both in the sedentary group with cell as in the trained group without cells, suggesting stabilization of cardiac function. This stabilization may be justified by the benefit of physical activity in the trained group and the action of bone marrow mononuclear stem cells in the sedentary group, which has also been identified in other studies [15].

Regarding the trained group with cells, we identified functional benefit, which can be explained by the action of both mononuclear stem cells as physical activity, by the mechanisms above justified. Comparing the sedentary 548

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groups without cell (control) and trained with cells, this result was evident. However, when comparing the trained groups with and without cells it was also identified benefit in the group with cells, suggesting that the benefit of bone marrow mononuclear stem cells may have been more significant.

Assessing only the animals that underwent physical activity, or that is, those trained, it was found that the animals that received the bone marrow mononuclear stem cells showed myocardial protective effect compared to animals that received no cells. It is true that when assessed the intragroup LVEF parameter, even in the trained group without cells, there was stabilization of LVEF as a decrease of 21.49% to 20.71% it is considered irrelevant. Thus, we suggest that the protective effect of physical activity in this model, although it was identified higher percentage of collagen, or that is, myocardial fibrosis in this group.

When we assessed the sedentary animals, it was observed that the animals that received no cells can be considered the control group, as they were infarcted, did not practice physical activity and also not received cells.

In the sedentary group that received cells, we identified a decrease in LVEF from 25.18% to 23.85%, variation also considered no significant, suggesting a protective mechanism of transplanted myocardial cells.

Regarding LV EDV, the four groups showed an increase over the 60 days of AMI. In the control group, as a result of deterioration of ventricular function after AMI, it already was expected that ventricular remodeling would happen. However, the sedentary group with cells showed statistically significant ventricular dilation, which was also identified in a study published by the same group [14]. Regarding the trained group with cells, although ventricular dilation is identified, it was considered that there was stabilization of ventricular remodeling.

Regarding LV ESV, the sedentary groups with and without cells and trained group without cells showed an increase over the same period, suggesting a loss of contractile capacity, however the trained group with cells identified a decrease in this parameter. Although not significant, it is suggested a functional protective capability of the combined treatment proposed.

As animals with LVEF less than 35% were included in the study and as already had significant ventricular dysfunction with increased ventricular volumes before transplantation, it is difficult to understand that transplantation of cells can exert an antiremodeling because treatment is only regional. It is believed that the benefits associated with physical activity can justify these results.

According to Ferraz et al. [16], heart failure should not be considered as a pure and simple disease, but as a complex syndrome that involves: endothelial dysfunction,

Cosmo S, et al. - Effect of exercise associated with stem cell transplantation on ventricular function in rats after acute myocardial infarction

abnormal composition of peripheral skeletal striated muscle fibers, abnormalities of blood flow and the chemoreflex ventilatory control. All these changes result in lower exercise tolerance and lower functional capacity.

Guimar達es et al. [17] described the limiting effects to training in patients with heart failure, highlighting the behavior of central and peripheral chemoreceptors. In these patients, there is increased sensitivity in peripheral chemoreceptors, which results in greater activation of the sympathetic nervous system, increasing blood pressure, ventilation and peripheral vascular resistance. This phenomenon is described as mecanoreflex. Moreover, during the exercises, patients with heart failure present early ventilatory muscle fatigue, resulting in higher demand of afferent stimuli to the central nervous system by the fibers of the phrenic nerve, activating the sympathetic nervous system and triggering peripheral vasoconstriction and lower tolerance to training. This phenomenon was described as metaboreflex [17,18].

Due to mecanoreflex and metaboreflex, there is a change in the composition of peripheral muscle fibers of patients with heart failure. According to Schulze et al.

[19], patients with heart failure suffer tonic fiber atrophy, due to the reduction in the number of mitochondria and myoglobin present in these fibers as a result of low blood flow allowed by increased peripheral vascular resistance.

Thus, the type II muscle fibers (phasic) become more active, and the anaerobic glycolysis as the main power supply to perform movements, resulting in increased lactic acidosis and lower exercise tolerance. Thus, patients with heart failure tend to have higher lactate production at rest, compared to patients without left ventricular dysfunction.

This behavior is similar in rats.

Aerobic exercise and or respiratory muscle training reduce the effects caused by metaboreflex and the mecanoreflex. Chiappa et al. [20] showed that individuals who have respiratory muscle training reduced peripheral vascular resistance, improving perfusion due to better conditioning and diaphragmatic inhibition of the sympathetic nervous system action. Ferraz et al. demonstrated that aerobically trained patients present similar response [16-20].

Therefore, in this study it was expected that, with aerobic training, the animals presented decrease in lactate values at rest, according to Li et al. [21]. Furthermore, with the injection of mononuclear stem cells and possible improve of ventricular function, the effects of heart failure could be minimized and composition of peripheral muscle fibers reorganized properly, allowing better utilization as oxidative energy substrate [21].

The remarkable point is that the rats that received cells and trained increased lactate at rest, which can be a sign that in this group the effects caused by the mecanoreflex

Rev Bras Cir Cardiovasc 2012;27(4):542-51

and metaboreflex were not controlled. The difference between lactate values at rest before and after 30 days of physical activity was significant with P=0.019, but it is important to note that in both groups there was an increase in home values.

When comparing the groups two by two with respect to lactate parameter, significant differences were found when compared the sedentary group without cells with the trained group with cells. This result suggests a readaptation to oxidative system of energy sources from peripheral muscle fibers in the group receiving cells. Another significant difference was found between the sedentary group that received cells and trained group with cells.

This difference was significant, since the amount of lactate at rest of sedentary mice that received cells decreased, whereas those who have been trained increased. This demonstrates favorable peripheral adaptation of the fibers of the rats that receive cells, while the group that received training did not improve peripheral blood perfusion.

Ferraz et al. [16] demonstrated that patients undergoing low intensity training (anaerobic threshold intensity-equivalent) improved aerobic capacity more than those who trained at high intensity (near the ventilatory compensation point). This may have happened because the trained group with cells trained during the period at an intensity above lactate threshold or anaerobic threshold.

A limiting factor of this study was the fact of not having been determinded the point of lactate threshold or training stable state. Accordingly, the rats may have been trained constantly and anaerobically, which may have resulted in little improvement in exercise tolerance or lactate levels at rest.

Through the technique of morphometric analysis, quantitative assessments of collagen in hearts after 60 days of AMI were performed. The main result of this study with regard to the collagen assessment in the area of AMI was observed as a significantly less quantity in the group trained with cells. It is believed that factors released due to paracrine effect of stem cells can promote reduction of the fibrosis area, suggesting recovery of left ventricular function, which can be corroborated with improved LVEF and limiting ventricular remodeling. These two mechanisms may also be explained by the angiogenic potential of bone marrow mononuclear stem cells, previously described in other studies and the mechanisms of vasodilation produced by physical activity [14,15].

A study by Bolli et al. [22] demonstrated, after direct injection of mesenchymal stem cells in ischemic hearts, decreased fibrosis, apoptosis, and increased LVEF. In another study by Xu et al. [23], they have shown that, in infarcted trained rats, after early physical activity, the percentage of collagen in the trained group was significantly higher in the sedentary group, suggesting 549

Cosmo S, et al. - Effect of exercise associated with stem cell transplantation on ventricular function in rats after acute myocardial infarction

Rev Bras Cir Cardiovasc 2012;27(4):542-51

that early training after MI reduces the metalloproteinases expression. In this study, this finding was not identified because there was a greater presence of collagen in the trained group without cells. However, it was found reduced expression of collagen when associated with mononuclear cell transplantation. These results suggest that physical training with the help of bone marrow mononuclear stem cells improved physical and functional capacity of these animals.

7. COBEA. Princípios éticos na experimentação animal.

Disponível em: http:// www.cobea.org.br/. Acesso: maio de 2008

CONCLUSION Based on this study we can conclude that, after 60 days of AMI, we found that transplantation of bone marrow mononuclear stem cells associated with training minimized the deleterious effects of ventricular remodeling.

8. Carvalho KA, Cunha RC, Vialle EN, Osiecki R, Moreira GH, Simeoni RB, et al. Functional outcome of bone marrow stem cells (CD45(+)/CD34(-)) after cell therapy in acute spinal cord injury: in exercise training and in sedentary rats. Transplant Proc. 2008;40(3):847-9.

9. Boyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl.

1968;97:77-89.

10. Freimann S, Scheinowitz M, Yekutieli D, Feinberg MS, Eldar M, Kessler-Icekson G. Prior exercise training improves the outcome of acute myocardial infarction in the rat. Heart structure, function, and gene expression. J Am Coll Cardiol.

2005;45(6):931-8.

11. Rebuelto M, Ambros L, Montoya L, Bonafine R. Treatment-time-dependent difference of ketamine pharmacological response and toxicity in rats. Chronobiol Int 2002;19(5):937-45.

12. McArdle WD. Fisiologia do exercício: energia, nutrição e desempenho humano. 5ª ed. Rio de Janeiro: Guanabara;2003.

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14. Guarita-Souza LC, Carvalho KAT, Rebelatto C, Senegaglia A, Hansen P, Furuta M, et al. A comparação entre o transplante de células tronco mononucleares e mesenquimais no infarto do miocárdio. Rev Bras Cir Cardiovasc. 2005;20(3):270-8.

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2006;111(3):423-9.

3. Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A. 1998;95(15):8801-5.

4. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106(24):3009-17.

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5. Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003;361(9351):45-6.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):552-61

Cavo-pulmonary anastomosis associated with left ventricular in comparison with biventricular circulatory support in acute heart failure Anastomose cavo-pulmonar associada ao suporte circulatório esquerdo comparada à assistência biventricular na falência cardíaca aguda

Luis Alberto Saraiva Santos1, Anderson Benício2, Ewaldo de Mattos Júnior3, Luiz Alberto Benvenutti4, Idágene Aparecida Cestari5, Noedir Antonio Groppo Stolf6, Luiz Felipe Pinho Moreira7 DOI: 10.5935/1678-9741.20120097

RBCCV 44205-1422

Abstract Objective: Right ventricular (RV) failure during left ventricular assist device (LVAD) support can result in severe hemodynamic compromise with high mortality. This study investigated the acute effects of cavo-pulmonary anastomosis on LVAD performance and RV myocardial compromise in comparison with biventricular circulatory support, in a model of biventricular failure.

Methods: LVAD support was performed by centrifugal pump in 21 pigs with severe biventricular failure obtained

by FV induction. Animals were randomized to be submitted to cavo-pulmonary anastomosis, to biventricular circulatory support or to control group. They were maintained under circulatory support and hemodynamic monitoring for 3h. Venous lactate and cytokines serum levels were also

obtained. Endocardium samples were analyzed by electronic microscopy.

Results: FV maintenance was responsible for acute LVAD impairment after 180 min in the control group. cavo-pulmonary anastomosis resulted in non-significant improvement of LVAD pump flow in relation to control group (+55±14 ml/kg/min, P=0.072), while animals under biventricular support maintained higher LVAD flow (+93±17 ml/kg/min, P=0.012). Mean arterial pressure remained constant only in biventricular group (P<0.001), which also presented decrease of right atrial and ventricular pressures.

Similar increases in lactate and cytokines levels were observed in the three groups. Ultra-structural analysis documented low levels of myocardial swelling in the biventricular group (P=0.017).

1. Federal University of Amazonas, Cardiac Physician Surgeron. Major author.

2. Heart Institute at Clinics Hospital of the University of São Paulo Medical School; PhD in Sciences (Thoracic and Cardiovascular Surgery) at University of São Paulo, Physician Collaborative Professor at University of São Paulo Medical School.

3. Heart Institute at Clinics Hospital of the University of São Paulo Medical School; Collaborative Researcher of the Bioengineering Department of the Heart Institute at Clinics Hospital of the University of São Paulo Medical School.

4. Heart Institute at Clinics Hospital of the University of São Paulo Medical School; Physician of the Pathology Service of the Heart Institute at Clinics Hospital of the University of São Paulo Medical School.

5. Heart Institute at Clinics Hospital of the University of São Paulo Medical School; Research and Development Director of the Bioengineering Department of the Heart Institute at Clinics Hospital of the University of São Paulo Medical School.

6 PhD in Sciences at University of São Paulo; Emeritus Professor of the Cardiovascular Surgery Department at Heart Institute at Clinics Hospital of the University of São Paulo Medical School.

7. Heart Institute at Clinics Hospital of the University of São Paulo Medical

School; Full Professor at University of São Paulo; Associate Professor of the Cardiovascular Surgery Discipline at University of São Paulo Medical School.

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This study was carried out at Heart Institute at Clinics Hospital of the University of São Paulo Medical School, São Paulo, SP, Brazil.

Correspondence address: Luis Alberto Saraiva Santos Av. Dr. Enéas Carvalho de Aguiar, 44 – 2º andar, bloco 2, sala 13 – São Paulo, SP, Brazil – Zip code: 05403-000.

E-mail: l_saraiva@ig.com.br Support: Foundation for Research Support of the State of São Paulo (FAPESP).

Article received on May 8th, 2012 Article accepted on September 5th, 2012

Santos LAS, et al. - Cavo-pulmonary anastomosis associated with left ventricular in comparison with biventricular circulatory support in acute heart failure

Abbreviations, acronyms and symbols LA LVAD VF EM OM LAP MAP PAP PTFE CVP RVP RV LV

Left atrium Left ventricular assist devices Ventricular fibrillation Transmission electron microscopy Optical microscopy Left atrial pressure Mean arterial pressure Pulmonary artery pressure Expanded polytetrafluoroethylene Central venous pressure Right ventricular pressure Right ventricle Left ventricle

Conclusion: The concomitant use of cavo-pulmonary anastomosis during LVAD support in a pig model of severe biventricular failure resulted in non-significant improvement of hemodynamic performance and it did not effectively replace the use of biventricular support.

Descriptors: Heart-assist devices. Heart failure.

Ventricular dysfunction, right. Heart bypass, right. Swine.

Resumo Objetivo: Este estudo avaliou o desempenho hemodinâmico e as alterações miocárdicas decorrentes do emprego de dispositivos de assistência ventricular esquerda (DAVE), associado ou não à descompressão do ventrículo direito por meio de derivação cavo-pulmonar, sendo esses achados comparados ao emprego de assistência circulatória biventricular.

INTRODUCTION Heart failure has been associated with poor prognosis and high morbidity and, despite optimal medical therapy, mortality remains unacceptably high, which justifies the search for alternative treatments. In this context, we can find mechanical circulatory support devices, which provide for this group of patients better quality and life expectancy [1-3].

One of the main complications of the implantation of left ventricular assist devices (LVAD) alone is the circulatory dysfunction of the right ventricle (RV), which

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Métodos: Vinte e um suínos foram submetidos à indução de insuficiência cardíaca através de fibrilação ventricular, sendo a atividade circulatória mantida por DAVE durante 180 minutos. No grupo controle, foi apenas implantado o DAVE. No grupo derivação, além do DAVE foi realizada cirurgia de derivação cavo-pulmonar. No grupo biventricular, foi instituída assistência biventricular. Foram monitoradas as pressões intracavitárias por 3 horas de assistência e amostras do endocárdio dos dois ventrículos foram coletadas e analisadas à microscopia óptica e eletrônica.

Resultados: O lactato sérico foi significativamente menor no grupo biventricular (P=0,014). A diferença observada entre o fluxo do DAVE nos grupos derivação e controle (+55±14 ml/kg/min, P=0,072) não foi significativa, enquanto que o fluxo no grupo biventricular foi significativamente maior (+93±17 ml/kg/min, P=0,012) e se manteve estável durante o experimento. A pressão arterial média (PAM) se manteve constante apenas no grupo biventricular (P<0,001), que também apresentou diminuição significativa das pressões em câmaras direitas. Na análise ultraestrutural, notou-se menor presença edema miocárdico no ventrículo direito no grupo biventricular (P=0,017).

Conclusão: Os resultados apresentados demonstram que o desempenho hemodinâmico da assistência ventricular esquerda associada à derivação cavo-pulmonar, neste modelo experimental, não foi superior ao observado com a assistência de ventrículo esquerdo isolada e não substituiu a assistência biventricular de maneira efetiva.

Descritores: Coração auxiliar. Insuficiência cardíaca.

Disfunção ventricular direita. derivação cardíaca direita.

Suínos.

has an incidence varying between 13% and 44% [1,3,4].

Although controversial, most authors report that the institution of biventricular assistance should be performed as early as possible if the RV failure is hemodynamically important [4,5]. But with double of cannulation and pumps “sites", the adverse effects of this type of circulatory support increase[6].

Another alternative that has been suggested recently to acute right ventricular failure is the use of its surgical volume decompression volume through the cavopulmonary shunt [7,8]. The effectiveness of this procedure has been proven previously in experimental studies [9] and there 553

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is one report in the literature of patients who obtained clinical success of weaning from RV circulatory assist device, facilitated by the construction of cavopulmonary shunt when in use of biventricular assist device [8].

The aim of this study was to assess the hemodynamic performance and myocardial changes in the employment of LVAD, with or without RV decompression through cavopulmonary anastomosis in an experimental model of acute biventricular dysfunction in pigs and to compare these effects to those seen with the use of biventricular circulatory assistance. The influence of the types of circulatory assistance imposed on inflammatory response and tissue perfusion of animals was also assessed.

Additional doses of fentanyl were administered as needed.

Intubation using 6.5 Fr cannula was performed and then a ventilator was introduced (Harvard ventilator 708, South Natik, MA, USA). Before the surgery, electrodes were placed on the animal, for continuous electrocardiogram recording.

A venous line (right femoral vein) was accessed for collection of serum samples, and if required, additional volume infused. For fluid infusion, a maximum of 100 ml/kg was established in order to keep the central venous pressure (CVP) at normal values (10-14 mmHg). The temperature was obtained through a sensor inserted into the rectum, urinary output was measured by catheterization through cystostomy. Vasoactive drugs were not used in this protocol. An arterial line (right femoral artery) was obtained for monitoring of mean arterial pressure (MAP) and blood gas assessment and the right internal jugular vein was dissected for CVP monitoring.

The exposure of the heart was obtained through a median sternotomy and, after opening the pericardial sac, purse string sutures were performed in the left atrium (LA) and RV and micromanometers were inserted (5F, Model PC-350, Millar Instruments, Inc. Houston, USA) for continuous monitoring of intracavitary pressures. All sutures were performed in purses using prolene 4.0 wire, except the tip of the left ventricle, which was performed using Mersilene 2.0 polifilamentar wire.

After completion of the monitoring and cannulation of the animals, FV was induced, which was maintained by itself because it is not reversed by means of electrical defibrillation. The flow was maintained as large as possible, taking as parameter the LA pressure, which had as its goal the value close to zero, thus connoting good blood return to the pulmonary territory and good LV drainage. In biventricular group, the begining of assistance at the right side of the heart was simultaneously to the left and in this flow was maintained at values lower than 20% than the left sides.

METHODS Twenty-one pigs, weighing between 25-35 kg, underwent induction of acute biventricular failure obtained from the onset of the rhythm of ventricular fibrillation (VF) by direct contact of a 12 volt electric charge battery with the anterior heart wall. The circulatory activity was maintained by the institution of LVAD. This study was approved by the Research Ethics Committee of the institution under protocol (SDC-1649/00/10) and all animals underwent surgery according to the rules set in “Manual on the Care and Use of Laboratory Animals” and “European Convention on Animal Care”.

Protocol of animal experiments The animals were randomly divided into three groups of seven pigs, called control group, bypass group and biventricular group. The surgical preparation was similar in the three groups. In the control group, LVAD was installed with centrifugal pump (Biopump, Medtronic, Inc.) with aortic cannulation, with angled 12 Fr wireframe arterial cannula (Medtronic, Inc.) and the tip of the left ventricle (LV), with single stage wireframe 24 Fr cannula (Medtronic, Inc.). In bypass group (Figure 1A), in addition to biopump on the left side of the heart was performed cavopulmonary anastomosis between the superior vena cava and the pulmonary artery using a non-wired No 16 expanded polytetrafluoroethylene (PTFE) tube, which was made before the circulatory assistance. In the biventricular group (Figure 1B), in addition to the left circulatory support, biopump has also been installed on the right side of the heart, through cannulation of the pulmonary artery and right atrial appendage, with tubes similar to those previously described.

Anesthetic and surgical preparation The animals underwent general anesthesia with ketamine (30 mg/kg im), midazolam (0.2 mg/kg, intravenously) and fentanyl (0.005 mg/kg, intravenously).

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A

B

Fig. 1 - Schematic diagram of the surgical preparation. A: Bypass group B: biventricular group

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Hemodinamic assessment The LV rhythm was maintained for 180 minutes and during this period were recorded MAP, CVP, RV pressure (PVD) and left atrial pressure (LAP) in 30-minute intervals until the end of the protocol.

Evaluation of tissue perfusion and inflammatory response Changes in tissue perfusion and myocardial infarction were assessed before the procedure and every 30 minutes through collection of blood samples for analysis of blood gases, hematocrit, and lactate. Samples were collected for analysis of changes in the inflammatory response at the time of initial preparation and subsequently every 60 minutes during the period of circulatory support. Serologic blood tests of TNF α, interleukin-1β and interleukin-6 through specific antibody for pigs (Duo-Set, R & D Systems, Minneapolis, MN, USA) were performed.

cellular edema was characterized by the presence of one or more areas of clear separation of organelles by edema.

The mitochondrial swelling was defined by the presence of irregular areas of vacuolization of the mitochondrial matrix, sometimes rupture of ridges present in several mitochondria. The electron-dense bodies were defined by the presence of multiple electron-dense corpuscles in the mitochondrial matrix and, ultimately, myofilaments lysis was characterized by the presence of multiple areas of dissolution of myofilaments sarcomeres.

To avoid the appearance of post-mortem lesions that might distort the analysis of the material after removal of the heart, it was set maximum time of 15 minutes between the removal of the organ and fixing the material in glutaraldehyde.

Ultramicroscopic assessment Changes of myocardial cells in the three groups were assessed by optical microscopy (OM) and transmission electron microscopy (EM). Samples were taken at the RV free wall, in the interventricular septum and the LV free wall, obtained at the end of the experiment by removing the heart. The examiner was blind to the groups, after the result/report of the pathologist in charge, groups were revealed and the final result of this data was then made.

The samples were assessed by optical microscopy, being noted that they could be grouped into three distinct patterns of progressive gravity, as follows: • Grade 0/+: Myocardium preserved or presenting small and scattered foci of recent necrosis of cardiomyocytes, characterized by cytoplasmic hypereosinophilia, contraction bands and nuclear pyknosis present only in the subendocardial region which presents no interstitial hemorrhage.

• Grade ++: Multiple foci of recent necrosis of cardiomyocytes in the subendocardial region, encompassing groups of cells, characterized by cytoplasmic hypereosinophilia, contraction bands and nuclear pyknosis, with or without small foci, sparse, of necrosis in mid-layer wall. It is the usual the presence of foci of hemorrhage in the subendocardium.

• Grade +++: Multiple foci of recent necrosis of cardiomyocytes in subendocardial and mid-mural region encompassing clusters of cells, characterized by cytoplasmic hypereosinophilia, contraction bands and nuclear pyknosis. Foci of hemorrhage in the subendocardium and crisp interstitial edema.

Under EM, the presence or absence of cellular swelling and swollen mitochondria, electron-dense bodies and lysis of myofilaments was assessed, and the first two being considered lesions of mild to moderate intensity, and the last two, lesions of moderate to severe intensity. The

Statistical Analysis The statistical analysis was performed using the Graphpad Prism 5.2 software. The data were statistically assessed according to the type of distribution of variables.

Parametric variables were expressed as mean ± standard error of the mean and were assessed by the two-tailed test of variance with repeated measures on the factor “time”, complemented by the Bonferroni t test. The variables of non-parametric distribution were expressed as medians and percentiles, and were assessed by profile analysis. The level of significance was set at 5%.

RESULTS After the phase of protocol standardization, 21 full experiments were performed, seven in each group. The weight of the animals ranged from 25 to 32 kg, with a mean of 29 ± 3 kg, 30 ± 3 kg and 27 ± 4 kg in the control groups, bypass and biventricular, respectively. Comparable amount of fluid was administered in the three groups. The values of arterial blood gases, hematocrit and hemoglobin were similar between groups. Serum lactate was significantly lower in biventricular group (Table 1).

Hemodynamic performance assessment The hemodynamic data are shown in Table 2. LVAD flows observed were similar in the control groups and cavopulmonary bypass, while flow in biventricular group was significantly higher throughout the experiment (Figure 2).

The study of the pressure behavior in the left circulation has shown the maintenance of normal levels of MAP throughout the period of circulatory assistance only in the biventricular group, while the other groups showed a progressive decrease of this parameter. This drop, however, was not statistically significant and shows satisfactory maintenance of levels by the end of the experiments in 555

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Santos LAS, et al. - Cavo-pulmonary anastomosis associated with left ventricular in comparison with biventricular circulatory support in acute heart failure

Table 1. Serum lactate results.

Control Bypass Biventricular

Pre 0.81±0.06 1.20±0.50 0.72±0.34

1 hour 2.47±2.06 3.55±3.59 1.60±1.31

Lactate 2 hours 3.31±2.90 4.34±4.11 1.75±1.36

P=0.014

3 hours 3.62±2.87 5.21±4.76 1.98±1.61

Control = control group; Bypass = bypass group, Biventricular = biventricular group.

Table 2. Hemodynamic results.

MAP Control Bypass Biventricular

Pre

30’

60’

90’

120’

150’

180’

51.99 ± 7.53 58.95 ± 9.81 58.19 ± 5.03

42.66 ± 14.49 45.49 ± 12.21 53.80 ± 11.13

38.93 ± 15.24 43.51 ± 10.89 55.03 ± 11.97

36.97 ± 15.02 44.66 ± 13.49 52.55 ± 14.34

37.63 ± 14.12 42.58 ± 13.81 53.24 ± 11.43

3607 ± 15.87 42.07 ± 12.91 51.43 ± 12.68

32.52 ± 15.61 42.02 ± 11.92 51.12 ± 12.84

CVP Control Bypass Biventricular

5.20 ± 1.37 5.60 ± 2.99 5.20 ± 1.13

10.68 ± 2.98 13.19 ± 5.35 9.03 ± 2.14

10.97 ± 1.94 13.54 ± 4.39 8.55 ± 3.12

11.21 ± 2.04 13.48 ± 3.14 8.08 ± 3.28

10.88 ± 2.44 13.26 ± 3.04 10.37 ± 2.42

11.08 ± 2.72 13.39 ± 2.85 9.60 ± 3.92

10.37 ± 3.00 13.48 ± 2.98 8.89 ± 3.71

LAP Control Bypass Biventricular

7.78 ± 2.84 8.35 ± 2.59 8.15 ± 1.98

3.09 ± 3.25 2.57 ± 3.13 2.87 ± 2.96

2.71 ± 3.33 3.45 ± 3.23 2.50 ± 1.38

1.39 ± 1.86 3.84 ± 3.44 3.58 ± 2.16

2.44 ± 2.34 3.21 ± 3.66 4.13 ± 2.36

2.61 ± 2.77 3.01 ± 3.05 3.42 ± 2.74

2.87 ± 2.84 1.72 ± 2.60 3.29 ± 3.02

RVP Control Bypass Biventricular

12.14 ± 2.63 11.09 ± 3.68 9.77 ± 3.45

13.89 ± 5.45 13.31 ± 6.07 11.66 ± 2.74

14.84 ± 5.84 14.01 ± 4.94 12.09 ± 2.69

13.75 ± 5.62 14.12 ± 3.79 12.51 ± 2.13

15.32 ± 6.38 14.01 ± 3.62 12.32 ± 2.05

15.82 ± 5.28 14.00 ± 3.20 12.35 ± 2.05

16.74 ± 5.64 14.02 ± 3.47 11.54 ± 2.10

Control = control group; Bypass = bypass group; Biventricular = biventricular group, MAP = mean arterial pressure, CVP = central venous pressure; LAP = left atrial pressure; RVP = right ventricular pressure.

of pressure in the superior vena cava and right ventricle of the animals in the control group and cavopulmonary bypass group (Figures 4A and 4B).

Fig. 2 - Ventricular assist device flow.

Left Ventricular Assist Device Flow (LVAD). Values in mean ± standard error of the mean.

Difference between groups: P = 0.012

the three groups studied (Figure 3A). The LVP assessment demonstrated effective performance of left ventricular assist in all experiments (Figure 3B).

Regarding the behavior of the pressure in the right chambers, we observed the existence of lower values only in the biventricular group, being observed similar values 556

Inflammatory response assessment The assessment results of the inflammatory response through serum cytokine dosage are presented as medians and percentiles. Although there was a trend to higher levels of TNFa with maintaining circulatory assistance for longer periods in the biventricular group, this difference was not significant from a statistical standpoint. There were also no significant differences between the groups in relation to the interleukins 6 and 1β values (Figure 5).

Assessment of changes in myocardial cells Table 3 shows the changes under OM observed in the groups. There were no significant differences in the degree of damage of myocardial fibers in the LV and RV, while the biventricular group showed fewer changes considered more severe in the septum.

The results of the changes observed under EM are

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Rev Bras Cir Cardiovasc 2012;27(4):552-61

shown in Table 4. We can observe the occurrence of more cases with the presence of cellular edema and mitochondrial edema in the control group and cavopulmonary bypass group in relation to the biventricular group in the RV free

wall. The increased presence of cellular edema in the interventricular septum also observed in the control group and cavopulmonary bypass group, but was not significant from a statistical standpoint.

3A

3B

Fig 3 - Pressures of the left side of the heart.

3A. Mean Arterial Pressure (MAP); Values in mean ± standard error of the mean. 3B - Left Atrium Pressure (LAP); Values in mean ± standard error of the mean. Difference between groups: P=0.074

4A

4B

Fig. 4A - Right Ventricular Pressure (RVP) Values in mean ± standard error of the mean. Difference between groups: P = 0.341 4B. Central Venous Pressure (CVP) Values in mean ± standard error of the mean.

Difference between groups: P=0.043

Fig. 5 - Markers of the inflammatory response

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Santos LAS, et al. - Cavo-pulmonary anastomosis associated with left ventricular in comparison with biventricular circulatory support in acute heart failure

Table 3. Results of optical microscopy.

Cellular changes pattern Right ventricle Septum Left ventricle

Control

Bypass

Biventricular

Grade 0/+ (5) Grade ++ (1) Grade +++ (1) Grade 0/+ (3) Grade ++ (0) Grade +++ (4) Grade 0/+ (1) Grade ++ (2) Grade +++ (4)

Grau 0/+ (4) Grade ++ (1) Grade +++ (2) Grade 0/+ (1) Grade ++ (3) Grade +++ (3) Grade 0/+ (1) Grade ++ (2) Grade +++ (4)

Grade 0/+ (4) Grade ++ (2) Grade +++ (1) Grade 0/+ (5) Grade ++ (0) Grade +++ (2) Grade 0/+ (3) Grade ++ (0) Grade +++ (4)

P = 0.885 P = 0.053 P = 0.462

Numbers indicate the positive cases (total cases)

Table 4. Changes in electron microscopy.

Control Right ventricle Septum Left ventricle

6 (7) 6 (7) 2 (7)

Right ventricle Septum Left ventricle

2 (7) 4 (7) 2 (7)

Right ventricle Septum Left ventricle

0 (7) 2 (7) 1 (7)

Right ventricle Septum Left ventricle

0 (7) 2 (7) 0 (7)

Bypass Cellular edema 5 (7) 5 (7) 5 (7) Mitochondrial edema 4 (7) 2 (7) 2 (7) Electron-dense bodies 1 (7) 0 (7) 3 (7) Lise Myofibrillar 0 (7) 0 (7) 3 (7)

Biventricular 1 (7) 2 (7) 5 (7)

P=0.017 P=0.072 P=0.173

0 (7) 1 (7) 4 (7)

P=0.061 P=0.223 P=0.446

1 (7) 1 (7) 4 (7)

P=0.575 P=0.311 P=0.243

1 (7) 1 (7) 2 (7)

P=0.349 P=0.311 P=0.159

Numbers indicate the positive cases (total cases)

DISCUSSION The RV failure occurs in 13% to 44% of patients undergoing implantation of LVAD devices alone, being the major cause of postoperative mortality of this procedure [1]. The use of uni- or biventricular assistance is the key to therapeutic success in treating patients with heart failure [10,11]. However, it is difficult to predict who patients are at increased risk of developing RV failure, because there is no consensus on criteria for preoperative risk among these studies [10-12].

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Cavopulmonary anastomosis seems to be able to increase the effective pulmonary flow because volumetrically decompresses the RV, restoring its geometric shape [7,13].

There are clinical [8] and experimental [7,9] suggestions in the literature that the partial exclusion of the RV is beneficial in the treatment of right failure.

Danton et al. [9] demonstrated in an experimental model of acute myocardial infarction in pigs, the effectiveness of cavopulmonary anastomosis in RV decompression volume. Succi et al. [7] succeeded in demonstrating an experimental model in dogs that cavopulmonary

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Rev Bras Cir Cardiovasc 2012;27(4):552-61

anastomosis is able to provide adequate support to the RV, when combined with mechanical assistance to LV in biventricular failure. However, despite hemodynamic improvement evidenced in this study, the authors received major criticism for certain technical aspects, as the local drainage of the left system, which was performed by LA, the short time in which the animal was kept in failure (90 minutes), and questions about the choice of the use of continuous flow pumps and non-pulsatile flow.

In the present study, when the cavopulmonary anastomosis associated to LAVD was compared to LVAD alone, unlike the previous study, there was no significant hemodynamic improvement with the use of the method as compared to control, both being lower than the biventricular circulatory assistance. Perhaps technical changes in the performance of the cavopulmonary anastomosis, as the anastomosis in the pulmonary artery trunk and the use of synthetic tube instead of autologous tissue, have influenced results.

Classic cavopulmonary anastomosis already clinically demonstrated efficacy in the presence of circulatory support in a situation in which it was helpful in the case of a patient with biventricular assist weaning with the right circulatory support facilitated by such surgery [8].

The option of making the cavopulmonary anastomosis was modified motivated by technical difficulties in performing the classic form. As a result we chose to use the synthetic tube (PTFE No. 16), which, despite having adequate caliber, it is speculated that it has less complacency than the native tissue vena cava. Danton et al. [9] performed an experimental study of acute RV failure and obtained satisfactory decompression of this chamber, when performing cavopulmonary anastomosis using modified autologous inferior vena cava, demonstrating the effectiveness of the method to decompress the RV presenting acute failure.

Another factor to be considered is again the time, because even though the animals have been exposed in this study to VF twice as long compared to the protocol used previously in the study by Succi et al. [7], there was no significant hemodynamic deterioration during the period of observation, and so maybe cavopulmonary anastomosis decompression has not shown the expected hemodynamic efficacy.

It should also be highlighted the question, in the present study, the local chosen for left drainage was the LV, which is set as the default location for this type of assistance [14], perhaps contributing to the less pronounced hemodynamic failure observed in this model. The use of pigs in this experiment, instead of dogs, directly influenced the final outcome, because they are different species with different behavioral and physiological responses to trauma.

There are numerous causes of failure of Glenn' surgery, including variations in pulmonary artery pressure, and high

pulmonary vascular resistance among the major causes. In this sense there are recommendations, not consensual, to perform such surgery only in cases where the pulmonary artery pressure (PAP) is less than 18 mmHg, and ideally less than 15 mmHg, with pulmonary vascular resistance less than 2.0 Wood units [ 13]. In the present study, we used young animals without previous diseases, a fact that makes it unlikely that they have some kind of native pulmonary vascular disease. Furthermore, PAP was measured prior in all animals, which was within normal limits.

Moreover, it is known that the biventricular assistance is effective in decompressing the dilated RV, when it enters into failure and there are suggestions in the literature that such behavior should be instituted as early as possible in order to avoid irreversible damage to target organs [14,15]. However, despite the observed hemodynamic improvement, it is known that this type of assistance, despite the technological advances offered by new devices, it still remains high incidence of complications [7,14,16].

To that end, numerous studies are listed in an attempt to elucidate the criteria that could predict which patients are at higher risk of developing RV failure after the LVAD institution.

In the experimental model presented here, the circulatory support was instituted by centrifugal pump. This system is widely available in a specialized environment, has low cost, is easy to handle and there are several reports of successful clinical use in the literature. However, there are guidelines that its use should not be extended, because this type of assistance mechanism exacerbates the inflammatory response over time [17]. This statement is controversial and some studies claim that the low flow resulting from circulatory collapse, common at the time of institution of this kind of assistance would be primarily responsible for this exacerbation, and so successfully demonstrated that, after normalization of tissue perfusion obtained with assistance, there is decrease in inflammatory cytokines [18]. This observation corroborates the findings of this protocol, which showed no significant increase in inflammatory cytokines studied thus assuming that there was adequate tissue perfusion during the experiment.

Regarding the assessment of myocardial cells, it has been demonstrated in experimental model of infarction in pigs that irreversible ultrastructural lesions begin in just 15 minutes and that in 30 minutes, mitochondrial destruction occurs, thus characterizing cell death [19]. Moreover, it is widely accepted that during acute myocardial infarction myocardial ischemia propagates from subendocardial region to epicardial region, a phenomenon called â&#x20AC;&#x153;Wavefront Phenomenonâ&#x20AC;? [20]. It has also been shown the occurrence in dilated cardiomyopathy, early ultrastructural changes, characterized by degeneration of mitochondrial and myofibrillar lysis [21].

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Based on these concepts, samples collected from the subendocardial region of the RV, LV and septum were assessed under OM and EM. Under OM and EM, we observed decrease in the occurrence of cellular and mitochondrial swelling in the RV in the biventricular group. This fact can be explained by adequate drainage provided with such assistance, which decreases the chance of endocardial injury by increase of intracavity voltage.

The outcomes demonstrated in this study are subject to several limitations. Again, the short observation period can be considered the major limitation. Moreover, technical problems such as the assistance provided by centrifugal pumps and cannulae used in the experiments that were not manufactured for such purpose, may be greatly influenced the quality of the circulatory assist provided in the model. It is woth emphasizin that these are closer to the reality experienced by most specialized centers in our country. Functional evaluation methods, such as echocardiography, have their effective in assessing cardiac function in pigs proven in the literature and would be useful in this protocol [22]. In addition to these methods, it has recently been demonstrated that pulsatile flow pumps are as effective as the continuous flow pumps in relation to hemodynamic performance, but with less activation of part of the inflammatory system [23]. Another factor of great importance was the direct measurement of PAP, through which it would be possible to calculate pulmonary vascular resistance, which may have influenced the proper functioning of the cavopulmonary shunt.

The results of this study demonstrated that RV volumetric decompression through the cavopulmonary anastomosis modified in acute biventricular failure, while using LVAD mechanisms alone, was not superior than that observed by the institution of biventricular assistance and therefore should not be used as routine in surgical practice.

However, more studies are needed to define the use of biventricular assist as standard procedure in the presence of acute RV failure.

diameter ratio and prediction of right ventricular failure with continuous-flow left ventricular assist devices. J Heart Lung Transplant. 2011;30(1):64-9.

2. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATH) Study Group. Long-term use of left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):1435-43.

3. Kaul TK, Fields BL. Postoperative acute refractory right ventricular failure: incidence, pathogenesis, management and prognosis. Cardiovasc Surg. 2000;8(1):1-9.

4. Chen JM, Levin HR, Rose EA, Addonizio LJ, Landry DW, Sistino JJ, et al. Experience with right ventricular assist devices for perioperative right-sided circulatory failure. Ann Thorac Surg. 1996;61(1):305-10.

5. Hetzer R, Portner PM. Discussion of univentricular versus biventricular support. Ann Thorac Surg. 1996;61:357-8.

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9. Danton MH, Byrne JG, Flores KQ, Hsin M, Martin JS, Laurence RG, et al. Modified Glenn connection for acutely ischemic right ventricular failure reverses secondary left ventricular dysfuction. J Thorac Cardiovasc Surg.

2001;122(1):80-91.

10. Farrar DJ, Hill JD, Pennington DG, McBride LR, Holman WL, Kormos RL. Preoperative and postoperative comparison of patients with univentricular and bivaentricular support with the thoratec ventricular assist device as a bridge to cardiac transplantation. J Thorac Cardiovasc Surg.

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12. Fitzpatrick JR 3rd, Frederick JR, Hsu VM, Kozin ED, Oâ&#x20AC;&#x2122;Hara ML, Howell E, et al. Risk score derived from preoperative data analysis predicts the need for biventricular

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19. Spinale FG, Schulte BA, Crawford FA. Demonstration of early ischemic injury in porcine right ventricular myocardium. Am J Pathol. 1989;134(3):693-704.

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15. Fitzpatrick JR 3rd, Frederick JR, Hiesinger W, Hsu VM, McCormick RC, Kozin ED, et al. Early planned institution of biventricular mechanical circulatory support results in improved outcomes compared to delayed conversion of left ventricular assist device to a biventricular assist device. J Thorac Cardiovasc Surg. 2009;173(4):971-7.

21. Jindal N, Talwar KK, Chopra P. Ultraestructural and histological study of endomyocardial biopsies from patients of dilated cardiomyopathy: a comparative evaluation and their clinical correlation. Indian Heart J. 1994;46(6):329-34.

16. Genovese EA, Dew MA, Teuteberg JJ, Simon MA, Bhama JK, Bermudez CA, et al. Early adverse events as predictors of 1-year mortality during mechanical circulatory support. J Heart Lung Transplant. 2010;29(9):981-8.

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17. Pedemonte VO, Aránguiz Santander E, Torres HH, Merello NL, Vera PA, Díaz NR, et al. Asistecia ventricular derecha com bomba centrifuga. Rev Med Chile. 2008;136(3):359-66.

23. Loebe M, Koster A, Sänger S, Potapov EV, Kuppe H, Noon GP, et al. Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and pulsatile Novacor device.

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18. Hasper D, Hummel M, Kleber FX, Reindl I, Volk HD. Systemic

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):562-9

Clinical and functional capacity of patients with dilated cardiomyopathy after four years of transplantation Evolução clínica e capacidade funcional de pacientes com cardiomiopatia dilatada após quatro anos do transplante

Daniela Gardano Bucharles Mont'Alverne1, Lara Maia Galdino2, Marcela Cunha Pinheiro2, Cíntia Souto Levy3, Glauber Gean de Vasconcelos4, João David de Souza Neto5, Juan Alberto Cosquillo Mejía6 DOI: 10.5935/1678-9741.20120098

RBCCV 44205-1423

Abstract Objective: To evaluate patient with cardiomyopathy's progress after cardiac transplant, by analyzing his survival, complications and cardiovascular responses after nearly four years of surgery.

Methods: The survey was conducted from February to May 2011, with patients undergoing cardiac transplantation at Dr. Carlos Alberto Studart Gomes Hospital - Messejana Hospital (HDM). The sample consisted of all transplanted patients in 2007 in this hospital. Initially an evaluation form developed by the researchers, which was based on collected data from patients' medical records, was applied, about trans and postoperative period. After collecting these informations, patients underwent the six-minute walk test (6WT). The marks found in walking distance were compared with reference marks expected for this population by using Enright and Sherrill's equation.

Results: From all the 24 patients who underwent cardiac transplantation in HDM in 2007, 14 were evaluated and 10 were excluded. Regarding the complications, in the transoperatory period, the most evident was the right ventricular dysfunction (64.3%) and tachycardia (64.3%) was more evident on the postoperative period. Analyzing the 6WT it was observed a decrease of 11.6% in walking distance when compared with the estimated distance (486 ± 55 m, 550 ± 59 m, respectively).

Conclusion: Survival of heart transplant patients was equivalent to about 70%. The results of this study before the 6WT showed that patients' cardiovascular responses are below the estimated, nevertheless within the normal range established.

1. PhD in Sciences at University of São Paulo (USP), Head of the Research Division at University of Fortaleza (UNIFOR), Professor of the Physiotherapy Discipline at UNIFOR. (Head of the Research Division) – Adviser, Fortaleza, CE, Brazil.

2. Physiotherapist, Graduation at University of Fortaleza, Fortaleza, CE, Brasil.

3. Specialist in Cardiorespiratory Physiotherapy at University of Fortaleza, Fortaleza, CE, Brazil.

4. Specialist in Cardiology and Ergometry at Brazilian Society of Cardiology, Physician at Heart Transplantation and Insufficiency Unit at Messejana Hospital Dr. Carlos Alberto Studart Gomes, Fortaleza, CE, Brazil.

5. Specilist in Cardiology and Intensive Therapy. Teaching and Research Director and Coordinator at Heart Transplantation and Insufficiency Unit at Messejana Hospital Dr. Carlos Alberto Studart Gomes, Fortaleza, CE, Brazil.

6. Master's Degree in Medical Clinics at Federal University of Ceará, Surgical Coordinator at Heart Transplantation and Insufficiency Unit at Messejana Hospital Dr. Carlos Alberto Studart Gomes, Fortaleza, CE, Brazil.

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Descriptors: Cardiomyopathies. Cardiomyopathy, dilated.

Heart transplantation. Walking.

This study was carried out at Messejana Hospital Dr. Carlos Alberto Studart Gomes and University of Fortaleza, Fortaleza, CE, Brazil.

Correspondence address: Daniela Gardano Bucharles Mont'Alverne Rua Marcos Macedo, 1255/301 – Fortaleza, CE, Brazil. Zip code: 60150-190 E-mail: daniela.gardano@globo.com Article received on March 15th, 2012 Article accepted on September 5th, 2012

Mont'Alverne DGB, et al. - Clinical and functional capacity of patients with dilated cardiomyopathy after four years of transplantation

Abbreviations, acronyms and symbols IAC CPB RVD EF HDM

Intra-aortic balloon Cardiopulmonary bypass Right ventricular dysfunction Ejection Fraction Hospital de Messejana – Dr. Carlos Alberto Studart Gomes CHF Congestive heart failure BMI Body mass index CMP Cardiomyopathy LL Lower limbs NO Nitric oxide PO Postoperative SOLVD Studies Of Left Ventricular Dysfunction SIRS Systemic inflammatory response syndrome 6MWT Testing of the six-minute walk Tx Transplant

Resumo Objetivo: Avaliar a evolução do paciente miocardiopata após transplante (Tx) cardíaco, analisando sua sobrevida, complicações trans e pós-operatórias e respostas cardiovasculares após cerca de quatro anos do procedimento cirúrgico.

Métodos: A pesquisa foi realizada no período de fevereiro a maio de 2011, com pacientes submetidos a Tx cardíaco

INTRODUCTION The cardiomyopathies (CMP) are a group of diseases associated with mechanical and/or electrical myocardial dysfunction. This disorder is often accompanied by dilation or inappropriate ventricular hypertrophy and heart failure [1]. Patients with this impairment may progress to progressive heart failure that consequently can lead to death of cardiovascular origin or physical disability [2].

When the CMP reaches an advanced stage of heart failure (NYHA functional classes III and IV), cardiac transplantation (Tx) becomes a form of treatment able to restore hemodynamic function, improve quality of life and survival of patients with return to functional class I [3].

Therefore, it is indicated for patients whose symptoms do not respond to drug therapies or other means of surgical repair [4].

The heart Tx, being a major surgery, can cause several complications. Among them we can highlight

Rev Bras Cir Cardiovasc 2012;27(4):562-9

no Hospital Dr. Carlos Alberto Studart Gomes - Hospital de Messejana (HDM). A amostra foi composta de todos os pacientes transplantados no ano de 2007 no referido hospital.

Inicialmente, foi aplicada uma ficha de avaliação, coletando dados dos prontuários, sobre a evolução do paciente no período trans e pós-operatório até a alta hospitalar. Após a coleta dessas informações, os pacientes foram submetidos ao teste da caminhada dos seis minutos (TC6). Os valores encontrados na distância percorrida foram comparados aos valores de referência esperados para a população utilizando a equação de Enright e Sherrill.

Resultados: Do total de 24 pacientes que realizaram Tx cardíaco no HDM no ano de 2007, 14 foram avaliados e 10 excluídos do estudo. Com relação às complicações, no período transoperatório, a mais evidenciada foi a disfunção do ventrículo direito (64,3%) e, no pós-operatório, quadro de taquicardia (64,3%). Analisando o TC6 observou-se diminuição de 11,6% na distância percorrida quando comparada à distância estimada (486 ± 55 m, 550 ± 59 m, respectivamente).

Conclusão: Os resultados obtidos neste estudo perante o TC6 evidenciam que as respostas cardiovasculares dos pacientes avaliados estão abaixo do estimado, contudo dentro da faixa de normalidade estabelecida.

Descritores: Cardiomiopatias. Cardiomiopatia dilatada.

Transplante de coração. Caminhada.

bleeding and gas, coronary or systemic embolism through maneuvers to remove air from the cardiac chambers, initially inefficient (reperfusion). Additionally, there may be changes resulting from prolonged cardiopulmonary bypass (CPB) as hypotension, decreased cardiac output, coagulation disorders, dysfunction of pulmonary mechanics, immunological rejection, graft failure for countless reasons, among others [5,6].

The graft failure from different causes is considered the leading cause of death postoperatively (PO) and the Tx, in the immediate phase, predominates nosocomial infections associated with intraoperative contamination; later, opportunistic infections are common. Another major cause of early mortality is the right ventricular dysfunction in the immediate postoperative period, which constitutes 50% of all complications [6,7].

In Tx surgery, the donor's heart is completely disconnected from the sympathetic and parasympathetic innervation, and heart denervation is a complication 563

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of the immediate postoperative period, on which bradyarrhythmias are observed. Arterial hypertension is also common after the Tx and affects 50% to 95% of the receptors due to the use of cyclosporine. Rejection episodes, a result from immune response of the recipient to the donor heart are more frequent and severe in the first few months after Tx, becoming more sporadic and benign later [8].

Regarding quality of life after heart Tx, most patients return to their normal activities and work, with few restrictions, leaving virtually no dyspnea on exertion (NYHA functional class I). Some studies have compared the quality of life of patients before and after cardiac Tx, showing that the procedure's success means not only ensuring the improvement of symptoms and survival of patients in end-stage heart disease, but allow them to achieve good levels of ability and physical quality of life [9-11].

After the clinical indication of cardiac Tx for cardiomyopathic patients, the therapeutic follow in the pre-transplant is delicate and expensive and assessments and monitoring of functional capacity on a regular basis should be performed. The cardiopulmonary assessment is the most accurate method, but its periodic execution is difficult, thus impeding a possible more detailed control of the patient who is in severe conditions [12].

However, the test of the six-minute walk test (6MWT) may be indicated as an alternative exercise tolerance assessment, which is a simplified, reproducible, inexpensive and easy to apply, and may provide clues as to the clinical stage, response to interventions, functional capacity, cardiorespiratory fitness, functional class, cardiovascular prognosis and quality of life [12].

Moreover, the kind of effort required by the test can be considered as a submaximal test, since it resembles more the daily activities than a maximal test [13].

Since 1980, there has been a growth in the use of the 6MWT in clinical practice, especially in heart failure. In the SOLVD study (Studies of Left Ventricular Dysfunction), the distance walked during six minutes was identified as independent variable and indicator of mortality and morbidity in patients with heart failure functional class II and III [13]. The emergence of this study allowed several correlations and better understanding of the 6MWT value [14].

Due to all the complications arising from a patient after cardiac Tx, the importance of this study is related to the improvement of care for these patients, once identified major complications in the postoperative period and the later patient's functional condition, most effective techniques can be used to minimize these complications in other cases. Thus, the aim of this research was to assess the patient's cardiac Tx myocardiopathy after assessing

their survival, trans- and postoperative complications and cardiovascular responses after about 4 years of surgery.

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METHODS We performed quantitative, cohort and retrospective cross-sectional study from February to May 2011, with patients undergoing cardiac Tx in Messejana Hospital - Dr. Carlos Alberto Studart Gomes (HDM), in Fortaleza, CE. This study was approved by the Ethics Committee of the institution (Report No. 104/2011) and followed the ethical principles according to Resolution 196/96 of the National Health Council, which established the principles for research involving human subjects [15], and all of participants signed a written informed consent.

The sample was composed of all patients transplanted in 2007 in that hospital. Inclusion criteria were considered: age above 18 years, regardless of gender, preoperative diagnosis of CMP progressing to heart failure functional class IV, having performed the cardiac Tx in 2007, presenting conditions and willingness to cooperate voluntarily with the study.

The study excluded transplanted patients who were in hemodynamically unstable condition in the period of data collection, defined by use of vasoactive drugs intravenously, and therefore in hospital, those with motor or neurological sequel that hindered the march and those who died up to the research.

Initially, we applied an assessment form developed by the researchers based on data collected from medical records of patients transplanted in HDM in 2007. This form contained items such as gender, age, weight, height, body mass index (BMI), duration of CPB, preoperative diagnosis, ejection fraction (EF) previous intraoperative impairments, postoperative impairments, age, donor's gender, donor/recipient weight ratio and ischemia time. We also collected information regarding the immunosuppression regimen and pulmonary vascular resistance.

After collecting this information, patients underwent the 6MWT according to the protocol recommended

by Ferreira et al. [16]. The parameters measured were distance, Borg scale of dyspnea and lower limb (LL) at rest and after six minutes of the test. The values found on the distance traveled were compared to reference values for the expected population using the Enright & Sherrill equation [17].

Demographic and surgical characteristics Of the total 24 patients who underwent cardiac Tx in HDM in 2007, 14 were assessed and 10 were excluded from the study, and two were hemodynamically unstable, one was younger than 18 years and seven died. Of these,

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three died in the immediate postoperative period, a 5 months after surgery due to rejection presentation and three after 1, 2 and 3 years of surgery, respectively, in the heart failure presentation. Among those assessed, 12 were male and 2 female, mean age 55 ± 11 years, weight 71 ± 12 kg, height of 1.66 ± 0.05 m and BMI 25 ± 4 kg/m².

The patients presented a mean left ventricular EF before Tx of 23±4%. The preoperative diagnosis of the study participants ranged in three types of dilated CMP: idiopathic (nine patients), ischemic (three patients) and Chagas' disease (two patients). Regarding the donors' gender, 12 were male and only two female and presented a mean age of 32 ± 8 years. All recipients had pulmonary vascular resistance less than 5 wood after test drug (sodium nitroprusside or inhaled nitric oxide), a criteria used for this transplant indication.

The weight ratio between the donor and recipient was 1.1 ± 0.5. The CPB time during Tx averaged from 157 ± 36 minutes and the period of ischemia ranged from 20 to 69 minutes, with a mean of 46 ± 12 minutes.

The immunosuppression regimen used in the hospital was Cyclosporin A (dose guided by cyclosporin), mycophenolate mofetil (720 mg/day) and prednisone.

During the assessment of patients (4 years after transplantation), medication remained the same excepted by prednisone.

Data were assessed using descriptive statistics with mean values, standard deviations and percentage through the SPSS statistical software, version 16.0. For inferential statistics we used the paired Student's t test when observed sample normality. In the variables that did not show normal distribution we applied the Mann-Whitney test for data normalization. We considered statistically significant when P < 0.05.

Table 1. Surgical complications of 14 assessed transplanted patients Complications Total number (%) 9 (64.3%) Right ventricular dysfunction Use of nitric oxide 5 (35.7%) 1 (7.1%) Left ventricular dysfunction Difficult to disconnect CPB 2 (14.3%) Bleeding during CPB disconnection 3(21.4%) 2 (14.3%) Hypertension Hypotension 2 (14.3%) Temporary pacemaker 2 (14.3%) 1 (7.1%) SIRS Cardiorespiratory arrest 1 (7.1%) 1 (7.1%) Total atrioventricular block

RESULTS Surgical complications The patients presented as more frequent intraoperative complication right ventricular dysfunction (RVD), nine (64.3%) patients with this complication, of which five (35.7%) used nitric oxide (NO), and only one (7.1%) had left ventricular dysfunction, under use of dobutamine.

These changes were diagnosed by direct visualization of the organ and confirmed by measurement of pulmonary artery pressure using Swan-Ganz catheter. Two (14.3%) patients had difficulty to be disconnected from CPB and three (21.4%) had bleeding during disconnection. Two patients had hypertension and two hypotension, two required a temporary pacemaker, one had a systemic inflammatory response syndrome (SIRS), one had cardiac arrest, one had complete atrioventricular block and only one patient had no intraoperative complication, as described in Table 1.

Postoperative Complications All patients had postoperative complications, such as tachycardia, abnormal sensory level, low-output presentation, pericardial effusion, sudden bradycardia, congestive heart failure (CHF), hypotension, hypertension, use of intra-aortic balloon (IAB), thrombocytopenia, rejection, sepsis, reoperation for bleeding (exploratory mediastinostomy), and renal dysfunction requiring hemodialysis (Table 2).

Table 2. Postoperative complications of 14 assessed transplanted patients Total number (%) Complications 9 (64.3%) Tachycardia 4 (28.6%) Sensorimotor level change 1 (7.1%) Low cardiac output 7 (50%) Pericardial effusion 1 (7.1%) Sudden bradycardia Congestive heart failure (CHF) 2 (14.3%) Hypotension 7 (50%) 3 (21.4%) Hypertension 1 (7.1%) Intraórtico balloon (IAB) 3 (21.4%) Thrombocytopenia 2 (14.3%) Rejection Reoperation for bleeding 2 (14.3%) Sepsis 1 (7.1%) 3 (21.4%) Renal failure Hemodialysis 1 (7.1%) Table 3. Postoperative respiratory complications of 14 assessed transplanted patients Complications Total number (%) Pleural effusion 6 (42.9%) Atelectasis 8 (57.1%) Respiratory infection 2 (14.3%) Pulmonary infarction 1 (7.1%) Respiratory failure 3 (21.4%) Reintubation 2 (14.3%)

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Some patients also had pulmonary complications, such as pleural effusion, atelectasis, respiratory infection, pulmonary infarction, respiratory failure and reintubation, as shown in Table 3.

increased CPB time, over 120 minutes, compared to other transplanted.

In this research, the RVD was also the complication that had the highest percentage (64.3%) of all complications in the immediate postoperative period. Of the nine (64.3%) patients with RVD, five (55.5%) made use of vasodilator therapy with NO and all of these also had a prolonged cardiopulmonary bypass time, over 120 minutes, which explains such complications.

Many factors during CPB, as the exposure of blood to nonphysiologic conditions and surfaces and the increase of pulsatile flow in a continuous stream, results in the development of SIRS [20]. This limited biocompatibility of materials causes multiorgan dysfunction after systemic perfusion, expressed by myocardial depression, vasomotor dysfunction, respiratory, renal and hepatic failure, cognitive imbalance and of thermal regulation for coagulopathy for bleeding, which characterizes the SIRS. It is the cause of mortality of CPB, manifesting in different degrees and in different organs, and its greatest manifestations affecting the heart and lungs [21]. All these factors may explain the occurrence of the various postoperative complications found in this study.

The distribution of the incidence of infectious processes follows the curve of rejection, being more frequent and more severe in the first few months after Tx, because in this phase the immunosuppression is more intense [3].

Despite advances in immunosuppressive therapy in the last decade, the acute cellular rejection of the transplanted heart remains an important factor associated with longterm morbidity and mortality [22].

Among the later complications such as rejection and infection, those related to graft vascular disease or side effects of immunosuppressive agents can affect the functioning of the kidneys and liver and increase blood pressure. In the study by Moraes Neto et al. [23] they observed that, of the 35 heart transplant patients followed up, seven (20%) died in the immediate postoperative period and thirteen (37.1%) had non-fatal complications, including rejection (five cases), infection ( four cases), renal failure requiring hemodialysis (four cases) and bleeding requiring surgical exploration (three cases).

In this study, the results were similar: it was found that, of 24 heart transplant patients in HDM in 2007, seven (29%) died and fourteen (58.3%) had non-fatal complications such as rejection (two cases), respiratory infection (three cases), acute renal failure (three cases, one of whom required hemodialysis) and reoperation for bleeding (two cases).

Six-minute walk test Assessing the 6MWT we observed a decrease of 11.6% in distance traveled when compared to estimated distance calculated using the Enright & Sherrill equation [17] (486 ± 55 m and 550 ± 59 m, respectively), considered a statistically significant result (P = 0.011).

In assssing the Borg scale of lower limbs, it was found that there was a change, with an increase of 69.2% compared with the rest of the test's 6 minutes (0.4 ± 0.7 and 1.3 ± 1, respectively), presenting, therefore, statistical significance (P = 0.016).

In Borg scale of dyspnea we also observed changes, with an increase of 85.7% when compared with the rest of the test's 6 minutes (0.2 ± 0.7 and 1.4 ± 1.2, respectively), with statistical significance (P = 0.004).

Regarding the SOLVD study, the average of the results obtained with the 6MWD was 3.6 ± 0.4, and all patients achieved level 3 or 4, classifying them as functional class I or II. DISCUSSION The life expectancy of heart transplant patients has improved considerably, due to the very favorable results of cardiac Tx in recent years, with current survival rate of 80%, 70% and 60% at one, five and ten years, respectively [18]. This study corroborates this estimate, once found the value of 70.8% survival after approximately four years of cardiac Tx. Among the complications in the immediate postoperative period of cardiac Tx, the pulmonary hypertensive crisis and RVD are secondary to this concern, since they have high percentage (50%), which can lead to high mortality and decreased life of the graft.

In more severe cases, when there is no adequate response to therapy employed and persistence of severe pulmonary hypertensive crisis, NO inhalation is used because it is a selective pulmonary vasodilator. This gas aims at reducing pulmonary arterial pressure and hence improve the right ventricle performance [19].

In the study by Mejia et al. [19], they used the NO in a group of five cardiac transplant patients who had pulmonary hypertensive crisis and RVD and who have not responded well to the therapy. They identified in the group 566

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The postoperative pulmonary complications are factors that contribute to morbidity and mortality in any type of upper abdominal or thoracic surgery. Respiratory insufficiency in the PO can be triggered by anesthesia and central nervous system depression caused by it, by ineffectiveness of coughing, by limiting the ventilation due to pain and the use of prosthetic mechanical ventilation [24].

With a common history of cardiac Tx in 2007 and preoperative diagnosis of CMP progressing to heart failure functional class IV, subjects in the study showed significant improvement in cardiovascular function, assessed from the 6MWT outcomes, currently focusing on functional classes I and II (mean 3.6 ± 0.4 as the level of the SOLVD study).

The SOLVD study was the first to demonstrate a strong correlation between the 6MWT and mortality. With the assessment of 898 patients with left ventricular dysfunction or radiological evidence of pulmonary congestion with a median follow-up of 242 days, a substudy of SOLVD group showed that mortality was 10.23% in patients who walked less than 350 m in the 6MWT (level 2), compared with 2.99% (P < 0.01) of patients who walked more than 450 m in the test (level 4) [25].

Similarly, the study by Cipriano Júnior et al. [12] used the 6MWT in pre-heart transplant assessment, in which the analysis of the relationship between the 6MWT and clinical staging and cardiovascular prognosis primarily revealed that, despite belonging to an apparently homogenous group, both also now eligible for Tx heart they had a functional capacity, estimated by the distance traveled, very diverse, mainly for four patients who traveled a distance less than 300 meters [26].

Enright & Sherrill [17] proposed a reference equation for healthy individuals to predict 6MWD, considering variables such as age, gender, weight and height.

However, there are few studies that verify the degree of deconditioning when compromising physical performance of transplanted heart individuals.

Regarding the distances traveled and predicted, this study observed difference between them for cardiac transplant patients. However, although this difference was statistically significant (P = 0.011), the mean distance (486 ± 55 m) was found within the range of normality established by equation (mean of 399 ± 69 m), or that is, patients walked 21.8% above the lower limit defined as normal according to the calculation provided by Enright & Sherrill [17].

As expected, the results of the lower limbs and dyspnea Borg scale suffered increased when compared the rest with

six minutes of the test, with both statistical significance (P = 0.016 and P = 0.004, respectively). However, this increase is not enough to be of clinical significance, ranging from just extremely lightweight for something between very light and mild on the scale of the lower limbs, and something between none and extremely lightweight for something between very light and mild in dyspnea scale.

The post-heart transplant patients have better quality of life. But also often have physical deconditioning, muscle weakness and atrophy and lower aerobic capacity [27]. Regular physical activity plays an important posttransplant role and should be started early to restore physical capacity, enabling transplanted patients back to perform most of their daily activities and also recreation.

When implementing a basic program of mobilization and respiratory therapy, cardiac transplant patients were able to retrieve the values of lung volumes and capacities and improve the useful functional capacity [28].

Recently, studies have demonstrated the usefulness of TC6 in the Tx area of solid organ, and the outcomes of the studies varied. The organ Tx is the ideal intervention for various terminal diseases that affect multiple organs such as the heart, lungs, kidneys, pancreas and liver. Although transplant patients may survive the surgery, all have reduced ability to exercise. Even as a submaximal exercise test, 6MWT assists in making the most appropriate therapeutic measures[24]. Moreover, it presents itself as a promising tool in the field of medical research, so Tx experts should also be aware of its both pre- and postoperatively advantages [29].

Although the present study has covered all heart transplant patients in HDM in 2007, taking into account the exclusion criteria, it was limited by the number of participating patients, so that the population assessed corresponded to a total of 58.3% of all patients transplanted in 2007 in that hospital. It is known that this might have favored or not the results.

Thus, it is believed that further studies should be performed with this profile of patients in the future, so they can have their increased survival with improved quality of life. For this, it is necessary to implement a cardiac rehabilitation program in our State as early as possible.

CONCLUSION A further evident complication in the perioperative period was right ventricular dysfunction, and the most frequently observed postoperatively, was tachycardia. The test results of submaximal functional capacity as assessed 567

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by the 6MWT, after four years of transplantation are lower than estimated, but within the normal established range.

9. Stolf NAG, Sadala MLA. Os significados de ter o coração transplantado: a experiência dos pacientes. Rev Bras Cir Cardiovasc. 2006;21(3):314-23.

THANKS Our sincere thanks to the staff of the Pulmonary Rehabilitation team and the secretary of the department of Cardiac Transplantation of Messejana Hospital, Antônio Igor Sobral de Andrade, by the promptness and all the support during the data collection for this study.

10. Paris W, White-Williams C. Social adaptation after cardiothoracic transplantation: a review of the literature. J Cardiovasc Nurs. 2005;20(5 Suppl):S67-73.

11. De Vito Dabbs A, Dew MA, Stilley CS, Manzetti J, Zullo T, McCurry KR, et al. Psychosocial vulnerability, physical symptoms and physical impairment after lung and heart lung transplantation. J Heart Lung Transplant.

2003;22(11):1268-75.

12. Cipriano Júnior G, Yuri D, Bernardelli GF, Mair V, Buffolo E, Branco JNR. Avaliação da segurança do teste de caminhada dos 6 minutos em pacientes no pré-transplante cardíaco. Arq Bras Cardiol. 2009;92(4):312-9.

13. Rubim VSM, Neto CD, Romeo JLM, Montera MW. Valor prognóstico do teste de caminhada de seis minutos na insuficiência cardíaca. Arq Bras Cardiol. 2006;86(2):120-5.

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2. Matsubara BB, Barreto ACP. Cardiomiopatias. In: Serrano Júnior CV, Timerman A, Stefanini E, eds. Tratado de cardiologia SOCESP. Vol.1. 2ª ed. Barueri: Manole;2009. p.1133-4.

3. Fiorelli AI, Coelho GHB, Oliveira Júnior JL, Oliveira SA. Insuficiência cardíaca e transplante cardíaco. Rev Med. 2008;87(2):105-20.

4. Costa S, Guerra MP. O luto no transplantado cardíaco. Psic Saúde Doenças. 2009;10(1):49-55.

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7. Meija JAC, Pinto Júnior VC, Barroso HB, Mesquita FA, Carvalho Júnior W, Castelo JMB, et al. Baixas doses de óxido nítrico na seleção dos pacientes candidatos a transplante cardíaco com hipertensão pulmonar. Rev Bras Cir Cardiovasc.

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18. Carlos DMO, França FCQ, Sousa Neto JD, Silva CAB. Impacto da variabilidade de peso na estabilidade metabólica dos pacientes transplantados cardíacos no Ceará. Arq Bras Cardiol. 2008;90(4):293-8.

19. Mejia JAC, Souza Neto JD, Carvalho Jr W, Pinto Jr VC, Mesquita FA, Brasil HB, et al. Uso do óxido nítrico inalatório no tratamento da crise hipertensiva pulmonar no pósoperatório de transplante cardíaco. Rev Bras Cir Cardiovasc.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):570-82

Minimally invasive aortic valve replacement: an alternative to the conventional technique Troca valvar aórtica minimamente invasiva: uma alternativa à técnica convencional

Jeronimo Antonio Fortunato Júnior1, Alexandre Gabelha Fernandes2, Jeferson Roberto Sesca2, Rogério Paludo3, Maria Evangelista Paz4, Luciana Paludo5, Marcelo Luiz Pereira6, Amélia Araujo7

DOI: 10.5935/1678-9741.20120099

RBCCV 44205-1424

Abstract Objectives: To demonstrate the use of minimally invasive surgery for aortic valve replacement and compare its results with the traditional method.

Methods: Between 2006 and 2011 sixty patients underwent surgery on aortic valve, after written consent, 40 of them by minimally invasive technique with right anterior minithoracotomy access (Group 1/G1) and 20 by median sternotomy (Group 2/G2). Compare the operating times and postoperative evolution intra-hospital.

Results: The average times of bypass and aortic crossclamp in G1 were, respectively, 142.7 ± 59.5 min and 88.6 ± 31.5 min and, in G2, 98.1 ± 39.1 min and 67.7 ± 26.2 min (P < 0.05), a difference in medians of 39 minutes in bypass time and 23 minutes in aortic cross-clamp were observed in favor

of conventional technique. The blood loss by the thoracic drains was significantly lower in the Group: minimally invasive 605.1 ± 679.5 ml (G1) versus 1617 ± 1390 ml (G2) (P < 0.05).The average time of ICU and hospital stay were shorter in G1: 2.3 ± 1.8 and 5.5 ± 5.4 days versus 5.1 ± 3.6 and 10 ± 5.1 in G2 (P < 0.05), respectively. Vasoactive drug use was also less post-operative at 12.8% in minimally invasive group G1 versus 45% in G2.

Conclusion: Aortic valve replacement through minimally invasive techniques, although intraoperative times larger, did not demonstrate to affect postoperative results in this case proved to be better when compared to the traditional approach.

1. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University, Cardiac surgeon, Master of Surgery, Professor of Cardiovascular and Thoracic Surgery at Positivo University. Demonstration of an alternative technique to conventional cardiac surgery.

2. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University; Heart Surgery Resident.

3. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University; Perfusionist.

4. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University; Surgical instrumentator.

5. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University; Anesthesiologist.

6. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University; Assistant surgeon.

7. Brazilian Red Cross Hospital – (branch of Paraná) Positivo University; Cardiologist. Responsible for the pre- and postoperative follow-up period.

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Descriptors: Surgical procedures, minimally invasive.

Aortic valve/surgery. Heart valve diseases.

Work performed at the Brazilian Red Cross Hospital Brazilian (branch of Paraná) / Positivo University, Curitiba, Paraná, Brazil.

Correspondence Address: Jeronimo Antonio Fortunato Jr. 50 Amaury GG Matei Street, Santo Inácio - Curitiba, Paraná Brazil – Zip code: 82010-620.

E-mail: jfjunior@uol.com.br Article received on May 9th, 2012 Article accepted on October 3rd, 2012

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Fortunato Júnior JA, et al. - Minimally invasive aortic valve replacement: an alternative to the conventional technique

Abbreviations, acronyms and symbols CVA Cerebrovascular accident BIS Bispectral index MICS Minimally invasive cardiac surgery ECC Extracorporeal circulation G1 Group 1 G2 Group 2 HTK Histidine-tryptophan-ketoglutarate Min Minutes CVP Central venous pressure TEE Transesophageal echocardiography ICU Intensive Care Unit

Resumo Objetivo: Demonstrar o uso da cirurgia minimamente invasiva para tratamento da valva aórtica e comparar seus resultados com o método tradicional.

Métodos: Entre 2006 e 2011, 60 pacientes foram submetidos à cirurgia na valva aórtica, após consentimento escrito, destes 40 pela técnica minimamente invasiva com acesso por minitoracotomia ântero-lateral direita (Grupo 1/G1)e 20 por esternotomia mediana (Grupo 2/G2). Comparamos os tempos operatórios e a evolução pós-operatória intra-hospitalar.

INTRODUCTION The minimally invasive cardiac surgery (MICS) has increased in popularity over the past 15 years. The small incisions have been associated with good aesthetic result and less surgical trauma, consequently less pain and rapid postoperative recovery. For a while, these same arguments will not attract the attention of the physician population. This concept has been changing with the wider dissemination of the technique and best results in recent reports. The benefits of minimally invasive incisions are supported primarily with confirmation of reduction of hospital costs without harming the achieved results with median sternotomy [1-3].

Also in recent years, using access alternative, the percutaneous or transapical aortic valve and endovascular devices was developed, including aortic stenting and even annular ring reducers for mitral valve and devices for occlusion of interatrial or interventricular defects [4 - 8].

Nevertheless, the median sternotomy is still the traditional access to surgical treatment of heart disease because it allows excellent control of all cardiac structures and asserts itself as a safe technique with low morbimortality.

Resultados: Os tempos médios de circulação extracorpórea (CEC) e pinçamento aórtico no G1 foram, respectivamente, 142,7 ± 59,5 min e 88,6 ± 31,5 min e, no G2, 98,1 ± 39,1 min e 67,7 ± 26,2 min (P<0,05), uma diferença nas medianas de 39 minutos no tempo de CEC e 23 minutos no pinçamento aórtico foram observados a favor da técnica convencional. A perda sanguínea pelos drenos torácicos foi significativamente menor no grupo minimamente invasivo: 605,1 ± 679,5 ml (G1) versus 1617 ± 1390 ml (G2) (P<0,05). Os tempos médios de internamento em UTI e hospitalar foram menores em G1: 2,3 ± 1,8 dias e 5,5 ± 5,4 dias versus 5,1 ± 3,6 dias e 10 ± 5,1 dias em G2 (P<0,05), respectivamente. O uso de drogas vasoativas no pós-operatório também foi menor no grupo minimamente invasivo 12,8% em G1 versus 45% em G2.

Conclusão: Troca valvar aórtica com o uso de técnicas minimamente invasivas, apesar de demonstrar maiores tempos intraoperatórios, não afeta os resultados pósoperatórios, que nesta casuística mostraram-se melhores quando comparado ao método tradicional.

Descritores: Procedimentos cirúrgicos minimamente invasivos. Valva aórtica/cirurgia. Doenças das valvas cardíacas.

Our goal is to demonstrate the use of minimally invasive surgery for the treatment of aortic valve and compare its results with the conventional technique (median sternotomy).

METHODS This is a retrospective study and gathered all patients undergoing aortic valve surgery in the period from 2006 to 2011. Sixty patients underwent valve surgery, 40 of them by the minimally invasive technique and preferably with access the via right anterolateral thoracotomy (Group 1/G1) and 20 by median sternotomy (Group 2/G2). The preoperative clinical characteristics are described in Table 1. In selecting the data in Table 1, the presentation of the predominant aortic valve dysfunction was chosen: stenosis or insufficiency that defined the clinical and surgical indication, either by transvalvular gradient or aortic regurgitation on echocardiography.

Exclusion criteria for a minimally invasive procedure included: reoperation, need for concomitant CABG or patients who opted for the conventional technique. All patients in G1 signed authorization for the alternative procedure.

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Table 1. Preoperative clinical characteristics of surgical groups Variables Minimally invasive access Male sex 30/75% 52.4±15.1 Age 60.5±9.3 Ejection fraction Hypertension 27/67.5% Diabetes 2/5% Preoperative atrial fibrillation 5/12.5% Predominant valvular dysfunction 19/47.5% Failure Stenosis 21/52.5%

Median sternotomy 15/75% 58.6±14.3 55.4±11.8 16/80% 3/15% 3/15%

P-value Ns Ns Ns Ns Ns Ns

6/30.0% 14/70%

Ns Ns

Ns = not significant

Echocardiographic evaluation, coronariography and carotid artery Doppler were performed in all patients, while peripheral vascular Doppler and abdominal aorta only in patients undergoing cardiopulmonary bypass (CPB) and Peripheral circulation (G1).

All patients in this series underwent specific protocol for anesthesia, used systematically in the institution, with the intention of immediate extubation in the operating room. The technique used a device for continuous electroencephalogram analysis (BIS®), calculating the bispectral index to assess the depth of anesthesia and its superficialization at the end of the surgery. Ramifentanil® and propofol® were used. Patients with the following characteristics were extubated in the operating room: BIS above 60, level of responsive awareness, adequate pulmonary ventilation and hemodynamic stability in average time of 15 to 30 minutes (min) after skin suture.

In G1, a right minithoracotomy was performed (± 5 cm) on the 2nd or 3rd right intercostal space or upper J-shaped ministernotomy. The peripheral CPB was performed by the femoral vessels [9,10] to all G1 procedures which were performed with the aid of chest videoscopy.

In peripheral CPB, a manometer was used with negative pressure for vacuum-assisted venous drainage.

The arterial femoral cannulation (17 French) and venous kiys (21 French) especially designed for peripheral CPB, were used in all these cases (DLP®, Medtronic Inc., Minneapolis, USA).

Intermittent cold blood cardioplegia was performed in aortic root or the coronary ostia, in the first 20 cases of G1 and G2. In the last 20 of G1, histidine-tryptophanketoglutarate (HTK) or commercially known as Custodiol® in infusion of 20 ml/kg body weight was used in a single dose.

Transesophageal echocardiography (TEE) was performed in all patients in G1, both for introduction of arterial and venous cannulae as monitoring and 572

confirmation of the surgical outcome.

The instruments used in G1 involving a 5mm or 10mm diameter thoracoscope according to the need of the visual field and angle lens of 30°. The instruments (ESTECH® Inc, California, USA) specifically designed for cardiac surgery included: chest retractor, scissors, knot pushers, aortic clamp (Chitwood®), and needle holders. Other instruments such as forceps, electrocautery, video cameras and light source were the same ones used in conventional laparoscopy.

In G2, a median sternotomy was performed with CPB and cannulation of the aorta and right atrium, both by the conventional technique. Transthoracic clamping and intermittent blood cardioplegia were performed in all patients.

Surgical technique for minimally invasive access 1. In all cases from G1, an orotracheal intubation with Carlens® or Portecs® cannulae was performed, for occlusion of the right lung during surgery. In cases of ministernotomy, where right pleuron was not openned, this occlusion was not necessary.

2. After cannula insertion, and effective right unilateral occlusion was guaranteed and also maintaining oxygenation with a single lung.

3. Central vessel puncture, jugular or subclavian infusion of drugs and monitoring of central venous pressure (CVP). The punction was preferable on the right side, as pneumothorax as a complication, which was not diagnosed on the left side could be very serious and prevent occlusion of the right lung.

4. We used as a routine a protocol for immediate extubation in the operating room. The combination of Propofol® and Ramifentanil® was used and the depth of anesthesia was assessed by bispectral index (BIS).

5. Transthoracic defibrillation pads were placed in the left, anterior and posterior thoracic region.

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6. CPB was set up in a conventional manner, testing the vacuum system through a negative pressure gauge connected to the oxygenator venous reservoir. This test was done during the circuit filling and removal of bubbles.

Variations from 40 to 100 mmHg were used to allow adequate venous drainage.

7. We dissected the left femoral artery and punctured the right femoral vein, even before heparinization (Figure 1). The CPB tubes were directed to the surgical field, positioned under the lower limbs.

8. The right anterolateral minithoracotomy was used in patients with severe aortic insufficiency or stenosis with small or moderate calcification. We performed a right sternal incision extending laterally with 5 cm in length; the intercostal space was incised until we could observe the right mammary artery.

The 2nd intercostal space was accessed in short patients with small chest on chest radiograph and the 3rd intercostal space in the other patients (Figure 2).

9. Upper J-shaped ministernotomy was used marking the 3rd intercostal space and performing an incision of 5 cm, which began at this point, following the cranial direction. Sternotomy was performed from the sternal furcula to the 3rd intercostal space to the right, trying not to affect the right mammary artery. This last access was used in all patients with severe valvular and ring calcification (Figure 3).

10. Video-assisted thoracoscopy was used in all patients, being introduced in the 2nd intercostal space, laterally to the thoracic incision, either by anterolateral mini-thoracotomy or ministernotomy. This display option has expanded the visual field and helped visualization and cannulation of the right coronary ostium in cases of ostial cardioplegia, the observation of the left ventricle in cases of distension of this cavity (cardioplegia in the aortic root) and in the visualization and cleaning the interior of the left ventricle in search of debris or calcium emboli (Figure 4).

11. A ESTECH速 retractor thoracic with a 4 cm single metal blade was used for exposure of the cavity in both alternative techniques. The "Finochietto" pediatric retractor was used as a good option in some cases, but the size of the short blades prevented from more routine use.

12. We followed the dissection and the identification of the pericardium. The pericardium was opened on the ascending aorta from the pericardial deflection to the right atrium. Exposure points were used to keep the pericardium open and pulled the chest wall.

13. After heparinization, cannulation of the femoral vessels was performed, primarily through the right femoral vein, once punctured; we introduced a rigid metal tab that progressed to the right atrium, confirmed by TEE. Dilators were introduced sequentially to dilate the vessel until the cannula, with occlusive dilator, was introduced to the right atrium, again with the need to ensure its position with TEE. After the venous cannula was positioned, we fixed it to the skin and connected it to the CPB venous tube.

14. The same procedure was done with the arterial cannulation, only in this case, the progression of the cannula reached its maximum length in the abdominal aorta. Being connected to the arterial segment in the CPB tube, permeability and wrist were tested.

15. A 2 cm incision was performed in the 2nd intercostal space in the anterior axillary line for the placement of Chitwood速 transthoracic clamp in patients undergoing anterolateral minithoracotomy, the videoscopy helped aortic clamping performed laterally along the pericardial deflection. The transthoracic clamping in tge ministernotomy was performed by thoracic incision with conventional tweezers (DeBakey速) (Figure 5A).

Fig. 1 - Position of the patient, the surgical field and peripheral access for ECC. A: panoramic view of the surgical field, B: 2 cm incision in the left inguinal region for blood exposure and percutaneous puncture of the right femoral vein

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Fig. 2 - Right anterolateral minithoracotomy and use of Finochietto or ESTECH® pediatric retractor. A: panoramic view, B: lateral aortic clamping with Chitwood®, C: aortic exposure via minithoracotomy, D: Thoracoscopic visualization with calcific aortic valve, E: aortic prosthesis implantation, and observation of the incision size proportional to the prosthesis diameter: F: metallic prosthesis implanted

Fig. 3 – Upper J Mini sternotomy, from the 3rd intercostal space to the sternal notch. A: exposure with retractor and exposure of the ascending aorta after opening the pericardium. Trocar for videoscopy positioned laterally to the right by counterinsicion B: transthoracic clamping, with observation of the surgical field and start of cardioplegic infusion in the aortic root with rigid cannula, C: observation of left ventricular distention during cardioplegia in the aortic root; D: transverse aortotomy, E: cardioplegia performed in the coronary ostia, F: metallic prosthesis implanted

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Fig. 4 – Observation of the heart by videothoracoscopy. A: visualization of the ostium and right coronary leaflet, B: observation of the left ventricle; C: visualization of the left ventricle in search of emboli or calcium debris

Fig. 5 - Aortic clamping in minimally invasive procedures. A: placement of Chitwood® transthoracic clamp in patients undergoing anterolateral thoracotomy, the videoscopy assisted in clamping performed laterally to the aorta near the pericardial recess between the aorta and pulmonary artery, B: transverse aortotomy with equidistant points, placed on the anterior exposure to the aorta, C: mini sternotomy transthoracic clamping was performed by thoracic incision with conventional tweezers (DeBakey®), and cardioplegia in the aortic root

16. In this moment, the CPB began. The need for higher or lower drainage was oriented by the surgeon requesting variations in vacuum pressure, assessing the complete emptying of the right atrium.

17. Before the transthoracic clamping, we made a pouch in the aortic root for the introduction of the cardioplegia cannula, which was also used at the end of the procedure to remove air from the left cavities. This same cannula was withdrawn always on CPB and low flow, to reduce the risk of aortic dissection.

18. Hypothermic blood cardioplegia 4/1 were measured every 15 minutes and the CPB maintained between 28 and 30 degrees. In cases which HTK solution was used (Custodiol®), only one infusion (20 ml/kg) was made in the aortic root to perform the entire procedure, the coronary ostia were cannulated in case of predominant aortic insufficiency or where we can notice distention of the left ventricle by videoscopy. In such cases, it was extremely important to maintain 28º because HTK solution maintains its maximum effect [12].

19. At this time, we opened the heart cavity through transverse aortotomy. Only wires were used for exposure of the aortic valve: two equidistant polyester sutures in

the anterolateral and anteromedial proximal aorta sides (Figure 5B).

20. No vacuum was alternatively used to drain the left ventricle, for this purpose we used an aspiration cannula introduced by aortotomy into the left ventricle and, after placement of the prosthetic valve through the leaflets.

21. We continued with the aortic valve replacement in all cases using the conventional method.

22. After completion of primary surgical time, we tried to be very careful for maximum removal of air from the heart cavities, also guided by TEE. The first step was to conduct the maximum Trendelenburg position. The cardioplegia cannula, attached to the aortic root, was enough to suck all the residual air in the left ventricle. In this moment, the TEE confirmed the complete elimination of air from the heart chambers, before we could remove CPB. Periods of interruption of CPB with constant suction of aortic root helped deaeration.

23. Pacemaker wires (2) were placed in the right ventricle which was still on CPB, with the heart drained.

24. After review of hemostasis, protamine solution began (1/1) by continuous infusion. Before completing the heparin reversal, we withdrew the venous cannula. Since 575

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we had used percutaneous, only local compression was performed.

25. After reversing the anticoagulation, a 4-0 prolene "U" pouch was made in the artery around the femoral cannula for occlusion after its removal.

26. A chest tube was enough to make drainage, and was placed in the subxiphoid position in the ministernotomy or the 5th intercostal space with anterior axillary line in cases of anterolateral minithoracotomy.

27. After all sutures were done; we had anesthesia superficialization according to the anesthetic protocol. Patients with the following characteristics were extubated in the operating room: BIS above 60, level of responsive awareness, adequate pulmonary ventilation and hemodynamic stability in average time of 15 to 30 minutes after skin suture.

patients aged over 70 years received bioprosthetic implant (Braile Biomedica®). Upper J Ministernotomy to the right was performed on ten patients because they presented severe valve calcification and dilation of the ascending aorta, in other cases 75% (30/40 cases), we performed a right anterolateral minithoracotomy through the 2nd (5/30 cases) or 3rd intercostal space (25/30 cases) (Figure 6).

Among the 20 patients from G2, 7 received biological prostheses (Braile Biomedica®) and thirteen metallic prostheses (St. Jude Medical System®), median sternotomy was performed in all patients.

The mean CPB and aortic clamping in G1 were respectively: 142.7 ± 59.5 min and 88.6 ± 31.5 min and in G2, 98.1 ± 39.1 and 67.7 ± 26, 2 (P <0.05), a difference in the medians of 39 min on CPB and 23 min in aortic clamping was observed in favor of the conventional technique. In our service, we systematically use immediate extubation attempt, when the patient is still in the operating room. Almost all patients from G1 group were extubated immediately after the surgery, 92.5% of them, and only 75% were extubated in G2 (Table 2).

The total blood loss through chest tubes was significantly lower in the minimally invasive group: 605.1 ± 679.5 ml (G1) versus 1617 ± 1390 mL (G2) (P <0.05). Mean time of hospitalization in the intensive care unit (ICU) and hospital were lower in G1: 2.3 ± 1.8 and 5.5 ± 5.4 days versus 5.1 ± 3.6 and 10 ± 5.1 G2 (P <0.05), respectively.

The use of vasoactive drugs in the postoperative period was also lower in the minimally invasive group, 12.8% in G1 versus 45% in G2 (Table 3).

Two (5%) patients died in the group undergoing minimally invasive procedure and one (5%) in the median sternotomy group, without statistical significance.

Postoperative complications were observed in both groups and showed no significant difference being reported in Table 4.

Statistical Analysis Continuous data were expressed as mean ± standard deviation and categories evaluated in frequencies and percentages. To compare continuous variables, t-test or Fisher's exact test were used. The P-value <0.05 was considered statistically significant.

RESULTS The surgeries performed by median sternotomy were prior to the experience of the surgical team with minimally invasive procedures in aortic valve (13 patients) and were also performed in some cases requiring intervention besides valve replacement: 1) three cases of concomitant revascularization of the left anterior descending artery; 2) three cases of valvular reoperation and 3) a patient who opted for the open procedure.

In G1, aortic valve replacement was performed in all patients (40 cases). We decided to implant the metallic prosthesis in 33 cases (St. Jude Medical System®). Seven

Fig. 6 - Access options for minithoracotomies for surgical treatment of aortic valve. Right anterolateral minithoracotomy: A: Access via the 2nd right intercostal space, B: 3rd right intercostal space and upper hemisternotomy, C: access of the furcula to the 3rd J intercostal space

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Fortunato Júnior JA, et al. - Troca valvar aórtica minimamente invasiva: uma alternativa à técnica convencional

Table 2. Surgical times Variables ECC time (minutes) Median Mean+standard deviation Aortic clamping (minutes) Median Mean+standard deviation Extubation in the operating room Valve type Biological Metallic Ns= not significant

Minimally invasive access

Median sternotomy

P-value

127.0 142.7±59.5

88.0 98.1±39.1

0.004

80.0 88.6±31.5 37/92.5%

57.0 67.7±26.2 15/75.0%

0.012 0.031

7/17.5% 33/82.5%

7/35.0% 13/65%

Ns Ns

Minimally invasive access 1-10 2.0 2.3±1.8 2-25 3.5 5.5±5.4 100-2850 300 605.1±679.5 45 0.3 1.13±1.54 5 12.8%

Minimally invasive access 2-14 3.5 5.1±3.6 4-20 8.0 10.0±5.1 300-5000 925 1617.5±1390.8 40 1.5 2.0±1.9 9 45%

P-value

Minimally invasive access 1/5% 1/5% 2/10% 2/10% 3/15% 1/5% 1/5% 1/5% 2/10% __

P-value Ns Ns Ns Ns Ns Ns Ns Ns Ns Ns

Table 3. Postoperative variables Variables Intensive Care Unit (days) Median Mean+standard deviation Hospitalization period (days) Median Mean+standard deviation Total thoracic drainage (ml) Median Mean+standard deviation Hemoderivatives (units) Median Mean+standard deviation Vasoactive drugs (numbers) Mean+standard deviation

0.001 0.002 0.002 0.029 0.002

Table 4. Postoperative complications Variables Mortality Neurological events New atrial fibrillation Renal failure respiratory failure Pleural effusion Surgical wound infection Reoperation for bleeding Dissection of the ascending aorta Conversion to sternotomy

Minimally invasive access 2/5% 3/7.5% 3/7.5% 2/5% 2/5% 2/5% 0/0% 3/7.5% 3/7.5% 2/5%

Ns = not significant

DISCUSSION The concept of minimally invasive heart surgery incisions occurred in the mid-nineties. In the beginning, smaller incisions to access the mitral, aortic and coronary valves were introduced, such as the upper and lower hemi-sternotomy with transection of the sternum and the lateral thoracotomy [11,12]. Left thoracotomy for single revascularization of anterior descending and right artery

to give access to the mitral valve or coronary artery were also used. The right anterolateral thoracotomy had been used in the past with preference for mitral disease, but it was discontinued due to the best results with median thoracotomy or sternotomy [13-15].

Except for myocardial revascularization without CPB, minimally invasive surgery, mainly under the aortic valve, was once considered dangerous due to the high mortality rate when compared to the conventional 577

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technique. Bridgewater et al. [16] demonstrated a 43% mortality in minimally invasive surgery compared with 7% in the conventional surgery for the treatment of aortic valve. Even when other centers showed more encouraging results, still it would not attract the attention of cardiac surgeons in the world [17,18].

Currently, minimally invasive cardiac surgery has shown its best results when using the aid of videothoracoscopy.

Besides these video equipment, the extrathoracic access to CPB was implemented, the so-called "port-access technology", an innovative technique for vascular access and peripheral aortic endoclamping [9,18]. The inclusion of transthoracic clamping did not change the idea of the technique. Brinkman et al. [19] presented the favorable experience of using port-access surgical treatment of aortic valve using transthoracic clamp with flexible Cosgrove®.

Since 1995 multicenter studies have been presented to demonstrate the effectiveness of this new method. Galloway et al. [10] in 1999, gathered data from 121 centers and included 1063 patients who underwent minimally invasive techniques with results similar to those of the conventional surgery, with the advantage of less aggression and pain, and use of hemoderivatives, in addition to hospital discharge and return to daily activities much earlier. In 2009, Dr. Galloway reported their data from a decade of experience with the method [2]. Grossi et al. [20] and Greco et al. [21] in 2002 and Mishra et al. [22] in 2005, reported highly favorable experiences of video-assisted techniques.

Specifically in the aortic valve, Tabata et al. [23] presented their experience with 1005 patients undergoing minimally invasive technique to treat aortic diseases, including from simple valve replacement procedures and also procedures in the ascending aorta, aortic root and reoperation, with excellent postoperative results.

Cunningham et al. [24] in 2011, reported 101 patients after a short learning curve and results similar to those found with the conventional technique, when the aortic valve was treated by minithoracotomy.

In Brazil, Jatene et al., in 1997, Souto et al., in 2000, and Salerno et al., also in 2000, reported their initial experience with video-assisted surgery, but still in the vicinity of the heart. Mulinari et al. [25] in 1997 presented their experiences with ministernotomy under direct vision, including, among others, also with aortic valve procedures and concluded that the ministernotomy is a safe access and is associated with low morbidity. Dias et al. [26] in 2001 reported their positive experience with ministernotomy in relation to the aortic valve treatment.

Other national authors also have used the ministernotomy to treat aortic valve and defined the alternative technique as comparable to the traditional procedure. In this cases series, CPB was used in a conventional manner and was not vacuum-assisted since

the cannulation was transthoracic occupying the same surgical field. This surgical option required larger chest incisions, reducing the aesthetic benefit and the expected reduction of postoperative discomfort [27-29].

Only in 2005 after the beginning of our experience [30-32] and Poffo et al. studies, in 2006 [33], a new phase of minimally invasive cardiac surgery started in our environment, including video-assisted surgery, the intracardiac procedures through peripheral CPB, vacuum assistance and minithoracotomy.

The right anterolateral minithoracotomy was the most used in this series, performed on the 2nd or 3rd intercostal space with variable incision between 4 and 7 cm and the aid of video-assisted surgery allowed adequate visualization of the aortic valve, making it possible to exchange them.

Gersak et al. [34] in 2003 were the pioneers in aortic valve replacement performed under complete indirect vision, in other words, by video-assisted surgery. In order to do that,a 3cm submammary incision was used close to the 3rd intercostal space, which allowed perpendicular view of the aortic valve and prevented any aid by direct vision. Plass et al. [35] used the anterolateral minithoracotomy in most of their cases and the best intercostal space was defined by CT three-dimensional analysis.

The videosurgery is most used in atrioventricular disorders and assists in several surgical intrathoracic attitudes. Although they were not emphasized in the minimally invasive procedures for the treatment of aortic valve, we observed in our study, that the use of videoscopy expands the visual field. The visualization of the right coronary ostium is difficult even in large incisions, as the right coronary cusp. The cleaning of the left ventricle can be performed more safely when using an indirect visionassisted procedure, including in conventional surgery.

All these procedures can be implemented with the aid of videosurgery. The video-assisted procedure also helps in the transthoracic clamping in right minithoracotomy because it allows excellent visualization of the aorta, pulmonary artery and left atrium, decreasing the risk of injury to these structures, as it is observed when treating diseases of the atrioventricular valves [19].

In most of our patients (30/40 cases), we used the access via a 5cm right anterolateral minithoracotomy in the 3rd intercostal space. In ten (25%) patients with aortic disease, the access was performed in J hemisternotomy.

We chose this access in cases where the ascending aorta was dilated or when the aortic valve was too calcified, since with this technique direct vision facilitates the aortic clamping and handling the compromised valve. Other accesses as in inverted T, H or L hemisternotomy to the left have also been suggested by some authors, but they are associated with greater trauma, minor aesthetic benefits and / or anti pain [36-38].

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The CPB time and myocardial anoxia were longer in G1, similar to those found in the literature, but without sacrificing the benefits of the technique [19,39]. Other authors have shown that, with more experience with the method, these times become almost similar to those of the sternotomy [23,40,41]. In our series, the minimally invasive access group demonstrated CPB and aortic clamping times, respectively: 142.7 Âą 59.5 min and 88.6 Âą 31.5 min. These data were comparable to those presented

by Plass et al. [35] in an article published about the subject in 2009, were longer than those with median sternotomy, but similar in relation to morbimortality [42,43].

The times of postoperative outcome reduced in the minimally invasive group in this series were also confirmed by other authors [44]. These authors suggest that less contact with the chest cavity maintains the expandability and lung function, facilitating earlier extubation and a postoperative recovery to be faster. This fact was also identified when we demonstrated the high rate of immediate extubation in our G1 (92.5%). The maintenance of lung function, the increased thoracic stability associated with reduced postoperative pain are probably responsible for shorter hospital times, when compared to the times of recovery after median sternotomy [45,46].

The need for inotropic support was greater in G2 (42%) and only 12% in cases of minimally invasive procedures. This fact is rarely discussed in articles presented in the literature, but it was reported by Moustafa et al. [46] comparing 0% versus 50% of inotropes used only in cases of conventional sternotomy. Szwerc et al. [47] compared the partial and total sternotomy in aortic valve surgery and also observed a reduction in the use of inotropes in the alternative procedure.

Surgical bleeding, especially during the postoperative period was reduced in G1 compared to the conventional approach (P <0.05). The use of hemoderivatives was also lower in our series. These elements are much emphasized by several authors who report, in addition to shorter hospital times, reduced blood loss and need for hemoderivatives in cases of minimally invasive surgery [11,48,49].

Reoperation for bleeding was low and similar in both groups analyzed (7.5% vs. 5%). Vanoverbeke et al. [41] showed 7.5% reexploration by bleeding in the minimally invasive group with no difference when comparing with the conventional technique and Brinkman et al. [19] in 2010, 8.1% of reoperations for bleeding in patients undergoing port-access procedures.

The use of access via femoral artery, considered as a complicating factor in minimally invasive surgery was not associated with major complications in our series. Only 1 patient in G1 showed complications at the site of arterial cannulation, which underwent reexploration. The femoral cannulation (extrathoracic) facilitates the use of smaller incisions, because it does not occupy space in the surgical

field. Comments about additional costs, among cannulas and instruments, have been challenged by many authors, who confirmed the reduction of total hospital costs when using the minimal accesses [44,45,50].

The conversion to sternotomy occurred in two (5%) cases of G1, both by dissection in the ascending aorta that impossible to be treated by the minimal incisions.

A third case of dissection was successfully corrected by minithoracotomy. It was noted that when we use the minithoracotomy, we find greater difficulty in correcting minor bleeding in the aortic suture, sometimes progressing to larger dissections. Reflecting on these complications, a complementary care was used by our team with aortic clamping at low pressures, the aortotomy raffia in two planes, the cardioplegia cannula removal and control of bleeding (even if minimal) always on CPB and at low pressures. A meta-analysis published in 2009 [48] included 4856 patients undergoing aortic valve replacement procedures for minimally invasive or conventional procedures, referring 3% conversion to sternotomy. In this same report there was no difference in mortality, although CPB and aortic clamping times were longer.

Three (7.5%) patients developed cerebrovascular accident (CVA) in G1 and 1 (5%) in G2, with no significant difference between groups, and both direct relationship was observed with complication of severe calcification of the aortic valve suggest with no relationship with air embolism. Only one patient from G1 progressed to permanent sequel. Modi et al. [51] also reported a 2.6% of CVA in 12 years of use of minimally invasive surgery.

Other minor complications, such as atrial fibrillation, pleural effusion, and others, were similar in both groups.

Regarding mortality and postoperative complications, we found that morbimortality was the same in both groups.

A 2009 report published by the European Association of Cardiothoracic Surgery, Scarci et al. [49] reviewed 115 articles and confirmed that minimally invasive procedures do not increase the risk of death or other major complications, and it depends on the patient's preference or the experience of the surgical team using this method.

Six patients in the open surgery group (sternotomy) had concomitant procedures. In the three cases of associated revascularization of the anterior descending coronary artery, due to the minimal increase in surgical time, we do not consider it as an influencing factor in perioperative outcomes. The reoperations could be seen as a bias in this study, but the small number of cases did not apparently change the outcome. Many international authors have also used smaller incisions in aortic valve reoperations, but we chose not to use it in this early experience [23]. The main emphasis of this work was to demonstrate the feasibility of this method and its similarity in postoperative results, especially in relation to morbimortality.

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CONCLUSION The major advantages of the minimally invasive technique were observed due to a minimal surgical trauma, in less postoperative pain and reduced blood loss; as a result we had less use of hemoderivatives and shorter periods of postoperative recovery, statistically lower when compared to those found for the conventional technique.

In this sample we could demonstrated that the minimally invasive technique can be used safely and effectively in cases of aortic valve surgery without changing the results already found for the median sternotomy.

The access by ministernotomy in cases of severely calcified aortic stenosis is a good option to the right minithoracotomy technique, thus keeping the idea of smaller incisions.

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36. Suenaga E, Suda H, Katayama Y, Sato M, Yamada N. Limited upper sternotomy for minimally invasive aortic valve replacement. Kyobu Geka. 2000;53(12):1028-31.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):583-91

Risk factors for hospital mortality in valve replacement with porcine bioprosthesis at an universitary institution Fatores de risco hospitalar para pacientes submetidos à substituição valvar com a bioprótese porcina em instituição universitária

Ana Carolina Tieppo Fornari1, Luís Henrique Tieppo Fornari1, Juan Victor Piccoli Soto Paiva1, Pauline Elias Josende1, João Ricardo Michelin Sant’Anna2, Paulo Roberto Prates3, Renato A. K. Kalil3, Ivo A. Nesralla4

DOI: 10.5935/1678-9741.20120100

RBCCV 44205-1425

Abstract Objective: Study designed to identify characteristics of patients related to increased hospital mortality after valve replacement, assumed as risk factors.

Methods: Retrospective study including 808 patients submitted to the implant of St. Jude Biocor porcine bioprosthesis between 1994 and 2009 at Instituto de Cardiologia do Rio Grande do Sul. Primary outcome was hospital death and hospital mortality was related to demographic and surgical characteristics. Statistics include t-test, qui-square test and logistical regression analysis.

Results: There were 80 (9.9%) hospital deaths. Risk factors identified with univariable logistical analysis (and

respective odds-ratio) were: tricuspid surgery (OR 6.11); mitral valve replacement (OR 3.98); left ventricular ejection fraction < 30% (OR 3.82); diabetes mellitus (OR 2.55); atrial fibrillation (OR 2.32); pulmonary arterial hypertension (OR 2.30); serum creatinine ≥ 1,4 mg/dL (OR 2.28); previous cardiac surgery (OR 2.17); systemic arterial hypertension (OR 1.93); functional class III e IV (OR 1.92); coronary bypass (OR 1.81); age ≥ 70 years-old (OR 1.80); congestive heart failure (OR 1.73); e female gender (OR 1.68). Multivariable logistic regression for independent factors identified preponderant risk factors mitral valve replacement (OR 5.29); tricuspid surgery (OR 3.07); diabetes mellitus (OR 2.72); age ≥ 70 years-old (OR 2.62); coronary

1 - Medical Student with Scholarship at the Support Research Fund of the Institute of Cardiology of Rio Grande do Sul / University Cardiology Foundation (IC / FUC), Porto Alegre, RS, Brazil.

2 - PhD at IC / FUC, Advisor, Porto Alegre, RS, Brazil.

3 - Cardiovascular Surgeon at Cardiovascular Surgery Team of IC / FUC, Porto Alegre, RS, Brazil.

4 - Leader of the Cardiovascular Surgery Team at IC / FUC and CEO of University Cardiology Foundation, Porto Alegre, RS, Brazil.

Correspondence address: João Ricardo Michelin Sant'Anna Av. Princesa Isabel Avenue, 395 - Porto Alegre, RS, Brazil – Zipcode: 90620-000 E-mail: santana.pesquisa@cardiologia.org.br

Work performed at the Institute of Cardiology of Rio Grande do Sul / University Cardiology Foundation. Porto Alegre, Rio Grande do Sul, Brazil.

Article received on July 23rd, 2012 Article accepted on September 5th, 2012

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Abbreviations, acronyms and symbols CABG DM AF LVEF SAH CI CHF NYHA OR

Coronary artery by-pass grafting Diabetes mellitus Atrial fibrillation Left ventricular ejection fraction Systemic arterial hypertension Confidence interval Congestive heart failure New York Heart Association Odds ratio

bypass (OR 2.43); previous cardiac surgery (OR 1.82); e systemic arterial hypertension (OR 1.79).

Conclusions: Mortality rate is within values found in literature. Identification of risk factors could contribute to changes in surgical indication and medical management in order to reduce hospital mortality.

Descriptors: Risk factors. Prosthesis implantation. Heart valve prosthesis implantation. Prostheses and implants.

Cardiac surgical procedures.

Resumo Objetivo: Identificar fatores de risco hospitalar em pacientes submetidos ao implante de bioprótese porcina no Instituto de Cardiologia do Rio Grande do Sul. Métodos: Estudo retrospectivo, com informações de prontuário, de 808 pacientes submetidos ao implante de pelo menos uma bioprótese porcina St. Jude Medical

INTRODUCTION The valve replacement surgery is the accepted treatment in structural heart valve disease, representing approximately 20% of all cardiac surgeries performed and accounts for 30% of the total surgery mortality rate [1]. The mortality rate recorded in the literature for this type of surgery ranges from 1% to 15%, regardless of the type of the implanted prosthesis [2-9]. This variation is justified by differences in demographic and clinical characteristics of patients considered for surgery, the surgical techniques, the 584

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Biocor, no período entre 1994 e 2009. Foi analisada a relação entre mortalidade hospitalar e características clínicas e demográficas definidas em estudos reconhecidos, visando identificar fatores de risco. Foram utilizados testes qui-quadrado, t de Student e regressão logística uni e multivariável (P≤0,05).

Resultados: Ocorreram 80 (9,9%) óbitos hospitalares.

Fatores de risco identificados na regressão logística univariável foram: plastia tricúspide (odds ratio 6,11); lesão mitral (OR 3,98); fração de ejeção de ventrículo esquerdo < 30% (OR 3,82); diabete melito (OR 2,55); fibrilação atrial (OR 2,32); hipertensão pulmonar (OR 2,30); creatinina ≥ 1,4 mg/dL (OR 2,28); cirurgia cardíaca prévia (OR 2,17); hipertensão arterial sistêmica (OR 1,93); classe funcional III e IV (OR 1,92); revascularização miocárdica (OR 1,81); idade ≥ 70 anos (OR 1,80); insuficiência cardíaca congestiva (OR 1,73); e sexo feminino (OR 1,68). Pela regressão logística multivariável, para fatores independentes, identificados: lesão mitral (OR 5,29); plastia tricúspide (OR 3,07); diabete melito (OR 2,72); idade ≥ 70 anos (OR 2,62); revascularização miocárdica (OR 2,43); cirurgia cardíaca prévia (OR 1,82); e hipertensão arterial sistêmica (OR 1,79).

Conclusões: A mortalidade observada nesta casuística é compatível com literatura. Fatores de risco preponderantes são reconhecidos e devem motivar programas específicos de neutralização.

Descritores: Fatores de risco. Implante de prótese.

Implante de prótese de valva cardíaca. Próteses e implantes.

Procedimentos cirúrgicos cardíacos.

position of the valve implantation, the associated surgical procedures [9,10] and in the postoperative care. Retrospective studies with large numbers of patients were performed to identify characteristics that may affect the surgery outcome and create models of individual risk stratification for different institutions [2-5,11]. The importance of these studies lies in the prospect of identifying patients at increased surgical risk by assessing their demographic, clinical and operative characteristics, neutralizing or minimizing the risk factors in order to reduce surgical mortality and morbidity, as well as the cost of care [12].

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Rev Bras Cir Cardiovasc 2012;27(4):583-91

About 500 valve surgeries are performed annually at the Institute of Cardiology of Rio Grande do Sul. The porcine bioprostheses are used in approximately 40% of patients who underwent implantation of biological valve replacements, however, the results of these procedures have not been evaluated, unlike what happened with the surgical valve replacement with a bovine pericardial prostheses [13,14] and mechanical prostheses[15], whose analysis has allowed to stratify the implant surgical risk and decrease the operative mortality.

This study objective is to characterize the population of patients undergoing implantation of a porcine biological valve prosthesis model at the Institute of Cardiology of Rio Grande do Sul, and also evaluate deaths and identify risk factors for hospital mortality.

hypothermic crystalloid cardioplegia with St. Thomas II solution. After surgery, the patients were taken to the recovery room, where they received intensive care for at least 24 hours; the patients were discharged on the fifth postoperative day [16]. After discharge, patients were referred to the clinical assistant or were followed-up at the institution outpatient clinic.

The number of operated patients was 808605 (74.9%) underwent first heart surgery, 178 (22%) had previously undergone heart surgery and 25 (3.1%) two or more heart surgeries earlier. We performed 193 (23.9%) isolated bioprosthetic mitral implants, 552 (68.3%) isolated bioprosthetic aortic implants and 63 (7.8%) implants associated with mitral and aortic bioprostheses. The valve replacement surgeries were combined with coronary artery bypass grafting (CABG) in 156 (19.3%) patients and with tricuspid valvuloplasty in 21 (2.6%). During hospitalization for surgical interventions, 52 (6.4%) patients were reoperated.

METHODS Study Design A retrospective cohort study Population We included all patients undergoing implantation of at least one St. Jude Medical Biocor porcine bioprosthesis, from January 1994 to December 2009 at the Institute of Cardiology of Rio Grande do Sul - University Cardiology Foundation, totaling 808 patients. Among them, 351 (43.4%) were female and 457 (56.6%) were male. Their ages ranged between 16 and 90 years, with a mean of 66.5 years and a standard deviation of Âą 11.3 years. The functional class according to the standards of the New York Heart Association (NYHA) was I in 75 (10.3%) patients, II in 247 (34%), III in 279 (38.4%) and IV in 125 (17.2%). The left ventricular ejection fraction (LVEF) was over 50% in 620 (81.4%) patients, between 30 and 50% in 124 (16.3%) and less than 30% in 18 (2.4%). Congestive heart failure (CHF) was present in 137 (17%) patients, atrial fibrillation (AF) in 179 (22.2%), systemic arterial hypertension (SAH) in 442 (54.8%), pulmonary hypertension in 212 (26.5%), and diabetes mellitus (DM) in 116 (14.4%). The value of serum creatinine was <1.4 mg / dL in 702 (87.4%) patients and â&#x2030;Ľ 1.4 mg / dL in 101 (12.6%).

Valve surgery Surgical procedures and postoperative care were performed as previously described routines. All patients underwent surgery with cardiopulmonary bypass, membrane oxygenation, variable levels of hemodilution and hypothermia and myocardial preservation by

Outcomes and definition of risk factors Deaths during hospitalization for surgical valve replacement with porcine bioprosthesis were considered as primary outcomes.

Deaths were classified according to the preponderant factors in: a surgical cause (such as bleeding), due to cardiac causes (such as acute myocardial infarction and heart failure) or non-cardiac causes (such as infection and nervous, renal and pulmonary complications).

The demographic, clinical and operative characteristics analyzed were: gender, age, functional class (according to the model proposed by NYHA), LVEF, CHF, atrial fibrilation, SAH, pulmonary arterial hypertension (systolic blood pressure greater than 100 mmHg), DM, serum creatinine, previous cardiac surgery, valvular lesion (mitral, aortic or mitral-aortic), associated CABG, associated tricuspid valve replacement and reoperation during hospitalization.

The characteristics associated with the increased hospital mortality were considered as predictors of risk.

Ethical Considerations This research project was submitted to the Research Institute of Cardiology of Rio Grande do Sul, which was approved by the Institute Research Ethics Committee, being registered under No. 3734/05. Norms related to patient privacy and confidentiality in the handling of medical information was respected. The data used in this study were obtained from records of the Department of Cardiovascular Surgery and hospital records.

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Collecting and analyzing data This research was based on four phases: selection of patients, chart review with data logging, tabulation of data and statistical analysis. The latter included the distribution of demographic, clinical and operative characteristics in the study population, determining the percentage of deaths, the mortality ratio with the selected features and the identification of risk factors for hospital mortality.

We used univariate and multivariate statistical analysis using SPSS for Windows, version 14.0 to determine predictors of prevailing and independent hospital mortality risk. In order to obtain this information, Chi-square test, Student's t test and logistic regression were used. In multivariate analysis, the variables were used in the form that had greater discriminatory power. All significant characteristics (P â&#x2030;¤ 0.05) in univariate analysis were considered for multivariate analysis.

We considered risk characteristics those with significant association with hospital mortality, for an alpha level of 0.05. The odds ratio (OR) with a 95% confidence interval was obtained by logistic regression analysis to estimate the relative risk of each analyzed characteristic.

characteristics analyzed, also their distribution in the study population and the association with hospital mortality.

These variables were significantly associated (P < 0.05) with increased hospital mortality, except for reoperation during hospital admission (P = 0.064, ns). Characteristics associated with greater absolute mortality were associated procedure of tricuspid valve repair (38.1%), LVEF less than 30% (27.8%) and the presence of mitral valve disease (21.2%), as can be noted in Table 1.

In order to increase the discriminatory power of the statistical analysis, the variables with multiple categories (age, functional class, LVEF, heart valve lesion and previous cardiac surgery) were transformed into dichotomous variables, and its distribution and association with hospital mortality are shown in Table 2.

RESULTS Characterization of the valve disease Among the 808 patients included in this study, 65 (8%) patients had rheumatic valvular disease and 14 (1.7%) with congenital valve alteration, in which the bicuspid aortic valves were the most common one, 31 (3.8%) patients had valve lesion determined by infective endocarditis and 14 (1.7%) ischemic disease, 684 (84.6%) patients did not have the etiology of valve lesions identified in their medical record.

The most common signs and symptoms reported by patients at the time of hospital admission were, in decreasing order of frequency: dyspnea (57.9%), angina / chest pain (31.3%), syncope (10.3%), fatigue (8.7%), dizziness (6.8%), palpitations (3%), lower limb edema (1.4%) and fever (1.3%). About 4% of all patients undergoing valve replacement surgery were asymptomatic.

Hospital mortality There were 80 (9.9%) deaths. As for the causes of death, 10% were due to surgery, 46% of cardiac causes and 44% of non-cardiac causes.

Risk Factors Table 1 shows the demographic, clinical, surgical 586

Estimating the relative risk By logistic regression analysis OR values were obtained in order to estimate the relative risk of the characteristics considered. Table 3 shows the OR values and their respective 95% confidence intervals (95% CI). Risk factors for hospital mortality with higher OR (OR> 3) were age groups above 60 years (variable OR, but greater than 3), associated tricuspid valve repair (OR 6.111, 95% CI 2.451 to 15.235), mitral valve lesion (OR 3.984, 95% CI 2.481 to 6.396) and LVEF less than 30% (OR 3.824, 95% CI 1.323 to 11.048), although other characteristics have demonstrated OR> 1, a value considered significant.

Independent risk factors The characteristics that were significantly associated with increased hospital mortality in univariate analysis were considered for multivariate analysis, and also sought to show independent risk factors. The variables were used in the dichotomous form, which showed greater discriminatory power in the statistical analysis.

Multiple logistic regression was used by the method Backward Stepwise with 0.05 P value input and a 0.10 Q output, leaving the last step of the method the following characteristics expressed in decreasing OR: mitral valve disease (OR 5.291, 95% CI 2.898 to 9.615), associated tricuspid vale repair(OR 3.074, 95% CI 1.013 to 9.327), diabetes (OR 2.722, 95% CI 1.437 to 5.157), age greater than or equal to 70 years (OR 2.620, CI 95% from 1.478 to 4.646), associated CABG (OR 2.435, 95% CI 1.290 to 4.596), previous cardiac surgery (OR 1.816, 95% CI 1.005 to 3.281) and hypertension (OR 1.791, 95% CI 0.991 to 3.237) (Figure 1).

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Fornari ACT, et al. - Risk factors for hospital mortality in valve replacement with porcine bioprosthesis at an universitary institution

Table 1. Hospital mortality according to demographic, clinical and operative characteristics Characteristics Frequence Gender Female 351 Male 457 Age group < 50 years 57 50 - 59 years 133 60 - 69 years 280 70 - 79 years 268 â&#x2030;Ľ 80 years 70 Functional Class (NYHA) I 75 II 247 III 279 IV 125 LVEF > 50% 620 30 - 50% 124 < 30% 18 Congestive heart failure Absent 668 Present 137 Atrial Fibrillation Absent 626 Present 179 Systemic arterial hypertension Absent 364 Present 442 Pulmonary arterial hypertension Absent 587 Present 212 Diabetes mellitus Ausent 691 Present 116 Serum Creatinine < 1,4 mg/dL 702 â&#x2030;Ľ 1,4 mg/dL 101 Valvular Lesion Mitral 193 Aortic 552 Mitro-aortic 63 Previous heart surgery No 605 1 surgery 178 2 surgeries or more 25 Myocardial Revascularization Associated No 652 Yes 156 Tricuspid valve repair associated No 787 Yes 21 Reoperation in hospital stay No 756 Yes 52

%

Deaths

%

P

43.4 56.6

44 36

12.5 7.9

0.028

7.1 16.5 34.7 33.2 8.7

1 7 28 32 12

1.8 5.3 10 11.9 17.1

0.012

10.3 34 38.4 17.2

5 17 30 20

6.7 6.9 10.8 16

0.032

81.4 16.3 2.4

52 16 5

8.4 12.9 27.8

0.009

83 17

60 20

9 14.6

0.045

77.8 22.2

50 30

8 16.8

0.001

45.2 54.8

25 55

6.9 12.4

0.008

73.5 26.5

45 34

7.7 16

< 0.001

85.6 14.4

58 22

8.4 19

< 0.001

87.4 12.6

61 18

8.7 17.8

0.004

23.9 68.3 7.8

41 35 4

21.2 6.3 6.3

< 0.001

74.9 22 3.1

48 28 4

7.9 15.7 16

0.005

80.7 19.3

57 23

8.7 14.7

0.024

97.4 2.6

72 8

9.1 38.1

< 0.001

93.6 6.4

71 9

9.4 17.3

0.064 n.s.

NYHA: New York Heart Association, LVEF: left ventricular ejection fraction

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Fornari ACT, et al. - Risk factors for hospital mortality in valve replacement with porcine bioprosthesis at an universitary institution

Table 2. Hospital mortality as modified variables.

Characteristics Frequence Age < 70 years 470 ≥ 70 years 338

%

Deaths

%

P

58.2 41.8

36 44

7.7 13

0.012

Functional Class(NYHA) I / II III / IV

322 404

44.4 55.6

22 50

6.8 12.4

0.013

LVEF ≥ 30% < 30%

744 18

97.6 2.4

68 5

9.1 27.8

0.008

Valvular lesion Mitral Aortic / Mitro-aortic

193 615

23.9 76.1

41 39

21.2 6.3

< 0.001

Previous heart surgery No Yes

605 203

74.9 25.1

48 32

7.9 15.8

0.001

NYHA: New York Heart Association, LVEF: left ventricular ejection fraction

Table 3. Odds ratios and 95% confidence intervals (95% + OR) for risk factors.

Characteristics

Odds ratio

Female 1.676 50 - 59 years 3.111 60 - 69 years 6.222 70 - 79 years 7.593 ≥ 80 years 11.586 Functional Class II 1.035 Functional Class III 1.687 Functional Class IV 2.667 LVEF 30 – 50% 1.618 LVEF < 30% 4.201 Congestive heart failure 1.732 Atrial Fibrillation 2.319 Systemic arterial hypertension 1.927 Pulmonary hypertension 2.301 Diabetes mellitus 2.554 Serum Creatinine ≥ 1,4 mg/dL 2.279 Mitral valve lesion 3.984 Mitro-aortic valve lesion 1.001 1 previous heart surgery 2.166 Previous surgeries > 2 2.21 Myocardial Revascularization 1.805 Associated tricuspid valve repair 6.111 Reoperation in hospital stay 2.019 LVEF: left ventricular ejection fraction

588

95% CI 1.053 2.667 0.374 25.888 0.829 46.697 1.016 56.759 1.458 92.074 0.369 2.905 0.631 4.509 0.956 7.437 0.891 2.94 1.441 12.245 1.006 2.982 1.425 3.775 1.175 3.161 1.429 3.705 1.494 4.368 1.285 4.043 2.451 6.478 0.344 2.917 1.314 3.57 0.729 6.701 1.074 3.034 2.451 15.235 0.945 4.313

Fig. 1- Risk factors for hospital mortality, with expression value in the odds ratios and 95% confidence limit

DISCUSSION The identification of risk factors for patients undergoing valve replacement surgery has been studied for over 20 years [17]. The quantification of the factors identified and its neutralization by clinical and operative measures have decreased the risk of surgery [18]. Patients with severe valvular disease and minor systemic repercussions

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are being considered for surgery, due to their tendency to intervene earlier in the disease state, reflecting lower prevalence / intensity of recognized risk factors and, thus, resulting in lower hospital mortality [19]. But if some of the demographic or operative characteristics, which in the past increased surgical mortality and morbidity, can now have its influence minimized, and surgical indication progressively increased of older patients (and with more comorbidities) in different surgical series, can also induce changes in the profile of patients considered for valve surgery [20]. Thus, it is justified the periodic study of risk factors and keep this subject up-to-date.

The study of risk factors begins with the selection of demographic and surgical characteristics that characterize the population evaluated and the procedures performed.

Overall, we can state that the surgical experience confirms the influence of characteristics such as advanced age, low body mass index, renal insufficiency, low LVEF, indication for emergency surgery, heart surgery and others in the increased in-hospital mortality of patients with valvular heart diseases, and these must receive greater attention from physicians involved in their clinical and surgical management [21-23].

In this research, we used recognized characteristics from the literature [3,4,9,17,18], focusing on those presented by Ambler et al. [2]. This attitude is justified by the ready availability of medical information considered as part of the hospital record, and also because they had been previously used by the authors [13-15]. We opted to include pulmonary arterial hypertension as an additional factor, but other recognized factors were excluded, such as chronic obstructive pulmonary disease and peripheral vascular disease [3], which were not always correctly referred or quantified in hospital records.

The risk factors identified were female gender, age greater than or equal to 70 years, NYHA functional class III and IV, LVEF less than 30%, congestive heart failure, atrial fibrillation, hypertension, pulmonary hypertension, diabetes, serum creatinine greater than or equal to 1.4 mg / dL, mitral valve disease, previous cardiac surgery and CABG or associated tricuspid valve. It is interesting to note that these factors participate with their own score in the risk stratification model for heart valve surgery proposed by Ambler et al. [2]. These authors highlight the performance of previous cardiac surgery (regardless of type), emergency surgery; age over 79 years and renal failure with dialysis as strong predictors of increased mortality.

For Nowicki et al. [24] in a study on independent risk

factors for surgical aortic valve replacement, previous heart surgery represent a risk factor associated with age over 70 years, small body surface, elevated creatinine, NYHA class IV, previous cardiac arrest, CHF, AF, emergency and associated MR. For the mitral valve surgery, the statistically significant characteristics were: female patients, advanced age, DM, CABG, previous cerebrovascular accident, elevated creatinine, NYHA class IV, emergency situations and CHF. Roques et al. [25], in the EuroSCORE study, which configures program with score predictor of hospital mortality, found that previous heart surgery and concomitant CABG were associated with increased surgical risk. Other variables significantly associated with high mortality were: advanced age, creatinine, low LVEF, heart failure, pulmonary hypertension, emergency situations, multiple valve replacement or tricuspid procedure.

Edwards et al. [26] identified as independent risk factors for isolated valve replacement surgery, emergency situations, renal failure and cardiac arrest, and also the need for reoperation. This was also identified by Jamieson et al.

[3] as well as emergency surgery, renal failure (whether or not on dialysis), low LVEF, and NYHA functional class IV (NYHA). The need for reoperation during hospitalization was not identified in this study as a risk factor.

The use of odds ratio or OR as a resource for statistical analysis made it possible to estimate the surgical risk determined by each of the evaluated characteristics [27].

The predictors of increased risk in this study, in descending order, as the clinical characteristics were LVEF below 30%, DM, AF and pulmonary hypertension and as surgical characteristics were concomitant tricuspid valve surgery, mitral valve lesion and previous heart surgery.

Interestingly, age greater than or equal to 70 years, while contributing to increased mortality, it is quantified in reduced values in the OR, when compared to other factors.

Although elderly patients with valvular heart diseases may show more severe cardiac or systemic involvement (and comorbidities may contribute individually as risk factors), it is difficult to deny surgical treatment, so that specific perioperative care should be developed. This factor has been providing reduction in mortality, as stated in surgical experiments with groups of patients over the age of 70 [28] or 80 [29]. It is possible that the diffusion of percutaneous valve interventions may modify the surgical indication for older patients and may help to reduce surgical mortality.

However, consideration of age as a risk factor to be noted is illustrated when comparing current results with those of a study conducted by the authors regarding the 589

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definition of hospital risk for mechanical valve prosthesis implantation [15], in which hospital mortality observed was 3.9%, in favor of the present series, 9.9%. It is possible that several demographic characteristics determine the difference in mortality, taking into account the mean age of patients referred for mechanical prostheses implantation and bioprostheses implantation, higher in the latter group (46.8 years and 66.5 years, respectively). Studies comparing results with implantation of a bioprosthesis or mechanical prosthesis in populations with overlapping patients as clinical characteristics, similar to that performed by Feguri et al. [30] can determine whether the observed differences in relation to mortality and risk factors are due to the type of valve replacement or to several characteristics of populations with indications for different cardiac valves.

4. Jin R, Grunkemeier GL, Starr A; Providence Health System Cardiovascular Study Group. Validation and refinement of mortality risk models for heart valve surgery. Ann Thorac Surg. 2005;80(2):471-9.

CONCLUSIONS Hospital mortality observed in this study (9.9%) is consistent with the literature results. Risk factors for hospital mortality identified (associated tricuspid valve repair, mitral valve disease, LVEF less than 30% DM, AF, pulmonary hypertension, serum creatinine greater than or equal to 1.4 mg / dL, previous heart surgery, SAH functional class III and IV, associated CABG, aged greater than or equal to 70 years, CHF and female sex) had already been reported by other authors.

The possible neutralization of risk factors through changes in criteria for surgical indications, better clinical preoperative compensation and postoperative routine changes, may contribute to the reduction of surgical morbidity and mortality, as well as the costs of care.

5. Bueno RM, Ávila Neto V, Melo RFA. Fatores de risco em operações valvares: análise de 412 casos. Rev Bras Cir Cardiovasc. 1997;12(4):348-58.

6. Braile DM, Leal JC, Godoy MF, Braile MCV, Paula Neto A. Substituição valvar aórtica por bioprótese de pericárdio bovino: 12 anos de experiência. Rev Bras Cir Cardiovasc.

2003;18(3):217-20.

7. Almeida AS, Picon PD, Wender OCB. Resultados de pacientes submetidos à cirurgia de substituição valvar aórtica usando próteses mecânicas ou biológicas. Rev Bras Cir Cardiovasc.

2011;26(3):326-37.

8. Brandão CMA, Pomerantzeff PMA, Brandão LCA, Grinberg M, Stolf NAG, Verginelli G, et al. Análise da evolução tardia de 291 pacientes submetidos a substituição valvar por próteses metálicas. Rev Bras Cir Cardiovasc. 1995;10(1):50-5.

9. Anderson AJ, Barros Neto FX, Costa MA, Dantas LD, Hueb AC, Prata MF. Predictors of mortality in patients over 70 yearsold undergoing CABG or valve surgery with cardiopulmonary bypass. Rev Bras Cir Cardiovasc. 2011;26(1):69-75.

10. Oliveira Jr JL, Fiorelli AI, Santos RHB, Pomerantzeff PAM, Dallan LAO, Stolf NAG. A doença coronária aumenta a mortalidade hospitalar de portadores de estenose aórtica submetidos à substituição valvar? Rev Bras Cir Cardiovasc.

2009;24(4):453-62.

11. Guaragna JC, Bodanese LC, Bueno FL, Goldani MA. Proposed preoperative risk score for patients candidate to cardiac valve surgery. Arq Bras Cardiol. 2010;94(4):541-8.

12. Andrade IN, Moraes Neto FR, Oliveira JP, Silva IT, Andrade TG, Moraes CR. Assesment of the EuroSCORE as a predictor for mortality in valve cardiac surgery at the Heart Institute of Pernambuco. Rev Bras Cir Cardiovasc. 2010;25(1):11-8.

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2. Ambler G, Omar RZ, Royston P, Kinsman R, Keogh BE, Taylor KM. Generic, simple risk stratification model for heart valve surgery. Circulation. 2005;112(2):224-31.

3. Jamieson WR, Edwards FH, Schwartz M, Bero JW, Clark RE, Grover FL. Risk stratification for cardiac valve replacement.

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13. De Bacco MW, Sant’Anna JRM, De Bacco G, Sant’Anna RT, Santos MF, Pereira E, et al. Fatores de risco hospitalar para implante de bioprótese valvar de pericárdio bovino. Arq Bras Cardiol. 2007;89(2):125-30.

14. De Bacco G, De Bacco MW, Sant’Anna JRM, Santos MF, Sant’Anna RT, Prates PR, et al. Aplicabilidade do escore de risco de Ambler para pacientes com substituição valvar por bioprótese de pericárdio bovino. Rev Bras Cir Cardiovasc.

2008;23(3):336-43.

15. De Bacco MW, Sartori AP, Sant’Anna JRM, Santos MF, Prates PR, Kalil RAK, et al. Fatores de risco para mortalidade hospitalar no implante de prótese valvar mecânica. Rev Bras Cir Cardiovasc. 2009;24(3):334-40.

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16. Pereira E, Costa AR, Santos MF, Davidt NS, Lara RFA. Avaliação pré-operatória. In: Nesralla I, ed. Cardiologia cirúrgica: perspectivas para o ano 2000. São Paulo: BYK;1994. p.93-100.

compared to isolated aortic valve replacement. Thorac Cardiovasc Surg. 2006;54(7):459-63.

17. Scott WC, Miller DC, Haverich A, Dawkins K, Mitchell RS, Jamieson SW, et al. Determinants of operative mortality for patients undergoing aortic valve replacement. Discriminant analysis of 1,479 operations. J Thorac Cardiovasc Surg.

1985;89(3):400-13.

24. Nowicki ER, Birkmeyer NJ, Weintraub RW, Leavitt BJ, Sanders JH, Dacey LJ, et al; Northern New England Cardiovascular Disease Study Group and the Center for Evaluative Clinical Sciences, Dartmouth Medical School.

Multivariable prediction of in-hospital mortality associated with aortic and mitral valve surgery in Northern New England.

Ann Thorac Surg. 2004;77(6):1966-77.

18. Florath I, Rosendahl UP, Mortasawi A, Bauer SF, Dalladaku F, Ennker IC, et al. Current determinants of operative mortality in 1400 patients requiring aortic valve replacement. Ann Thorac Surg. 2003;76(1):75-83.

25. Roques F, Nashef SA, Michel P; EuroSCORE study group.

Risk factors for early mortality after valve surgery in Europe in the 1990s: lessons from the EuroSCORE pilot program. J Heart Valve Dis. 2001;10(5):572-7.

19. Hellgren L, Kvidal P, Stahle E. Improved early results after heart valve surgery over the last decade. Eur J Cardiothorac Surg. 2002;22(6):904-11.

26. Edwards FH, Peterson ED, Coombs LP, DeLong ER, Jamieson WR, Shroyer ALW, et al. Prediction of operative mortality after valve replacement surgery. J Am Coll Cardiol. 2001;37(3):885-92.

20. Hokken RB, Steyerberg EW, Verbaan N, van Herwerden LA, van Domburg R, Bos E. 25 years of aortic valve replacement using mechanical valves. Risk factors for early and late mortality. Eur Heart J. 1997;18(7):1157-65.

27. Hamilton MA. Choosing the parameter for 2 x 2 table or a 2 x 2 x 2 table analysis. Am J Epidemiol. 1979;109(3):362-75.

21. Mistiaen W, Van Cauwelaert P, Muylaert P, Wuyts F, Harrisson F, Bortier H. Risk factors and survival after aortic valve replacement in octogenarians. J Heart Valve Dis. 2004;13(4):538-44.

22. Albeyoglu SC, Filizcan U, Sargin M, Cakmak M, Goksel O, Bayserke O, et al. Determinants of hospital mortality after repeat mitral valve surgery for rheumatic mitral valve disease.

Thorac Cardiovasc Surg. 2006;54(4):244-9.

23. Litmathe J, Boeken U, Kurt M, Feindt P, Gams E. Predictive risk factors in double-valve replacement (AVR and MVR)

28. Tseng EE, Lee CA, Cameron DE, Stuart RS, Greene PS, Sussman MS, et al. Aortic valve replacement in the elderly. Risk factors and long-term results. Ann Surg.

1997;225(6):793-802.

29. Melby SJ, Zierer A, Kaiser SP, Guthrie TJ, Keune JD, Schuessler RB, et al. Aortic valve replacement in octogenarians: risk factors for early and late mortality. Ann Thorac Surg.

2007;83(5):1651-6.

30. Feguri GF, Macruz H, Bulhões D, Neves A, Castro RM, Fonseca L, et al. Troca valvar aórtica com diferentes próteses.

Existem diferenças nos resultados da fase hospitalar? Rev Bras Cir Cardiovasc. 2008;23(4):534-41.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):592-9

In vivo study of lyophilized bioprostheses: 3 month follow-up in young sheep Estudo in vivo do comportamento de bioprótese liofilizada: seguimento de 3 meses em carneiros jovens

Fábio Papa Taniguchi1, Marina Junko Shiotsu Maizato2, Rafael Fávero Ambar3, Ronaldo Nogueira de Moraes Pitombo4, Adolfo Alberto Leiner5, Luiz Felipe Pinho Moreira5, Idágene Aparecida Cestari6, Noedir Antônio Groppo Stolf7

DOI: 10.5935/1678-9741.20120101

RBCCV 44205-1426

Abstract Objective: Glutaraldehyde is currently used in bovine pericardium bioprosthesis to improve mechanical and immunogenic properties. Lyophilization is a process that may decrease aldehyde residues in the glutaraldehyde treated pericardium decreasing cytotoxicity and enhancing resistance to calcification. The aim of this study is to evaluate bioprosthetic heart valves calcification in adolescent sheep and to study the potential of lyophilization as a mechanism to protect calcification.

Methods: Two groups were evaluated: a control group in which a bovine pericardium prosthetic valve was implanted in pulmonary position and a lyophilized group in which the bovine pericardium prosthetic valve was lyophilized and further implanted. Sixteen sheeps 6 months old were submitted to the operation procedure. After 3 months the sheeps were euthanized under full anesthesia.

Results: Six animals of the control group reached 95.16 ± 3.55 days and six animals in the lyophilized group reached

91.66 ± 0.81 days of postoperative evolution. Two animals had endocarditis. Right ventricle/pulmonary artery (RV/PA) mean gradient, in the control group, at the implantation was 2.04 ± 1.56 mmHg, in the lyophilization group, the RV/PA mean gradient, at the implantation was 6.61 ± 4.03 mmHg. At the explantation it increased to 7.71 ± 3.92 mmHg and 8.24 ± 6.25 mmHg, respectively, in control and lyophilization group.

The average calcium content, after 3 months, in the control group was 21.6 ± 39.12 μg Ca+2/mg dry weight, compared with an average content of 41.19 ± 46.85 μg Ca+2/mg dry weight in the lyophilization group (P=0.662).

Conclusion: Freeze drying of the bovine pericardium prosthesis in the pulmonary position could not demonstrate calcification mitigation over a 3 month period although decreased inflammatory infiltration over the tissue.

1. State Civil Servants Hospital - IAMSPE; Postgraduate Doctor of Thoracic and Cardiovascular Surgery - USP, São Paulo, SP, Brazil.

2. Heart Institute - HCFMUSP; PhD in Engineering - UNICAMP, São Paulo, SP, Brazil.

3. State Civil Servants Hospital - IAMSPE; Resident in General Surgery, São Paulo, SP, Brazil.

4. School of Chemistry - University of São Paulo; Professor, São Paulo, SP, Brazil.

5. Heart Institute - HCFMUSP; Tenured Professor, São Paulo, SP, Brazil.

6. Heart Institute - HCFMUSP; PhD in Biological Sciences from UNIFESP, São Paulo, SP, Brazil.

7. Heart Institute - HCFMUSP; Emeritus Professor of Cardiovascular Surgery, São Paulo, SP, Brazil.

Work performed at the Heart Institute - HCFMUSP, São Paulo, SP, Brazil.

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Descriptors: Animal experimentation. Bioprosthesis.

Cardiac surgical procedures. Freeze drying.

Correspondence address Fabio P. Taniguchi 202 Itapeva Street - Block 91 - Sao Paulo, SP, Brazil – Zip code: 01332-001 E-mail: taniguchi@sbccv.org.br Support: FAPESP (process no 04/0566-8) Article received on May 8th, 2012 Article approved on August 27th, 2012

Taniguchi FP, et al. - In vivo study of lyophilized bioprostheses: 3 month follow-up in young sheep

Abbreviations, acronyms and symbols LBPB ECC IC SPSS ACT RV RV/PA

Lyophilized bovine pericardial bioprosthesis Extracorporeal circulation Interatrial communication Statistical Package for the Social Sciences Activated clotting time Right ventricle Right ventricle / Pulmonary artery

Resumo Objetivo: Para melhorar as propriedades mecânicas e imunogênicas, o glutaraldeído é utilizado no tratamento do pericárdio bovino que é utilizado em biopróteses. A liofilização do pericárdio bovino tratado com glutaraldeído diminui os radicais aldeído, com provável redução do potencial para calcificação. O objetivo deste estudo é avaliar os efeitos da liofilização em biopróteses valvares de pericárdio bovino como mecanismo protetor na diminuição da disfunção estrutural valvar.

Métodos: Foi realizado o implante de biopróteses de pericárdio bovino tratado com glutaraldeído, liofilizadas

INTRODUCTION The prostheses are used in cardiovascular surgery for being viable alternatives in the treatment of heart valve dysfunction when they present significant functional and morphological dysfunction. Bioprostheses must provide long-lasting performance in the role, but the structural valvular dysfunction can occur precociously due to the calcification of the biological tissues [1-3].

The need for reoperation for structural valve dysfunction has been less than 5% in 5 years; less than 10% in 10 years and over 70% in 15 years. When this structural dysfunction occurs, it is necessary to replace the bioprosthesis, with increased surgical morbimortality [1,4,5].

Lyophilization is a process of drying a previously frozen product where the solvent is removed by sublimation.

Through this process high quality dehydrated products can be obtained, preserving their structure and minimizing loss of volatiles products that are not observed during drying by conventional means.

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ou não, em carneiros de 6 meses de idade, sendo os animais eutanasiados com 3 meses de seguimento. As biopróteses foram implantadas em posição pulmonar, com auxílio de circulação extracorpórea. Um grupo controle e outro grupo liofilizado foram avaliados quanto ao gradiente ventrículo direito/artéria pulmonar (VD/AP) no implante e explante; análise quantitativa de cálcio; inflamação; trombose e pannus. O nível de significância estabelecido foi de 5%.

Resultados: O gradiente médio VD/AP, no grupo controle, no implante, foi 2,04 ± 1,56 mmHg e, no grupo de liofilização, foi 6,61 ± 4,03 mmHg. No explante, esse gradiente aumentou para 7,71 ± 3,92 mmHg e 8,24 ± 6,2 mmHg, respectivamente, nos grupos controle e liofilização. O teor de cálcio médio, após 3 meses, nas biopróteses do grupo controle foi 21,6 ± 39,12 µg Ca+2/mg de peso seco, em comparação com um teor médio de 41,19 ± 46,85 µg Ca+2/mg de peso seco no grupo liofilizado (P = 0,662).

Conclusão: A liofilização de próteses valvares com pericárdio bovino tratado com glutaraldeído não demonstrou diminuição da calcificação neste experimento.

Descritores: Experimentação animal. Bioprótese.

Procedimentos cirúrgicos cardíacos. Liofilização.

Lyophilized biological tissues for implantation in animals and humans have already been used. In the 1960s, lyophilized aortic valve heterografts were used, but the results were unfavorable [6,7].

Previous works from our group with the annealing protocol showed that the lyophilization process does not significantly alter the mechanical characteristics of bovine pericardium treated with glutaraldehyde [8], but significantly decreases the amount of residual aldehydes that the cytotoxicity relate to inflammatory processes and tissue calcification [9].

We designed a protocol in which bovine pericardial bioprostheses treated with glutaraldehyde were lyophilized and implanted in chronic animal model. The implant was performed in young sheeps, because it is known that this model allows the study of biological processes inherent to calcification and consequent structural valve dysfunction after some months after implantation [10].

The objective of this study is to evaluate the effects of annealing lyophilized in bovine pericardial bioprostheses treated with glutaraldehyde in chronic animal model.

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METHODS All animals used in this study were treated according to the "Guide for the Care and Use of Laboratory Animals" published by the National Institute of Health (NIH publication 85-23, revised 1996). Ethics Committee Heart Institute, University of São Paulo approved the study (protocol 994/05).

Definition of groups Two groups were formed. The first one was called control group, in which a bovine pericardial bioprosthesis (Braile Biomédica, São José do Rio Preto, Brazil) was implemented, and the other group was called lyophilized bovine pericardial bioprosthesis (LBPB), in which a bovine pericardial bioprosthesis (Braile Biomédica, São José do Rio Preto, Brazil) was lyophilized and subsequently implanted.

Lyophilized bovine pericardial bioprosthesis (LBPB) Initially, the biological prosthesis was rinsed in saline solution to remove all the aldehyde. The bioprosthesis was lyophilized in a FTS Systems TDS-00209-A Model (DuraStop, Dura-Dry-MP, FTS Systems, Stone Ridge, NY, USA). The freezing process was initiated by placing the bioprosthesis in a ultrafreezer for 2 hours at -50°C. After that, it was heated back to 20°C for 1 hour.

Finally, the prostheses were cooled to -50°C and lyophilized. The primary drying was performed at -5°C at atmospheric pressure of 160 mTorr. For the secondary drying, the temperature was raised to 25°C in the same atmospheric pressure.

Surgical implant We used Santa Inês sheep in this study. Sixteen lambs with 6 months of age and an average weight of 36.53 ± 3.42 kg (ranging from 28.5 kg to 42 kg) underwent the procedure successfully.

Anesthesia The animals were fasted for 36 hours. Anesthesia was induced with ketamine (8 mg / kg) and Midazolam (0.5 mg / kg). Isoflurane and fentanyl (5 mg / kg) were used for maintenance of anesthesia. In induction, cefuroxime (750 mg) was administered intravenously as antibiotic prophylaxis.

Extracorporeal Circulation (ECC) The ECC circuit was filled with 400 ml of Lactated Ringer's solution, 50 ml of 20% mannitol, 10 mL of 10% calcium gluconate, 10 mL of 10% magnesium sulfate, 500 mg of hydrocortisone, 750 mg of cefuroxime and 5000 IU heparin.

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Normothermia at 36°C was used during circulation with non-pulsatile blood flow of 2.4 L/min/m2 with a centrifugal pump (FlowPump 6000S, IBC, Austin, Texas, USA) to maintain perfusion pressure 60 to 80 mmHg. A set of tubes, a venous blood reservoir and arterial filter (Braile Biomédica, São José do Rio Preto, Brazil) were used.

Surgical Procedure We performed left anterolateral thoracotomy in the fourth intercostal space to expose the heart after pericardiotomy. Heparin sodium was administered (4 mg / kg) to achieve an activated clotting time (ACT) greater than 480 seconds. To perform the circulatory bypass of the right atrium to the pulmonary artery, a 20F arterial cannula was placed in the pulmonary artery, 1 cm below the left branch, and a 34F venous cannula was placed in the right atrium. Cardiac arrest did not occur and the pulmonary ventilation was maintained.

The pulmonary artery was clamped, proceeding to the longitudinal arteriotomy in the pulmonary trunk section of the annulus and the right ventricle outflow tract. Pulmonary cusps were removed. A bioprosthetic valve-in-ring implantation was performed with a 5-0 polypropylene continuous suture. A bovine pericardial patch was treated with non-lyophilized glutaraldehyde which was used to enlarge the right ventricle outflow and pulmonary artery. All animals were implanted with bovine pericardial prosthetic valve No 23 (Braile Biomédica, São José do Rio Preto, Brazil). Prior to implantation in the control group and LBPB, the bioprostheses were washed with saline solution for 30 minutes. The ECC was stopped and the entire volume was infused to achieve mean arterial pressure of 80 mmHg. Protamine sulfate was not administered to any animal.

Pressure Gradient While evaluating the transvalvular gradient, we punctured the pulmonary trunk and the right ventricle (RV) outflow tract with a 0.9 mm needle connected to a multiparameter analyzer (5900 CAGE Signal Conditioner, Gould Inc., Valley View, Ohio, USA ). Ten cycles were analyzed with a software system (v.2.19 Windaq, Dataq Instruments, Inc., Akron, OH, USA), which used the average systolic pressures in 10 cycles for analysis. The same procedure was performed at the time of euthanasia.

Prosthesis Excision After three months, the animals were euthanized under general anesthesia. The heart was dissected through the right atrium and all the blood was drained. The excision of the prosthesis was performed with a segment of the pulmonary artery, the anterior wall of the right ventricle and non-lyophilized bovine pericardial patch.

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Each prosthetic cusp was named according to the anatomical relationshiop with the aorta, the left atrium and the non-lyophilized patch. Subsequently, the prosthetic cusps were removed, divided into two symmetrical parts for performing histological staining with hematoxylin and eosin, von Kossa staining and determining the amount of calcium by atomic absorption spectrophotometry. The nonlyophilized bovine pericardial patch was also analyzed by the methods described.

Clinically, all animals that completed the study had normal physical activity from the first day after surgery.

The animals did neither show any symptoms of heart failure nor general health problems during the study.

Macroscopic evaluation Each bioprosthesis was carefully post mortem examined for morphological evaluation after implantation.

We evaluated the cusp mobility, lacerations, pannus, calcification, vegetations and thrombus formation.

Microscopic evaluation Anatomopathological examinations were performed with hematoxylin-eosin and von Kossa staining for specific analysis of calcium. In the segments examined, we evaluated inflammation, thrombus and pannus presence and intensity of calcification. Intensity was used as the criterion, being classified as absent; (-) rare detection; (+ +) dispersed but consistent, (+ + +) present with uniformity and (+ + + +) generalized distribution.

Quantification of calcium The determination of calcium amount was performed after acid hydrolysis in a flame atomic absorption spectrophotometer (Analytik Jena, AAS Vario 6, Jena, Germany).

Statistical Analysis Data from atomic absorption spectroscopy were expressed as mean ± standard deviation. Groups were compared using the Mann-Whitney test. Scores for calcium, thrombus, inflammation and pannus were evaluated by means of a continuous scale. The significance level was set at 5%. We used the Statistical Package for the Social Sciences v.11.0 (SPSS, Chicago, IL, USA).

RESULTS Among the 16 animals that underwent surgery, 12 had the expected survival of 90 days. Six animals in the control group reached 95.1 ± 3.5 days (91 to 99 days) of postoperative outcome. Two animals died on the 37th and 48th days, both from pneumonia. An animal that survived for 91 days was not considered in the analysis for measurement of calcium, due to the presence of endocarditis.

In the LBPB group, six animals reached 91.6 ± 0.8 days (91 to 93 days), two animals in this group died within 51 and 68 days, due to pneumonia and endocarditis.

Right ventricle gradient / pulmonary artery (RV / PA) In the control group, the mean gradient RV / PA in implantation was 2.04 ± 1.56 mmHg, ranging from 0 to 4.38 mmHg, while in explants there was an increase to 7.71 ± 3.92 mmHg, ranging from 3.25 to 11.95 mmHg. In the LBPB group, the mean gradient RV / PA in implantation was 6.61 ± 4.03 mmHg, ranging from 4.55 to 11.84 mmHg, while in explant there was an increase to 8.24 ± 6.25 mmHg, ranging from 3.78 to 17.48 mmHg. Figure 1 shows the evolution of the gradient for each animal in the control group and LBPB group. In this chart, the excluded animals were not shown.

Fig. 1 - Analysis of the transvalvular gradient RV / PA

Post mortem observations At euthanasia, all animals had dense adhesions among the pleura, the pericardium and heart. The bovine pericardial patch was flexible, with scattered sites of calcification.

Macroscopic evaluation Presence of thrombi or lacerations was not found in any implanted bioprosthesis. The cusps of the two groups had their mobility partially impaired, with non-homogeneous sites of calcification. All prostheses in the control group and the LBPB group developed pannus.

Microscopic evaluation There has been significant development of pannus in the bioprostheses in both groups. It was observed that, descriptively, more intense inflammation in bioprostheses in the control group compared to LBPB group (Figure 2), which showed lower inflammatory infiltrate (Table 1).

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Taniguchi FP, et al. - In vivo study of lyophilized bioprostheses: 3 month follow-up in young sheep

Control

Lyophilized

Fig. 2 - Valve prostheses calcification evidenced by Von Kossa method

Control

Lyophilized

Fig. 3 - Inflammatory infiltrate in bioprostheses

Table 1. Histological changes after bioprostheses implantation.

Prosthesis Implanted Inflammation Pannus inflammation bioprosheses intensity of formation pericardial patch +++ Control 1 ++++ ++++ +++ Control 2 ++++ ++++ +++ Control 3 ++++ ++++ + Control 4 ++++ ++++ + Control 5 ++++ +++++ Control 6 ++++ Lyophilized 1 + +++++ Lyophilized 2 + ++ + Lyophilized 3 + +++ Lyophilized 4 + ++++ Lyophilized 5 ++ ++++ + Lyophilized 6 +++ +++ (-) = absent; (+) = rare, (+ +) = dispersed, (+ + +) = uniform; (+ + + +) = generalized

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The presence of calcification was seen in the control group and in the LBPB group (Figure 3).

Quantitative analysis of calcium The average amount of calcium in the cusps of the control group was 21.60 ± 39.12 mg Ca+2 / mg dry weight, compared with an average amount of 41.19 ± 46.85 mg Ca+2 / mg dry weight in the LBPB group (P = 0.818). The animal excluded from the control group due to endocarditis had an average amount of calcium in the cusps of 11.63 ± 6.45 mg Ca+2 / mg dry weight and 0.63 ± 0.01 mg Ca+2 / mg dry weight in the pericardial patch.

In the control group, the average amount of calcium in the patch was 1.52 ± 0.98 mg Ca+2 / mg dry weight, and 1.14 ± 0.51 mg Ca+2 / mg dry weight in the LBPB group. There was no statistical difference between groups (P = 0.662).

Table 2 shows the average amount of calcium (Ca+2 mg / mg dry weight) in the cusps and in the pericardial patch, as well as the control groups and LBPB group.

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Table 2. Determination of calcium by atomic absorption spectrophotometry.

fixing agents [18-20]. The development of methods for the extraction of derivatives of glutaraldehyde showed that the calcification process rests on dialdehydes and their polymerization products [20,21]. Our group evaluated the possibility of a bovine pericardial valve bioprosthesis, chemically treated with glutaraldehyde, which when subjected to freeze-drying process by annealing could present less calcification in the follow-up period, since glutaraldehyde residual is considered as a calcification factor.

Although there are works from the 1960s regarding the lyophilization of homografts with unfavorable results [6,7], the present study differs by using bovine pericardial bioprosthesis treated with glutaraldehyde and subsequently lyophilized by a technique which incorporates the annealing process.

In the interatrial septum, after the creation of an interatrial communication (IC) in dogs, and implantation of a bovine pericardial patch treated with lyophilized glutaraldehyde, a slight pannus formation was reported [22]. In our study, the formation of pannus was relevant in both lyophilized and non- lyophilized bioprostheses.

Although we have used bioprostheses while SantibáñezSalgado et al. interatrial septal patch, we believe that the formation of pannus in our study may be related to low pressure in the right atrium and the pulmonary artery.

In bovine pericardial bioprostheses, the presence of inflammatory cells is related to increased structural valve degeneration, resulting in cusp lacerations [23]. In this study, we found that the control group showed greater inflammatory response when compared to the LBPB group, indicating a possible protective mechanism of the lyophilization process for the inflammatory response.

In an experiment with a 5-month postoperative period after implantation in the mitral prosthesis with bovine pericardium (Arbor Surgical Technologies Inc, Irvine, CA), there was an average of 1.05 mg Ca+2 / mg dry weight (ranging from 0, 65 to 2.58 mg Ca+2 / mg dry weight), and the Carpenier-Edwards Perimount prosthesis (Edwards Lifesciences, Irvine, CA, USA) the average was 3.23 mg Ca +2 / mg dry weight (ranging from 1.52 to 23.8 mg Ca +2 / mg dry weight) [10]. In our experiment with implantation during three months in the pulmonary position, there was a higher average amount of calcium with 21.60 ± 39.12 mg Ca+2 / mg dry weight (ranging from 0.92 to 91.43 mg Ca+2 / mg dry weight) in the control group. It was not observed in this experiment that lyophilization decreases calcification, because the average amount of calcium was 41.19 ± 46.85 mg Ca+2 / mg dry weight in LBPB group (ranging from 1.93 to 114.60 mg Ca+2/ mg dry weight).

It is also important to mention that the final gradient through the bioprosthesis during the period of three months showed similar results between groups (7.71 ± 3.92 versus

Determination of calcium (µgCa+2/mg dry weight ) Control Group 1 2 3 4 5

Cusps

Pericardial patch

91.43 ± 55.77 1.72 ± 0.79 0.92 ± 0.35 5.37 ± 8.34 8.87 ± 7.32

0.67 ± 0.04 1.66 ± 0.01 2.83 ± 0.02 2.00 ± 0.20 0.44 ± 0.01

LBPB Group 1 2 3 4 5 6

1.93 ± 0.71 114.60 ± 38.63 65.60 ± 69.64 60.9 ± 75.46 1.23 ± 0.28 2.89 ± 0.75

0.75 ± 0.03 1.34 ± 0.09 0.70 ± 0.03 1.92 ± 0.03 0.67 ± 0.01 1.47 ± 0.03

DISCUSSION Bioprostheses are viable alternatives in the treatment of cardiac valves in patients with significant morphological and functional valvular dysfunction [1,2]. Even with the technological advances in the technical processing and handling of biological tissues, clinical studies continue to demonstrate that patients also suffer from structural bioprosthesis deterioration [11-14].

Previous studies from our group demonstrated that lyophilized bovine pericardium treated with glutaraldehyde promotes reduction of aldehyde residuals, from the treatment with glutaraldehyde tissue [9]. As it is known, glutaraldehyde is used in the pericardium as an alternative treatment of biological tissues in order to improve mechanical and immunogenic properties and because it stabilizes the structure of collagen, increase resistance to enzymatic degradation, reduces thrombogenicity and antigenicity [15,16]. The disadvantage of this method is that during the process of fixation with glutaraldehyde there is a loss of endothelial cells, interstitial cell viability and also loss of inhibitors of calcification process because the fragmentation of cellular membranes progresses with the release of phospholipids which allow the deposition of phosphates calcium.

Unfortunately, these processes increase the biological tissue calcification [15,16]. Furthermore, the free aldehyde groups and the phospholipids in combination with calcium ions circulation can induce calcification [11,17]. Different strategies to prevent calcification have been reported, including use of inhibitors of calcification in fixed tissue, removal or modification of calcifying components, modification in the process of fixing and using other

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8.24 ± 6.25 mmHg) despite the difference in the implant (2.04 ± 1.56 mmHg vs. 6.61 ± 4.03 mmHg). We believe that this result is due to the LBPB group not has been fully hydrated during the 30 minutes wash with saline solution, causing greater rigidity in their cusps in the initial phase.

There are some limiting factors in this study. This is an experimental study which was conducted with a reduced initial sample of animals. Late survival involved multiple variables in the treatment of the animals that were under strict veterinary supervision, however it was not standardized. The postoperative follow-up for the assessment of bioprostheses calcification, although debatable, could include more time for observation. The implantation in pulmonary position evaluated the system with bioprostheses in lower pressure, which reduced the processes of structural valve degeneration. Although this study failed to show that lyophilization was a protection for calcification, it signaled an improvement in the inflammatory aspect, which in our view is an advantage in the aspect of bioprostheses structural degeneration.

In addition to that, it has the advantage of easy handling and preservation, since the bioprosthesis can be stored dry and sterilized by conventional means such as gamma radiation. We should also improve the bioprostheses hydration by changing some parameters of lyophilization with annealing, so that complete hydration occurs in less time. The fact that there was no statistical difference in calcification in the control group and in the LBPB group may also mean that the calcification factor in bovine pericardial bioprostheses due to residual glutaraldehyde from the treatment of pericardial membranes is not a major cause for either calcifying the bioprostheses or not.

2. David TE, Armstrong S, Maganti M. Hancock II bioprosthesis for aortic valve replacement: the gold standard of bioprosthetic valves durability? Ann Thorac Surg. 2010;90(3):775-81.

CONCLUSION Finally, we conclude that this study failed to demonstrate the protective mechanism of freeze drying as an anticalcification agent of bovine pericardium treated with glutaraldehyde. Histologic evaluation showed a smaller inflammatory process of the lyophilized tissue, but it requires further studies.

3. Clark JN, Ogle MF, Ashworth P, Bianco RW, Levy RJ. Prevention of calcification of bioprosthetic heart valve cusp and aortic wall with ethanol and aluminum chloride. Ann Thorac Surg. 2005;79(3):897-904.

4. Ruel M, Kulik A, Rubens FD, Bédard P, Masters RG, Pipe AL, et al. Late incidence and determinants of reoperation in patients with prosthetic heart valves. Eur J Cardiothorac Surg.

2004;25(3):364-70.

5. Poirer NC, Pelletier LC, Pellerin M, Carrier M. 15year experience with the Carpentier-Edwards pericardial bioprosthesis. Ann Thorac Surg. 1998;66(6Suppl):S57-61.

6. Duran CG, Gunning AJ, Whitehead R. Experimental aortic valve heterotransplantation. Thorax. 1967;22(6):510-8.

7. Duran CM, Whitehead R, Gunning AJ. Implantation of homologous and heterologous aortic valves in prosthetic vascular tubes. Thorax. 1969;24(2):142-7.

8. Borgognoni CF, Maizato MJ, Leirner AA, Polakiewicz B, Beppu MM, Higa OZ, et al. Effect of freeze-drying on the mechanical, physical and morphological properties of glutaraldehyde-treated bovine pericardium: evaluation of freeze-dried treated bovine pericardium properties. J Appl Biomater Biomech. 2010;8(3):186-90.

9. Maizato MJ, Higa OZ, Mathor MB, Camillo MA, Spencer PJ, Pitombo RN, et al. Glutaraldehyde-treated bovine pericardium: effects of lyophilization on cytotoxicity and residual aldehydes.

Artif Organs. 2003;27(8):692-4.

10. Flameng W, Meuris B, Yperman J, De Visscher G, Herijgers P, Verbeken E. Factors influencing calcification of cardiac bioprostheses in adolescent sheep. J Thorac Cardiovasc Surg.

2006;132(1):89-98.

11. Schoen FJ, Levy RJ. Calcification of tissue heart valve substitutes: progress toward understanding and prevention.

Ann Thorac Surg. 2005;79(3):1072-80.

This project received financial assistance from FAPESP (process no 04/0566-8).

12. McClure RS, Narayanasamy N, Wiegerinck E, Lipsitz S, Maloney A, Byrne JG, et al. Late outcomes for aortic valve replacement with the Carpentier-Edwards pericardial bioprosthesis: up to 17-year follow-up in 1,000 patients. Ann Thorac Surg. 2010;89(5):1410-6.

REFERENCES

13. Jamieson WR, Lewis CT, Sakwa MP, Cooley DA, Kshettry VR, Jones KW, et al. St Jude Medical Epic porcine bioprosthesis: results of the regulatory evaluation. J Thorac Cardiovasc Surg.

2011;141(6):1449-54.e2.

1. Rahimtoola SH. Choice of prosthetic heart valve in adults an update. J Am Coll Cardiol. 2010;55(22):2413-26.

14. ISTHMUS Investigators. The Italian study on the Mitroflow postoperative results (ISTHMUS): a 20-year, multicentre

ACKNOWLEDGMENTS

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evaluation of Mitroflow pericardial bioprosthesis. Eur J Cardiothorac Surg. 2011;39(1):18-26.

19. Hahn SK, Ohri R, Giachelli CM. Anti-calcification of bovine pericardium for bioprosthetic heart valves after surface modi- fication with hyaluronic acid derivatives. Biotechnol Bioprocess Eng. 2005;10:218-24.

15. Beauchamp RO Jr, St Clair MB, Fennell TR, Clarke DO, Morgan KT, Kari FW. A critical review of the toxicology of glutaraldehyde. Crit Rev Toxicol. 1992;22(3-4):143-74.

16. Golomb G, Schoen FJ, Smith MS, Linden J, Dixon M, Levy RJ. The role of glutaraldehyde-induced cross-links in calcification of bovine pericardium used in cardiac valve bioprostheses. Am J Pathol. 1987;127(1):122-30.

17. Guldner NW, Jasmund I, Zimmermann H, Heinlein M, Girndt B, Meier V, et al. Detoxification and endothelialization of glutaraldehyde-fixed bovine pericardium with titanium coating: a new technology for cardiovascular tissue engineering. Circulation. 2009;119(12):1653-60.

18. Clark JN, Ogle MF, Ashworth P, Bianco RW, Levy RJ. Prevention of calcification of bioprosthetic heart valve cusp and aortic wall with ethanol and aluminum chloride. Ann Thorac Surg. 2005;79(3):897-904.

20. Zilla P, Fullard L, Trescony P, Meinhart J, Bezuidenhout D, Gorlitzer M, et al. Glutaraldehyde detoxification of aortic wall tissue: a promising perspective for emerging bioprosthetic valve concepts. J Heart Valve Dis. 1997;6(5):510-20.

21. Weissenstein C, Human P, Bezuidenhout D, Zilla P. Glutaraldehyde detoxification in addition to enhanced amine cross-linking dramatically reduces bioprosthetic tissue calcification in the rat model. J Heart Valve Dis. 2000;9(2):230-40.

22. Santibáñez-Salgado JA, Olmos-Zúñiga JR, Pérez-López M, Aboitiz-Rivera C, Gaxiola-Gaxiola M, Jasso-Victoria R, et al. Lyophilized glutaraldehyde-preserved bovine pericardium for experimental atrial septal defect closure. Eur Cell Mater.

2010;19:158-65.

23. Zilla P, Brink J, Human P, Bezuidenhout D. Prosthetic heart valvae: catering for the few. Biomaterials. 2008;29(4):385-406.

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ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):600-6

Does diabetes mellitus increase immediate surgical risk in octogenarian patients submitted to coronary artery bypass graft surgery?

Diabetes mellitus aumenta risco cirúrgico imediato em pacientes octogenários submetidos à cirurgia de revascularização miocárdica?

Fernando Pivatto Júnior1, Edemar M. C. Pereira2, Felipe H. Valle3, Guaracy F. Teixeira Filho3, Ivo A. Nesralla4, João R. M. Sant’Anna4, Paulo R. Prates3, Renato A. K. Kalil5

DOI: 10.5935/1678-9741.20120102

RBCCV 44205-1427

Abstract Introduction: Diabetes is a well known risk factor for early and late adverse outcomes in patients undergoing coronary artery bypass graft surgery (CABG); however, few studies have investigated the impact of this risk factor in the group of older patients, especially octogenarians.

Objectives: To compare in-hospital mortality and morbidity of diabetic and nondiabetic patients aged ≥ 80 years submitted to CABG. Methods: A total of 140 consecutive cases were studied, of whom 37 (26.4%) were diabetics, in a retrospective crosssectional study, that included all patients aged ≥ 80 years submitted to isolated/associated CABG. The patients’ mean age was 82.5 ± 2.2 years and 55.7% were males.

Results: The hospital mortality rate did not significantly differ in multivariate analysis: 16.2% diabetic x 13.6% nondiabetic (P = 0.554), as well as morbidity: 43.2% x 37.9%, respectively (P = 0.533). Regarding to operative morbidity, the occurrence of stroke was significantly higher in diabetic patients in the univariate analysis (10.8% x 1.9%, P = 0.042).

In multivariate analysis, however, the incidence of stroke was not associated with the presence of diabetes (P = 0.085), but it

was associated with atrial fibrillation (P = 0.044). There was no significant difference related to other complications.

Conclusion: In this small consecutive retrospectively analyzed series, there was no significant increase in hospital mortality and morbidity related to diabetes for CABG in octogenarian patients. The impact of the results of this study is limited by the sample size and might be confirmed by future randomized clinical trials.

1 - MD, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC) – Main author 2 - MD, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC) and Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) - Co-authorship 3 - MD, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC) - Co-authorship 4 - MD, PhD, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC) - Co-authorship 5 - MD, PhD, Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC) and Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA) - Co-authorship

From the Post-Graduation Program in Cardiology of Instituto de Cardiologia / Fundação Universitária de Cardiologia (IC / FUC), Porto Alegre, Brazil.

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Descriptors: Myocardial revascularization. Aged. Aged, 80 and over. Diabetes mellitus.

Resumo Introdução: O diabetes é um fator de risco conhecido para eventos adversos precoces e tardios em pacientes submetidos à cirurgia de revascularização miocárdica (CRM); entretanto, poucos estudos investigaram sua influência no grupo de pacientes mais idosos, especialmente nos octogenários.

Objetivos: Comparar a mortalidade e a morbidade hospitalar de pacientes com idade ≥ 80 anos diabéticos e nãodiabéticos submetidos à CRM.

Correspondence address: Renato A. K. Kalil – Research Unit of IC/FUC. Av. Princesa Isabel, 370 – Porto Alegre, RS, Brazil – Zip Code: 90620-000 E-mail: kalil@cardiologia.org.br Article received on June 25th, 2012 Article accepted on September 23rd, 2012

Rev Bras Cir Cardiovasc 2012;27(4):600-6

Pivatto Júnior F, et al. - Does diabetes mellitus increase immediate surgical risk in octogenarian patients submitted to coronary artery bypass graft surgery?

Abbreviations, acronyms & symbols ADA CPB CABG HbA1c IC/FUC IABP LVEF NYHA ROC

American Diabetes Association Cardiopulmonary bypass Coronary artery bypass grafting Glycosilated hemoglobin Instituto de Cardiologia do Rio Grande do Sul Intra-aortic balloon pump Left ventricle ejection fraction New York Heart Association Receiver operating characteristic

Métodos: Foram estudados 140 casos consecutivos, sendo 37 (26,4%) diabéticos, em um estudo transversal retrospectivo incluindo todos os pacientes com idade ≥ 80 anos submetidos à CRM isolada/associada. A idade média dos pacientes foi de 82,5 ± 2,2 anos e 55,7% eram do sexo masculino.

Resultados: A taxa de mortalidade hospitalar não diferiu de maneira significativa na análise multivariada entre os

INTRODUCTION Diabetes is a well-known risk factor for ischemic heart disease. Coronary artery disease is not only more prevalent in diabetic patients (55%) compared with the rest of the population (2% to 4%) but tends to be more extensive, involving multiple vessels and being rapidly progressive. Moreover, diabetes is also a significant risk factor for early and late adverse outcomes after myocardial revascularization with coronary artery bypass grafting (CABG) [1].

Approximately 20% of patients who undergo CABG have diabetes mellitus. Diabetes has been associated with higher perioperative morbidity as well as decreased survival after this procedure. Diabetic patients who undergo surgical revascularization of coronary arteries represent a large and complex subgroup of bypass patients [2].

The elderly are expected to have a higher rate of morbid outcomes after surgery than younger patients, despite recent advancements in technology, pharmacotherapy, and perioperative management that are improving postoperative outcomes. Coronary artery disease is increasingly prevalent in the elderly population. With advances in surgical technique, the incidence of CABG surgery performed in elderly patients has been increasing over recent years [3].

Octogenarians are an expanding group of patients

grupos, 16,2% diabéticos x 13,6% não-diabéticos (P=0,554), assim como a morbidade pós-operatória, 43,2 x 37,9%, respectivamente (P=0,533). Em relação à morbidade, a ocorrência de acidente vascular cerebral foi significativamente maior em pacientes diabéticos na análise univariada (10,8% x 1,9%; P = 0,042). Na análise multivariada, no entanto, a incidência dessa complicação não foi associada com a presença de diabetes (P=0,085), mas com a presença de fibrilação atrial (P=0,044). Não se observou nenhuma diferença significativa em relação às outras complicações.

Conclusão: Nessa pequena série de casos retrospectiva, não houve um aumento significativo da morbimortalidade hospitalar no grupo de pacientes octogenários diabéticos. O impacto dos resultados desta série é limitado pelo tamanho amostral e poderá ser confirmado por futuros ensaios clínicos randomizados.

Descriptors: Revascularização miocárdica. Idoso. Idoso de 80 anos ou mais. Diabetes mellitus.

referred for cardiac surgery. Patients in this age group tend to have higher rates of comorbidities and risk factors, which may result in more frequent and severe complications, and higher mortality rates [4].

Few studies [5] have investigated the impact of diabetes in the group of older patients, especially octogenarians.

This study aimed to compare mortality and morbidity in diabetic and nondiabetic octogenarian patients undergoing CABG. METHODS This retrospective cross-sectional study included consecutive patients aged 80 years or older who were submitted to CABG at Instituto de Cardiologia do Rio Grande do Sul (IC/FUC). The variables analyzed were age, gender, hypertension, severe 3-vessel or left main artery disease, New York Heart Association (NYHA) heart failure functional class, previous myocardial infarction, urgency/emergency surgery, left ventricle ejection fraction (LVEF), atrial fibrillation, renal dysfunction, previous CABG, associated surgery performed, cross-clamp and cardiopulmonary bypass (CPB) times.

Diabetes mellitus diagnosis was performed in order to American Diabetes Association (ADA) guidelines [6]: glycosilated hemoglobin (HbA1c) ≥ 6.5%, or fasting serum glycemia ≥ 126 mg/dL, or serum glycemia ≥ 200 601

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mg/dL after ingestion of 75 g of glucose, or random serum glycemia ≥ 200 mg/dL accompanied by symptoms atributed to hyperglycemia. In the absence of unequivocal hyperglycemia, the first three criteria mentioned before, should be repeated to seal diagnosis.

Renal dysfunction, both pre- and postoperative, was defined as serum creatinine level ≥ 2 mg/dL. Coronary artery disease was considered severe if reduction of luminal area exceeded 70% in a coronary artery or 50% in the left main coronary artery. The involvement of the three main coronary arteries and their branches was analyzed to categorize the number of vessels involved. Low cardiac output was considered all hemodynamic instability requiring vasoactive drugs or intra-aortic balloon pump support (IABP). Focal neurological deficits or changes in level of consciousness for a period exceeding 24 hours were defined as stroke.

Hospital mortality was defined as the occurrence of death during hospitalization, regardless of its duration.

Operative morbidity was defined as the occurrence of any of the following complications: trans-operative myocardial infarction, low cardiac output, need for IABP support, sepsis, operative wound or lower limb infection, renal dysfunction, stroke, bleeding requiring reoperation or prolonged mechanical ventilatory support (over 48 hours).

Cardiopulmonary bypass was performed in all cases, and it was established by cannulation of the ascending aorta and right atrium and maintained under mild hypothermia of 34ºC. Distal anastomosis were carried out under aortic clamping and myocardial protection using cardioplegic crystalloid solution model St. Thomas II, injected

anterogradaly through puncture of the ascending aorta.

Topycal hypothermia was performed during the ischemic phase with frozen saline solution and/or amorphous ice made of saline solution, that was put into pericardial cavity.

The proximal aorta anastomosis were carried out under partial ascending aortic clamping with Lambert-Kay type clamp, performed during rewarming.

Data were collected directly from patients’ records, and analyzed with the SPSS 15.0 software. The descriptive analysis for qualitative variables was performed from the distribution of absolute and relative frequency, and the quantitative as mean and standard deviation. The comparison of groups was performed by Student’s t test for quantitative variables and by chi-square for categorical variables. In situations of low frequency, we used the Fisher exact test. Multivariate analysis was performed by logistic regression: there were included in the regression, all variables that showed P < 0.30 in univariate analysis, The level of significance in all tests was 5%.

This study is a subanalysis of a previous study [7] that was submitted to and approved by the local Research Ethics Committee, approved in January of 2008.

RESULTS The sample included 140 patients aged 80 years or greater of whom 37 (26.4%) were diabetics. In the diabetic group, nine (24.3%) patients were in use of insulin therapy. The demographic characteristics are described in Table 1: no significant difference in variables between the two groups was observed.

Table 1. Demographic baseline characteristics of diabetic and nondiabetic patients.

Variable Mean age (±SD) Male (%) Hypertension (%) Severe 3-vessel disease (%) NYHA functional class III/IV (%) Severe left main artery disease (%) Previous MI (%) Non-elective surgery (%) LVEF < 50% (%) Atrial fibrillation (%) Renal dysfunction (%) Previous CABG (%) Associated CABG (%) Cross-clamp time ≥ 90 min (%) CPB bypass time ≥ 120 min (%)

Diabetic (n=37) 82.7 ± 2.5 21 (56.8) 31 (83.8) 25 (67.6) 13 (35.1) 8 (21.6) 11 (29.7) 6 (16.2) 5 (13.5) 4 (10.8) 1 (2.7) 1 (2.7) 13 (35.1) 5 (13.5) 4 (10.8)

Nondiabetic (n=103) 82.4 ± 2.1 57 (55.3) 71 (68.9) 67 (65.0) 32 (31.1) 32 (31.1) 26 (25.2) 16 (15.5) 9 (8.7) 4 (3.9) 6 (5.8) 2 (1.9) 37 (35.9) 8 (7.8) 10 (9.7)

Total

P value

82.5 ± 2.2 78 (55.7) 102 (72.9) 92 (65.7) 45 (32.1) 40 (28.6) 37 (26.4) 22 (15.7) 14 (10.0) 8 (5.7) 7 (5.0) 3 (2.1) 50 (35.7) 13 (9.3) 14 (10.0)

0.388 1.000 0.127 0.940 0.803 0.379 0.754 1.000 0.523 0.208 0.675 1.000 1.000 0.328 1.000

SD, standard deviation; NYHA, New York Heart Association; MI, myocardial infarction; LVEF, left ventricle ejection fraction; CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass

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From the 140 CABG surgeries performed, 90 were isolated and 50 associated with other procedures. The implantation of an aortic bioprosthesis was the major associated procedure.

The list of procedures performed is described in Table 2.

The hospital mortality rate was slightly higher in diabetic patients, as well as morbidity; however, this difference was not significant in univariate and multivariate analysis. The results of these analyses are described in Figure 1.

In regard to operative morbidity, the occurrence of stroke was significantly higher in diabetic patients in the univariate analysis: no significant difference in relation to other complications was observed. In multivariate analysis, the incidence of stroke was not associated with the presence of diabetes, but it was associated with the presence of atrial fibrillation (P = 0.044). The occurrence of complications that were summarized in the surgical morbidity endpoint is described in Table 3.

Table 2. Surgical procedures performed.

Surgery Isolated CABG Associated CABG Aortic bioprosthesis Carotid endarterectomy Aortic valvuloplasty Mitral valve repair Mitral bioprosthesis Aortic bioprosthesis + Aortoplasty Aortic bioprosthesis + Mitral valve repair Endoaneurysmorrhaphy Patent ductus arteriosus correction

n (%) 90 (64.3) 50 (35.7) 28 (20) 5 (3.6) 5 (3.6) 3 (2.1) 3 (2.1) 2 (1.4) 2 (1.4) 1 (0.7) 1 (0.7)

CABG - coronary artery bypass graft

Fig. 1 - Comparison of diabetic and nondiabetic patients regarding to the occurrence of mortality and morbidity outcomes. *Univariate analysis; **Multivariate analysis: adjusted for hypertension and atrial fibrillation

DISCUSSION In this relatively small series of patients, it was not observed higher rate of fatal or nonfatal outcomes in diabetics, as compared to nondiabetic octogenarian patients, similarly to other previous studies that are cited in this section. However, the majority of these studies did not analyze specifically octogenarian patients, beyond it did not specifically evaluate the impact of diabetes as a preoperative risk factor.

The reported incidence of postoperative complications after coronary artery bypass procedures in diabetic patients has varied. Fietsam et al. [8] found an increase in morbidity among diabetic patients; however, they did not find any increase in the occurrence of reoperation, stroke, or perioperative myocardial infarction, in agreement with our findings in this series. In contrast, Kuan et al. [9] reported that diabetics had an increased risk of stroke, hemorrhage, and perioperative myocardial infarction [2].

Brazilian studies observed association of diabetes with general infections in the post-operative period [10],

Table 3. Comparison of diabetic and nondiabetic patients for the occurrence of postoperative morbidity.

Complication Low cardiac output (%) Renal dysfunction (%) Mechanical ventilation > 48h (%) IABP support (%) Bleeding requiring reoperation (%) Peri-operative MI (%) Sepsis (%) Stroke (%) Operative wound infection (%) Lower limb infection (%)

Diabetic (n=37) 13 (35.1) 4 (10.8) 6 (16.2) 2 (5.4) 2 (5.4) 1 (2.7) 1 (2.7) 4 (10.8) 2 (5.4) 1 (2.7)

Nondiabetic (n=103) 26 (25.2) 10 (9.7) 7 (6.8) 8 (7.8) 6 (5.8) 6 (5.8) 6 (5.8) 2 (1.9) 3 (2.9) 2 (1.9)

Total

P value*

39 (27.9) 14 (10.0) 13 (9.3) 10 (7.1) 8 (5.7) 7 (5.0) 7 (5.0) 6 (4.3) 5 (3.6) 3 (2.1)

0.348 1.000 0.105 1.000 1.000 0.675 0.675 0.042 0.608 1.000

P value**

0.085

IABP, intra-aortic balloon pump; MI, myocardial infarction. * Univariate analysis. ** Multivariate analysis: adjusted for hypertension and atrial fibrillation

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sternal wound infection [11] and mediastinitis [12,13]. In this series, there was not higher incidency of sepsis, sternal wound infection or lower limb wound infection, probably due to lack of statistical power, due to its relatively small sample to show such relation.

Thourani et al. [2] found that diabetic patients had worse in-hospital and long-term outcome after CABG. Diabetic patients had a higher incidence of postoperative death (3.9% versus 1.6%) and stroke (2.9% versus 1.4%) (both, P < 0.05). Diabetics had lower survival (5 years, 78% versus 88%; 10 years, 50% versus 71%; both, P < 0.05) and lower freedom from percutaneous transluminal coronary angioplasty (5 years, 95% versus 96%; 10 years, 83% versus 86%; latter, P < 0.05). In our report, although there was numerically higher mortality in diabetic patients, it was not observed statistically significant difference in regard to mortality. In relation to the higher incidence of stroke in the diabetic patients observed initially, it was shown further, in multivariate analysis, that it was in fact related to atrial fibrillation.

Herlitz et al. [14] reported that diabetic patients undergoing CABG more frequently required reoperation and had a higher incidence of peri- and postoperative neurological complications. In addition, they observed that diabetic patients during the 2 years after CABG had 2-fold increase in mortality rate compared to nondiabetic patients, both early and late after surgery: 30-day mortality was 6.7% in diabetic patients and 3.0% in nondiabetics (P < 0.01) and between 30 days and 2 years 7.8% and 3.6%, respectively (P < 0.01).

Postoperative glycemic control in this series (150-200 mg/dL) was not aggressive. In relation to this issue, two recent randomized clinical trials observed no benefit of aggressive glycemic control (90-120 mg/dL) compared with moderate glycemic control (120-180 mg/dL) [15,16].

In an interesting study performed by Halkos et al.

[17], an elevated hemoglobin A1c level was strongly associated with adverse events after CABG, suggesting that a preoperative hemoglobin A1c testing may allow for more accurate risk stratification in patients undergoing this procedure. An elevated hemoglobin A1c level predicted in-hospital mortality after CABG: odds ratio 1.40 per unit increase (P = 0.019). Receiver operating characteristic (ROC) curve analysis revealed that hemoglobin A1c greater than 8.6% was associated with a 4-fold increase in mortality. For each unit increase in hemoglobin A1c, there was a significantly increased risk of myocardial infarction and deep sternal wound infection.

On the other hand, regarding specifically to octogenarian patients undergoing CABG, Bardakci et al. [3] did not observe the presence of diabetes as an independent risk factor for hospital mortality, similar to data observed in this study. Previous studies involving octogenarian patients

undergoing cardiac procedures had already described the lack of association of diabetes with this outcome [1824]. Studying even older patients, Speziale et al. [25] described the non-elective surgery and the existence of previous myocardial infarction as predictors of mortality in nonagenarian patients undergoing cardiac procedures, not observing the presence of diabetes as a risk factor for this outcome.

In a Brazilian study performed by Alves Júnior et al.

[26], including patients 70 years or greater submitted to CABG or heart valve surgeries, diabetes was not associated with increased risk for in-hospital mortality. In the other hand, Iglézias et al. [27], while analyizing patients also with 70 years or greater, that had been submitted to CABG, found that diabetes was associated with surgical mortality. In a study that included patients aged 80 years or more, similarly to this, Guimarães et al. [28] also did not observed diabetes as a predictor of mortality; although, this study was not designed with this objective.

In this study, there was no association of diabetes with increase in the incidence of postoperative complications. López-Rodríguez et al. [29], when analyzed patients older than 75 years, did not observe this association as well. Ji et al. [5] reported that diabetic patients aged over 70 years had a higher rate of deep sternal wound infection, while sharing similar rates for other morbidities compared with nondiabetic patients aged over 70 years. Nagpal et al. [4], when analyzed octogenarian patients undergoing CABG with or without cardiopulmonary bypass, described that diabetes was not as a risk factor for the occurrence of the combined endpoint of death and major complications.

Patients aged 80 years and over have a significantly higher risk for any complication with cardiac surgery, including neurologic events, pneumonia, dysrhythmias, and wound infection. Independent predictors of cerebrovascular accident, coma, or stupor are proximal aortic atherosclerosis, history of neurologic disease, age greater than 70 years, and history of pulmonary disease.

The strongest predictor of focal cerebrovascular accident (4-fold increase in risk) is proximal aortic atherosclerosis as judged by surgeons’ intraoperative palpation. Older age also seems to be a predictor of more subtle neurologic injury, such as memory deficit and cognitive decline [30].

Regarding to pre-operative atrial fibrillation as a risk factor for stroke, Tarakji et al. [31] in a recent study reported an odds ratio of 2.4 (95% confidence interval 1.38-4.2) for intra-operative stroke and 3.0 (95% confidence interval 1.64-5.4) for stroke in the postoperative period. Risk factors common to both intraoperative and postoperative stroke were older age, smaller body surface area, previous stroke, preoperative atrial fibrillation, and on-pump CABG with hypothermic circulatory arrest.

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In relation to long-term survival, the literature is inconsistent in defining diabetes as an unfavorable prognostic factor in octogenarian patients undergoing cardiac procedures. Kohl et al. [20] noted that octogenarian patients undergoing cardiac procedures did not have lower survival compared to nondiabetics. On the other hand, Peterson et al. [21], in a large study involving 24,461 patients undergoing CABG, reported that the presence of complicated diabetes was a risk factor for mortality in 3 years. Long term survival of patients included in this report is being analyzed, and it will be reported further.

6. American Diabetes Association. Standards of medical care in diabetes 2011. Diabetes Care. 2011;34(Suppl 1):S11-61.

CONCLUSIONS In this small consecutive retrospectively analyzed study, there was no significant increase in in-hospital mortality for CABG in octogenarian diabetic patients and the rate of nonfatal complications was similar to nondiabetic octogenarians. The impact of the results found in this report is limited by its small sample size and might be confirmed by future clinical trials. Other limitations of this report are its retrospective method and to be done in a single center; however, results found in this study suggest, based on previous findings, that CABG may be performed in diabetic octogenarians without increase of risk related to diabetes.

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2. Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM, Jones EL, et al. Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. Ann Thorac Surg. 1999;67(4):1045-52.

3. Bardakci H, Cheema FH, Topkara VK, Dang NC, Martens TP, Mercando ML, et al. Discharge to home rates are significantly lower for octogenarians undergoing coronary artery bypass graft surgery. Ann Thorac Surg. 2007;83(2):483-9.

4. Nagpal AD, Bhatnagar G, Cutrara CA, Ahmed SM, McKenzie N, Quantz M, et al. Early outcomes of coronary artery bypass with and without cardiopulmonary bypass in octogenarians.

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5. Ji Q, Mei Y, Wang X, Feng J, Cai J, Sun Y, et al. Impact of diabetes mellitus on patients over 70 years of age undergoing coronary artery bypass grafting. Heart Lung. 2010;39(5):404-9.

7. Pivatto Júnior F, Kalil RA, Costa AR, Pereira EM, Santos EZ, Valle FH, et al. Morbimortality in octogenarian patients submitted to coronary artery bypass graft surgery. Arq Bras Cardiol. 2010;95(1):41-6.

8. Fietsam R Jr, Bassett J, Glover JL. Complications of coronary artery surgery in diabetic patients. Am Surg. 1991;57(9):551-7.

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11. Farsky PS, Graner H, Duccini P, Zandonadi EC, Amato VL, Anger J et al. Fatores de risco para infecção de ferida esternal e aplicação do escore da STS em pacientes submetidos à cirurgia de revascularização miocárdica. Rev Bras Cir Cardiovasc.

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12. Guaragna JC, Facchi LM, Baião CG, Cruz IBM, Bodanese LC, Albuquerque L, et al. Preditores de mediastinite em cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2004;19(2):165-70.

13. Sá MP, Soares EF, Santos CA, Figueiredo OJ, Lima RO, Escobar RR, et al. Risk factors for mediastinitis after coronary artery bypass grafting surgery. Rev Bras Cir Cardiovasc.

2011;26(1):27-35.

14. Herlitz J, Wognsen GB, Emanuelsson H, Haglid M, Karlson BW, Karlsson T, et al. Mortality and morbidity in diabetic and nondiabetic patients during a 2-year period after coronary artery bypass grafting. Diabetes Care. 1996;19(7):698-703.

15. Desai SP, Henry LL, Holmes SD, Hunt SL, Martin CT, Hebsur S, et al. Strict versus liberal target range for perioperative glucose in patients undergoing coronary artery bypass grafting: a prospective randomized controlled trial. J Thorac Cardiovasc Surg. 2012;143(2):318-25.

16. Lazar HL, McDonnell MM, Chipkin S, Fitzgerald C, Bliss C, Cabral H. Effects of aggressive versus moderate glycemic control on clinical outcomes in diabetic coronary artery bypass graft patients. Ann Surg. 2011;254(3):458-63.

17. Halkos ME, Puskas JD, Lattouf OM, Kilgo P, Kerendi F, Song HK, et al. Elevated preoperative hemoglobin A1c level is predictive of adverse events after coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2008;136(3):631-40.

18. Alexander KP, Anstrom KJ, Muhlbaier LH, Grosswald RD, Smith PK, Jones RH, et al. Outcomes of cardiac surgery in patients > or = 80 years: results from the National Cardiovascular Network. J Am Coll Cardiol. 2000;35(3):731-8.

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19. Kirsch M, Guesnier L, LeBesnerais P, Hillion ML, Debauchez M, Seguin J, et al. Cardiac operations in octogenarians: perioperative risk factors for death and impaired autonomy.

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20. Kolh P, Kerzmann A, Lahaye L, Gerard P, Limet R. Cardiac surgery in octogenarians: peri-operative outcome and longterm results. Eur Heart J. 2001;22(14):1235-43.

26. Alves Júnior L, Rodrigues AJ, Évora PRB, Basseto S, Scorzoni Filho A, Luciano PM, et al. Fatores de risco em septuagenários ou mais idosos submetidos à revascularização do miocárdio e ou operações valvares. Rev Bras Cir Cardiovasc. 2008;23(4):550-5.

21. Peterson ED, Cowper PA, Jollis JG, Bebchuk JD, DeLong ER, Muhlbaier LH, et al. Outcomes of coronary artery bypass graft surgery in 24,461 patients aged 80 years or older. Circulation.

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27. Iglézias JCR, Oliveira Jr. JL, Dallan LAO, Lourenção Jr. A, Stolf NAG. Preditores de mortalidade hospitalar no paciente idoso portador de doença arterial coronária. Rev Bras Cir Cardiovasc. 2001;16(2):94-104.

22. Schmidtler FW, Tischler I, Lieber M, Weingartner J, Angelis I, Wenke K, et al. Cardiac surgery for octogenarians: a suitable procedure? Twelve-year operative and post-hospital mortality in 641 patients over 80 years of age. Thorac Cardiovasc Surg.

2008;56(1):14-9.

28. Guimarães IN, Moraes F, Segundo JP, Silva I, Andrade TG, Moraes CR. Fatores de risco para mortalidade em octogenários submetidos a cirurgia de revascularização miocárdica. Arq Bras Cardiol. 2011;96(2):94-8.

23. Stoica SC, Cafferty F, Kitcat J, Baskett RJ, Goddard M, Sharples LD, et al. Octogenarians undergoing cardiac surgery outlive their peers: a case for early referral. Heart.

2006;92(4):503-6.

24. Williams DB, Carrillo RG, Traad EA, Wyatt CH, Grahowksi R, Wittels SH, et al. Determinants of operative mortality in octogenarians undergoing coronary bypass. Ann Thorac Surg.

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29. López-Rodríguez FJ, González-Santos JM, Dalmau MJ, Bueno M. Cardiac surgery in the elderly: comparison between mediumterm clinical outcomes in octogenarians and the elderly from 75 to 79 years. Rev Esp Cardiol. 2008;61(6):579-88.

30. Richards NM. Outcomes in special populations undergoing cardiac surgery: octogenarians, women, and adults with congenital heart disease. Crit Care Nurs Clin North Am. 2007;19(4):467-85.

31. Tarakji KG, Sabik JF 3rd, Bhudia SK, Batizy LH, Blackstone EH. Temporal onset, risk factors, and outcomes associated with stroke after coronary artery bypass grafting. JAMA. 2011;305(4):381-90.

ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):607-13

Evaluation of maximal inspiratory and sniff nasal inspiratory pressures in pre- and postoperative myocardial revascularization Avaliação das pressões inspiratória máxima e inspiratória nasal sniff no pré e pós-operatório de revascularização do miocárdio

Juliana Paula Graetz1, Antonio Roberto Zamunér2, Marlene Aparecida Moreno3

DOI: 10.5935/1678-9741.20120103

RBCCV 44205-1428

Abstract Objective: The objective of this study was to evaluate and correlate inspiratory muscle strength using maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Pnsn) in patients with coronary artery disease in pre- and postoperative of myocardial revascularization surgery.

Methods: Thirty-eight men were studied, divided into a control group (CG) comprised of healthy individuals (n=18), age 55.52 ± 7.8 years and a myocardial revascularization group (MRG), comprised of patients with coronary artery disease submitted to myocardial revascularization (n=20), age 58.44 ± 9.3 years. All volunteers were submitted to MIP and Pnsn measurement, and the MRG was evaluated in the preoperative period and on the first postoperative day (PO1).

Results: MRG presented MIP (80.60 ± 26.60 cmH2O) and Pnsn (74.70 ± 31.80 cmH2O) values inferior to CG (MIP: 112.22 ± 32.00 cmH2O; Pnsn: 103.70 ± 34.10 cmH2O), and there was significant reduction of these values on PO1 (MIP: 40.05 ± 15.70 cmH2O; Pnsn: 40.05 ± 16.60 cmH2O). There was correlation and concordance between evaluation methods in both groups studied, as well as in pre- and postoperative MRG conditions.

Conclusions: The results showed that the studied patients presented reduced MIP and Pnsn pre- and post-operative myocardial revascularization. Also, the Pnsn correlated with MIP and can be considered suitable for assessing inspiratory muscle strength in this population.

1. Master of Physical Therapy, Physiotherapist, Physical Therapist, Hospital Fornecedores de Cana de Piracicaba, Piracicaba, SP, Brazil.

2. Master of Physical Therapy, Federal University of São Carlos, São Carlos, SP, Brazil.

3. PhD, Professor, Postgraduate Program in Physical Therapy, Methodist University of Piracicaba, Piracicaba, SP, Brazil.

Correspondence address: Marlene Aparecida Moreno Rodovia do Açúcar, km 156 – Taquaral – Piracicaba, SP Brazil – Zip Code: 13.400-901 E-mail: ma.moreno@terra.com.br

Work performed at Universidade Metodista de Piracicaba, Piracicaba, SP, Brazil.

Descriptors: Myocardial revascularization. Muscle strength. Respiratory muscles. Coronary Artery Disease.

Resumo Objetivo: O objetivo deste estudo foi avaliar e correlacionar a força muscular inspiratória, pelas medidas da pressão inspiratória máxima (PImáx) e pressão inspiratória nasal sniff (Pnsn), em pacientes com doença arterial coronariana no pré e pós-operatório de revascularização do miocárdio.

Métodos: Foram estudados 38 homens, divididos em grupo controle (GC), composto por indivíduos saudáveis (n=18), idade 55,52 ± 7,8 anos, e grupo revascularização do miocárdio (GRM), composto por pacientes com doença arterial coronariana submetidos à revascularização do miocárdio (n=20), idade 58,44 ± 9,3 anos. Todos os voluntários

Article received on May 18th, 2012 Article accepted on July 20th, 2012

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Graetz JP, et al. - Evaluation of maximal inspiratory and sniff nasal inspiratory pressures in pre- and postoperative myocardial revascularization

Abbreviations, acronyms & symbols CAD BMI CG COPD CS FCR IMS MIP MR MRG Pnsn PO1

Coronary artery disease Body mass index Control group Chronic obstructive pulmonary disease Cardiac surgery Functional residual capacity Inspiratory muscle strength Maximal inspiratory pressure Myocardial revascularization Myocardial revascularization group Sniff nasal inspiratory pressure First postoperative day

foram submetidos à mensuração da PImáx e da Pnsn, sendo o GRM avaliado no pré (pré-op) e primeiro pós-operatório (PO1).

INTRODUCTION Cardiovascular diseases are the main causes of morbimortality and currently represent the highest costs for the health care system. Among these diseases, coronary artery disease (CAD) stands out. Alterations in muscular function have been described in cardiac patients, particularly in those with congestive heart failure, and include reductions in resistance and respiratory muscle strength that can lead to muscle failure [1-3].

Cardiac surgery (CS) has been used to treat these patients and presents expressive postoperative complication rates [4,5], particularly respiratory complications such as decreased oxygenation, pulmonary function and respiratory muscle strength, which increases the risk of postoperative morbi-mortality [6-8]. Respiratory mechanics are also affected in postoperative CS and may promote mechanical disadvantage which, being associated with pain, reduces the ability of respiratory muscles to generate tension [9]. In addition, this factor, which is promoted by reflex inhibition of the phrenic nerve and diaphragmatic paresis, is associated with diaphragmatic dysfunction and impairs respiratory function [10].

Maximal inspiratory pressure (MIP), which is used to measure inspiratory muscle strength (IMS), is an objective measurement of diaphragmatic dysfunction [11].

Alterations in ventilatory mechanics and IMS may cause difficulties in performing this procedure and, consequently, lead to inadequate results [12,13].

Sniff nasal inspiratory pressure (Pnsn) is a noninvasive, accurate and reproducible alternative for evaluating IMS [14].

Some studies has used this technique for the evaluation of 608

Resultados: O GRM apresentou valores de PImáx (80,60 ± 26,60 cmH2O) e Pnsn (74,70 ± 31,80 cmH2O) inferiores ao GC (PImáx: 112,22 ± 32,00 cmH2O; Pnsn: 103,70 ± 34,10 cmH2O), ocorrendo ainda redução significativa destes valores no PO1 (PImáx: 40,05 ± 15,70 cmH2O; Pnsn: 40,05 ± 16,60 cmH2O). Houve correlação e concordância entre os métodos de avaliação nos dois grupos estudados, assim como nas condições pré e pós-operatória do GRM. Conclusão: Os resultados demonstraram que os pacientes estudados apresentaram redução da PImáx e da Pnsn no pré e pós-operatório de revascularização do miocárdio, e que a Pnsn correlacionou-se com a PImáx, sendo adequada para avaliar a força muscular inspiratória nessa população.

Descritores: Revascularização miocárdica. Força muscular. Músculos respiratórios. Doença da artéria coronariana.

different populations, such as chronic obstructive pulmonary disease (COPD), spinal cord injuries and neuromuscular diseases because it is a simple measurement and requires no sustained effort, thus allowing muscle recruitment [13, 15-17]. However, no reports were found in the literature regarding IMS measurement by means of Pnsn in cardiac patients submitted to myocardial revascularization (MR).

Therefore, the objectives of the present study were to evaluate and compare IMS obtained using the MIP and Pnsn measurements of volunteer cardiac patients in preand postoperative stages of MR surgery and to evaluate the concurrent validity of Pnsn for measuring IMS by correlating it with MIP. METHODS This study was approved by the Research Ethics Committee of the Methodist University of Piracicaba (protocol 75/09). Volunteer selection was based on sample calculations performed in GraphPad StatMate, v.1.01i and applied to the MIP variable. For a confidence level of 95% and a power of 85%, the number of volunteers suggested for each group was 18.

Thirty-eight male volunteers participated in the study (Table 1) in Hospital Fornecedores de Cana de Piracicaba and were divided into two groups: a control group (CG) including 18 apparently healthy volunteers, and a MR group (MRG) including 20 volunteers with CAD who were scheduled for MR. There was a sample loss of two MR group volunteers in the post-operative period due to hemodynamic instability, and so the total number of participants in this group was 18. CG volunteers were selected from the

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community and evaluated in the institution’s laboratory where the study was carried out. Volunteers with CAD were selected based on the weekly surgery map provided by the hospital unit where the patients were admitted and evaluated.

Inclusion criteria for the CG were: a body mass index (BMI) between 18 and 29.9 kg/m², a sedentary life style according to the International Physical Activity Questionnaire [18], no history of respiratory and respiratory disorders, assessed by spirometry, no cardiac or neuromuscular diseases, no thoracic deformities, rhinitis or sinusitis, no nasal septal deviation, no fever for at least three weeks and no cold/flu in the week previous to the evaluation, as well as no use of oral corticosteroids, central nervous system depressants, barbiturates or muscle relaxants. Subjects who were smokers or were incapable of performing the procedures were excluded from the study.

Inclusion criteria for the GRM comprised, in addition to those described for GC: coronary insufficiency diagnosed by scintigraphy and confirmed by catheterization, elective MR surgery and clinical and hemodynamic stability. Exclusion criteria included: the development of postoperative respiratory complications, and difficulty understanding the procedures.

Application of the evaluation methods was randomized.

At the end of the first measurement, the subject rested for 15 minutes before proceeding to the next method. CG patients were evaluated once and MRG patients were evaluated twice: once during the preoperative period and again on the first postoperative day (PO1).

MIP was measured in cmH2O using an MVD 300 digital vacuum gauge (GlobalMed, Porto Alegre, RS, Brazil) according to the methodology proposed by Black & Hyatt [19].

Measurements for CG and MRG during the preoperative period were carried out with volunteers seated on a chair.

On PO1 of the MRG, the measurements were taken with the volunteers seated on their beds since they could not be moved for the evaluation. Their nostrils were occluded with a nose clip to prevent air leakage. MIP was measured during maximal inspiratory effort, which was based on functional residual capacity (FRC) [13].

Volunteers performed at least five technically satisfactory maximal inspiratory efforts, i.e., without nasal air escape and with similar values among efforts (≤ 10%).

The highest value in which inspiration was maintained for at least one second was used for analysis [19,20].

Inspiratory pressure generated at nose level was measured using the same equipment and with the volunteers in the same position. Measurement was carried out with one nostril occluded by a silicone nasal plug, which was connected to the vacuum gauge by an approximately 1 mm diameter catheter [21]. The maneuver consisted of a

maximal sniff performed by the contralateral (free) nostril with the mouth closed, and was based on FRC values. The sniff test included ten repetitions [22] with a 30-second interval between each. A sniff was considered acceptable when there was gradual elevation of pressure until a peak lasting between 0 and 5 seconds was reached [13]. All values were recorded in each individual’s file and the highest pressure value was used for data analysis.

The predicted values of MIP were calculated using the equation proposed by Neder et al. [20]: Predicted MIP = (-0.8 x age) + (0.48 x weight) + 119.7; and for the predicted values of Pnsn, the equation proposed by Uldry & Fitting [13] was used: Pnsn predicted = -0.42 x age + 126.8.

Data distribution analysis was performed with the Shapiro-Wilk test. The hypothesis of normality was rejected for all variables, so non-parametric tests were used: Mann-Whitney for unpaired samples and Wilcoxon for paired samples. Spearman’s correlation coefficient was used to verify the relation between variables and the Bland-Altman method [23] was used to analyze the agreement between methods. The significance level for all statistical tests was 5%. Statistical procedures were carried out with GraphPad InStat v.3.05 and Medcalc v.11.5.0.

RESULTS Table 1 presents the characteristics of the volunteers studied in the CG and the MRG in the preoperative period.

There is no significant difference for any variable.

MIP and Pnsn values obtained were below predicted values only in the MRG (Table 2).

Table 1. Baseline characteristics of participants.

Characteristics CG (n=18) 55.52±7.8 Age (years) Anthropometric characteristics 81.34±15 Body mass (kg) Height (cm) 171.76±7.8 BMI (kg/m2) 27.4±3.5 Risk factors Smoking (n, %) SAH (n, %) Diabetes Mellitus (n, %) Life style IPAQ irregularly active Medications Beta-blockers (n, %) ACE inhibitors (n, %) Hypolipidemics (n, %) Hypoglycemics (n, %) Diuretics (n, %) Antiplatelet (n, %)

RMG Pre (n=20) 58.44±9.3 77.00±11.3 171.94±7.6 25.98±3.7 3 (15) 8 (40) 8 (40) irregularly active 11 (55) 10 (50) 9 (45) 3 (15) 1 (5) 18 (90)

BMI: body mass index; SAH: systemic arterial hypertension; IPAQ: international physical activity questionnaire; ACE: angiotensin converting enzyme. Mann-Whitney test

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Table 2 also shows that there was no significant difference between the MIP and Pnsn variables in the intragroup analysis. In the intergroup analysis, the MRG evaluated in the preoperative period presented lower MIP and Pnsn values than the CG.

Comparing the preoperative and PO1 periods, the MRG presented a significant decrease in MIP and Pnsn values.

However, when MIP and Pnsn variables were compared, both in the preoperative period and on PO1, no significant differences were observed (Table 3).

The values obtained between MIP and Pnsn presented positive and significant correlation in both groups studied.

For the MRG, the relation was present in both the preoperative and postoperative conditions (Figures 1 to 3).

Table 2. Predicted and obtained values of maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Pnsn) for the control group (CG) and myocardial revascularization group (MRG) during the preoperative period. Values expressed in mean and standard deviation.

Variables GC (n=18) RMG (n=20) Predict MIP (cmH2O) 114.30±9.8 109.66±10.2 Obtained MIP (cmH2O) 112.22±32 80.60±26.6*# Predict Pnsn (cmH2O) 103.47±3.2 101.82±3.9 Obtained Pnsn (cmH2O) 103.70±34.1 74.70±31.8*# * P<0.05 predicted vs. obtained values (Wilcoxon test). # p<0.05 values obtained for the CG vs. values obtained for the RMG (Mann-Whitney test)

Table 3. Values of maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Pnsn) of the myocardial revascularization group (MRG) (n=18), in the preoperative period (Pre) and on the first postoperative day (PO1).

Variables Pre MIP (cmH2O) 82.61±27.3 Pnsn (cmH2O) 76.77±32.7 * P<0.05 Pre vs. PO1 (Wilcoxon test)

Fig 1 - A: Graph representing correlation analysis between the variables maximal inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Pnsn). B: scatter graph for the difference and average between the variables MIP and Pnsn of the control group (CG)

Fig 2 - A: Graph representing correlation analysis between the variables maximum inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Pnsn). B: scatter graph for the difference and average between the variables MIP and Pnsn of the myocardial revascularization group on the preoperative period (MRG Pre)

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PO1 40.05±15.7* 40.05±16.6*

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Fig 3 - A: Graph representing correlation analysis between the variables maximum inspiratory pressure (MIP) and sniff nasal inspiratory pressure (Pnsn). B: scatter graph for the difference and average between the variables MIP and Pnsn of the myocardial revascularization group on the first postoperative day (MRG PO1)

DISCUSSION This results of this study revealed lower IMS in the MRG than the CG in the preoperative period and showed agreement between the MIP and Pnsn evaluation methods.

In the preoperative period, the MIP and Pnsn values in MRG were lower than both the predicted values and those of the CG. The findings of this study are further reinforced by the significant negative correlation between MIP and Pnsn and the presence of CAD, suggesting that the disease can lead to decreased values of the variables studied.

MRG patients presented ischemic cardiomyopathy, particularly acute myocardial infarction (50% of the patients) and multivessel disease. Of the volunteers in this group, 18.75% had been submitted to unsuccessful angioplasty, which led to the recommendation of MR surgery. Thus, a probable justification for the reduced IMS found in this study is decreased blood supply to skeletal musculature in cardiopathies, including respiratory muscles [1,24], due to impairment of myocardial perfusion by coronary problems [1] and to reduced myocardial contraction, which is caused by myocardial ischemia [25].

Despite the lack of investigations on respiratory muscle strength in CAD patients, our results agree with those of studies on congestive heart failure, in which reduced IMS was observed in this population [1,26]. Furthermore, the literature reports that reductions in capillary density and oxidative enzymes in cardiopathies can lead to generalized muscular hypotrophy [25] and can even compromise the diaphragm muscle [27]. Another relevant factor is the chronic systemic inflammatory process caused by atherosclerosis and present in ischemic cardiomyopathy.

This process can affect the respiratory system and lead to decreased respiratory function [28].

The significant decrease of both MIP and Pnsn after MR compared to preoperative values could have been due to direct or indirect injury of respiratory muscles during the surgery, as well as to diaphragm dysfunction as a result of phrenic nerve injury, which can be detected by x-ray and electromyography [6]. Such injury can promote reflex inhibition and diaphragm paresis, which impair ventilatory dynamics and pulmonary function [6,9,10,29,30].

According to Borghi-Silva et al. [9], respiratory mechanics presents damage after CS, which may lead to mechanical disadvantage that, being associated with pain, reduces the capacity of respiratory muscles to generate tension. Another negative factor is the low cardiac output found after MR, which can cause muscle fatigue, decreased thoracic mobility and superficial breathing [30]. General anesthesia should also be considered as a contributing factor because it depresses the respiratory system and can lead to alveolar hypoventilation, decreased FRC, alveolar collapse, and development of atelectasis during the postoperative period [6,9,31].

These factors are associated with median sternotomy and the presence of chest drains and may cause unsatisfactory performance of the MIP measurement maneuver [12]. For this reason, in order to minimize the difficulties of measuring IMS in postoperative MR patients, new evaluation methodologies should be proposed for situations in which conventional measurement is difficult for the patient.

Pnsn is among the measurement methods used and validated for evaluating IMS. It is a simpler technique than that used to measure MIP, involving less risk of fatigue since it is a natural, easy and short maneuver that demands less time at peak pressure [32].

Several studies have applied this methodology to 611

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healthy subjects [13] and to patients with neuromuscular diseases [14,17,22], spinal cord injury [16] and chronic obstructive pulmonary disease [17,33]. However, no studies measuring the IMS of CAD and postoperative MR patients by means of Pnsn were found.

Pnsn correlated with a simultaneous criterion, MIP, which was used as a parameter to analyze the accuracy of Pnsn, for concurrent validity. MIP was used because it is a noninvasive reference standard for measuring IMS. The high correlations between MIP and Pnsn and the agreement between methods demonstrated by the BlandAltman [23] analysis identify Pnsn as an accurate method for measuring the IMS of these volunteers.

The results of this study, in demonstrating that IMS is better expressed by esophageal pressure during a maximal sniff (sniff POES) than by MIP [13], make an important contribution to the literature. However, even though sniff POES has limited clinical use because it is invasive and demands an esophageal balloon catheter system, Uldry & Fitting [13] demonstrated that it can be estimated in a noninvasive form by means of Pnsn.

Even though no studies with cardiac patients were found in the literature, Prigent et al. [32] affirm that Pnsn can be used as a first-choice method for evaluating IMS in healthy subjects due to the fact that it reproduces predicted values.

Therefore, the relation between MIP and Pnsn values is advantageous for IMS measurement, particularly in postoperative CS patients. Whereas MIP demands sustained effort, Pnsn requires only a quick effort, and its performance is easy and natural. Furthermore, Nava et al. [34] demonstrated in a study of diaphragm muscle peak EMG amplitude in both methods that Pnsn allows recruitment of 100% of the diaphragm muscle fibers, whereas only 61% are recruited in MIP performance.

It is important to point out the significant correlation between the MIP and Pnsn values obtained on PO1, considering that when Plmax values are low, Pnsn provides a way to distinguish inspiratory muscle weakness from difficulty performing sustained and continuous effort against an occluded airway [13]. Therefore, we can infer from this that pre- and postoperative CAD patients, in fact, presented reduced maximum inspiratory pressure since the values were reduced even during a maneuver that demanded less effort.

This study also gathered patient feedback about Pnsn.

Their responses indicated that Pnsn was more comfortable and easier to perform than MIP, which reinforces its advantages, particularly in postoperative MR. However, scales for evaluating pain and the degree of satisfaction were not applied. Thus, we suggest that these variables be investigated in future studies.

The results demonstrate that both methodologies

present similar values when evaluating this population.

This study, therefore, can serve as starting point for other investigations.

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CONCLUSION In conclusion, the results demonstrated that the patients evaluated in this study showed reduced IMS in pre-and post-operative myocardial revascularization, and that the Pnsn correlated with MIP, which can be considered, therefore, the first-choice method when it aims to assess IMS in this population.

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3. Forgiarini Jr LA, Rubleski A, Garcia D, Tieppo J, Vercelino R, Dal Bosco A, et al. Avaliação da força muscular respiratória e da função pulmonar em pacientes com insuficiência cardíaca.

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4. Staton GW, Williams HW, Mahoney EM, Hu J, Chu H, Duke PG, et al. Pulmonary outcomes of off-pump vs on-pump coronary artery bypass surgery in a randomized trial. Chest.

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5. Franco AM, Torres FCC, Simon ISL, Morales D, Rodrigues AJ. Avaliação da ventilação não-invasiva com dois níveis de pressão positiva nas vias aéreas após cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2011;26(4):582-90.

6. Siafakas NM, Mitrouska I, Bouros D, Georgopoulos D. Surgery and the respiratory muscles. Thorax.

1999;54(5):458-65.

7. Borghi-Silva A, Mendes RG, Costa FS, Di Lorenzo VA, Oliveira CR, Luzzi S. The influences of positive end expiratory pressure (PEEP) associated with physiotherapy intervention in phase I cardiac rehabilitation. Clinics. 2005;60(6):465-72.

8. Laizo A, Delgado FEF, Rocha GM. Complicações que aumentam o tempo de permanência na unidade de terapia intensiva na cirurgia cardíaca. Rev Bras Cir Cardiovasc.

2010;25(2):166-71.

9. Borghi-Silva A, Pires Di Lorenzo VA, Oliveira CR, Luzzi S. Comportamento da função pulmonar e da força muscular

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respiratória em pacientes submetidos a revascularização do miocárdio e a intervenção fisioterapêutica. Rev Bras Ter Intens.

2004;16(3):155-9.

22. Lofaso F, Nicot F, Lejaille M, Falaize L, Louis A, Clement A, et al. Sniff nasal inspiratory pressure: with is the optimal number of sniffs? Eur Respir J. 2006;27(5):980-2.

10. Guizilini S, Gomes WJ, Faresin SM, Bolzan DW, Alves FA, Catani R, et al. Avaliação da função pulmonar em pacientes submetidos à cirurgia de revascularização do miocárdio com e sem circulação extracorpórea. Rev Bras Cir Cardiovasc.

2005;20(3):310-6.

23. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement.

Lancet. 1986;1(8476):307-10.

11. Clanton TL, Diaz PT. Clinical assessment of the respiratory muscles. Phys Ther. 1995;75(11):983-95.

24. Dall’Ago P, Chiappa GR, Güths H, Stein R, Ribeiro JP. Inspiratory muscle training in patients with heart failure and inspiratory muscle weakness: a randomized trial. J Am Coll Cardiol. 2006;47(4):757-63.

12. Leith DE, Bradley M. Ventilatory muscle strength and endurance training. J Appl Physiol. 1976;41(4):508-16.

25. Auler Jr. JOC. Isquemia miocárdica transoperatória. Rev Bras Anestesiol. 1988;38(3):205-14.

13. Uldry C, Fitting JW. Maximal values of sniff nasal inspiratory pressure in healthy subjects. Thorax. 1995;50(4):371-5.

26. Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation. 1992;85(4):1364-73.

14. Stefanutti D, Benoist MR, Scheinmann P, Chaussain M, Fitting JW. Usefulness of sniff nasal pressure in patients with neuromuscular or skeletal disorders. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1507-11.

15. Héritier F, Rahm F, Pasche P, Fitting JW. Sniff nasal inspiratory pressure. A noninvasive assessment of inspiratory muscle strength. Am J Respir Crit Care Med. 1994;150(6 Pt 1):1678-83.

16. Rocha AP, Mateus SRM, Horan TA, Beraldo PSS. Determinação não-invasiva da pressão inspiratória em pacientes com lesão medular traumática: qual é o melhor método? J Bras Pneumol.

2009;35(3):256-60.

17. Martínez-Llorens J, Ausín P, Roig A, Balañá A, Admetlló M, Muñoz L, et al. Nasal inspiratory pressure: an alternative for the assessment of inspiratory muscle strenght? Arch Bronconeumol. 2011;47(4):169-75.

18. Craig CL, Marshall AL, Sjöström M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35(8):1381-95.

19. Black LF, Hyatt RE. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis. 1969;99(5):696-702.

20. Neder JA, Andreoni S, Lerario MC, Nery LE. Reference values for lung function tests. II. Maximal respiratory pressures and voluntary ventilation. Braz J Med Biol Res. 1999;32(6):719-27.

21. Ruppel G. Lung volume tests. In: Manual of pulmonary function testing. 6th ed. St Louis: Mosby; 1994. p.1-25.

27. Meyer FJ, Zugck C, Haass M, Otterspoor L, Strasser RH, Kübler W, et al. Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure. Basic Res Cardiol.

2000;95(4):333-42.

28. Schroeder EB, Welch VL, Couper D, Nieto FJ, Liao D, Rosamond WD, et al. Lung function and incident coronary heart disease: the Atherosclerosis Risk in Communities Study.

Am J Epidemiol. 2003;158(12):1171-81.

29. Beluda FA, Bernasconi R. Relação entre força muscular respiratória e circulação extracorpórea com complicações pulmonares no pós-operatório de cirurgia cardíaca. Rev Soc Cardiol Estado de São Paulo. 2004;14(5 supl):1-9.

30. Weissman C. Pulmonary function after cardiac and thoracic surgery. Anesth Analg. 1999;88(6):1272-9.

31. Rock P, Rich PB. Postoperative pulmonary complications.

Curr Opin Anaesthesiol. 2003;16(2):123-31.

32. Prigent H, Lejaille M, Falaize L, Louis A, Ruquet M, Fauroux B, et al. Assessing inspiratory muscle strength by sniff nasal inspiratory pressure. Neurocrit Care. 2004;1(4):475-8.

33. Kyroussis D, Johnson LC, Hamnegard CH, Polkey MI, Moxham J. Inspiratory muscle maximum relaxation rate measured from submaximal sniff nasal pressure in patients with severe COPD. Thorax. 2002;57(3):254-7.

34. Nava S, Ambrosino N, Crotti P, Fracchia C, Rampulla C. Recruitment of some respiratory muscles during three maximal inspiratory manoeuvres. Thorax. 1993;48(7):702-7.

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SPECIAL ARTICLE

Cardiac surgery: the infinite quest Cirurgia cardíaca: a busca infinita

Rodolfo A. Neirotti1

DOI: 10.5935/1678-9741.20120104

INTRODUCTION Man’s Search for Meaning “The secret of life is to have a task, something you devote your whole life to, something you bring everything to every minute of the day for your whole life. And the most important thing is — it must be something you cannot possibly do!”

Henry Moore What are these series of articles about? Hopefully the readers can find in them a series of concepts and their potential applications to daily practice — some borrowed from my previous work and some from others, in an attempt to expand the horizon of my knowledge. Although I have already presented and written on these subjects, the aim in returning to some of them, as well as adding new ones, is not just to offer new information but more importantly to propose some provocative viewpoints and theories for everyone involved with each and every encounter. I am challenging the reader in the belief that a continuous reassessment of our thoughts and convictions by defying reality can be helpful to verify the sustainability of previous judgments: “By studying how new observations led to the revision of important theories one can see that science is not about immutable laws but provisional explanations that get revised when a better one comes along.” The

1. MD, MPA, PhD, FETCS, Honorary Member of the Brazilian Society of Cardiovascular Surgery.

RBCCV 44205-1429

repeated `trial` of a certain event is precisely what leads to new understandings — which in turn can instigate even newer understandings [1].

When Albert Einstein wrote “The significant problems we face cannot be solved at the same level of thinking we were at when we created them” he was suggesting that if we always think the way we have always thought, we will always do what we have always done, and if we advocate and do what we have always done, we will get what we have always gotten — stagnation of thinking. In addition, his observation remains us of the need to reflect on the issues, challenges, and opportunities in front of the profession and specialty — a future that most likely will be quite different from the recent past. “History is where the future begins” [2]. “You only look to the past to create a solution for the future. If you look down, you can only see a few feet, but if you look up, the view is infinite” [3].

As J. Matloff put it, “The future of medicine would evolve almost entirely as a function of leadership and management capabilities. Beyond whether this evolution could happen, concern was expressed having to do with where that leadership would emerge from government, business, or medicine” [4]. Therefore, it is important that physicians and health professionals take an active role in the political, economic, and social aspects of society — social cure — in order to defend the interests of those suffering. The time has come when those involved have to decide if they will continue to be a part of the problem, or

Correspondence address: 1199 Beacon St, Unit 2.

Brookline, MA 02446 USA Email: RA_Neirotti@ksg06.harvard.edu Article received on September 10th, 2012 Article accepted on December 13th, 2012

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Abbreviations, Acronyms and Symbols OECD

Organization for Economic Co-operation and Development

whether they will be part of the solution delving more into potential answers to improving their institutions and as a result the troubled health care system.

In recent visits to some leading centers I was able to perceive that they are already applying many of the concepts that will be discussed in the different sections. Like in the universe, in the world of pediatric cardiac surgery there are visible galaxies emitting light and five times as much dark matter. The purpose of introducing theories and ideas from other disciplines attempts to lighting up — if that is the appropriate word — the dark matter of our specialty and if possible contribute to diminish its size.

Because of its length, the manuscript will be divided in three parts that will be published in consecutive issues of the Journal, following the suggestion of the Editor.

PART I Approaching our profession and specialty in new and different ways Ultramini-abstract: Thinking of the big picture matters because the health care is multidimensional and therefore it is affected by the economy, social issues and politics, particularly in the developing world. An array of topics will be discussed for the sake of a better understanding of subtleties and depths of the problem. The purpose of combining a mix of ideas and perspectives intended to avoid a piece structured around narrow fields of view.

THE CHALLENGE How do we generate the necessary cohesion to implement reforms? We need to transform exogenous ideas into endogenous dreams through leadership, persuasion, and empowerment. By breaking down complexity into individuals, activities, connections, and pathways, it should be possible to act on the different levels, particularly on individuals to build the system of work required in successful organizations. Since institutions are defined not by buildings, endowments, or traditions but by people with vision, an effort should be made to attract the most talented people that can be found, never ending the pursuit of that perfect candidate. I invite the reader to share my vision rejecting the formalism that continuously hinders our perception and at the same time I encourage them to keep their eyes open.

In general, people with the ideas do not have the power

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to implement them, whereas the people with the power are so embedded in the system that they are unlikely to come up with new thoughts. In addition, it is important to bear in mind the principle-policy/implementation gap — an important barrier to modernization nicely explained by the public choice theory, which results in fewer implementations — just 10% of good ideas. Often, people tend to agree when principles and policies are discussed but the support diminishes when those bearing the costs — interest groups, more influential than those who would benefit from action — have rational incentives to do precisely what they are doing even though the want of the greater part is differing. "The politician becomes a statesman when he thinks of the next generation and not in the next election." Winston Churchill (1874 – 1965) Thoughts on changes brings possibilities - but also pains “Inflexible mentality remains the biggest stumbling block to change” Mikhail Gorbachev In almost every system — country, government, community, organization — there is something broken, flawed or maladaptive. The diagnostic challenge of leadership is to establish what aspects of the system are broken, defective, or maladaptive and the extent to which those features exist in the values, habits, practices and priorities of the people [5].

What is it about how our brains are wired that resists change so tenaciously? Why do we fight even what we know to be in our own vital interests? Resistance of people to change and human nature’s tendency to apply the “minimal risk” and “least effort” strategies that result in incomplete adaptive work allowing subsistence but no optimal result, explain the frequency and persistence of maladaptive practices. Maladaptive practices eventually become permanent adaptive challenges that do not subside with the application of technical skills provided by a profession because people are unwilling to probing their values, habits, practices and priorities. The values and practices that might be viewed as weaknesses are those values and practices that people adhere to and in doing so stay away from dealing with reality. Instead of scrutinizing these features, they prefer to look outside their structure for the cause of what is erroneous. Yet, solutions often reside not in the executive suite but in the collective intelligence of employees at all levels, who need to use one another’s resources, and learn their way to those solutions. The answer is leadership, an important component of the leadership/ management philosophy that fosters transformation by encouraging creative thinking, challenging the status quo, 615

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removing barriers and promoting “bottom up” changes.

To think creatively means to think “outside the box.” That kind of thinking needs role models, whom we count on to bring us new visions and possibilities [5].

It is difficult to discuss the future with people who live in the present, but even more so if they live in the past. Cultural stagnation, based on the sameness of world view caused by social, intellectual, educational, and professional inbreeding, is a real problem and a barrier to progress. These are people who travel in the same circles, go to the same parties, talk to the same people, compare their ideas to people with the same ideas, and develop a standard view on issues that make any deviation from them seem somehow marginal, or even weird. Everybody must believe the same things they do — thinking stagnation without diversity of thoughts — or their contributions will not be constructive. Opposite poles have always more to say to each other than people who share exactly the same views. “You don't make peace with friends. You make it with very unsavory enemies.” Isaac Rabin, former Prime Minister of Israel.

Suggestion: be receptive to changes and new ideas — allow yourself to be changed!

Complex change requires vision, skills, incentives, resources, and an action plan. In addition, a framework for problem diagnostics may be necessary to identify the changes and adaptive work required according to context throughout the system. When goals and objectives have been achieved, and successful change has occurred, it is important for the institution to recognize, celebrate, and if possible reward these accomplishments.

In summary, “It is not the strongest of the species that survive, nor the most intelligent, but the one most responsive to change”— Charles Darwin The Health Care Public health is a system of systems: The health care system goes beyond the care supply system which includes doctors, nurses and hospitals. It also brings in government infrastructure, business, university circles, society and media. It seems to be difficult to get all of those involved to agree on the best way to improve this intricate milieu.

Reinventing ourselves can contribute to the reinvention of the public health domain. The “Fine Art of Reinvention” means specifically taking something that already exist and seeing what it can become. That is, what can happen when circumstances permit you to evolve or, perhaps, force you to evolve? In my end is my beginning, leading to constant redefinition: re-think, re-imagine, re-discover, and reinvent yourself and/or your institution.

Improving the quality of health care and reducing its costs, requires real innovation with leaders focused less on treating disease and more on systemic changes, i.e., 616

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considering health care as an integrated whole calling for revamping by means of innovation [6].

Innovations: Considering innovations in the health care is essential, as the technological opportunities for improved health, the search for better and more equitable services, and the ever swelling costs of health, threaten the economic and social stability of nations worldwide.

“It is unlikely that the existing institutions will solve the current problems of the health care. They have to get people who actually know about public health in positions of power” [7].

Continuous Innovation Requires: As Persaud has so aptly put it, in order sciences to continue to improve, we must have 1) Knowledge development adding value by processing existing information to create new knowledge which could be used to define and solve problems. 2) Cross-fertilization of ideas — networking & physical proximity among well informed people. New knowledge comes from people with time and resources to discuss, think, and experiment. 3) Strong university-industry linkages. 4) Good governance — especially with regards to the legal protection of innovations [8].

A word of caution about expanding too far the lessons from the industry; hospitals do not manufacture anything and the raw material — patients — are defective to start with. Although concepts from non medical sources will be applicable —such as the business value added process, when a patient is admitted and discharged after a sequence of tests and/or procedures are performed— they should be patient centered.

Technology and human capital: The general belief that buildings are important has resulted in new facilities spread around in many towns, schools, universities, hospitals, research centers and even convention centers, without realizing that the quality of the crew — less visible — is the real determining factor for progress. The belief, that increasing buildings and machinery is the fundamental determinant of growth, is sometimes called “capital fundamentalism” by the economists. The conventional wisdom that investing in buildings and machinery is the key to long-run development is another panacea that has not met expectations unless it is combined with human capital — attributes gained by a worker through education and experience. As I have written elsewhere, societies can grow rapidly by relying on a well-trained, educated, hardworking, and conscientious labor force that makes excellent use of modern technologies [9].

Crossing Boundaries, Collaborating for Solutions: Improvement in health care performance requires stakeholders to understand the problems and the need of partnerships among hospitals and with business adopting pathways that can result in clinical solutions for the patient’s well-being, as well as combining evidence-based

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standard medicine with complementary care. Translational research and cooperation among sciences, establishing communication vessels, and removing barriers to interdisciplinary alliances, can contribute to finding answers by the exchange of knowledge. The following examples show that medicine is not unique in benefiting from a multidisciplinary environment with its vast quantity of knowledge: Network Science examines network representations and interconnections in complex systems, of physical, biological, and social phenomena, developing product space maps and analyzing structures of production.

It seeks for common principles, and tools that govern network behavior, in order to increase collaboration across disciplines by sharing knowledge. Research is searching for mathematical models to predict performance, according to network size, complexity, and environment [10]. There are several areas outside medicine that can contribute to solving our problems. For example the aviation and space industry provide tools for safety in medicine and rescue operations, etc. Engineering and technology’s contribution to the progress of precision medicine and its impact on quality is undeniable. In addition, “Clinical Economics” is a new approach, introducing diagnostic tools from Clinical Medicine for international aid to developing countries in the quests for improvements and grow [11]. And finally, economists, in the wake of the recent global financial crisis, are borrowing tools from other sciences — mathematics, biology, and medicine — in the search for certainty to explain and predict complex systems behavior. To prevent another meltdown, financial regulators may need to focus on the health of networks, not individual banks by thinking more like epidemiologists [12].

Innovative Reforms in Education “The commonwealth requires the education of the people as the safeguard of order and liberty”, inscription at the Boston Public Library emphasizing the value of education in society.

The Importance of Teaching, training and learning: Needless to say, the intellectual, cultural, and moral benefits of education for individuals and society are undeniable, particularly if it is based in quality rather than quantity.

Formal advanced education does not by itself speak to success; it is always what one does with education (or lack thereof) that counts, not the degree itself. “Education is a substantial determinant of success — one of the most relevant — but it is less important than most people think.

If everyone had the same education, the inequality of achievements would persist. The consequence of focusing on education alone is to neglect the myriad of other factors that determine people’s future” [13].

It would be easy to give a list of many famous and

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influential people with basic schooling. With this truth in mind, it is important to judge people on the basis of their ability and if possible, without bias. Nevertheless, to prosper, a nation needs a well educated workforce. Efforts to accomplish it should start early before students move forward to university. The countries that get excellent scores in reading, mathematics and science tests — OECD, a club of rich countries — are not necessarily those that spend more. “The variation in achievement cannot be explained by how much is spent but rather to how it is spent. High achieving countries have classes taught by great teachers.

They have raised teacher’s status by making it harder to become and remain one. Their salaries are according to their quality” [13]. When people are not properly paid, the workplace philosophy inspires: “they pretend to pay us, while we pretend to work.”

Which are the industries, professions and professionals that will be needed in the 21st century? is a question that no one seems able to answer. It is important for societies to attempt to anticipate which sectors are expected to offer the best prospect for the future, therefore, it is the right time to work on the jobs yet to come and thinking seriously about how to prepare our institutions and professionals.

This is a challenge not only for Medical Schools, Schools of Public Health and Medical Centers but also for many other disciplines since we are educating young people for jobs that do not even exist just yet with programs of study from the previous century.

Potential new path to success: “In America, only three in 10 young people earn a bachelor’s degree by the age of 22, while 40 percent never attend a community college or university. In addition, high schools do not offer alternatives that prepare students to enter the working world. Therefore in a recent report called “Pathways to Prosperity” the authors reason that students could benefit from vocational training to learn the job skills they will need down the road. Just as high schools encourage students to consider college, they should also prepare their graduates to enter apprenticeships, certificate programs, or community colleges that can teach those jobs skills.” This pathway could results in a better educated workforce in high-demand fields generating advances in science, health and society that benefit all of us [14].

Education of Health Care Professionals Modernizing education even further may be needed at some point in time, moving to a competency based transformative learning. This approach in which knowledge objectives drives the curriculum — requires institutional design as well instructional design — curricula—individualizing the process according to specific contexts [15].

The implementation of “twinning programs” is a 617

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successful tool for improving training, quality, and access to care. Medical schools in all countries have benefited from twinning programs that foster exchange, share resources, and undertake collaborative work for mutual advance.

Collaboration, a potent tool of academic systems, describes the opportunities to advance educational quality and output through sharing of information, academic exchange, quest of joint efforts, and synergies between institutions. It ultimately involves the relationship between individuals, but it can be structured and sustained through formalized institutional arrangements that promote, finance, and carry on relationships over time. The institutional objective in education, research, and service can be advanced through sharing of curricula, exchange of faculty, students, and joint research [15].

At the 2005 meeting of the American Board of Thoracic Surgery, a proposal to establish a subspecialty certificate in congenital heart surgery was unanimously approved by the Board of Directors. This proposal was prompted by the recognition that the discipline of congenital heart surgery requires unique skills and education that are not currently provided in a standard thoracic surgery residency.

According to this concept, a curriculum is needed to define what skills are required to become an independent surgeon.

In addition, education should not be limited to surgical trainees but should also include other related non medical patient caregivers and support services — all members of the health team — moving education beyond interaction only between surgeons to: 1) Attending physicians; 2) Charge nurses/leaders and bedside nurses; 3) Resident/Fellows; 4) Community MDs; 5) Emergency Departments and Outpatient Clinics. Due to the lack of any formal educational process to prepare individuals for the administrative role of a division chief, these efforts should also include those aspiring to these positions in order to promote scholarships in thoracic and cardiovascular surgery. To put it another way, the most important function of the system is the production of the producers.

The teaching-learning process can be improved by linking the matter being taught — whenever possible — to present-day situations in a non-punitive fashion learning oriented error reporting program. Doing so will make it much easier to understand the subject, in addition to making it more pertinent and effective as it relates to today's needs. Furthermore, institutions and professional organizations should be encouraged to use technology to considerably enhance the relevance and quality of education. Unfortunately, everybody gives lip service to education, but only a few are willing to funds it.

Potential Barriers: For many years physicians, and surgeons, have been able to implement new treatments with minimal oversight. As the general public becomes better informed about the inside working of hospitals, 618

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medical care, and their doctors, physicians have come under more scrutiny and monitoring than ever before.

Society is more critical of the actions of the medical profession. The learning curve has changed, standards are stricter and the measuring sticks more exacting (E. Bove.

Seminars in Thoracic and Cardiovascular Surgery, 2003.).

In addition, the impact of interventional cardiology and the shift to early repair have resulted in fewer straightforward cases. Furthermore, some common beliefs among surgeons such as, “observing is the best way of learning,” “the real surgeon must do the entire case,” and “not perceiving that the time spend helping a resident is part of the operation” worsen the situation [16].

Teaching Professionals How to Learn. Not so simple: “Professionals embody the learning dilemma: they are enthusiastic about continuous improvement — often the biggest obstacle to its success. For them, learning means solving problems by focusing on identifying and correcting errors in the external environment. Managers and employees must also look inward. They need to reflect critically on their own behavior, identify the ways they often inadvertently contribute to the organization’s problems and then change how they act.” In order to be part of the solution they need to admit that they are part of the problem. For years, General Motors executives became practiced at the art of explaining their problems and attributing blame to everyone but themselves, rather than recognize their inability to admit mistakes [17].

Skilled professionals, almost always successful at what they do, often react defensively blaming others for their problems, in a closed single loop learning that shut down their ability to learn. Persistence of the problems and lack of progress are the consequences of failing backward.

There’s a difference between defending what you have done than being defensive [17].

Less commonly, smart people are able to learn from failure — “failing forward” by using critical thinking and productive reasoning — and this is called double loop learning. Continuous improvement is the result of how they think, design, and implement their actions combining a top down approach with a “bottom up” one [17,18]. It would be hard to accept that maybe people do not want to learn?; Maybe people have not learned how to learn?; Maybe there is a fear of the unknown and therefore the amount and level of stimulation taken in must be inferior to one’s own “wisdom”?

National/International Cooperation, Diagnosis and Recipient Selection: Because the world faces many formidable problems, we cannot expect to solve the maldistribution and poor access to cardiac surgery through the regular channels for international aid. Currently, there

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are numerous groups around the world involved with structured international projects, but without coordination among them. In humanitarian medicine, there is room for cooperation rather than competition, because the people in need outnumber those able to provide assistance.

Unfortunately, there are not humanitarian solutions for humanitarian problems. Answers that are more comprehensive are needed, in which humanitarianism would play only a part.

To avoid squandering energy and resources it is important to identify places, “fertile sites”, and their needs, with receptive individuals where good work is being done.

The majority of donor programs focus on developing an ongoing relationship with a host program. This relationship involves visiting teams, teaching, training, collaborative research, and donation of equipment. The “twinning process” results in a transfer of knowledge, ideas and skills and the visiting team usually includes: surgeon, anesthesiologist, cardiologist, perfusionist, critical care specialist, interventional cardiologist, and nurses. To maximize training effectiveness in other cultures, trainers need to understand how cultural differences may affect the expectations of their audiences. Volunteerism, a core value of many peer programs, eventually wears thin as volunteers have other obligations resulting in weakening of early successes. This approach will be most effective when local governments, doctors, and hospitals have a genuine learning interest. In those instances, eventually the host program becomes autonomous, with the donor program assuming a consultant role.

Professional Organizations: Professional organizations can be extremely helpful by coordinating the efforts, and taking maximum advantage of contemporary technology in communications and educational techniques for fostering the transfer of knowledge, skills, and ideas of its members beyond borders for the benefit of patients in lesser-developed countries. In addition to their role in education, lively and energetic local and international professional organizations can respond to the initiatives of the members, to the changes of the specialty and to the evolution of treatment modalities.

Professional networks allow physicians to share insights with each other, almost on real time without enduring the unwieldy rules and delays involved in traditional academic publishing [7].

Accreditation: Evaluation of centers, surgeons, training programs and other health professionals: It is necessary to provide a formal recognition to the trainee that has completed the process. National accreditation systems should develop a criterion for assessment, define metrics of output, and shape the competencies of graduates to meet societal health needs. Probably the most difficult and at the same time the most important issue is how to evaluate the genuine technical skills of surgeons, which

will not be reflected in references, written examinations and interviews. Professional organizations can arrange visits of a group of experts to evaluate the function of the entire team as well as their training programs through interviews with residents and fellows. Although it is done in some countries it is not yet widely accepted.

Inferences ● To-date, particularly in developing countries, we have been unable to secure support from governments, professional organizations, philanthropists, patients, or peers for our specialty. ● The existing curriculum of medical schools, developed a century ago, need modernization to produce health care professionals that can adapt to the broad range of therapeutic options offered by the rapidly growing technology. ● Basic sciences may introduce an unthinkable scenario requiring redefinition of the regulatory bodies with a multidisciplinary approach in which innovation should be coupled to early evaluation in order to determine the value of new procedures [19,20]. ● Many obstacles remain, but physicians and professional societies can and must play an important role in overcoming them. ►Part II will be published in the next issue of the RBCCV Cardiac Surgery: issues around and beyond the operating room Ultramini-abstract: In addition to our clinical and technical work, there is a need to cross boundaries searching for collaboration as well as lessons from other complex systems that has identified common solutions for common problems, indicating that the general theory is independent of any particular industry or activity. An innovative partnership among the government, the private sector and foundations can let to major advancement of the health system.

REFERENCES 1. Willingham D. Trust me, I’m a scientist. Sci Am. 2011;304(5):12.

2. Faust D. History is where the future begins. Harvard Magazine.

2012. p.63. Available at: http://harvardmag.com/pdf/2012/07pdfs/0712-63.pdf 3. Shorow S. A life reborn, a story now told. Harvard University Gazette; 2012. p.16-7. Available at: http://news.harvard.edu/ gazette/story/2012/02/a-life-reborn-a-story-now-told/

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4. Matloff JM. The practice of medicine in the year 2010. Ann Thorac Surg. 1993;55(5):1311-25.

5. Williams D. Real leadership: helping people and organizations face their toughest, challenges. San Francisco:Berrett-Koehler Publisher; 2005.

6. Berwick D. Institute of health improvement. In: Frieden J, ed.

Quality improvement must be included in reform. Elsevier Global Medical News. Thoracic Surgery News; 2009.

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AA. Would you be happier if you were richer? A focusing illusion. Princeton University. CEPS Working Paper No. 125; May 2006. Available at: http://www.princeton.edu/~ceps/ workingpapers/125krueger.pdf 14. Symonds W, Schuartz R, Ferguson R. Pathways to prosperity: meeting the challenge of preparing young Americans for the 21st century. Boston: Harvard University Graduate School of Education; February 2011.

7. Christensen CM, Grossman JH, Hwang J. The innovatorâ&#x20AC;&#x2122;s prescription: a disruptive solution for health care. New York:Mc Graw Hill;2009.

15. Frenk J, Chen L, Bhutta Z, Cohen J, Crisp N, Evans T, et al.

Health professionals for a new century: transforming education to strengthen health systems in an interdependent world.

Lancet. 2010;376(9756):1923-58.

8. Persaud A. The knowledge gap. Foreign Affairs.

2001;80(2):107-17.

16. Kron I. Surgical mentoring. Presidential Address. 91st AATS Annual Meeting. Philadelphia;2011.

9. Neirotti RA. Cardiac surgery: complex individual and organizational factors and their interactions. Concepts and practices. Rev Bras Cir Cardiovasc. 2010;25(1):VI-VII.

17. Argyris C. Teaching smart people how to learn. Harvard Business Review; May-June 1991.

10. Hausmann R, Rodrik D, Velasco A. Competitive advantage of nations growth diagnosis. Boston:Harvard University; 2004.

18. Maxwell JC. Failing forward turning mistakes into stepping stones for success. Thomas Nelson Inc, April 3, 2007.

11. Sachs J. The end of poverty: economic possibilities for our time. New York:Penguin Books; 2006.

19. Berkes F, Colding J, Folke C. Navigating social-ecological systems: building resilience for complexity and change.

Cambridge:Cambridge University Press; 2003.

12. Power C. Too contagious to fail: why bankers should think more like epidemiologists. Scientific American April 15, 2011.

13. Kahneman D, Krueger AB, Schkade D, Schwarz N, Stone

20. McCulloch P, Altman DG, Campbell WB, Flum DR, Glasziou P, Marshall JC, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374(9695):1105-12.

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EXPERIMENTAL WORK

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Sanguineous normothermic, intermittent cardioplegia, effects on hypertrophic myocardium. Morphometric, metabolic and ultrastructural studies in rabbits hearts Efeitos da cardioplegia sanguínea normotérmica intermitente, em miocárdio hipertrófico. Estudos morfométricos, metabólicos e ultraestruturais em corações coelhos

Clovis Carbone Junior1, José Eduardo de Salles Roselino2, Valder Rodrigues Mello3, Paulo Roberto Barbosa Evora4, Albert Amin Sader5

DOI: 10.5935/1678-9741.20120105

RBCCV 44205-1430

Abstract Objectives: The present investigation aimed to study the protective effect of intermittent normothermic cardioplegia in rabbit's hypertrophic hearts.

Methods: The parameters chosen were 1) the ratio heart weight / body weight, 2) the myocardial glycogen levels, 3) ultrastructural changes of light and electron microscopy, and 4) mitochondrial respiration.

Results: 1) The experimental model, coarctation of the aorta induced left ventricular hypertrophy; 2) the temporal evolution of the glycogen levels in hypertrophic myocardium demonstrates that there is a significant decrease; 3) It was observed a time-dependent trend of higher oxygen consumption values in the hypertrophic group; 4) there was a significant time-dependent decrease in the respiratory coefficient rate in the hypertrophic group; 5) the stoichiometries values of the ADP: O2 revealed the downward trend of the values of the

hypertrophic group; 6) It was possible to observe damaged mitochondria from hypertrophic myocardium emphasizing the large heterogeneity of data.

Conclusion: The acquisition of biochemical data, especially the increase in speed of glycogen breakdown, when anatomical changes are not detected, represents an important result even when considering all the difficulties inherent in the process of translating experimental results into clinical practice. With regard to the adopted methods, it is clear that morphometric methods are less specific. Otherwise, the biochemical data allow detecting alterations of glycogen concentrations and mitochondria respiration before the morphometric alterations should be detected

1. MD. PhD Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo - Experimental execution, data evaluation and text review; Ribeirão Preto, SP, Brazil.

2. MD, PhD Department of Biochemistry and Immunology, Ribeirão Preto Faculty of Medicine, University of São Paulo - Data evaluation and review; Ribeirão Preto, SP, Brazil.

3. BsC, PhD Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo - Data evaluation and review; Ribeirão Preto, SP, Brazil.

4. Full Professor Department of Surgery and Anatomy, Ribeirão Preto Faculty of Medicine, University of São Paulo (Docente da Divisão de Cirurgia Torácica e Cardiovascular) - Paper review data and writing; Ribeirão Preto, SP, Brazil.

5. Full Professor Department of Surgery and Anatomy, Ribeirão Preto

Faculty of Medicine, University of São Paulo - Study design, data evaluation and text review; Ribeirão Preto, SP, Brazil.

Descriptors: Heart arrest, induced. Hypertrophy, left ventricular. Cardiovascular surgical procedures.

Work carried out at Ribeirão Preto Faculty of Medicine, University of São Paulo, Ribeirão Preto/São Paulo, Brazil.

Correspondence address: Paulo Roberto Barbosa Evora Rua Barbosa, 367 – apt. 15 – Centro – Ribeirão Preto, SP, Brazil.

Zip code: 14015-120 E-mail: prbevora@fmrp.usp.br Article received on September 5th, 2012 Article accepted on October 1st, 2012

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Abbreviations, Acronyms & Symbols ADP Adenosine diphosphate LVW/BW Left ventricular and body weight ratio RCR Respiratory control ratio

Resumo Objetivos: O presente estudo teve como objetivo estudar o efeito protetor da cardioplegia normotérmica intermitente em corações hipertróficos de coelhos.

Métodos: Os parâmetros escolhidos foram: 1) relação peso cardíaco/peso corporal; 2) níveis de glicogênio nos músculos cardíacos; 3) alterações ultraestruturais por microscopia óptica e eletrônica; e 4) respiração mitocondrial.

Resultados: 1) O modelo experimental de coarctação da aorta induziu hipertrofia ventricular esquerda; 2) a evolução temporal dos níveis de glicogênio no miocárdio hipertrófico demonstra que há diminuição significativa; 3) observou-se tendência dependente do tempo para

INTRODUCTION The current success of cardiac surgery was provided, among other relevant factors, by better understanding the myocardium protection. The timeline of this understanding includes: 1) systemic hypothermia [1]; 2) intra-operative cardiac arrest induced by potassium citrate [2]; 3) anoxic arrest of the heart [3]; 4) the use of chemicals that could rapidly determine cardiac arrest [4]; 5) Miscellaneous studies relating to the composition, temperature and mode of drug administration named cardioplegic solution [5-7], and; 6) normothermic cardioplegia [8,9].

In cardiac hypertrophy, whether it is induced in an experimental model or observed clinically, energy metabolism is compromised highlighting that Sink et al.

[10] demonstrated that the hypertrophic heart must be stopped immediately emphasizing the need of additives to the cardioplegia solution. It is noteworthy that Cooley et al., in 1972, described the "Stone Heart", i.e., ischemic contracture, more frequent and severe in the hypertrophic heart [11]. This ischemia/reperfusion phenomenon allowed the resumption of the discussion, and final conclusion, about the pivotal role of myocardial protection as a means of avoiding this extremely serious intraoperative complication. Therefore, even after more than 60 years, continued studies of the hypertrophic myocardium energy metabolism under the action of cardioplegia are still necessary to improve surgical procedures in this pathological condition.

Most of experimental researches on cardioplegia were made in hearts of normal animals. Thus, specifically, the 622

maiores valores do consumo de oxigênio para o grupo hipertrófico; 4) houve diminuição dependente do tempo da taxa de coeficiente respiratório no grupo hipertrófico; 5) os valores estequiométricos da ADP: O2 revelou a tendência decrescente no grupo hipertrófico; 6) observaram-se lesões mitocondriais do miocárdio hipertrófico, enfatizando a grande heterogeneidade dos dados.

Conclusão: A aquisição de dados bioquímicos, principalmente o aumento na velocidade de quebra do glicogênio, quando mudanças anatômicas não são detectadas, representa um resultado importante, mesmo quando se consideram todas as dificuldades inerentes ao processo translacional de resultados experimentais para a prática clínica. No que diz respeito aos métodos adotados, é evidente que os métodos morfométricos são menos específicos. Os dados bioquímicos permitem a detecção de alterações das concentrações de glicogênio e respiração mitocondrial antes das alterações morfométricas serem detectadas.

Descritores: Parada cardíaca induzida. Hipertrofia ventricular esquerda. Procedimentos cirúrgicos cardiovasculares.

present investigation aimed to study the protective effect of intermittent normothermic cardioplegia in rabbits hypertrophic hearts. The parameters chosen were 1) the ratio heart weight/body weight to evaluate the myocardium hypertrophy, 2) the heart muscle glycogen levels, 3) ultrastructural changes by light and electron microscopy, and 4) mitochondrial respiration. As a secondary objective, the study aimed to evaluate the adequacy of the adopted methods.

METHODS Experimental design New Zeland rabbits (n=76; 1.7 - 2.5 kg) were anesthetized using pentobarbital sodium (30 mg/kg intravenous). The animals underwent tracheostomy, and they were ventilated using an endotracheal tube (3.0 mm, Rusch, Teleflex Medical, Durham, NC, USA) with 100% O2 in a pressure-controlled mode (Takaoka 600, K. Takaoka Indústria e Comércio Ltda, São Bernardo do Campo, SP, Brazil). The ear marginal vein was cannulated for volemic reposition with saline solution (NaCl 0.9%, 10 ml/kg/h).

The Institutional Animal Care and Use Committee of the Ribeirão Preto Faculty of Medicine, University of São Paulo, Brazil reviewed and approved the procedures for animal handling, which were in accordance with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996).

The study adopted two lines of investigation (biochemical and morphological) for which the animals were randomly divided into two main groups: Group I/

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normal (n=36) and Group II/hypertrophy (n=40). The number of rabbits was based on literature data, mainly involving mitochondria respiration. Also, rabbits were elected as experimental animal based on those studies. The samples were collected immediately, 60 and 90 minutes after cardioplegia infusion.

Cardiac hypertrophy was induced by coarctation of the abdominal aorta just distal to the diaphragm, according the technique of Leclercq et al. [12], using a midline laparotomy as access. The aorta was dissected and looped with cotton thread 00 (two zeros), the stenosis of the artery was calibrated with a 2 mm needle (50% stenosis), which was removedafter tying the artery. The wall plans were sutured, and the waiting time for the induction of cardiac hypertrophy was 14 days.

On the morning of the fourteenth postoperative day, under anesthesia, all animals were submitted to median sternotomy, identification and fast excision of the heart after sectioning of its vessels (superior and inferior vena cava, aorta artery and pulmonary artery and vein).

The whole heart was immediately immersed in a beaker containing 0.9% saline solution and, ice cooler stored to keep the temperature between 0 and 3oC. The hearts were subjected to cardiac arrest by normothermic blood cardioplegia solution (37°C), composed of 40% blood and 60% solution of sodium chloride 0.9% to 50 mEq/L of potassium chloride to induce cardiac arrest and 30 mEq/L for maintenance doses. After cardioplegic arrest, the hearts were subjected to a period of myocardial ischemia of 60 and 90 minutes, kept in a water bath at 37°C, using multidose intermittent antegrade blood cardioplegia every 20 minutes, the proportion of 5 ml/kg body weight. The group with zero time of ischemia was used as the control.

The atria were extracted, and the ventricles were cut into small fragments of about 2 mm. During this procedure, repeated washings were done with 0.9% saline solution at a temperature of 0 to 3oC. For each time was carried out biochemical determination of the following parameters: analysis of mitochondrial oxygen consumption and measurement of the glycogen concentration.

final concentration. State III (activated respiration) was obtained after the addition of 400 nmoles of adenosine diphosphate (ADP). State IV (basal respiration) was measured when all ADP had been converted to ATP, a condition indicated by the return to basal respiratory levels.

The ratio of respiration rate after the addition of ADP (state III) to respiration rate during the basal state (state IV) corresponded to the respiratory control ratio (RCR). The parameters of oxidative phosphorylation were calculated according to Chance and Williams [15] and Estabrook and Pullman [16] and were expressed in nanoatoms of oxygen used per mg protein per minute. Mitochondrial protein content was determined by the biuret method [17].

Mitochondrial function The mitochondrial fraction was isolated by the method of Bullock et al. [13] Mitochondrial function was determined by a polarographic method [14], using an OXY 5 polarograph-oxygraph (Gilson Medical Eletronics, Inc., W. Beltline Middeton, WI, USA). The respiration medium contained 0.23 M sucrose, 8 mM potassium phosphate, 9.5 mMTris, pH 7.0, 0.14 mg/ml albumin, and 1 mM EDTA. The mitochondrial fraction was assayed at 1 2 mg/ml protein concentration in the oxygraph chamber.

Substrates were added as a mixture of malate, pyruvate, keto-glutarate, and b-hydroxy-butyrate, each at 48 mM

Measurements of myocardial glycogen Glycogen was extracted with 30% KOH from 500 mg of the left ventricle myocardium. After centrifugation at 800g for 10 min, 1 mL of supernatant solution was transferred to a tube incubated on ice and mixed with 2 mL fluid with anthrone. The mixture was boiled for 10 min and then cooled immediately on ice, followed by incubation at room temperature for 10 min. The absorbance was read at 620 nm by a spectrophotometer and, the values were expressed in % of humid weigh [18].

Morphologic study A cross-sectional slice of the left ventricle chamber was obtained after the cardioplegic arrest was immersed and fixed in Bouin solution for 24 hours, dehydrated in ethanol and included in Paraplast. Cuts (5 µm) were stained with hematoxylin-eosin, Mallory’s trichrome and PicroSirius Red with the aid of a digitizing tablet (MINIMOP - Kontron Elektronics). Measurements were taken directly on the blades and the values are expressed in millimeters (final images 800 Xs).

For transmission electron microscopy, a group of blocks was selected and processed for ultrathin sections. The areas of cytoplasm, where mitochondria predominated, were photographed under a microscope Philips EM 208 (Transmission Electron Microscopy) at original magnification of 20.000X. The negatives were double enlargedand copied yielding the final images at 40.000X. These amplifications were analyzed for the determination of mitochondrial diameters (maximum and minimum) through the use of the tablet (MINI-MOP - Kontron Elektronics), and the results were expressed in micrometers as the correction was made for the magnification factor.

Statistical analysis For statistical analysis of the body weight and to assess the ventricular induction of myocardial hypertrophy was used the t-test to compare values with similar and different variances for significance of 5%.

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For the biochemical parameters (glycogen and mitochondrial respiration), statistical comparisons were carried out between control and hypertrophic myocardium groups, and among times of ischemia. Initially, tests were normal (Shapiro and Wilk) not finding suitable conditions for the application of parametric statistics. It was decided then to apply the Kruskal-Wallis test on each group separately (normal versus hypertrophic) in order to study the effect of ischemia time on biochemical variables, adopting the significance level of 5%.

The Mann-Whitney test was carried out in each subgroup of time (0, 60 and 90). For multiple comparisons among the subgroups of time (0, 60 and 90), for each biochemical variable mentioned above, it was used the method of Dunn.

Figure 1C shows the values of the left ventricular and body weight ratio (LVW/BW in g/kg) with the statistical t-test showing a significant increase (significance of 5%) in the hypertrophied heart at all ischemic times.

Figure 1D demonstrates the dispersion of the ratio values of ventricular weight/body weight in normal and hypertrophic groups, but corresponding to 0 min ischemia.

This analysis aims to characterize the eventual presence of cardiac hypertrophy in the control group, when it is supposed that the intracellular edema factor was absent, making sure that the values reflected the myocardium hypertrophy in this study group.

Induction of experimental cardiac hypertrophy In Figure 1A, are represented the values of body weight of all animals studied during cardioplegic arrest times of 0, 60 and 90 min. It is observed a similarity between Groups I and II (significance of 5%).

In Figure 1B are represented the values of ventricular myocardium weight with the statistical t-test showing a significant increase (significance of 5%) in the hypertrophied heart at all ischemic times.

Glycogen and mitochondrial function Figure 2 represents the glycogen levels found in normal and hypertrophic myocardium of rabbits when subjected to infusion of normothermic blood cardioplegia.

Statistical analysis was performed between samples; the Mann-Whitney analysis of normal and hypertrophic group revealed no significant differences (significance of 5%). However, the Kruskal-Wallis test that analyzes the temporal evolution of the glycogen levels in hypertrophic myocardium demonstrates that there is a significant decrease (significance of 5%) at 90 minutes compared to time 0 (zero), whereas normal myocardium did not differ in any time (significance of 5%).

Fig. 1 - A - body weight (kg), B â&#x20AC;&#x201C; left ventricle weight (g), C - left ventricle weight LVW/body weight (BW) ratio (g/kg); D â&#x20AC;&#x201C; values of the ratio LVW/BW (g/kg) characterizing the data dispersion.

Normal myocardium (column textured) and hypertrophic (full column) underwent infusion of cardioplegia at ischemia times of 0 min, 60 min and 90 min. The columns represent the mean values and the bars above the columns the standard error of the mean. In the figure D, values in the x-axis correspond to increasing numbers of samples and the line which bisects the graph corresponds to the value LVW/BW of 2.3 g/kg. The asterisk means significant difference between groups, with P <0.05

Fig. 2 - Shows the levels of glycogen in normal hearts (black circles) and hypertrophic hearts (red squares) of rabbits submitted to cardioplegic arrest for 60 and 90 minutes and its respective control group. Normothermic blood cardioplegia was used, and the glycogen concentration values are expressed in % of wet weight.

The symbols represent the average values with the corresponding standard deviation. Group I, normal heart (control/n = 12; time 60 min/n = 13 and time 90 min/n = 11); Group II, hypertrophic heart (control/n = 19; time 60 min/n = 12, and; time 90 min/n = 12).

The asterisk refers to a significant difference (P <0.05) between time 0 and 90 min of the hypertrophic group

RESULTS

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Figure 3Arepresents the values of the state III mitochondrial oxygen consumption, demonstrating the effect of ischemia time on the group of normal and hypertrophic myocardium.

The analysis between groups by Mann-Whitney, at 90 min, showed a trend of higher values for the hypertrophic group.

The Kruskal-Wallis test found no difference among samples obtained at different times (significance of 5%).

Figure 3B represents the values of the state IV mitochondrial oxygen consumption, at times 0, 60 and 90 min, found in normal and hypertrophic myocardium after infusion of normothermic cardioplegic solution. The MannWhitney test shows a significant increase in values at 90 min (significance of 5%) of the hypertrophic group when compared to normal. The Kruskal-Wallis test did not show differences among the results (significance of 5%).

The values of the respiratory control ratio (RCR) observed

in Figure 3C, were measured in normal and hypertrophic myocardium after infusion of cardioplegic solution at 0, 60 and 90 min. The Mann-Whitney test found no significant differences between groups (significance of 5%). However, the analysis between the different times observed by the Kruskal-Wallis test, showed a significant decrease in the RCR (significance of 5%), in the hypertrophic group, at 90 min of ischemia when compared with time zero.

Figure 3D represents the stoichiometric values of the ADP:O2 found in normal and hypertrophic myocardium after normothermic cardioplegic arrest. The MannWhitney test revealed a downward trend of the values of the hypertrophic group when compared with normal myocardium. For the hypertrophic group, the KruskalWallis test showed differences between them with a significant decrease (P <0.05) values for ADP:O2.

A

C

B

D

Fig. 3 - Analysis of mitochondrial respiration: A - State III, B - State IV, C - Respiratory Control Ratio (RCR), and D - mitochondrial oxygen consumption (ADP:O2). Comparison between normal hearts (black circles) and hypertrophic hearts (red squares) of rabbits submitted to the infusion of normothermic blood cardioplegic solution with cardiac arrest of 60 and 90 minutes and the control group. The mitochondria (1 mg protein/ml) were tested at 30°C using Alpha-ketoglutarate as respiratory substrates. Breathing was activated with 400 nanomoles of ADP. Values are expressed in oxygen nanoatoms O2/mg protein.min. The symbols represent the average values with the corresponding standard deviation. Group normal heart (control n = 12, n = 60 min n=13, 90 min n = 12); Group hypertrophic heart (control/n = 16; 60 min/n=12; 90 min/n = 12). A â&#x20AC;&#x201C; No significant differences; B - The asterisks (**) refer to the significant increase (P <0.05) in the hypertrophic group compared with the normal at 90 min, C - The asterisk refers to a significant difference (P <0.05) between the time 0 and 90 min of the hypertrophic group, D - the asterisk refers to a significant difference (P <0.05) between 60 and 90 min and 0 and 90 min of the hypertrophic group

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Fig. 4 - The graphs represent the minor (Group IA and Group IIB) and major (Group IC and IID) mitochondrial diameters analyzed by electron microscopy, increased 40.000x. One can observe a large heterogeneity of data, why were divided by its frequency. There was a trend to higher mitochondrial diameter in Group II, and the data of minor diameters are most similar in its distribution. However, in Group II and its respective subgroup of 60 min of ischemia, there was a marked increase in both mitochondrial diameters, demonstrating intracellular edema with cardioplegic arrest

The graphs of Figure 4 represent the minor (A and B) and major (C and D) mitochondrial diameters analyzed by electron microscopy, increased 40.000x. One can observe a large heterogeneity of data, when divided by its frequency.

Comparing data from Groups I and II and their respective subgroups of cardioplegic arrest in time zero, there was a higher trend in Group II of increasing the mitochondrial diameter. The data of minor mitochondrial diameters are most similar in its distribution. However, in Group II and its respective subgroup of 60 min of ischemia, there was a marked increase in both mitochondrial diameters, demonstrating intracellular edema with cardioplegic arrest.

Figure 5 presents light (A, B) and electron (B, C) micrographs of transverse sections of the myocardium 626

of rabbits submitted to cardioplegic cardiac arrest.

A - micrograph (block No. 11647b) belonging to the subgroup 0 minutes in Group I, shows myocardial fibers involving the interstitium where it is observed blood vessels and collagen (800X); B - micrograph (block No. 11597g) belonging to 0 minutes subgroup in Group II reveals a significant increase in the transverse diameter of myocardial fibers occupying the space of interstitium (800X); C - micrograph (block No 11647h) belonging to the subgroup 0 minutes in group I reveal various aspects of normal mitochondria (40.000X), and; D - Micrograph (block No 11692f) belonging to the subgroup 0 minutes in Group II shows mitochondria with increased diameter and loss of their morphological characteristics (40.000X).

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Fig. 5 - Light (A, B) and electron (C, D) micrographs of transverse sections of the myocardium of rabbits submitted to cardioplegic cardiac arrest. A – micrograph of a specimen belonging to the subgroup 0 minutes in Group I, shows myocardial fibers sectioned transversely,and in the involved interstitium is observed blood vessels and collagen (800X); B – micrograph of a specimen belonging to 0 minutes subgroup in Group II reveals a significant increase in the transverse diameter of myocardial fibers occupying the space of interstitium (800X), C - micrograph belonging to the subgroup 0 minutes in group I reveals various aspects of normal mitochondria (40.000X), D - Micrograph belonging to the subgroup 0 minutes in Group II shows mitochondria with increased diameter and loss of their morphological characteristics (40.000X)

DISCUSSION Myocardial hypertrophy is considered the most efficient event, among the compensatory mechanisms of heart diseases, when the muscle is exposed to overload depending on extramyocardial disease. Several mechanical and neurohormonal factors act as myocardial growth factors and change the pattern of protein synthesis, resulting in a ventricular remodeling. The several mechanisms in response to the decrease of cardiac performance, initially adaptive, became developmentally pernicious [19].

The basic data of the present investigation were: 1) the experimental model, coarctation of the aorta induced left ventricular hypertrophy; 2) the temporal evolution of the glycogen levels in hypertrophic myocardium demonstrates that there is a significant decrease; 3) It was observed a time-dependent trend of higher oxygen consumption values for the hypertrophic group; 3) there was a significant time-dependent decrease in the respiratory coefficient rate in the hypertrophic group; 4) the stoichiometric values of the ADP: O2 revealed the downward trend of the values of the hypertrophic group; 5) It was possible to observe damaged mitochondria from hypertrophic myocardium emphasizing the large heterogeneity of data.

Experimental model Concerning the experimental model, coarctation of

the aorta induced left ventricular hypertrophy. Indeed, there has been a bandage of the aorta in order to cause a pressure overload in the proximal portion. The sustained high pressure trigger a complex process whose ultimate expression was the increased thickness of the myocardium without enlargement of the ventricular cavity as a consequence of adaptive morphological response [20]. The data, confirming the appropriateness of the methodology are shown in Figure 1A markedly and significant weight of the left ventricle of rabbits in the experimental hypertrophy protocol can be observed. To rule out the possible influence of the number of experiments the dispersion values of the ratio ventricular weight/body weight in normal and hypertrophic groups, were considered at 0 min ischemia.

This analysis aims to characterize the presence of cardiac hypertrophy in the control group, when the intracellular edema factor is absent and thus ensure greater safety margin for the values of biochemical analysis related to the cellular metabolism of the hypertrophic myocardium.

In the present study, we found in the control group average of 2.2 for the ratio LVW/BW, which is quite similar to the threshold value of 2.3 for LVW/BW, based on studies of Hatt et al. [21] in rabbit’s hypertrophic heart induced by aortic regurgitation. It is logical to assume that increased values of LVW/BW are associated to earlier left ventricle failure. In the same study, the average LVW/BW for animals with questionable myocardial failure was 3.0, 627

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and 3.9 for obvious failure. In this initial understanding of myocardial hypertrophy, it is reasonable to distinguish two types of cardiac hypertrophy: a physiological normal or increased contractility, and, a pathologically reduced contractile function [22].

of the quality. The values of the state III mitochondrial oxygen consumption, which denotes the effect of ischemia time, showed at 90 min, a trend of higher values for the hypertrophic group, but, analyzing the temporal evolution it was not observed differences among the results. The values of the state IV showed a significant increase of the hypertrophic group when compared to normal, at 90 minutes, without differences in the temporal evolution. The RCR did not show significant differences between normal and hypertrophic group. However, the analysis of the evolution time line showed significant RCR decrease in the hypertrophic group, at 90 min of ischemia, when compared with time zero. The stoichiometric values of the ADP: O2 found in the normal and hypertrophic myocardium after normothermic cardioplegic arrest revealed the downward trend of the values of the hypertrophic group with the time line statistical analysis revealing decreased values.

Observing the respiratory values, all together, the only possible conclusion is that the hypertrophic myocardium is more susceptible to changes elicited by prolonged ischemia.

Glycogen metabolism Considering hypertrophy as a disease process, not just a physiological response, and its risk factor role for clinical complications commonly present in cardiac surgery, the biochemical approach of myocardial protection is mandatory. Thus, the present study in rabbits used intermittent antegrade blood cardioplegia which, admittedly, provides protection to the myocardium reduces the energy expenditure and decreases the rate of glycogenolysis. The normothermia experimental option experiment was adopted, based on studies performed in our laboratory showing a larger decrease glycogen levels in normothermic condition, compared with hypothermia [23]. In the present study, there was no difference in glycogen concentration (time zero x 90 minutes) within the control group samples. Surely, this observation is due to the influence of the variability of sample values in an experimental situation in which there was an increase of glycogen breakdown. However, the decrease in the concentrations of the samples occurred at lower speed when compared to the drop rate observed in hypertrophic hearts. The results of the muscle glycogen content showing high variability are already referred in the scientific literature [24]. The statistical analysis did not establish a difference in the levels of myocardium glycogen after ninety minutes of ischemia. The variability factor, as already mentioned in the preceding paragraph, must have contributed to the lack of difference. One data to be highlighted in this research is that it was possible to observe significant differences among the values of muscle glycogen in hypertrophic hearts, considering the values obtained after ninety minutes of cardioplegia infusions. As simplest interpretation of these results, one should consider that glycogenolysis is established more rapidly in the muscle subjected to conditions which favor hypertrophy. In order to complete the conceptualization of the study, it is necessary to emphasize that metabolic adaptation to anaerobic condition is made by the degree of the glycogenolytic pathway activation. This may explain the differences among positive results observed in normal hearts, and negative results observed in hearts subjected to conditions that promote hypertrophy.

Mitochondrial respiration The first detail to be discussed concerning the preparation of mitochondria is the control samples that presented RCR close to 10, which is a valuable indicator 628

Morphometric analysis Electron microscopy revealed many aspects of normal myocardial fibers, while the hypertrophic hearts showed significantly increased transverse diameters occupying the interstitial space. The same occurred in relation to the diameters of the mitochondria showed an increase in their diameters and loss of their morphological characteristics (Figures 4 and 5). However, onecan observe the large heterogeneity of data, when were divided by frequency.

Demonstrating intracellular edema with cardioplegic arrest, in a study of ultrastructural analysis of hypertrophic rabbits myocardium, Goldstein et al. [25] showed a range from 7 to 142 days for clinically manifestations be confirmed anatomically. Furthermore, these authors reported that the pleomorphism variations make it difficult, or almost impossible, to estimate the number or size of normal mitochondria. Perhaps this fact explains the difficulty in finding clearest results in relation to the values of mitochondrial diameter during the period studied.

However, the trend of population shift to higher values is clearly shown in frequency histograms.

Concluding remarks The acquisition of biochemical data, especially the increase in speed of glycogen breakdown, when anatomical changes are not detected, represents an important result even when considering all the difficulties inherent in the process of translating experimental results into clinical practice. Regarding the temperature, the route of cardiac arrest and delivery of cardioplegic solution is still at the surgeon discretion, including his practice and

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expertise, always seeking for the best. At last, regarding hypertrophied heart protection, experimental studies have shown the superiority of tepid blood cardioplegia in relation to hypothermic crystalloid solution. Cardioplegic strategies to protect the hypertrophic heart during cardiac surgery is, surely, the most controversial subject concerning cardioprotection and an eternal challenge since all tested cardioplegic techniques confer suboptimal myocardial protection. Therefore, we should always have in mind that the state-of-the-art was not achieved yet [26-30].

7. Bretschneider HJ, Hübner G, Knoll D, Lohr B, Nordbeck H, Spieckermann PG. Myocardial resistance and tolerance to ischemia: physiological and biochemical basis. J Cardiovasc Surg (Torino). 1975;16(3):241-60.

Limitations of the study The investigation showed that normothermic sanguineous, intermittent cardioplegia protects the hypertrophic myocardium against the deleterious effects of ischemia followed by reperfusion. But, no comparative studies with other techniques of myocardial protection.

Therefore, any attempt to clinical correlation would be speculative.

As the induction of ventricular hypertrophy was performed by an aortic coarctation for 14 days, it is likely to consider the physiological type because this is an adaptation to a pressure overload. This doubt about the type of hypertrophy can be considered a possible limitation of the study. At least two well-conducted studies by Brazilian authors proved the adequacy of myocardial hypertrophy induced by the technique of aortic coarctation [31,32].

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10. Sink JD, Pellom GL, Currie WD, Hill RC, Olsen CO, Jones RN, et al. Response of hypertrophied myocardium to ischemia: correlation with biochemical and physiological parameters. J Thorac Cardiovasc Surg. 1981;81(6):865-72.

11. Cooley DA, Reul GJ, Wukasch DC. Ischemic contracture of the heart: "Stone heart". Am J Cardiol. 1972;29(4):575-7.

12. Leclercq JF, Sebag C, Swynghedauw B. Experimental cardiac hypertrophy in rabbits after aortic stenosis or incompetence or both. Biomedicine. 1978;28(3):180-4.

13. Bullock G, Carter EE, White AM. The preparation of mitochondria from muscle without the use of a homogeniser.

FEBS Lett. 1970;8(2):109-11.

14. Sordahl LA, Besch HR Jr, Allen JC, Crow C, Lindenmayer GE, Schwartz A. Enzymatic aspects of the cardiac muscle cell: mitochondria, sarcoplasmic reticulum and nonovalent cation active transport system. Methods Achiev Exp Pathol.

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15. Chance B, Williams GR. The respiratory chain and oxidative phosphorylation. Adv Enzymol Relat Subj Biochem.

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16. Estabrook RW, Pullman ME. Oxidations and phosphorylations.

New York:Academic Press;1967. p.7-8.

17. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem.

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18. Colowick SP, Kaplan NO. Methods in enzymology. New York:Academic Press;1957. p.34.

19. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990;322(22):1561-6.

20. Grossman W, Barry WH. Diastolic pressure-volume relations in the diseased heart. Fed Proc. 1980;39(2):148-55.

21. Hatt PY, Berjal G, Moravec J, Swynghedauw B. Heart failure: an electron microscopic study of the left ventricular papillary

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muscle in aortic insufficiency in the rabbit. J Mol Cell Cardiol.

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Angelini GD, et al. Myocardial injury in hypertrophic hearts of patients undergoing aortic valve surgery using cold or warm blood cardioplegia. Eur J Cardiothorac Surg.

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22. Wikman-Coffelt J, Parmley WW, Mason DT. The cardiac hypertrophy process. Analyses of factors determining pathological vs. physiological development. Circ Res. 1979;45(6):697-707.

23. Carbone Jr C; Roselino JES, Carneiro JJ, Sader AA. Análise comparativa da reserva de glicogénio do miocardio isquémico de coelhos submetidos a cardioplegia hipotérmica ou normotérmica. Rev Bras Cir Cardiovasc. 1992;7(1):9-13.

24. Steenbergen C, Perlman ME, London RE, Murphy E. Mechanism of preconditioning. Ionic alterations. Circ Res. 1993;72(1):112-25.

25. Goldstein MA, Sordahl LA, Schwartz A. Ultrastructural analysis of left ventricular hypertrophy in rabbits. J Mol Cell Cardiol. 1974;6(3):265-73.

26. Gomes WJ, Ascione R, Suleiman MS, Bryan AJ, Angelini GD. Efeitos das cardioplegias sanguíneas hipotérmica e normotérmica nos substratos intracelulares em pacientes com corações hipertróficos. Rev Bras Cir Cardiovasc.

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29. Cressoni ES, Avanci LE, Braile DM, Lima-Oliveira AP, Taboga SR, Martins AS, et al. Effects of myocardial protection in hypertrophic rabbit hearts: structural and ultra structural analysis. Rev Bras Cir Cardiovasc. 2007;22(1):24-32.

30. Suleiman MS, Hancock M, Shukla R, Rajakaruna C, Angelini GD. Cardioplegic strategies to protect the hypertrophic heart during cardiac surgery. Perfusion. 2011;26(Suppl 1):48-56.

31. Martins AS, Aguilera NW, Matsubara BB, Bregagnollo EA. Experimental myocardial hypertrophy induced by a minimally invasive ascending aorta coarctation. Braz J Med Biol Res. 2001;34(3):413-5.

32. Souza Vilarinho KA, Petrucci O, Baker RS, Vassallo J, Schenka AA, Duffy JY, et al. Early changes in contractility indices and fibrosis in two minimally invasive congestive heart failure models. Eur J Cardiothorac Surg. 2010;37(2):368-75.

REVIEW ARTICLE

Rev Bras Cir Cardiovasc 2012;27(4):631-41

Off-pump versus on-pump coronary artery bypass surgery: meta-analysis and meta-regression of 13,524 patients from randomized trials Cirurgia de revascularização miocárdica com CEC versus sem CEC: meta-análise e meta-regressão de 13.524 pacientes de estudos randomizados

Michel Pompeu Barros de Oliveira Sá1, Paulo Ernando Ferraz2, Rodrigo Renda Escobar2, Wendell Nunes Martins2, Pablo César Lustosa2, Eliobas de Oliveira Nunes2, Frederico Pires Vasconcelos2, Ricardo Carvalho Lima3

DOI: 10.5935/1678-9741.20120106

RBCCV 44205-1431

Abstract Background: Most recent published meta-analysis of randomized controlled trials (RCTs) showed that off-pump coronary artery bypass graft surgery (CABG) reduces incidence of stroke by 30% compared with on-pump CABG, but showed no difference in other outcomes. New RCTs were published, indicating need of new meta-analysis to investigate pooled results adding these further studies.

Methods: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were searched for RCTs that compared outcomes (30-day mortality for all-cause, myocardial

infarction or stroke) between off-pump versus on-pump CABG until May 2012. The principal summary measures were relative risk (RR) with 95% Confidence Interval (CI) and P values (considered statistically significant when <0.05).

The RR’s were combined across studies using DerSimonianLaird random effects weighted model. Meta-analysis and meta-regression were completed using the software Comprehensive Meta-Analysis version 2 (Biostat Inc., Englewood, New Jersey, USA).

Results: Forty-seven RCTs were identified and included 13,524 patients (6,758 for off-pump and 6,766 for on-pump CABG). There was no significant difference between off-

1. MD, MSc, Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco (PROCAPE) and University of Pernambuco (UPE), Recife, PE, Brazil.

2. MD, Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco (PROCAPE) and University of Pernambuco (UPE), Recife, PE, Brazil.

3. MD, MSc, PhD, ChM, Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco (PROCAPE) and University of Pernambuco (UPE), Recife, PE, Brazil.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Sá, Ferraz, and Escobar.

Acquisition of data: Ferraz, Escobar, Martins, Lustosa and Nunes. Analysis and interpretation of data: Sá, Vasconcelos, Lima, Ferraz and Escobar.

Drafting of the manuscript: Sá. Critical revision of the manuscript for important intellectual content: Sá, Ferraz, Escobar, Martins, Nunes, Lustosa, Vasconcelos, Lima. Statistical analysis: Sá. Administrative, technical, and material support: Vasconcelos and Lima. Study supervision: Sá, Lima, Vasconcelos.

Work carried out at Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco (PROCAPE) and University of Pernambuco (UPE), Recife, PE, Brazil.

Correspondence address: Michel Pompeu Barros de Oliveira Sá Av. Eng. Domingos Ferreira, 4172 – Edf. Paquetá – apto. 405 – Recife, PE, Brazil – ZIP Code 51021-040 E-mail: michel_pompeu@yahoo.com.br

Financial Disclosure: All authors have no conflict of interests.

Funding/Support: All authors have no relationship to commercial funding or support.

Article received on September 3rd, 2012 Article accepted on November 8th, 2012

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Abbreviations, Acronyms & Symbols CABG CENTRAL/CCTR CI LILACS

MeSH PRISMA

RCTs RR SciELO

Coronary artery bypass graft surgery Cochrane Central Register of Controlled Trials Confidence Interval Literatura Latino-Americana e do Caribe em Ciências da Saúde Medical Subject Heading Preferred Reporting Items for Systematic Reviews and Meta-Analyses Randomized controlled trials Risk Ratio Scientific Electronic Library Online

pump and on-pump CABG groups in RR for 30-day mortality or myocardial infarction, but there was difference about stroke in favor to off-pump CABG (RR 0.793, 95% CI 0.6600.920, P=0.049). It was observed no important heterogeneity of effects about any outcome, but it was observed publication bias about outcome "stroke". Meta-regression did not demonstrate influence of female gender, number of grafts or age in outcomes.

Conclusion: Off-pump CABG reduces the incidence of post-operative stroke by 20.7% and has no substantial effect on mortality or myocardial infarction in comparison to onpump CABG. Patient gender, number of grafts performed and age do not seem to explain the effect of off-pump CABG on mortality, myocardial infarction or stroke, respectively.

Descriptors: Meta-Analysis. Coronary artery bypass, offpump. Cardiopulmonary bypass.

Resumo Introdução: A meta-análise mais recente de estudos randomizados controlados (ERC) mostrou que cirurgia de revascularização (CRM) sem circulação extracorpórea (CEC) reduz a incidência de acidente vascular cerebral em 30% em comparação com CRM com CEC, mas não

INTRODUCTION Rationale The most recent published meta-analysis examined randomized controlled trials (RCTs) comprising a total of 8,961 patients and showed that off-pump coronary artery bypass graft surgery (CABG) reduces the incidence of stroke by 30% compared with on-pump CABG, but showed no difference in 30-day mortality and myocardial infarction, which were not affected by age, gender or number of grafts [1]. After the publication of this meta-analysis [1], two new RCTs were published – CORONARY [2] and On-Off Study [3], which 632

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mostrou diferença em outros resultados. Novos ERCs foram publicados, indicando necessidade de nova meta-análise para investigar resultados agrupados adicionando esses estudos.

Métodos: MEDLINE, EMBASE, CENTRAL / CCTR, SciELO, LILACS, Google Scholar e listas de referências de artigos relevantes foram pesquisados para ERCs que compararam os resultados de 30 dias (mortalidade por todas as causas, infarto do miocárdio ou acidente vascular cerebral - AVC) entre CRM com CEC versus sem CEC até maio de 2012. As medidas sumárias principais foram o risco relativo (RR) com intervalo de confiança de 95% (IC) e os valores de P (considerado estatisticamente significativo quando <0,05).

Os RR foram combinados entre os estudos usando modelo de efeito randômico de DerSimonian-Laird. Meta-análise e meta-regressão foram concluídas usando o software versão Meta-Análise Abrangente 2 (Biostat Inc., Englewood, Nova Jersey, EUA).

Resultados: Quarenta e sete ERCs foram identificados e incluíram 13.524 pacientes (6.758 sem CEC e 6.766 com CEC). Não houve diferença significativa entre CRM com CEC e sem CEC no RR de mortalidade em 30 dias ou infarto do miocárdio, mas houve diferença em favor da CRM sem CEC no desfecho AVC (RR 0,793, IC 95% 0,660-0,920, P = 0,049). Não foi observado importante heterogeneidade dos efeitos sobre qualquer resultado, mas observou-se um viés de publicação sobre o desfecho "AVC". Meta-regressão não demonstrou influência do sexo feminino, o número de pontes ou idade nos resultados.

Conclusão: CRM sem uso da CEC reduz a incidência de acidente vascular cerebral pós-operatória de 20,7% e não tem efeito significativo sobre a mortalidade ou infarto do miocárdio em comparação com CRM com CEC. Sexo do paciente, número de enxertos realizados e idade não parecem explicar o efeito de RM sem CEC sobre a mortalidade, infarto do miocárdio ou acidente vascular cerebral, respectivamente.

Descritores: Metanálise. Ponte de artéria coronária sem circulação extracorpórea. Ponte cardiopulmonar.

contributed over 4,752 and 411 patients, respectively.

This represents a substantial increase of new patient data available in literature from RCTs as compared to what already exists, which indicates the need for execution of a new meta-analysis to investigate the pooled results adding these further studies.

Our meta-analysis attempts to determine if there is any real difference between off-pump and on-pump CABG in terms of outcomes.

Objectives We performed a meta-analysis and meta-regression of RCTs to compare off-pump CABG versus on-pump CABG,

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according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [4].

Data Items The endpoints were Risk Ratio (RR) for 30-day mortality (all-cause), myocardial infarction and stroke after off-pump versus on-pump CABG.

METHODS Eligibility criteria Using PICOS strategy, studies were considered if: (1) population comprised patients undergoing CABG; (2) compared outcomes between off-pump versus onpump CABG; (3) outcomes studied included 30-day mortality (all-cause), myocardial infarction or stroke; (4) were prospective randomized controlled trials.

The exclusion criteria were: (1) concomitant surgical intervention other than CABG, (2) concomitant medical intervention in one but not both of the two groups, (3) zero events in both groups, so that they could not contribute to the pooled analysis for a specific outcome.

Information Sources The following databases were used (until May 2012): MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), ClinicalTrials.gov, SciELO (Scientific Electronic Library Online), LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde – The Latin American and Caribbean Health Sciences), Google Schoolar and reference lists of relevant articles.

Search We conducted the search using Medical Subject Heading (MeSH) terms (‘coronary artery bypass, off-pump’ OR ‘off-pump coronary artery bypass’ OR ‘off pump coronary artery bypass’ OR ‘off-pump’ OR ‘coronary artery bypass, beating heart’ OR ‘beating heart cardiopulmonary bypass’ OR ‘cardiopulmonary bypass’ OR ‘cardiopulmonary bypasses’ OR ‘bypass, cardiopulmonary’ OR ‘bypasses, cardiopulmonary’) AND (‘randomized controlled trial’ OR ‘clinical trial’ OR ‘controlled clinical trials, randomized’ OR ‘clinical trials, randomized’ OR ‘trials, randomized clinical’).

Study Selection The following steps were done: (1) identification of titles of records through databases searching; (2) removal of duplicates; (3) screening and selection of abstracts; (4) assessment for eligibility through full-text articles; (5) final inclusion in study.

One reviewer followed the steps 1 to 3. Two independent reviewers followed step 4 and selected studies. Inclusion or exclusion of studies was decided unanimously. When there was disagreement, a third reviewer took the final decision.

Data Collection Process Two independent reviewers extracted the data. When there was disagreement about data, a third reviewer (the first author) checked the data and took the final decision about it. From each study, we extracted patient characteristics, study design, and outcomes (number of events and number of total groups).

Risk of Bias in Individual Studies Included studies were assessed for the following characteristics: (1) sequence generation, (2) allocation concealment, (3) blinding, (4) incomplete outcome data, (5) selective outcome reporting, and (6) other sources of bias. Taking these characteristics into account, the papers were classified into A (low risk of bias), B (moderate risk of bias) or C (high risk of bias).

Two independent reviewers assessed risk of bias.

Agreement between the two reviewers was assessed using kappa statistics for full text screening, and rating of relevance and risk of bias. When there was disagreement about risk of bias, a third reviewer (the first author) checked the data and took the final decision about it.

Summary Measures The principal summary measures were RR’s with 95% Confidence Interval (CI) and P values (considered statistically significant when <0.05). The meta-analysis was completed using the software Comprehensive MetaAnalysis version 2 (Biostat Inc., Englewood, New Jersey, USA).

Synthesis of Results Forest plots were generated for graphical presentations for clinical outcomes and we performed the I2 test and Chi2 test for assessment of heterogeneity across the studies [5]. Each study was summarized by the RR for off-pump CABG compared to on-pump CABG. The RR’s were combined across studies using weighted DerSimonianLaird random effects model [6]. The model was weighted by number of events in each study.

Risk of Bias Across Studies To assess publication bias, a funnel plot was generated (for each outcome), being statistically assessed by Begg and Mazumdar’s test [7] and Egger’s test [8].

Meta-regression Analysis Meta-regression analyses were performed to determine 633

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whether the effects of off-pump CABG were modulated by pre-specified factors. Meta-regression graphs describe the effect of off-pump CABG on the outcome (plotted as a log RR on the y-axis) as a function of a given factor (plotted as a mean or proportion of that factor on the x-axis). Metaregression coefficients show the estimated increase in log RR per unit increase in the covariate. Since log RR >0 corresponds to RR >1 and log RR <0 corresponds to RR<1, a negative coefficient would indicate that as a given factor increases, the RR decreases.

The pre-determined modulating factors to be examined were: sex (for mortality), number of bypass grafts (for myocardial infarction) and age (for stroke). Sex was represented as the proportion of females in the RCT. Number of bypass grafts was represented as the difference between the mean number of grafts (arterial and venous combined) performed in the off-pump CABG group minus the mean number of grafts performed in the on-pump CABG group in the RCT. Age was represented as the mean age of the patients participating in the RCT.

Study Characteristics Characteristics of each study are shown in Table 1. A total of 13,524 patients were studied with 6,758 undergoing off-pump CABG and 6,766 undergoing onpump CABG, including the years 2000 to 2012. We observed that most studies consisted of patients whose mean age was around the sixth decade of life, mostly male and on-pump CABG presenting higher mean coronary bypasses. The overall internal validity was considered moderate risk of bias.

RESULTS Study Selection A total of 1110 citations were identified, of which 108 studies were potentially relevant and retrieved as full-text.

Forty-seven [2,3,9-52] publications fulfilled our eligibility criteria. Interobserver reliability of study relevance was excellent (Kappa = 0.85). Agreement for decisions related to study validity was very good (Kappa = 0.81). The search strategy can be seen in Figure 1.

Synthesis of Results The RR of the risk of 30-day mortality in the off-pump group compared with on-pump group in each study is reported in Figure 2. There was no evidence for important heterogeneity of treatment effect among the studies for death. The overall RR (95% confidence interval) of 30day mortality showed no statistical significant difference between off-pump CABG compared to on-pump CABG (random effect model: RR 0.938, 95% CI 0.731 to 1.203, P = 0.612).

The RR of the risk of myocardial infarction in the off-pump group compared with on-pump group in each study is reported in Figure 3. There was no evidence for important heterogeneity of treatment effect among the studies for myocardial infarction. The overall RR (95% confidence interval) of myocardial infarction showed no statistical significant difference between off-pump CABG compared to on-pump CABG (random effect model: RR 0.904, 95% CI 0.773 to 1.057, P = 0.205).

The RR of the risk of stroke in the off-pump group compared with on-pump group in each study is reported in Figure 4. There was no evidence for important heterogeneity of treatment effect among the studies for stroke. The overall RR (95% CI) of stroke showed statistical significant difference in favor to off-pump CABG compared to on-pump CABG (random effect model: RR 0.793, 95% CI 0.660 to 0.920, P = 0.049).

Risk of Bias Across Studies Begg and Mazumdar’s and Egger’s tests did not reveal any evidence of publication bias, with the exception of stroke for which both tests were statistically significant (Figure 5).

Fig. 1 - Flow diagram of studies included in data search

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Meta-regression Analysis Meta-regression coefficients were not statistically significant for death and proportion of females (coefficient -0.02, 95% CI -0.05 to 0.01, P = 0.103), myocardial infarction and graft differential (coefficient -0.59, 95% CI -0.63 to 1.81, P = 0.344), stroke and mean age (coefficient 0.00, 95% CI -0.06 to 0.06, P = 0.984) - Figure 6.

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Sá MPBO, et al. - Off-pump versus on-pump coronary artery bypass surgery: meta-analysis and meta-regression of 13,524 patients from randomized trials

Table 1. Study characteristics Trial

CORONARY [2] ON-OFF [3] DOORS [9] MASS III [10] BBS [11] ROOBY [12] PRAGUE-11 [13] JOCRI [14] PRAGUE-4 [15] SMART [16] OCTOPUS [17] BHACAS-1 [18] BHACAS-2 [18] Souza Uva et al. [19] Fattouch et al. [20] Medved et al. [21] Tully et al. [22] Hernandez Jr. et al. [23] Sajja et al. [24] Motallebzadeh et al. [25] Al-Ruzzeh et al. [26] Niranjan et al. [27] Vedin et al. [28] Cavalca et al. [29] Paparella et al. [30] Nesher et al. [31] Rastan et al. [32] Alwan et al. [33] Gerola et al. [34] Légaré et al. [35] Lingaas et al. [36] Khan et al. [37] Motallebzadeh et al. [38] Selvanayagam et al. [39] Wehlin et al. [40] Carrier et al. [41] Lee et al. [42] Sahlman et al. [43] Muneretto et al. [44] Smith et al. [45] Baker et al. [46] Covino et al. [47] Güler et al. [48] Penttila et al. [49] Diegeler et al. [50] Kochamba et al. [51] Wandschneider et al. [52]

Off-Pump (n)

On-Pump (n)

Age (mean)

Female Gender (%)

2375 208 450 155 176 1104 40 81 204 98 142 100 100 73 63 30 30 99 56 108 84 40 33 25 15 60 20 35 80 150 60 54 15 30 21 28 30 24 88 21 12 21 19 11 20 29 41

2377 203 450 153 163 1099 40 86 184 99 139 100 101 74 65 30 36 102 60 104 84 40 37 25 16 60 20 35 80 150 60 49 20 30 16 37 30 26 88 23 14 16 18 11 20 29 67

67.5 73.5 74.0 60.0 75.4 62.8 66.0 59.5 62.5 62.4 61.3 62.0 62.5 65.3 62.0 60.7 65.5 NR 60.3 64.5 63.1 66.9 65.0 65.7 NR 67.5 64.2 63.5 59.0 62.9 64.5 63.3 63.9 60.5 64.9 70.0 65.8 62.7 66.5 61.0 64.0 NR 56.0 59.4 64.6 58.6 65.4

19.1 30.7 23.0 21.0 35.5 0.6 20.0 13.2 18.8 22.8 28.5 19.5 16.4 16.3 31.3 28.3 24.1 19.9 11.2 10.8 16.1 17.5 20.0 25.5 NR 25.0 20.0 30.0 34.4 19.7 21.7 12.6 8.6 13.3 18.9 23.1 23.3 18.0 39.2 15.9 19.2 10.8 NR 0.0 35.0 22.4 21.3

Off-Pump Grafts Per Patient (mean) 3.0 3.0 2.9 2.5 3.2 2.9 1.9 3.5 2.3 3.4 2.4 2.4 2.9 3.5 2.6 2.3 2.2 3.2 3.1 NR 2.7 3.9 3.0 2.5 2.7 2.3 3.0 2.3 1.7 2.8 2.6 3.0 2.2 2.8 3.0 3.0 3.1 3.2 2.7 2.7 2.2 1.5 NR 2.8 2.0 2.5 2.3

On-Pump Grafts Per Patient (mean) 3.2 3.3 3.0 3.0 3.3 3.0 2.4 3.6 2.7 3.4 2.6 2.5 3.0 3.5 2.8 2.5 2.5 3.2 3.9 NR 2.8 3.8 3.0 3.1 3.3 2.9 2.9 2.5 1.8 3.0 2.8 3.4 3.2 2.9 2.5 3.4 3.6 3.0 2.8 3.0 2.5 1.8 NR 3.3 3.5 2.5 3.1

Differential Number of Grafts Per Patient - 0.2 - 0.3 - 0.1 - 0.5 - 0.1 - 0.1 - 0.5 - 0.1 - 0.4 0.0 - 0.2 - 0.1 - 0.1 0.0 - 0.2 - 0.2 - 0.3 0.0 - 0.8 NR - 0.1 0.1 0.0 - 0.6 - 0.4 - 0.6 0.1 - 0.2 - 0.1 - 0.2 - 0.2 - 0.4 - 1.0 - 0.1 0.5 - 0.4 - 0.5 0.2 - 0.1 - 0.3 - 0.3 - 0.3 NR - 0.5 - 1.5 0.0 - 0.8

Risk of Bias

A A B A A C B B B A B B B B A B B B B C A B B B B C B B B B B B B B B B A B B B B C C B C B B

A – Low risk of bias; B – Moderate risk of bias; C – High risk of bias; NR – non reported

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Fig. 2 - Risk ratio and conclusions plot of 30-day mortality associated with off-pump versus on-pump CABG

Fig. 3 - Risk ratio and conclusions plot of myocardial infarction associated with off-pump versus on-pump CABG

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Fig. 4 - Risk ratio and conclusions plot of stroke associated with off-pump versus on-pump CABG

Fig. 5 - Publication bias analysis by funnel plot graphic for the outcomes

Fig. 6 - Meta-regression analysis by representative plots

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Sá MPBO, et al. - Off-pump versus on-pump coronary artery bypass surgery: meta-analysis and meta-regression of 13,524 patients from randomized trials

DISCUSSION Summary of Evidence The results of this meta-analysis demonstrate that there was statistical significant difference in favor to off-pump CABG compared to on-pump CABG in RR for stroke and no difference about death or myocardial infarction, being the summary measures free from the influence of heterogeneity of the effects. Only the outcome “stroke” was under the influence of publication bias. Metaregression did not demonstrate any influence of female gender, number of grafts performed and age on mortality, myocardial infarction or stroke, respectively.

Considerations about this Meta-Analysis To our knowledge, this is the largest meta-analysis of RCTs performed to date, providing incremental value by demonstrating that off-pump CABG reduces the incidence of post-operative stroke compared with on-pump CABG. Furthermore, this analysis confirms that off-pump CABG does not significantly reduce the incidence of shortterm all-cause mortality and post-operative myocardial infarction. The potential benefits of off-pump CABG on these outcomes do not appear to be determined by patient gender, number of grafts performed or age.

The effect of off-pump CABG on stroke has been a polemical topic, with most reports showing no beneficial effect [53-55]. The two largest trials to date – CORONARY [2] with 4,752 patients and ROOBY [12] with 2,143 patients – showed no effect or trend for reduction in stroke.

The most recent trial published – On-Off Study with 411 patients – also did not show any benefit on incidence of stroke. Afilalo et al. [1] emphasize that it would take more than 10,000 patients in a trial to obtain a probabilistic sample and detect statistically significant differences regarding the outcome “stroke”, which explains why no trial to date has been able to demonstrate substantial differences between the groups regarding this outcome. Something that could explain the lower incidence of stroke in off-pump CABG is less manipulation of the aorta in comparison to on-pump CABG. El Zayat et al. [56] demonstrated in a RCT the importance of avoiding clamp during off-pump CABG using clampless facilitating devices to reduce cerebral embolic events, which proves that the less manipulation of the aorta decreases the incidence of stroke.

According to some authors [57,58], female and elderly patients are thought to face higher risks associated with onpump CABG and therefore benefit more from off-pump CABG. The meta-regression analysis in this study refutes these hypotheses that differences in study population are responsible for the treatment effects observed across trials.

Although other meta-analyses have been published on this field, this analysis is important for some reasons.

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The pooled sample size was 66% larger than the largest previous published meta-analysis [1]. Our larger sample size translated into greater statistical power and precision, reducing the amount of uncertainty surrounding treatment effects. Two recently published trials – CORONARY [2] and On-Off Study [3] – had not been included in the largest prior meta-analysis and were included in this analysis (published in 2012 and contributed 5,163 out of the 13,524 patients).

Our meta-analysis summarized the results of best studies in medical literature regarding hard outcomes, strengthening the concept of off-pump CABG. Furthermore, the metaregression enhances consistency of pooled results.

Risk of Bias and Limitations This meta-analysis did not included data from nonrandomized and/or observational studies, which reflects the “real world”, but they are limited by treatment bias, confounders, and a tendency to overestimate treatment effects. Patient selection alters outcome and thus makes nonrandomized studies obviously less robust.

Although it was not observed statistical heterogeneity between trials, the differences in terms of operative technique and volume may have led to an influence of clinical heterogeneity not capable of perception by metaanalysis. Other factors not taken into consideration, for not being reported in trials and that may influence results, are the level of manipulation of the aorta and the level of atheromatosis of the aortic wall, which favors embolic cerebrovascular events during partial clamping.

There are inherent limitations with meta-analyses, including the use of cumulative data from summary estimates. Patient data were gathered from published data, not from individual patient follow-up. Access to individual patient data would have enabled us to conduct further subgroup analysis and propensity analysis to account for differences between the treatment groups.

CONCLUSIONS Off-pump CABG reduces the incidence of post-operative stroke by 20.7% and has no substantial effect on mortality or myocardial infarction in comparison to on-pump CABG. Patient gender, number of grafts performed and age do not appear to explain the effect of off-pump CABG on mortality, myocardial infarction or stroke, respectively.

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Hybrid treatment for correction of pseudoaneurysm after surgical treatment of aortic coarctation Tratamento híbrido para correção de pseudoaneurisma após tratamento cirúrgico de coarctação aórtica

João Carlos Ferreira Leal1, Victor Rodrigues Ribeiro Ferreira2, Valéria B. Braile Sternieri3, Rodolfo Wichtendahl4, Achilles Abelaira Filho5, Luis Ernesto Avanci6, Domingo Marcolino Braile7 DOI: 10.5935/1678-9741.20120107

RBCCV 44205-1432

Abstract The need for a new surgical procedure for correction of postoperative pseudoaneurysm of aortic coarctation makes the procedure especially challenging for the surgeon.ta abstract

Resumo A necessidade de uma nova intervenção cirúrgica para correção de pseudoaneurisma pós-operatório de coarctação de aorta torna o procedimento especialmente desafiante para o cirurgião.

Descriptors: Aortic coarctation. Aneurysm, false. Heart defects, congenital/surgery.

Descritores: Coartação aórtica.

Cardiopatias congênitas/cirurgia.

INTRODUCTION Aortic coarctation (AoC) is defined as the narrowing of the aortic lumen secondary to hypertrophy of the middle layer of posterior lateral wall and located in the left hemi-aortic arch between the junction of the left subclavian artery and the ductus arteriosus, so hinders

1. Master and PhD in Cardiovascular Surgery at the University of Campinas (UNICAMP), Adjunct Professor at FAMERP, São José do Rio Preto, SP, Brazil 2. Specialization in Cardiology, cardio-intensivist.

3. Clinical cardiologist, Director of the Institute Domingo Braile, Clinical Director of Hospital Beneficência Portuguesa of São José do Rio Preto, São Jose do Rio Preto, SP, Brazil.

4. Cardiovascular Surgery Resident.

5. Cardiovascular Surgeon, São José do Rio Preto, SP, Brazil.

6. Cardiovascular Surgeon; Coordinator of postoperative cardiovascular surgery Domingo Braille Institute, São José do Rio Preto, SP, Brazil.

7. Professor Emeritus and Senior FAMERP School of Medicine, UNICAMP, Editor-in-Chief of the Brazilian Journal of Cardiovascular Surgery, São José do Rio Preto, SP, Brazil.

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Falso

aneurisma.

irrigation to the bottom of the body. It is a common change between congenital heart disease and about 80% of cases are associated with bicuspid aortic valve [1]. Increases the work of the left ventricle and causes upper limb hypertension and lower limb hypotension.

The prevalence of recoarctation after surgery is around 60%, depends on the patient's age and time of

Work performed at Instituto Domingo Braile and Beneficência Portuguesa, São José do Rio Preto, SP, Brazil.

Correspondence address: João Carlos Ferreira Leal Rua Luiz Vaz de Camões, 3111 – Bairro Redentora – São José do Rio Preto, SP Brazil – Zip code:15015-750 E-mail: joaocarlos@braile.com.br Article received on February 7th, 2012 Article accepted on September 27th, 2012

Leal JCF, et al. - Hybrid treatment for correction of pseudoaneurysm after surgical treatment of aortic coarctation

Rev Bras Cir Cardiovasc 2012;27(4):642-4

Abbreviations, acronyms and symbols AoC CPB TEE BP TCA

Aortic coarctation Cardiopulmonary bypass Transesophageal echocardiogram Bovine pericardium Total circulatory arrest

outcome. However, aneurysm surgical site may occur in 50% of patients, particularly when using the flap dacron [2]. A variety of anatomical aneurysms indicates several mechanisms influencing its development. Another complication is pseudoaneurysm arising from the suture lines or at the isthmus of restenosis [3].

It was described by Morgagni in 1760, however, the first successful intervention occurred only in 1944 by Crafoord & Nylin [4]. From that time new operational strategies emerged with good results. Recently, endovascular treatment has become a new alternative in the treatment of aortic diseases, especially in acute aortic syndrome, with satisfactory results over the years. In AoC is also possible to intervene with endovascular and low mortality.

Meta-analysis compared endovascular treatment with conventional aortic coarctation. The outcome reintervention was more frequent in the group treated by endovascular approach [5]. However, this meta-analysis was based on scientific articles published before 1995, when the endovascular materials were coarser and simple.

Treating recoarctation is a challenge for the surgeon, especially in cases of pseudoaneurysm suture line in need of third surgical intervention. For this it is necessary to launch ideas of combined procedures between endovascular and conventional: it is the hybrid treatment [6]. It is this concept that we treat the patient in this short communication.

CLINICAL CASE Male patient, 30 years, sought medical attention for evaluation of the hemoptoic framework seven months ago.

In past medical history has a late follow-up of two surgical procedures for correction of AoC. The first intervention was aortoplasty using Teles' technique and the second a tube interposition of bovine pericardium (BP) between the aortic arch and the descending aorta.

The patient underwent computed tomography and angiography of the chest and thoracic aorta, respectively.

The results of these tests showed AoC with stenosis greater than 90% in left hemiarch, presence of extraanatomic BP pipe between the right anterolateral hemiarch and descending thoracic aorta. Near the distal anastomosis was observed a pseudoaneurysm of 42 mm in maximum

Fig. 1 - Preoperative angiography showing aortic coarctation and an aorto-aortic pseudoaneurysm with the distal anastomosis

transverse diameter associated with an pulmonary parenchymal opacity ground-glass appearance, suggesting a fistula (Figure 1).

Doppler echocardiogram demonstrated aortic coarctation with post-stenotic dilation, ascending aortic with moderate ectasia, aortic and mitral mild regurgitation and concentric moderate left ventricular hypertrophy.

The decision was a new intervention. However, the challenge was to decide on the best surgical strategy, endovascular or conventional? A conventional intervention was frightened by the following factors: third thoracotomy, pulmonary compliance and the site of the pseudoaneurysm.

Already by endovascular was unfeasible because there is no ideal proximal stub in the left hemi-arch or BP pipe.

Considering the seriousness and complexity of the disease, a multidisciplinary team, Heart Team, decided by the hybrid treatment.

The surgery began with left femoral artery puncture and introduction of the guide wire to the site of the pseudoaneurysm, maneuver aided by trans-esophageal echo (TEE). After full heparinization began cardiopulmonary bypass (CPB) with cannulation of the right axillary artery , interposition of a 8 mm Dacron tube, and bicaval venous cannulation type. Moderate hypothermia to 22째C and total circulatory arrest (TCA) were used strategies 643

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Rev Bras Cir Cardiovasc 2012;27(4):642-4

for identification and reconstruction of the stenosed area with tube BP No 27. The goal was to obtain a proximal stent surgical support. During the reconstruction of the left hemi-arch guidewire inserted progressed through the right femoral artery to the aortic arch. Thus it was possible to release the Self-Expandable Surgical Endoprosthesis Braile Biomédica® 28 mm in diameter and 11.5 cm length.

At the end of arterial reconstruction, CPB was resumed with warming of the patient, the PCT time was 27 minutes.

We employed antegrade/retrograde, blood, isothermal and low volume cardioprotection. Extra-anatomic BP was occluded with bandages and sutures in the proximal and distal thirds before the resumption of the heartbeat.

Although the post-examination control intervention is arteriography, in this case the first TEE examination was conducted to evaluate the stent, especially at the site of the pseudoaneurysm.

The images of the ETE were conclusive for the need

for another endoprosthesis according to the type I distal endoleak. Through the guide wire in the right femoral artery since the start of the intervention was possible to release a new Dominus Stent-Graft Endoprosthesis Braile Biomédica®, diameter 28 mm and length 7.5 cm, by endovascular approach. New control examinations were performed and demonstrated successful outcomes. Thus, the patient left CPB, time was 126 minutes and uneventful.

The postoperative evolution was satisfactory, without hemoptoic episodes.

After up to two months following the hybrid treatment, the patient was asymptomatic and new imaging examinations were performed. Computed tomography and angiography showed the stents positioned without leakage, exclusion of the pseudoaneurysm and no suggestive signs of pleuropulmonary changes (Figure 2). The complexity of this case reaffirms the use of hybrid treatment and the importance of the Heart Team.

REFERENCES 1. Yazar O, Budts W, Maleux G, Houthoofd S, Daenens K, Fourneau I. Thoracic endovascular aortic repair for treatment of late complications after aortic coarctation repair. Ann Vasc Surg. 2011;25(8):1005-11.

2. Oliver JM, Gallego P, Gonzalez A, Aroca A, Bret M, Mesa JM. Risk factors for aortic complications in adults with coarctation of the aorta. J Am Coll Cardiol. 2004,44(8):1641-7.

3. Hörmann M, Pavlidis D, Brunkwall J, Gawenda M. Longterm results of endovascular aortic repair for thoracic pseudoaneurysms after previous surgical coarctation repair.

Interact Cardiovasc Thorac Surg. 2011;13(4):401-4.

4. Crafoord C, Nylin G. Congenital coarctation of the aorta and its surgical treatment. J Thorac Surg. 1945;14:347-61.

Fig.2. Postoperative angiography demonstrated correction of coarctation of the aorta and exclusion of pseudoaneurysms with stent and graft positioned from the proximal segment of the descending thoracic aorta to the middle distal segment

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5. Carr JA. The results of catheter-based therapy compared with surgical repair of adult aortic coarctation. J Am Coll Cardiol.

2006;47(6):1101-7.

6. Ingrund JC, Nasser F, Jesus-Silva SG, Limaco RP, Galastri FL, Burihan MC, et al. Tratamento híbrido das doenças complexas da aorta torácica. Rev Bras Cir Cardiovasc. 2010;25(3):303-10.

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Endovascular correction of abdominal aortic aneurysm as a late complication of type A aortic dissection Correção endovascular de aneurisma de aorta abdominal em complicação tardia de dissecção de aorta tipo A

José Carlos Dorsa Vieira Pontes1, João Jackson Duarte2, Augusto Daige da Silva3, Amaury Mont’Serrat Ávila Souza Dias4 DOI: 10.5935/1678-9741.20120108

RBCCV 44205-1433

Abstract Aortic dissection type A has a great mortality in its acute phase with low annual survival without surgical treatment. Although the chronic cases are exceptions the late complications exist and should be treated.

Resumo A dissecção de aorta tipo A apresenta grande mortalidade em sua fase aguda, com baixa sobrevida anual sem tratamento cirúrgico. Embora os casos crônicos sejam exceções, as complicações tardias existem e devem ser tratadas.

Descriptors: Aortic aneurysm. Aneurysm, dissecting.

Aortic diseases. Endovascular procedures.

Descritores: Aneurisma aórtico. Aneurisma dissecante.

Doenças da aorta. Procedimentos endovasculares.

INTRODUCTION Type A aortic dissection is a cardiovascular event with the highest acute mortality rate when not treated in time [1]. In natural evolution in its acute phase, patients progress to sudden death in 3% of cases and in the absence of immediate appropriate care, the mortality rate can increase by 1% per hour for the first 24 hours, and 80% die within the first two weeks and 95% in one year [2].

CASE REPORT Chronic hypertensive patients, 74 years old in irregular treatment for hypertension, with several passages in units of emergencies due to hypertensive crisis. The patient

1. PhD, Director of the Center of the University Hospital at the Federal University of Mato Grosso do Sul (HU - UFMS), Campo Grande, Mato Grosso do Sul, Brazil.

2. Master; Cardiovascular Surgeon at HU - UFMS, Campo Grande, Mato Grosso do Sul, Brazil.

3. Interventional Cardiologist at HU - UFMS, Campo Grande, Mato Grosso do Sul, Brazil.

4. Cardiovascular Surgeon at HU - UFMS, Campo Grande, Mato Grosso do Sul, Brazil.

looked for elective care due to pain in the lumbar region.

It was also reported that about three years ago, the patient sought immediate medical treatment due to chest pain during an important hypertensive crisis. The individual was hospitalized for blood pressure control, obtaining remission of pain after blood pressure control.

A physical examination was carried out; the patient had a large pulsatile abdominal mass, approximately 7 cm.

Chest and abdominal computed tomography revealed a large abdominal aortic aneurysm, 65 mm (Figure 1) and a thrombosed false lumen in ascending and descending aorta (Figure 2).

The patient underwent endovascular repair of the abdominal aortic aneurysm with Braile Biomédica bifurcated prosthesis, obtaining successful aneurysm

Work performed at the University Hospital at the Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.

Correspondence Address: José Carlos Dorsa Vieira Pontes Rua Filinto Muller, 355t, Campo Grande, MS, Brazil – Zipcode: 79080-190 E-mail: carlosdorsa@uol.com.br Article received on June 5th, 2012 Article accepted on August 8th, 2012

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Pontes JCDV, et al. - Endovascular correction of abdominal aortic aneurysm as a late complication of type A aortic dissection

Abbreviations, acronyms and symbols IRAD

International Registry of Acute Aortic Dissections

exclusion with total thrombosis of the aneurysm sac, observed in control tomography 30 days after the procedure (Figure 1).

Fig. 1 - Infrarenal abdominal aortic aneurysm before and after endovascular correction. Antes - Before, Depois - After

Fig. 2 – Thrombosed false lumem of the ascending aortic arch and descending aorta: type A aortic dissection with spontaneous resolution. Trombos - Thrombi

treatment in acute aortic dissection, a third of patients who can be discharged are alive after a 3-day follow-up period [5]. Late complications in aortic dissection refer to distal branches obstruction, aneurysms formation and pseudoaneurysms. The abdominal aortic aneurysms are responsible for approximately 12,000 to 15,000 deaths per year in the United States and are a major cause of death in men over 65 years [6].

The DREAM [7], a Dutch multicenter study, showed lower surgical mortality (30 days) with the endovascular procedure, when compared to open surgery; however this lower surgical mortality is lost over the years.

The segments 2 and 4 years show that late mortality is similar in both groups, and the most of the deaths in the medium term are not related to aneurysm rupture but the degenerative diseases correlated with atherosclerosis, such as myocardial infarction and cerebrovascular accident, besides cancer.

According to current indications for surgical treatment of aortic diseases, the indication of surgery for abdominal aortic aneurysm is done for symptomatic cases and for those asymptomatic low-risk surgery cases, with a diameter greater than 5.5 cm or greater than 6.0 cm for high-risk patients [8]. Since they have favorable anatomy, endovascular treatment has recommendation grade "A" in these cases. In our environment, Saadi et al. [9] reported a series of 25 patients undergoing endovascular repair of abdominal aortic aneurysm with 96% of patients alive and free of further intervention, up to a 27-month follow-up period.

This case demonstrates a rare event, which is the spontaneous resolution of a type A aortic dissection with progression throughout the descending and abdominal aorta, and also shows the importance of monitoring the anatomic aortic changes with imaging tests, since this disease the distal vessel involvement is very common and often requires additional invasive procedure that can save a patient's life.

DISCUSSION The diagnosis of acute aortic dissection in approximately 38% of cases is not achieved at the first evaluation, and in 28% of cases the diagnosis is made during necropsy [3].

According to the International Registry of Acute Aortic Dissection (IRAD) [4], patients with type A aortic dissection who underwent medical treatment have a mortality rate of 58%, twice as those treated surgically, which was 26%. Also according to the IRAD, mortality was higher in the first seven days, and the most common cause of death was aortic rupture and cardiac tamponade (41.6%). Despite the high hospital mortality of medical 646

REFERENCES 1. Leal JC, Ferreira VRR, Avanci LE, Braile DM. O tratamento operatório da dissecção aórtica crônica tipo A em pacientes submetidos à revascularização cirúrgica do miocárdio. Rev Bras Cir Cardiovasc. 2010;25(3):403-5.

2. Anagnostopoulos CE, Prabhakar MJ, Kittle CF. Aortic dissections and dissecting aneurysms. Am J Cardiol.

1972;30(3):263-73.

Pontes JCDV, et al. - Endovascular correction of abdominal aortic aneurysm as a late complication of type A aortic dissection

Rev Bras Cir Cardiovasc 2012;27(4):645-7

3. Spittell PC, Spittell JA Jr, Joyce JW, Tajik AJ, Edwards WD, Schaff HV, et al. Clinical features and differential diagnosis of aortic dissection: experience with 236 cases (1980 through 1990). Mayo Clin Proc. 1993;68(7):642-51.

the treatment of descending thoracic aortic disease using endovascular stent-grafts. Ann Thorac Surg. 2008;85(1 Suppl):S1-41.

4. Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283(7):897-903.

5. Tsai TT, Evangelista A, Nienaber CA, Trimarchi S, Sechtem U, Fattori R; International Registry of Acute Aortic Dissection (IRAD), et al. Long-term survival in patients presenting with type A acute aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD). Circulation.

2006;114(1 Suppl):I350-6.

6. Svensson LG, Kouchoukos NT, Miller DC, Bavaria JE, Coselli JS, Curi MA; Society of Thoracic Surgeons Endovascular Surgery Task Force, et al. Expert consensus document on

7. Blankensteijn JD, de Jong SE, Prinssen M, van der Ham AC, Buth J, van Sterkenburg SM, et al; Dutch Randomized Endovascular Aneurysm Management (DREAM) Trial Group.

Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N Engl J Med. 2005;352(23):2398-405.

8. Albuquerque LC, Braile DM, Palma JH, Saadi EK, Gomes WJ, Buffolo E. Diretrizes para o tratamento cirúrgico das doenças da aorta da Sociedade Brasileira de Cirurgia Cardiovascular.

Rev Bras Cir Cardiovasc. 2007;22(2):137-59.

9. Saadi EK, Gastaldo F, Dussin LH, Zago AJ, Barbosa GV, Moura L. Tratamento endovascular dos aneurismas de aorta abdominal: experiência inicial e resultados a curto e médio prazo. Rev Bras Cir Cardiovasc. 2006;21(2):211-6.

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The positioning of the internal thoracic artery extra-pleural and perihilar in coronary artery bypass grafting Trajeto extrapleural, para-hilar da artéria torácica interna esquerda pediculada nos enxertos coronarianos

Hermes de Souza Felippe1, Marco Cunha1, Eduardo Sérgio Bastos1, Marcos Floripes da Silva2

DOI: 10.5935/1678-9741.20120109

RBCCV 44205-1434

Abstract The positioning of the internal thoracic artery extrapleural and perihilar in coronary artery bypass grafting to avoiding anterior aderences and prevent unnecessary damage arterial.

Resumo Variante técnica relacionada ao posicionamento da artéria torácica interna esquerda pediculada extrapleural e parahilar, evitando aderências ao mediastino anterior e protegendo o enxerto de possíveis lesões durante eventuais reoperações.

Descriptors: Myocardial revascularization. Internal mammary-coronary artery anastomosis. Coronary artery bypass/methods.

Descritores: Revascularização miocárdica. Anastomose de artéria torácica interna-coronária. Ponte de artéria coronária/métodos.

INTRODUCTION The left internal thoracic artery (LITA) is considered the “gold standard” in relation to patency compared to other allografts. The technical improvement and improvement of socioeconomic factors have provided increased survival of patients undergoing coronary artery bypass grafting

(CABG), thus making them subject to new thoracotomies for neorevascularizations or corrections of other cardiosurgical comorbidities. The reoperation procedures are at higher risk of complications and accidents, among these, the lesions of grafts.

The position adopted by the LITA in the chest cavity can have a direct influence on the immediate and late

1. Surgeon at Hospital Naval Marcílio Dias (HNMD), Clinical Physicianin-chief.

2. Head of the Cardiac Surgery Clinics at HNMD, Rio de Janeiro, RJ, Brazil.

Correspondence address: Hermes de Souza Felippe Rua Cesar Zama, 185 – Lins de Vasconcelos – Rio de Janeiro, RJ, Brazil – Zip code: 20725-220 E-mail: hermesfelippe@globo.com

This study was carried out at Hospital Naval Marcílio Dias, Rio de Janeiro, RJ, Brazil.

Article received on April 26th, 2012 Article accepted on August 21st, 2012

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Felippe HS, et al. - The positioning of the internal thoracic artery extrapleural and perihilar in coronary artery bypass grafting

Abbreviations, acronyms and symbols LITA CPB CABG ICU

Left internal toracic artery Cardiopulmonary bypass Coronary artery bypass grafting Intensive care unit

complications. Belatedly, substernal adhesions may include graft, making it vulnerable to various types of trauma during reinterventions.

Any new lesions during thoracotomy led the authors to use a simple, easily reproducible, in which the LITA is positioned in extrapleural and posterior perihilar position, in order to keep it along the mediastinum, protected by the surrounding structures, avoiding most these complications.

The LITA originates from the first portion of the bottom edge of the left subclavian artery in 90% of cases. The phrenic nerve crosses above the emergence of mammary about 70% of cases, the rest intersects the posterior region toward the pericardium [1]. Initially, it rests on the pleural anterior and apical region, directed to the inner chest wall and behind the upper six costal cartilages, inner intercostal muscles and lateral to the sternal border. Across the path, close contact with the parietal pleura is maintained until it is covered in the distal segment by the transverse muscle of the chest. The main branches of the LITA are pericardiophrenic, intercostal and perforating arteries. It ends on the sixth intercostal space, dividing, in most cases, into two terminal branches, the superior epigastric and musculophrenic arteries.

A careful dissection of the artery, preventing heat transfer by electrocautery and bruising, branches ligation causing constrictions and reduced handling are important measures to preserve its patency. Likewise, proper positioning, avoiding kinks, angulations, compression and stretching, is an important addition to its patency [2]. Anastomoses with more appropriate wires and needles and better understanding of the hemodynamic changes resulting from lesions in native vessels have given researchers subsidies to provide an approach that aims to maintain a longer patency of these grafts. These observations have contributed to reducing failures of the procedure and hence the number of reoperations [3].

The reoperations present additional risk for complications. Coltharp et al. [4] reported an incidence of approximately 5% (5/97 cases) of arterial lesions during reoperations in procedures in which the LITA was used previously. Currently, through angiotomographic assessments, we have studied the anterior mediastinum and the location of the grafts over the rib cage, establishing risk criteria, enabling an addressed surgical programming with more mitigated risk [5].

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TECHNIQUE DEVELOPMENT The techniques used for the detachment of the LITA have evolved substantially with the modernization of equipments that allow its better exposure and, in particular, dissectors that provide more effective and localized energy.

The most widely used technique in dissection of the LITA is the wide opening of the parietal pleura adjacent to its path, freeing the bed with branches ligation and pleuropericardial fenestration anterior to the phrenic nerve, to allow its access to the pericardial cavity.

The LITA dissection by maintaining the pleural integrity is more elaborated and susceptible to greater degree of complications, especially when the artery has limited length, which makes it more vulnerable to stretching during breathing movements and, belatedly, to substernal adhesions.

More recently, it has been reported dissection of the LITA with preservation of pleural integrity through robotics techniques [6]. Although promising, is still impractical in many centers, due to the equipment costs and training reproducibility.

The concern to preserve pleura without compromising the efficiency of the graft is what led us to seek methods that ally safety and proper positioning, thus avoinding immediate and late complications inherent to the technique.

SURGICAL TECHNIQUE The technique employed consists of the lateral and careful displacement of the parietal pleura adjacent to LITA exposing its entire path. The artery dissection is performed encompassing all the perimammary tissue â&#x20AC;&#x153;no touchâ&#x20AC;? between two parallel incisions. All branches are clamped, cut and mammary initially kept in bed until the establishment of cardiopulmonary bypass (CPB).

The pericardium was opened longitudinally, the great vessels and the heart are exposed. Thus, the making of purses for installation of CPB is performed, when used, followed by heparinization.

The pleura was kept intact and the preparation of the path is performed by tracting the left pericardial edge exposing its fat along the pleural reflection that is displaced. The release of the pericardium from the pleura is easily accomplished by countertraction of the pleura, which lies adhered by thin strands of loose connective tissue (Figure 1). The release of the pleura is performed toward the pulmonary hilum and anterior to the phrenic nerve, directed to the pericardium in the aorta. In this region and more posteriorly, the fat side of the mediastinum is loose and is in continuity with the apex of the pleural region.

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The proximal segment of the LITA lies on the pleura, which should be carefully moved, freeing up the vase. The region below the subclavian vein is filled by fatty tissue in continuity with the apical pleura and easily divulsed toward the mediastinum, building up a bed for a new path of the LITA. The fat attached to the mediastinum in continuity with the area of pleuropericardial dilatation should preferably be tunneled or sectioned for passage of the graft (Figure 2).

After the distal section of the LITA, its flow is assessed and the end is clamped. The artery is carefully moved through the apicopleural region under the mediastinal fat, so as to position itself along the divulsed region. It is performed an incision in the pericardium in the projection of the left atrium and through this, the LITA reaches the pericardial cavity (Figure 3).

The length of the graft fits easily to revascularizations

proposed, including exposure of the intermediate segments for use in sequential anastomosis or in addition to pedicled graft.

At the end of the operation, the LITA lies comfortably on the epicardium, providing a suitable length to bypass of one or more vessels (Figure 4).

This technique allows the pericardium can be approximated together with the all remaining thymic tissue being LITA protected, extrapleural, perihilar, supported on the mediastinum without prior contact with the tissues and the inner surface of the chest wall.

In any angiographic studies, LITA in this position presents proper positioning and flow. An observational assessment is that the preservation of pleural integrity has facilitated weaning from the respirator, reduced length of stay in the intensive care unit (ICU), substantial reduction of pain complaints by patients and the positioning of the LITA is also a better determinant of graft patency during this period.

Fig. 1 - Pleuropericardial divulsion: release of pericardial pleura (black arrow), undoing pleuropericardial adhesions (white arrow)

Fig. 2 - Tunneling of mediastinal fat (arrows)

Fig. 3 - Pericardial fenestration (arrows)

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Fig. 4 - LITA (black arrow) positioned on the epicardial bed (white arrow)

Felippe HS, et al. - The positioning of the internal thoracic artery extrapleural and perihilar in coronary artery bypass grafting

REFERENCES 1. Henriquez-Pino JA, Gomes WJ, Prates JC, Buffolo E. Estudo anatômico da artéria torácica interna aplicado à cirurgia cardiovascular. Rev Bras Cir Cardiovasc. 1997;12(1):83-8.

2. Sabik JF 3rd, Lytle BW, Blackstone EH, Houghtaling PL, Cosgrove DM. Comparison of saphenous vein and internal thoracic artery graft patency by coronary system. Ann Thorac Surg. 2005;79(2):544-51.

3. Spiliotopoulos K, Maganti M, Brister S, Rao V. Changing pattern of reoperative coronary artery bypass grafting: a 20year study. Ann Thorac Surg. 2011;92(1):40-7.

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4. Coltharp WH, Decker MD, Lea JW 4th, Petracek MR, Glassford DM Jr, Thomas CS Jr, at al. Internal mammary artery graft at reoperation: risks, benefits, and methods of preservation. Ann Thorac Surg. 1991;52(2):225-9.

5. K a m d a r A R , M e a d o w s T A , R o s e l l i E E , Gorodeski EZ, Curtin RJ, Sabik JF, et al. Multidetector computed tomographic angiography in planning of reoperative cardiothoracic surgery. Ann Thorac Surg. 2008;85(4):1239-45.

6. Jatene FB, Pêgo-Fernandes PM, Anbar R, Gaiotto FA, Barduco MS, Kalil Filho R. Dissecção robótica da artéria torácica interna direita por esternotomia mediana. Arq Bras Cardiol.

2010;94(6):e139-42.

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Letter to the Editor

DOI: 10.5935/1678-9741.20120110

RBCCV 44205-1435

Professor Paulo Manuel Pêgo Fernandes is Honored with FMUSP Institutional Centennial Medal As part of the Centenary Celebration of the School of Medicine of the University of São Paulo (FMUSP), on October 26 th, 2012, during the opening of the XXXI University Medical Congress (COMU), Associate Professor of the Department of Cardiology, University of São Paulo, Paulo Manuel Pêgo Fernandes, was awarded the FMUSP institutional Centenary Medal, created in order to honor individuals who have contributed in an exceptional and decisive manner for institutional, cultural, social and academic valorization.

The award was handed over by the vice rector of FMUSP, José Otávio Costa Auler Junior, by the idealization of the I University Medical Congress (COMU). The Congress was conceived by the Professor after his participation in academic conferences in other educational institutions during his medical graduation in the FMUSP. After two years of preparation, organization and diligent work, the professor jointly with the Department of Science of CAOC (Centro Acadêmico Oswaldo Cruz), today known as the Scientific Department of the School of Medicine of the USP, managed to realize the I COMU FMUSP, having as academic president its own founder.

Since then, COMU aims to promote scientific, cultural and social congregation of medical professionals and students.

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The vice director of FMUSP, José Otavio Costa Auler Junior (left), hands over the medal to Dr. Paulo Pêgo Fernandes

The teacher’s initiative of and his concern and help during the later editions were essential to the perpetuation of the congress. In 2011, the COMU reached its thirtieth edition and featured more than 600 registries for its courses, workshops and symposia. There were more than 250 professors and lecturers as well as 50 academics involved in the organization. The Congress gained national prominence and counts with the participation of scholars from various regions of the country.

Rev Bras Cir Cardiovasc 2012;27(4):653

BJCVS 27.4 Reviewers Below is a list of the names of those who assessed the studies published in this issue of the Brazilian Journal of Cardiovascular Surgery (BJCVS). To them, my thanks.

Domingo Braile Editor-in-Chief BJCVS

Alexandre C Hueb

Luis Alberto O Dallan

Alfredo Inácio Fiorelli

Manuel de Jesus Antunes

David Peitl

Marcelo Schafranski

Dorotéia Souza

Marcos Aurélio Barbosa Oliveira

Eduardo Keller Saadi

Mario Vrandecic

Enio Buffolo

Moacir Fernandes de Godoy

Fabio Antonio Gaiotto Fernando R. Moraes Neto Francisco Costa Frederico José Di Giovanni Gilberto Goissis Guilherme Agreli Helcio Giffhorn Isabella Martins de Albuquerque Jarbas Jakson Dinkhuysen João Carlos Leal

Orlando Petrucci Otoni Moreira Gomes Pablo M Alberto Pomerantzeff Paulo Roberto Brofman Reinaldo Bestetti Reinaldo Wilson Vieira Renata Gabaldi Renato A K Kalil Ricardo de Carvalho Lima

Juliana Bassalobre Carvalho Borges

Roberto Gomes de Carvalho

Leonardo Andrade Mulinari

Robinson Poffo

Lindemberg da Mota Silveira Filho

Rui M S Almeida

Luciana da Fonseca

Tomas Salerno

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NORMAS DA RBCCV Revista Brasileira de Cirurgia Cardiovascular/Brazilian journal of cardiovascular surgery Editor Prof. Dr. Domingo M. Braile Av. Juscelino Kubitschek de Oliveira, 1.505 – Jardim Tarraf I 15091-450 – São José do Rio Preto – SP - Brasil E-mail: revista@sbccv.org.br

Informações aos Autores. Os trabalhos enviados para publicação na Revista Brasileira de Cirurgia Cardiovascular – Brazilian Journal of Cardiovascular Surgery – devem versar sobre temas relacionados à cirurgia cardiovascular e áreas afins. Todas as contribuições ci entíficas são revisadas pelo Editor, Editores Associados, Membros do Conselho Editorial e Revisores Convidados e envolvem as seções de Artigos Originais, Editoriais, Revisões, Atualizações, Relatos de Casos, “Como–eu-Faço”, Comunicações Breves, Notas Prévias, Correlação Clínico Cirúrgica, Trabalho Experimental, Multimidia e Cartas ao Editor. A aceitação será feita baseada na originalidade, significância e contribuição científica.

Os manuscritos devem ser, obrigatoriamente, submetidos eletronicamente no site www.rbccv.org. br. Caso os autores ainda não tenham se cadastrado, é necessário fazê-lo antes de submeter o trabalho, seguindo as orientações que constam do site. Os textos devem ser editados em Word e as figuras, fotos, tabelas e ilustrações devem estar em arquivos separados. Figuras devem ter extensão jpeg e resolução mínima de 300dpi.

Para artigos com Publicação Duplicada, ver tópico específico.

Quando o artigo for aprovado, o autor será comunicado pelo e-mail cadastrado no site e deve encaminhar um resumo de até 60 palavras, em português e inglês, do artigo. Eles serão inseridos no mailing eletrônico enviado a todos os sócios quando a RBCCV/BJCVS estiver disponível on-line.

Norma. A Revista Brasileira de Cirurgia Cardiovascular – Brazilian Journal of Cardiovascular Surgery adota as Normas de Vancouver - Uniform Requirements for Manuscripts Submitted to Biomedical Journals, organizadas pelo International Committee of Medical Journal Editors – “Vancouver Group” (www.icmje.org).

Avaliação pelos pares (peer review). Todos os trabalhos enviados à Revista Brasileira de Cirurgia Cardiovascular serão submetidos à avaliação dos pares (peer review) por pelo menos três revisores selecionados entre os Editores Associados e os membros do Conselho Editorial. Os revisores responderão a um questionário no qual farão a classificação do manuscrito, sua apreciação rigorosa em todos os itens que devem compor um trabalho científico, dando uma nota para cada um dos itens do questionário.

Ao final farão comentários gerais sobre o trabalho e informarão se o mesmo deve ser publicado, corrigido segundo as recomendações ou rejeitado definitivamente.

654

De posse destes dados, o Editor tomará a decisão. Em caso de discrepâncias entre os avaliadores, poderá ser solicitada uma nova opinião para melhor julgamento. Quando forem sugeridas modificações, as mesmas serão encaminhadas ao autor principal e em seguida aos revisores para estes verificarem se as exigências foram satisfeitas. Após a editoração os manuscritos serão enviados ao autor para que este verifique se não há erros.

Todo o processo será realizado por via eletrônica e em cada fase serão exigidos prazos rigorosos de execução. Em caso de atraso, um novo avaliador será escolhido, o mesmo acontecendo se algum deles se recusar a analisar o trabalho.

Em casos excepcionais, quando o assunto do manuscrito assim o exigir, o Editor poderá solicitar a colaboração de um profissional que não conste da relação os Editores Associados e Conselho Editorial para fazer a avaliação.

Idioma. Os artigos devem ser redigidos em português (com a ortografia vigente) e em inglês. Para os trabalhos que não possuírem versão em inglês ou que esta seja julgada inadequada pelo Conselho Editorial, a revista providenciará a tradução com ônus para o(s) autor(es). A versão em inglês será publicada na íntegra no site da Scielo (www.scielo.br) e no da revista (www.rbccv.org.br) permanecendo “online” à disposição da comunidade internacional, com links específicos no site da nossa sociedade, aqui no Brasil e no nosso site, que está hospedado na CTSNET (www.ctsnet. org) nos Estados Unidos da América do Norte.

Pesquisa com seres humanos e animais. Os autores precisam citar no item Método que a pesquisa foi aprovada pelo Comissão de Ética em Pesquisa de sua Instituição, em consoante à Declaração de Helsinki – ver endereço eletrônico http://www.ufrgs.br/bioetica/helsin5.htm. Nos trabalhos experimentais envolvendo animais, as normas estabelecidas no “Guide for the Care and Use of Laboratory Animals” (Institute of Laboratory Animal Resources, National Academy of Sciences, Washington, D.C., 1996) e os Princípios éticos na experimentação animal do Colégio Brasileiro de Experimentação Animal (COBEA) devem ser respeitados (www.cobea.org.br/etica.htm).

Informações gerais.

Os artigos devem ser redigidos em processador de textos Word 97 ou superior (A 4); corpo 12; espaço 1,5; fonte Times News Roman (no caso de símbolos matemáticos, é necessário o uso da fonte “Symbol”); paginados e conter, sucessivamente: Versão em português. a) título em português e inglês;

Normas da RBCCV

b) nome completo dos autores; Instituição ou Serviço onde foi realizado o trabalho c) Resumo em português e inglês (máximo de 250 palavras, cada. Cem, cada, nos Relatos de Caso e “Como eu Faço”); d) Introdução; e) Método; f) Resultados; g) Discussão; h) Agradecimentos; i) Referências; j) Legendas das ilustrações k) Tabelas.

Seções do Manuscrito Primeira página. Deve conter o título do trabalho de maneira concisa e descritiva, em português e inglês, o nome completo dos autores e o nome e endereço da instituição onde o trabalho foi elaborado. A seguir o nome do autor correspondente, juntamente com o endereço, telefone, fax e e-mail. Se o trabalho foi apresentado em congresso, deve ser mencionado o nome do congresso, local e data da apresentação. Deve ser incluída a contagem de palavras. A contagem eletrônica de palavras deve incluir a página inicial, resumo, abstract, texto, referências e legenda de figuras.

Segunda Página - Resumo e Abstract. O resumo deve ser estruturado em quatro seções: Objetivo, Método, Resultados e Conclusão(ões). Devem ser evitadas abreviações. O número máximo de palavras deve seguir as recomendações da tabela. Nos Relatos de Casos e Comoeu-Faço, o resumo deve ser não-estruturado (informativo ou livre). O mesmo vale para o abstract. Correlações clínicocirurgicas e Multimidia não precisam de resumo e abstract.

Também devem ser incluídos de três a cinco descritores (palavras-chave), assim como a respectiva tradução para os Keywords (descriptors). Os descritores têm de ser consultados nos endereços eletrônicos: http://decs.bvs.br/, que contém termos em português, espanhol e inglês ou www.nlm.nih. gov/mesh, para termos somente em inglês, ou nos respectivos links no site da revista.

Texto. Artigos Originais devem ser divididos em Introdução, Método, Resultados, Discussão e Conclusão.

Relatos de Caso em Introdução, Relato do Caso e Discussão. Correlações clínico-cirúrgicas em Dados Clínicos, Eletrocardiograma, Radiograma, Ecocardiograma, Diagnóstico e Operação. Multimidia em Caracterização do Paciente e Descrição da Técnica Empregada. Artigos de Revisão e Atualização, a critério do autor. As referências devem ser citadas numericamente, por ordem de aparecimento no texto, entre colchetes. Se forem citadas mais de duas referências em seqüência, apenas a primeira e a última devem ser digitadas, sendo separadas por um traço (Exemplo: [6-9]). Em caso de citação alternada, todas as referências devem ser digitadas, separadas por vírgula (Exemplo: [6,7,9]).As abreviações devem ser definidas na primeira aparição no texto.

Agradecimentos. Devem vir após o texto.

Referências. De acordo com as Normas de Vancouver, as referências devem ser numeradas sequencialmente conforme aparição no texto. As referências não podem ter o parágrafo justificado, e sim alinhado à esquerda.

Rev Bras Cir Cardiovasc 2012;27(4):654-7

Comunicações pessoais e dados não publicados não devem ser incluídos na lista de referências, mas apenas mencionados no texto e em nota de rodapé na página em que é mencionado. Citar todos os autores da obra se forem seis ou menos ou apenas os seis primeiros seguidos de et al. se forem mais de seis. As abreviações das revistas devem estar em conformidade com o Index Medicus/ MEDLINE. Exemplos: Artigo de Revista 1. 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.

Instituição como Autor The Cardiac Society of Australia and New Zealand.

Clinical exercise stress testing. Safety and performance guidelines. Med J Aust 1996;116:41-2.

Sem indicação de autoria Cancer in South Africa. [editorial]. S Af Med j 1994;84-15.

Capítulo de Livro 1. Mylek WY. Endothelium and its properties. In: Clark BL Jr, editor. New frontiers in surgery. New York: McGrawHill; 1998. p.55-64.

Livro 1. Nunes EJ, Gomes SC. Cirurgia das cardiopatias congênitas. 2a ed. São Paulo: Sarvier; 1961. p.701.

Tese 1. Brasil LA. Uso da metilprednisolona como inibidor da resposta inflamatória sistêmica induzida pela circulação extracorpórea [Tese de doutorado]. São Paulo: Universidade Federal de São Paulo, Escola Paulista de Medicina, 1999.

122p. A EPM virou Universidade em 20 de dezembro 1994, de lá para cá se faz necessário colocar Unifesp e EPM. Eventos Silva JH. Preparo intestinal transoperatório. In: 45° Congresso Brasileiro de Atualização em Coloproctologia; 1995; São Paulo. Anais. São Paulo: Sociedade Brasileira de Coloproctologia; 1995. p.27-9.

Material eletrônico Artigo de revista Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis [serial online] 1995 Jan-Mar [cited 1996 Jun 5]; 1(1):[24 screens]. Available from: URL: http://www.cdc.gov/ncidod/EID/eid.htm Livros Tichenor WS. Sinusitis: treatment plan that works for asthma and allergies too [monograph online]. New York: Health On the Net Foundation; 1996. [cited 1999 May 27].

Available from: URL: http://www.sinuses.com Capítulo de livro Tichenor WS. Persistent sinusitis after surgery. In: Tichenor WS. Sinusitis: treatment plan that works for 655

Rev Bras Cir Cardiovasc 2012;27(4):654-7

Normas da RBCCV

asthma and allergies too [monograph online]. New York: Health On the Net Foundation; 1996. [cited 1999 May 27].

Available from: URL: http://www.sinuses.com/postsurg.htm Tese Lourenço LG. Relação entre a contagem de microdensidade vasal tumoral e o prognóstico do adenocarcinoma gástrico operado [tese online]. São Paulo: Universidade Federal de São Paulo; 1999. [citado 1999 Jun 10]. Disponível em: URL:http://www.epm.br/cirurgia/gastro/laercio Eventos Barata RB. Epidemiologia no século XXI: perspectivas para o Brasil. In: 4° Congresso Brasileiro de Epidemiologia [online].; 1998 Ago 1-5; Rio de Janeiro. Anais eletrônicos.

Rio de Janeiro: ABRASCO; 1998. [citado 1999 Jan 17].

Disponível em :URL: http://www.abrasco.com.br/epirio98 Legendas das Figuras. Devem ser formatadas em espaço duplo, em páginas numeradas e separadas, ordenadas após as Referências, uma página para cada legenda. As abreviações usadas nas figuras devem ser explicitadas nas legendas.

Tabelas e Figuras. Devem ser numeradas por ordem de aparecimento no texto, conter um título e estar em páginas separadas. As tabelas não devem conter dados redundantes já citados no texto. Devem ser abertas nos lados e com fundo totalmente branco. Abreviações usadas nas tabelas devem ser explicadas na legenda em ordem alfabética .

As tabelas e figuras somente serão publicadas em cores se o autor concordar em arcar com os custos de impressão das páginas coloridas.

Os manuscritos passam a ser propriedade da Revista Brasileira de Cirurgia Cardiovascular – Brazilian Journal

of Cardiovascular Surgery – não podendo ser reproduzidos sem consentimento por escrito do Editor. Os trabalhos aprovados e publicados na RBCCV não serão devolvidos aos autores. Aqueles não aprovados serão sistematicamente devolvidos.

Para a reprodução de qualquer material já previamente publicado ou disponível na mídia eletrônica (incluindo tabelas, ilustrações ou fotografias), deve ser anexada carta com permissão por escrito do Editor ou do detentor do copyright.

Artigos Duplicados. A convenção de Vancouver estabelece que artigos duplicados, no mesmo ou outro idioma, especialmente em países diferentes, podem ser justificáveis e mesmo benéficos. Assim, artigos publicados por autores brasileiros em revistas científicas de outros países poderão ser aceitos, se o editor considerar a relevância e a necessidade. Em nota de rodapé na primeira página da segunda versão deverá informar aos leitores, pesquisadores que o artigo foi publicado integralmente ou em parte e apresentar a referência da primeira publicação. A nota deve conter “Este artigo está baseado em estudo previamente publicado em (título da revista com referência completa)”.

Limites por tipo de artigo. Visando racionalizar o espaço da revista e permitir maior número de artigos por edição, devem ser observados os critérios abaixo delineados por tipo de publicação. A contagem eletrônica de palavras deve incluir a página inicial, resumo, texto, referências e legenda de figuras. Os títulos têm limite de 100 caracteres (contandose os espaços) para Artigos Originais, Artigos de Revisão e Atualização e Trabalho Experimental e de 80 caracteres (contando-se os espaços) para as demais categorias.

Artigo Original

Editorial

Artigo de Revisão/ Atualização

Relato de Caso

“Como eu faço”

Comunicação Breve/Nota Prévia

Carta ao Editor

Trabalho Experimental

Correlação ClínicoCirúrgica

Multimidia

Nº máximo de autores

8

4

8

4

4

8

4

6

4

4

Resumo Nº máximo de palavras

250

---

---

100

100

Nº máximo de palavras

5.000

1.000

6.500

1.500

1.500

2.000

400

5.000

800

800

Nº máximo de referências

25

10

75

6

6

6

6

25

10

10

Nº máximo de tabelas + figuras

8

2

8

2

4

2

1

8

2

1

656

250 ---

Rev Bras Cir Cardiovasc 2012;27(4):654-7

Normas da RBCCV

Exemplo de tabela

Exemplo de figura

Table 1. Lung Cancer Invading the Airway: Site of the Tumor and Number of Treatments Patients

Fig. 1 - Histogram showing effects of transdermal 17ß-estradiol on left internal mammary artery (LIMA) graft cross-sectional area. It increased by 30% (3.45 ± 1. 2 mm2 versus 4.24 ± 1 mm2; P = 0.039).

Treatments

Trachea

36 (13%)

43

Carina

28 (10%)

38

Main bronchi

154 (56%)

195

Bronchus intermedius 29 (11%)

38

Distal airway

26 (10%)

37

Total

273

351

Verifique antes de enviar o trabalho - Carta de submissão indicando a categoria do manuscrito - Declaração do autor e co-autores de que concordam com o conteúdo do manuscrito - Pesquisa aprovada pelo Comitê de Ética da Instituição, com o número do processo - Manuscrito redigido em processador de texto Word 97 ou superior (formatado para A 4); corpo 12; espaço 1,5; fonte Time News Roman; paginado; símbolos matemáticos e caracteres gregos utilizando a fonte Symbol - Manuscrito dentro dos limites adotados pela RBCCV para a sua categoria

A versão em inglês das Normas aos Autores da Revista Brasileira de Cirurgia Cardiovascular/Brazilian Journal of Cardiovascular Surgery está disponível nos sites: http://www.scielo.br/revistas/rbccv/iinstruc.htm ou http://www.rbccv.org.br/page/6

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Calendário de Eventos / Meetings Calendar 2013 Fevereiro 6 a 9 - 33rd Annual Cardiothoracic Surgery Symposium (CREF 2 013) - San Diego, Estados Unidos.

Informações: CREF - 793-A East Foothill Blvd, PMB # 119 - San Luis Obispo, CA 93405-1699.

Fone: 1 805 541-3118.

E-mail: info@crefmeeting.com Site: www.crefmeeting.com/ 9 a 13 - Minimally Invasive Techniques on Adult Cardiac Surgery (Surgical Training and Manpower Committee (STMP) of European Association of Cardiothoracic Surgery (EACTS). Teerã, Irã.

Informações: Louise McLeod - EACTS House - Maderia Walk - Windsor, Berkshire, SL6 6LE, UK. Fone: 44 1753 832166. Fax: 44 1753 620407.

E-mail: info@eacts.co.uk Site: www.eacts.org

Kiln Close - Calvert Green, Buckingham, MK18 2FD. Fone: 44 (0)1296 733 823. Fax: 44 (0)1296 733 823.

E-mail: lorrainerichardson1@btinternet.com Site: www.vatscourse.com 27 de fevereiro a 1o de março - Hands-on Cardiac Morphology (Spring Edition) - This 3 day course combines theory (lectures with video demonstrations) and handson examination of specimens covering the spectrum of congenital heart malformations. Londres, Inglaterra.

Informações: Carina Lim YP - Cardiac Morphology Unit, Brompton Hospital - Sydney Street - Londres SW3 6NP Inglaterra.

Fone: 44 (0) 207 351 8751. Fax: 44 (0) 207 351 8230 E-mail: Morphology@rbht.nhs.uk Site: www.cardiacmorphology.org/

Março

11 e 12 - ESTS School of Thoracic Surgery (Practical Course in the Laboratory). Paris, França.

Informações: Sue Hesford - ESTS Scientific Secretariat. 1 The Quadrant, Wonford Road, Exeter. EX2 4LE, UK Fone: 00441392430671 E-mail: sue@ests.org.uk Site: www.estsschool.org

2 a 9 - 31th Cardiovascular Surgical Symposium. Zuers/ Arlberg, Áustria.

Informações: Beatrix Seckl - Leopold-Gattringer-Str. 7/10 - Wolkersbergenstraße 1, 1130 Viena, Áustria.

Fone: 43 2236 38 27 32. Fax: 43 274 222 210 015.

E-mail: office@conventive.at Site: www.surgery-zurs.at

14 a 17 - 2nd Heart Care Heart International Heart Symposium - Innovation and New Frontier in Heart Care.

Chiangmai, Tailândia.

Informações: Heart Care Foundation - Divison of Surgery, Chest Disease Institute, Nonthaburi, Tailândia.

Fax: 662-591-8943 E-mail: info@cdiheartdisease.org Site: www.cdiheartdisease.org/

4 a 8 - Fundamentals in Cardiac Surgery: Part I. Windsor, Inglaterra.

Informações: Louise McLeod - EACTS House - Madeira Walk Windsor, Berkshire, SL4 1EU Phone: +44 1753 832166 Email: louise.mcleod@eacts.co.uk or info@eacts.co.uk

17 a 20 - 42 Annual Meeting of the German Society for Thoracic and Cardiovascular Surgery. Freiburg/Breisgau, Alemanha.

Informações: Andreas Beckmann, MD, CEO - German Society for Thoracic and Cardiovascular Surgery.

Luisenstr 58/59, 10117 Berlin Fone: 49-30-28004370. Fax: 49-30-28004379.

E-mail: sekretariat@dgthg.de or kongresspraesident@ dgthg.de Site: www.dgthg-jahrestagung.de nd

27 e 28 - 6th Advanced Video-Assisted Thorocoscopy and Thoracic Endoscopy Course Informações: Lorraine Richardson - L R Associates - 58 658

12 a 17 - ESTS School of Thoracic Surgery (Theoretical Course). Antalya, Turquia.

Informações: Sue Hesford - ESTS Scientific Secretariat 1 The Quadrant, Wonford Road, Exeter. EX2 4LE. Fone: 00441392430671 E-mail: sue@ests.org.uk Site: www.estsschool.org 13 e 14 - The Left Ventricular Outflow Tract Aortic Arch Surgery, Brain Development and Cerebral Protection.

Windsor, Inglaterra.

Informações: Louise McLeod - EACTS House - Madeira Walk - Windsor, Berkshire, SL4 1EU. Fone: 44 1753 832166 E-mail: louise.mcleod@eacts.co.uk or info@eacts.co.uk

Calendário de Eventos / Meetings Calendar

13 - Hypertrophic & Restrictive Cardiomyopathy: Genetics, Imaging and Emerging Treatments in Adult and Pediatric Patients. Nova York, Estados Unidos.

Informações: Stephanie Scheeler.

Fone: 1 201 346-7003. Fax: 1 201-346-7011.

E-mail: sas2258@columbia.edu Site: http://columbiasurgery.org/cme/event_ hcm_20130313.html 17 a 19 - SCTS Annual Meeting & Cardiothoracic Forum.

Brighton, Inglaterra.

Informações: Isabelle Ferner - 35-43 Lincoln's Inn Fields, Londres. WC2A 3PE. Fone: 44 (0)20 7869 6893. Fax: 44 (0)20 7869 6890 E-mail: sctsadmin@scts.org or tilly@scts.org Site: http://www.scts.org 20 a 22 - SCTS Annual Meeting & Cardiothoracic Forum.

Windsor, Inglaterra.

Informações: Louise McLeod - EACTS House - Madeira Walk - Windsor, Berkshire, SL4 1EU. Fone: 44 1753 832166.

E-mail: louise.mcleod@eacts.co.uk / info@eacts.co.uk 21 a 24 - 9th International Congress of Update in Cardiology & Cardiovascular Surgery. Antalya, Turquia.

E-mail: uccvs2013@marekon.org Site: www.uccvs2013.org/

Rev Bras Cir Cardiovasc 2012;27(4):658-60

Abril 4 a 7 - 21st Annual Meeting of the Asian Society for Cardiovascular and Thoracic Surgery. Kobe, Japão.

Site: www.ascvts2013.com/ 8 a 12 - Thoracic Surgery Part I. Windsor, Inglaterra.

Informações: Louise McLeod - EACTS House - Madeira Walk - Windsor, Berkshire, SL4 1EU. Fone: 44 1753 832166 E-mail: louise.mcleod@eacts.co.uk / info@eacts.co.uk 18 a 20 – 40º Congresso da Sociedade Brasileira de Cirurgia Cardiovascular. Florianópolis, SC, Brasil.

Informações: SBCCV – Rua Beira Rio, 45 – 7º and, conj. 72. São Paulo-SP. CEP 04548-050.

Fone: (11) 3849-0341. Fax (11) 5096-0079.

Site: /www.sbccv.org.br/40congresso/ 22 a 26 - Minimally Invasive Techniques on Adult Cardiac Surgery (Surgical Training and Manpower Committee (STMP) of European Association of Cardiothoracic Surgery (EACTS). Nieuwegein, Holanda.

Informações: Louise McLeod - EACTS House - Maderia Walk - Windsor, Berkshire, SL6 6LE, UK. Fone: 44 1753 832166. Fax: 44 1753 620407.

E-mail: info@eacts.co.uk Site: www.eacts.org

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Calendรกrio de Eventos / Meetings Calendar

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RBCCV em números 27 anos de circulação ininterrupta Fator de Impacto 1,239 Consultada por leitores de mais de 110 países

www.rbccv.org.br www.scielo.br/rbccv www.bjcvs.org

788.564 acessos no site próprio (www.rbccv.org.br) em 2012 709.180 acessos no site da SciELO (www.scielo.br/rbccv) em 2012 4092 visitantes diariamente 469,65 gigabytes (GB) transferidos, média de 1,28 GB por dia 47.232.073 impressões de páginas em 2012 (requisição do navegador de um visitante para uma página web que possa ser exibida), média diária de 129.049,38.

Presente em nas bases de dados Lilacs, Scielo, Latindex, Index Copernicus, Scopus, PubMed, Thomson Scientific (ISI), Google Scholar