Brazilian Journal of Cardiovascular Surgery 29.1 by Revista Brasileira de Cirurgia Cardiovascular

29.1 JANUARY/MARCH 2014

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR | BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

VOL. 29 Nยบ 1 JANUARY/MARCH 2014

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RBCCV REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

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 Camila Safadi PhD - São Paulo (BRA) S. José do Rio Preto (BRA) rosangela.monteiro@incor.usp.br camila@sbccv.org.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 • Carolina Zuppardi • Fernando Pires Buosi • Marcelo Almeida

• 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

Sociedade Brasileira de Cirurgia Cardiovascular

Rua Beira Rio, 45 • 7º andar - Cj. 72 • Vila Olímpia • Fone: 11 3849-0341. Fax: 11 5096-0079. Cep: 04548-050 • São Paulo, SP, Brasil E-mail RBCCV: revista@sbccv.org.br • E-mail SBCCV: sbccv@sbccv.org.br • Site SBCCV: www.sbccv.org.br • Sites RBCCV: www.scielo.br/rbccv / www.rbccv.org.br (também para submissão de artigos)

Publicação trimestral/Quarterly publication Edição Impressa - Tiragem: 250 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] 2013, 28: 1,2,3,4 2013, 28: 1 [supl] 2014, 29: 1

ISSN 1678-9741 - Publicação on-line 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 • 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

• 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 • EBSCO www2.ebsco.com/pt-br

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 2014 - 2015 Presidente: Vice-Presidente: Secretário Geral: Tesoureiro: Diretor Científico:

Marcelo Matos Cascudo (RN) Fábio Biscegli Jatene (SP) Henrique Murad (RJ) Eduardo Augusto Victor Rocha (MG) Rui M.S. Almeida (PR)

Conselho Deliberativo:

Bruno Botelho Pinheiro (GO) Henrique Barsanulfo Furtado (TO) José Pedro da Silva (SP) Luciano Cabral Albuquerque (RS) Ricardo de Carvalho Lima (PE)

Editor da Revista: Editor do Site: Editores do Boletim:

Domingo Marcolino Braile (SP) João Carlos Ferreira Leal (SP) Walter José Gomes (SP) Domingo Marcolino Braile (SP) Orlando Petrucci (SP) Luciano Cabral Albuquerque (RS) Fernando Moraes Neto (PE)

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

Vinícius José da Silva Nina (MA) Marcelo Sávio da Silva Martins Rubens Tofano de Barros Rodrigo de Castro Bernardes Jorge Luiz França de Vasconcelos (MS) Marcela da Cunha Sales Luiz César Guarita Souza Milton de Miranda Santoro

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

Luiz Fernando Canêo (SP) Juan Alberto Cosquillo Mejia (CE) Cláudio José Fuganti (PR) Eduardo Keller Saadi (RS) Alexandre Ciappina Hueb (SP) José Carlos Dorsa V. Pontes (MS) Gabriel Liguori (SP) Francisco Siosney Almeida Pinto (AL)

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 - Online version ISSN 0102-7638 - Printed version RBCCV 44205

Impact Factor: 0.809

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brasil) jan/mar- 2014;29(1) 1-122

CONTENTS/SUMÁRIO

EDITORIALS/EDITORIAIS

BJCVS has record access in 2013 RBCCV tem acesso recorde em 2013 Domingo M. Braile.................................................................................................................................................................................. I

Cardiac resynchronization therapy for patients with chronic systolic heart failure secondary to Chagas cardiomyopathy in the 21st century Terapia de ressincronização cardíaca em pacientes com insuficiência cardíaca crônica sistólica secundária à cardiomiopatia da doença de Chagas no século 21 Reinaldo B. Bestetti............................................................................................................................................................................... IV

Cardiovascular and periodontal diseases Doença cardiovascular e doença periodontal Reinaldo W. Vieira............................................................................................................................................................................... VII ORIGINAL ARTICLES/ARTIGOS ORIGINAIS

1514 EuroSCORE II and the importance of a local model, InsCor and the future SP-SCORE EuroSCORE II e a importância de um modelo local, InsCor e o futuro SP-SCORE Luiz Augusto Ferreira Lisboa, Omar Asdrubal Vilca Mejia, Luiz Felipe Pinho Moreira, Luís Alberto Oliveira Dallan, Pablo Maria Alberto Pomerantzeff, Luís Roberto Palma Dallan, Maria Raquel B. Massoti, Fabio B. Jatene.............................................................1 1515 Use of EuroSCORE as a predictor of morbidity after cardiac surgery Uso do EuroSCORE como preditor de morbidade no pós-operatório de cirurgia cardíaca Isaac Newton Guimarães Andrade, Fernando Ribeiro de Moraes Neto, Tamirys Guimarães Andrade...................................................9 1516 Surgical treatment of aortic valve endocarditis: a 26-year experience Tratamento cirúrgico da endocardite da válvula aórtica: 26 anos de experiência Taylan Adademir, Eylem Yayla Tuncer, Serpil Tas, Arzu Antal Donmez, Ebru Bal Polat, Altug Tuncer..............................................16 1517 IL-10 and ET-1 as biomarkers of rheumatic valve disease IL-10 e ET-1 como biomarcadores de doença valvar reumática Sydney Correia Leão, Maria Regina Menezes Lima, Hertaline Menezes do Nascimento, Shirlei Octacilio-Silva, Tania Maria de Andrade Rodrigues...............................................................................................................................................................................................25 1518 Cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy: long-term follow up Terapia de ressincronização cardíaca em pacientes com cardiomiopatia chagásica crônica: seguimento de longo prazo Edgard Ferreira de Araújo, Eduardo Gregório Chamlian, Alexey Pomares Peroni, Wilson Lopes Pereira, Sylvio Matheus de Aquino Gandra, Luiz Antonio Rivetti.................................................................................................................................................................31

1519 Evaluation of patients' quality of life aspects after cardiac pacemaker implantation Avaliação de aspectos da qualidade de vida em pacientes pós-implante de marca-passo cardíaco Rubens Tofano de Barros, Sebastião Marcos Ribeiro de Carvalho, Marcos Augusto de Moraes Silva, Juliana Bassalobre Carvalho Borges. . .............................................................................................................................................................. 37 1520 Advanced age and incidence of atrial fibrillation in the postoperative period of aortic valve replacement Idade avançada e incidência de fibrilação atrial em pós-operatório de troca valvar aórtica Fernando Pivatto Júnior, Guaracy Fernandes Teixeira Filho, João Ricardo Michelin Sant'anna, Pablo Mondim Py, Paulo Roberto Prates, Ivo Abrahão Nesralla, Renato Abdala Karam Kalil...............................................................................................................................45 1521 Evaluation of the Society of Thoracic Surgeons score system for isolated coronary bypass graft surgery in a Brazilian population Avaliação dos escores da Society of Thoracic Surgeons para cirurgia de revascularização miocárdica isolada em uma população brasileira Dimas Tadahiro Ikeoka, Viviane Aparecida Fernandes, Otávio Gebara, José Carlos Teixeira Garcia, Pedro Gabriel Melo de Barros e Silva, Marcelo Jamus Rodrigues, Valter Furlan, Antônio Cláudio do Amaral Baruzzi.........................................................................51 1522 Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position Comparação da ocorrência de complicações tromboembólicas e hemorrágicas em pacientes portadores de prótese valvares cardíacas mecânicas com um e dois folhetos na posição mitral Nelson Leonardo Kerdahi Leite de Campos..........................................................................................................................................59 1523 Effects of periodontal therapy on C-reactive protein and HDL in serum of subjects with periodontitis Efeitos da terapia periodontal sobre proteína C-reativa e HDL no soro de indivíduos com periodontite Anne Carolina Eleutério Leite, Valéria Martins de Araújo Carneiro, Maria do Carmo Machado Guimarães.......................................69 SPECIAL ARTICLES/ARTIGOS ESPECIAIS 1524 Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study Proposta de correção virtual geométrica da projeção ostial da artéria renal no estudo operatório de aneurismas infrarrenais: resultados iniciais de um estudo piloto Giovani José Dal Poggetto Molinari, Andreia Marques de Oliveira Dalbem, Fabio Huseman Menezes, Ana Terezinha Guillaumon...........78 1525 Comparison of the solution of histidine-tryptophan-alfacetoglutarate with histidine-tryptophan-glutamate as cardioplegic agents in isolated rat hearts: an immunohistochemical study Comparação da solução de histidina-triptofano-alfacetoglutarato com histidina-triptofano-glutamato como agentes cardioplégicos em corações isolados de ratos: estudo imuno-histoquímico Marcos Aurélio Barboza de Oliveira, Lívia Carvalho Ferreira, Débora Aparecida Pires de Campos Zuccari, Antônio Carlos Brandi, Carlos Alberto dos Santos, Paulo Henrique Husseni Botelho, Orlando Petrucci, Domingo Marcolino Braile.....................................83 1526 Information technology implementing globalization on strategies for quality care provided to children submitted to cardiac surgery: International Quality Improvement Collaborative Program – IQIC A tecnologia da informação implementando a globalização nas estratégias de qualidade para o atendimento às crianças submetidas à cirurgia cardíaca: o Programa de Colaboração Internacional IQIC Adilia Maria Pires Sciarra, Ulisses Alexandre Croti, Fernando Batigália.............................................................................................89 REVIEW ARTICLE/ARTIGO DE REVISÃO 1527 Managing the inflammatory response after cardiopulmonary bypass: review of the studies in animal models Manejo da resposta inflamatória pós-circulação extracorpórea: revisão dos estudos em modelos animais Gabriel Romero Liguori, Alexandre Fligelman Kanas, Luiz Felipe Pinho Moreira..............................................................................93 BRIEF COMMUNICATION/COMUNICAÇÃO BREVE 1528 Transfixing cardiac injury with perforations in stomach, diaphragm and lung: unusual scenario in penetrating trauma Lesão cardíaca transfixante associada a perfurações gástrica, diafragmática e pulmonar: um cenário incomum em trauma penetrante Carlos Junior Toshiyuki Karigyo, Otávio Goulart Fan, Marcelo Miyazaki Yoshida, Roberto Jonathas Menescal, Marcos José Tarasiewich.................................................................................................................................................................................. 103

HOW TO DO IT/COMO EU FAÇO 1529 Mammary artery harvesting using the Da Vinci Si robotic system Dissecção da artéria mamaria com uso de sistema robótico Da Vinci Si Leonardo Secchin Canale, Johannes Bonatti.......................................................................................................................................107

1530 LETTERS TO THE EDITOR/CARTAS AO EDITOR........................................................................................................................110

Reviewers BJCVS 29.1/Revisores RBCCV 29.1.................................................................................................................................114

Impresso no Brasil Printed in Brazil

Grafic design and layout: 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

BJCVS has record access in 2013 RBCCV tem acesso recorde em 2013

Domingo M. Braile* DOI: 10.5935/1678-9741.20140001

n 2013, the Brazilian Journal of Cardiovascular Surgery (BJCVS) had special reasons to celebrate: the growth of over 65% in the number of visits to our site (www.rbccv.org.br) when compared to 2012. We went from 788,564 to 1,307,934 hits, averaging over 3,500 visitors/day, with a peak in April, 7,420 in just one day (Figure 1)! If we add the access via our website at SciELO (www.scielo.br/rbccv) there were over 1.9 million visits last year, averaging nearly 5,300 visitors per day. Internet users from over 110 countries were on our site.

The total number of page impressions in 2013 (request from a visitor’s browser to a web page that can be displayed) was 55,020,119, an increase of 16% over the previous year (47,232,073), an average of 150,740 in 2013, 11 per day (Figure 2). Regarding gigabytes (GB) transferred the increase reached 23%, up from 469.65 GB in 2012 to 578.47 GB last year. The daily average was 1.58 GB (Figure 3). There is a tendency to value the publications by the number of hits or by the number of GB arising from such hits. Certainly, this modern resource would be another marker of the importance and spread of a journal.

Fig. 1 – Graph showing the access to the RBCCV / BJCVS site in 2013.

Fig. 2 – Graph showing page impressions of RBCCV / BJCVS site in 2013.

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

Fig. 3 - Graph showing Gigabytes (GB) transferred in RBCCV / BJCVS site in 2013.

This performance leaves us extremely satisfied by proving the increasing visibility of BJCVS, and the importance of having the journal available in various media, enabling access anytime and anywhere. We finished the implementation of new technologies for online editing, as applications for smartphones and tablets, both on the iOS operating systems or Android. Thus, on any device connected to the Internet, our journal can be fully seen in its PDF extension. In all of them a symbol (Figure 4) will appear, and just click on it to access BJCVS Editions. We ask the readers to experience such ease and give us their feedback, which will be very useful for the constant improvement of our Journal.

H index, among others, that broaden the range of options and would give breath to hundreds of journals in the area of health, which, being restricted to specialty publications, as BJCVS (only consulted by a restricted community), cannot be compared to the New England Journal of Medicine, for example, that is of interest of different medical specialties, as well as researchers and professionals in related fields. Thus, the number of citations of specialty Journals never reaches the levels of a generic journal. The journals like ours, even in the first world, are irrelevant in general compute of IF (IF of the Journal of Thoracic and Cardiovascular Surgery is 3,526, the Annals of Thoracic Surgery, 3454, and the European Journal of Cardio-Thoracic Surgery, 2674) and cannot be compared to the aforementioned New England Journal of Medicine IF, which is 51,658! As obvious as these facts, CAPES is impervious to this reasoning. No Brazilian journal now reaches the level A1 or A2 demanding Qualis CAPES. The Brazilian Journal of Psychiatry, with 1,856, is the one with the highest IF among the 100 national publications that underlie the Thomson Reuters! Over three articles published in BJCVS were prominent among the “top 20” search from BioMedLib (www. biomedlib.com) site. This time, the performance is up to the articles of “Cardiac surgery: the infinite quest” series, by Dr. Rodolfo Neirotti, published in editions 27.4, 28.1 and 28.2. Another novelty is that, after 2 years, our journal was again awarded with editorial support from CNPq. The sum of R$ 30,000, although it is far from required, is useful to help pay the costs, ever increasing. Encouraged by the growth of accesses and this good news, we will continue to improve BJCVS, so that we can offer readers the best content and the best features that the computer has to offer. In this issue, two studies (“Proposal of renal artery’s ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study”, pag. 78, and “Mammary artery harvesting with the da Vinci Si robotic system”, pag. 107) add videos in their content.

Fig. 4 – App RBCCV / BJCVS symbol for Smartphones and Tablets.

Moreover, the performance of our journal reinforces my perception, as described above, that this kind of access to the contents of the journals should be taken into account by CAPES and by development agencies when classifying publications. So, a journal is not assessed only by current criteria, such as the Impact Factor (IF), SCImago Journal Rank,

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

Meeting of the Editorial Board of BJCVS with Associate Editors and Members of the Editorial Board On April 3, from 14h to 15h, in the auditorium 6, the meeting of the Editorial Board of BJCVS with the Associate Editors and members of the Board will take place, also open to all members wishing to participate. The effect of adoption of technologies will be discussed, as new applications for smartphones and tablets, both operating systems like iOS and Android. I count on the participation and suggestions from everyone.

We are finalizing, along with GN1, our partner since 2005, a tool that will allow the video to be sent by the website at the time of article submission. Change in the print edition Due to increased printing costs, driven by the rising dollar, the Editorial Board of the Journal, with approval of the Board of BSCVC decided that the images of the print edition will be published in black and white, even if they are sent in colors. Thus, it can reduce the value of print. When an article has originally sent pictures in color, there will be the notice in its end referring the reader to the online edition, where the figures, graphs and tables are presented in color, and can be copied with ease.

CME We have the following items with Continuing Medical Education in this issue: “EuroSCORE II and the importance of a local model, InsCor and the future SP-SCORE” (pag. 1), Use of EuroScore as a predictor of morbidity after cardiac surgery (pag. 9), “Advanced age and incidence of atrial fibrillation in the postoperative period of aortic valve replacement” (pag. 45) e “Comparison of the solution of histidine-tryptophan-alfacetoglutarate with histidine-tryptophan-glutamate as cardioplegic agents in isolated rat hearts: an immunohistochemical study” (pag. 83). We ask the readers to disclose this important learning teaching tool among students, residents, and anyone who wants to increase their knowledge. My warmest regards!

BSCVS Congress From 3 to April 5, the 41st Congress of the Brazilian Society of Cardiovascular Surgery (BSCVS) will be held in Porto de Galinhas, PE, along with 4th Symposium of Nursing in Cardiovascular Surgery, the 4th Symposium of Physical Therapy in Cardiovascular Surgery, the 4th Perfusion Symposium on Cardiovascular Surgery, in addition to the 3rd Academic Congress on Cardiovascular Surgery, demonstrating the importance of contact of students with professionals. The theme of this edition is “Heart Team - the patient first”. Professionals from different specialties, working together in order to provide the most appropriate treatment, of which derives the best outcome. I want to compliment the Board of BSCVS, chaired by Dr. Marcelo Cascudo, with support from other members, and the Organizing Committee, coordinated by Dr. Fernando Ribeiro Moraes Neto, who devoted all his efforts in its formatting.

*Editor-in-Chief BJCVS/RBCCV

III

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

Editorial

Reinaldo B. Bestetti, MD, PhD DOI: 10.5935/1678-9741.20140002

In the 21st century, Chagas disease continues to be a major health problem in South America because it affects 10 million people, and other 20 million are at risk of acquiring the disease [1]. It must be emphasized, however, that the disease is no longer confined to South America due to international immigration. In fact, Chagas disease has persistently been identified in non-endemic countries such United States, Spain, Canada, and Australia [1]. As a result, the global economic burden of the disease is impressive, reaching the figure of US 8 billion annually [2]. Chagas disease is caused by the protozoan Trypanosoma cruzi, which is transmitted to humans when the feces of a sucking bug contaminate a skin lesion or eye mucosae [1]. However, chronic Chagas disease appears many years after initial infection (in general, up two decades). Chagas cardiomyopathy is the protean clinical manifestation of the chronic disease, manifesting by ventricular dysrhythmias [3], sudden cardiac death [4], thromboembolism [5], and chronic heart failure (CHF) [6]. In Chagas disease patients, CHF is associated with reduced systolic function, as no case of CHF with preserved left ventricular function has been described in patients with this condition. The disease can affect up to 5% of patients of a population-based and about 50% of a referral center-based cohort [6]. Chagas disease heart failure has a higher annual mortality [7], and its prognosis is worse than that observed in non-Chagas disease heart failure [8]. Irreversible left ventricular systolic dysfunction is the most frequent mode of death in patients with this condition in the contemporary era [9]. The pathogenesis of Chagas disease heart failure is similar to that seen in non-Chagas disease heart failure, with the neurohormonal activation playing a pivotal role. In addi-

tion, an intracardiac autonomic imbalance [10] can expose the myocardium to the toxic effects of catecholamine [11]. Some studies suggest a benefit effect for angiotensin converting enzyme inhibitor as well as for beta-blocker therapy both experimentally [12] and in patients with this condition [8,13,14]. Obviously, other types of treatment modality are necessary, mainly in patients in the advanced stages of CHF. SEE ORIGINAL ARTICLE IN PAGES 31-36 Cardiac resynchronization therapy (CRT) is an established therapeutic modality for patients with non-Chagas heart disease heart failure to improve mortality in those with advanced heart failure and left bundle branch block [15,16]. In a Brazilian scenario, this therapy is also cost-effective [17]. By contrast, little is known about the effects of CRT in patients with CHF secondary to Chagas cardiomyopathy in view of the few studies carried out in patients with this condition. Silva Menezes [18] has clearly shown that CRT with bifocal right ventricular pacing has no effect on left ventricular reverse remodeling in the mid-term follow up, besides increasing the number of arrhythmic episodes. Silva et al. [19] studied 29 patients with CHF, 52% of them with CHF secondary to Chagas cardiomyopathy with permanent right ventricular pacing. They showed in this small sample that CRT improves clinical status and left ventricular ejection fraction in the mid-term follow up in patients with Chagas disease heart failure, although a definite conclusion could not be established because such a study was neither randomized nor double-blinded. Therefore, further studies on the effect of CRT on patients with CHF secondary to Chagas cardio-

Medicine Course, University of Ribeirão Preto, Ribeirão Preto, SP, Brazil. E-mail: rbestetti44@gmail.com

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REFERENCES 1. Chagas disease (American trypanosomiasis): fact sheet (revised in August 2012). Wkly Epidemiol Rec. 2012;87(51/52):519-22.

Abbreviations, acronyms & symbols CHF CRT

Chronic heart failure Cardiac resynchronization therapy

2. Lee BY, Bacon KM, Bottazzi ME, Hotez PJ. Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis. 2013;13(4):342-8.

myopathy are sorely needed if we are planning to improve morbidity and mortality in such patients. In this issue of the journal, Araújo et al. [20] presents a paper dealing with CRT in patients with CHF secondary to Chagas cardiomyopathy. The authors enrolled 72 patients in class III/IV, 100% on beta-blocker therapy (mean carvedilol daily dose=20 mg), 70% on angiotensin converting enzyme inhibitor/angiotensin receptor block, 47% with left bundle branch block, mean QRS duration 148.1 ± 17.5 msec, 15% on permanent right ventricular pacing, mean left ventricular systolic diameter 66.2 ± 7.6 mm, and mean left ventricular ejection fraction 27.3 ± 7.7%. After a mean follow-up of 47 months, only 13% were in class III/IV, there was an 81% increase in the left ventricular ejection fraction, and a 12% decrease in the left ventricular systolic diameter. Importantly, this is the largest cohort of patients with CHF secondary to Chagas cardiomyopathy receiving CRT thus far reported. Araújo et al. [20], therefore, did observe left ventricular reverse remodeling in such patients. However, it must be emphasized that such a study was neither randomized nor double-blinded. In the absence of evidence-based medicine support, it could be difficult to recommend CRT to treat patients with Chagas cardiomyopathy with CHF. Of course, a randomized, double-blinded controlled trial would be paramount to recommend or not to recommend CRT to Chagas disease patients. However, it should be borne out that Chagas disease is neglected, and therefore such a study will probably never be carried out in patients with this disease. Therefore, in a scenario like that, it seems to me to be reasonable to indicate CRT to patients with CHF secondary to Chagas cardiomyopathy with a clinical picture similar to that found in non-Chagas disease heart failure patients. This is an important question because even patients with non-Chagas disease heart failure have different types of heart disease, but have been treated similarly. This is the case, for example, for patients with CHF secondary to either idiopathic dilated cardiomyopathy or ischemic cardiomyopathy, which are distinct entities. With the limitations discussed earlier, the paper by Araújo et al. [20] may be seen as another block in the construction of the treatment of patients with CHF secondary to Chagas cardiomyopathy in the contemporary era. Furthermore, Araújo et al. paper lends support to the notion that such patients, treated with guideline drugs (at target doses) [21], with increased QRS complex duration (ideally with left bundle branch block), and advanced left ventricular remodeling (as detected by left ventricular ejection fraction < 30% and left ventricular systolic dimension > 50 mm), will benefit of CRT.

3. Bestetti RB, Santos CR, Machado-Júnior OB, Ariolli MT, Carmo JL, Costa NK, et al. Clinical profile of patients with Chagas’ disease before and during sustained ventricular tachycardia. Int J Cardiol. 1990;29(1):39-46. 4. Bestetti RB, Cardinalli-Neto A. Sudden cardiac death in Chagas’ heart disease in the contemporary era. Int J Cardiol. 2008;131(1):9-17. 5. Ribeiro AL, Nunes MP, Teixeira MM, Rocha MO. Diagnosis and management of Chagas disease and cardiomyopathy. Nat Rev Cardiol. 2012;9(10):576-89. 6. Bestetti RB, Theodoropoulos TA, Cardinalli-Neto A, Cury PM. Treatment of chronic systolic heart failure secondary to Chagas heart disease in the current era of heart failure therapy. Am Heart J. 2008;156(3):422-30. 7. Bertolino ND, Villafanha DF, Cardinalli-Neto A, Cordeiro JA, Arcanjo MJ, Theodoropoulos TA, et al. Prognostic impact of Chagas’ disease in patients awaiting heart transplantation. J Heart Lung Transplant. 2010;29(4):449-53. 8. Issa VS, Amaral AF, Cruz FD, Ferreira SM, Guimarães GV, Chizzola PR, et al. Beta-blocker therapy and mortality of patients with Chagas cardiomyopathy: a subanalysis of the REMADHE prospective trial. Circ Heart Fail. 2010;3(1):82-8. 9. Ayub-Ferreira SM, Mangini S, Issa VS, Cruz FD, Bacal F, Guimarães GV, et al. Mode of death on Chagas heart disease: comparison with other etiologies. a subanalysis of the REMADHE prospective trial. PLoS Negl Trop Dis. 2013;7(4):e2176. 10. Bestetti RB, Coutinho-Netto J, Staibano L, Pinto LZ, Muccillo G, Oliveira JS. Peripheral and coronary sinus catecholamine levels in patients with severe congestive heart failure due to Chagas’ disease. Cardiology. 1995;86(3):202-6. 11. Bestetti RB, Ramos CP, Figuerêdo-Silva J, Sales-Neto VN, Oliveira JS. Ability of the electrocardiogram to detect myocardial lesions in isoproterenol induced rat cardiomyopathy. Cardiovasc Res. 1987;21(12):916-21. 12. Bestetti RB, Sales-Neto VN, Pinto LZ, Soares EG, Muccillo G, Oliveira JS. Effects of long-term metoprolol administration on the electrocardiogram of rats infected with T cruzi. Cardiovasc Res. 1990;24(7):521-7. 13. Botoni FA, Poole-Wilson PA, Ribeiro AL, Okonko DO, Oliveira BM, Pinto AS, et al. A randomized trial of carvedilol after renin-

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angiotensin system inhibition in chronic Chagas cardiomyopathy. Am Heart J. 2007;153(4):544.e1-8.

patients with heart failure: the perspective of a middle-income country’s public health system. Int J Cardiol. 2013;163(3):309-15.

14. Bestetti RB, Otaviano AP, Cardinalli-Neto A, Rocha BF, Theodoropoulos TA, Cordeiro JA. Effects of beta-blockers on outcome of patients with Chagas’cardiomyopathy with chronic heart failure. Int J Cardiol. 2011;151(2):205-8.

18. Silva Menezes A. Outcome of right ventricular bifocal pacing in patients with permanent atrial fibrillation and severe dilated cardiomiopathy due to Chagas disease: three years of follow-up. J Interv Card Electrophysiol. 2004;11(3):193-8.

15. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-50.

19. Silva RT, Martinelli Filho M, Lima CE, Martins DG, Nishióka SA, Pedrosa AA, et al. Functional behavior of patients with conventional pacemakers undergoing cardiac resynchronization. Arq Bras Cardiol. 2008;90(2):138-43. 20. Araújo EF, Chamlian EG, Peroni AP, Pereira WL, Gandra SMA, Rivetti LA. Cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy: long-term follow up. Rev Bras Cir Cardiovasc. 2014;29(1):31-6.

16. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-49.

21. Bocchi EA, Marcondes-Braga FG, Bacal F, Ferraz AS, Albuquerque D, Rodrigues Dde A, et al. Updating of the Brazilian guideline for chronic heart failure – 2012. Arq Bras Cardiol. 2012;98(1 Suppl 1):1-33.

17. Bertoldi EG, Rohde LE, Zimerman LI, Pimentel M, Polanczyk CA. Cost-effectiveness of cardiac resynchronization therapy in

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Editorial

Cardiovascular and periodontal diseases Doenรงa cardiovascular e doenรงa periodontal

Reinaldo Wilson Vieira, MD, PhD DOI: 10.5935/1678-9741.20140003

Cardiovascular diseases, especially those associated with atherosclerosis, are still one of the main causes of death worldwide. There are well-established risk factors for cardiovascular diseases, one of them being elevated levels of serum lipids combined with infections such as odontogenic infections, which consist of dental caries and periodontal disease (gingivitis and periodontitis). Periodontal and cardiovascular diseases share many risk factors, such as age, educational level, gender, income level, smoking and drinking habits, hypertension, stress, depression, and diabetes. Several studies have shown that patients with periodontitis and acute ischemic syndromes share various characteristics. It should be noted that severe chronic periodontitis can alter lipid profiles as well as lead to acute coronary events. In addition, the presence of periodontal organisms in coronary arteries has been linked to the development and progression of atherosclerosis. The presence of Chlamydia pneumoniae in 35% of the coronary and internal thoracic arteries suggests that this bacterium plays an important role in the progression of atherosclerosis [1]. In the United States, 25% of adults age 60 and older lose all their teeth (edentulism), half of them due to periodontal disease; the other half, to caries [2]. Chronic periodontitis consist of chronic oral infections found on the surface of teeth and in adjacent tissues. Clinically, the onset is marked by gingival inflammation and is followed by formation of a periodontal pocket, which fosters the development and growth of anaerobic Gram-negative bacteria, including Porphyromonas gingivalis, Prevotella intermedia, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia, among others [3].

Experimental studies have convincingly demonstrated the release of inflammatory mediators from peripheral monocytes when taken from patients with periodontitis and exposed in vitro to bacterial lipopolysaccharides. The accumulation of bacteria in the periodontal microflora results in the production of lipopolysaccharides, which are released from the external membrane of Gram-negative bacteria. SEE ORIGINAL ARTICLE ON PAGES 69-77 Consequently, host response is immediately triggered by recruitment of inflammatory cells, which produce large quantities of proinflammatory cytokines, such as interleukin 6 (IL-6), prostaglandins E2 (PGE2), and matrix metalloproteinases (MMPS), which in turn contribute to the destruction of periodontal tissue. As a result of the high production of these metabolites, in the acute phase, there is a subsequent response from the liver, which produces and synthesizes proteins, one of them being the C-reactive protein found in the blood of patients with chronic periodontal diseases [4-6]. The relationship between odontogenic infections and cardiovascular disease has been described in several studies, including experimental ones, which have shown the release of inflammatory mediators in patients with periodontitis. Thus, diagnosis and treatment of periodontal diseases are important to maintain both oral and systemic health [7]. The past two decades have seen an increasing interest in the impact of oral health on atherosclerosis and, hence, on cardiovascular diseases. Therefore, it seems that periodontal disease may contribute to the development of cardiovascular disease [8].

Associate Professor of Cardiac Surgery at the Campinas State University Medical School. E-mail: rkv@uol.com.br

VII

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Abbreviations, acronyms & symbols IL-1B Interleukin 1 beta IL-6 Interleukin 6 INF-Y Interferon Y MMPS Matrix metalloproteinases PGE2 Prostaglandins E2 TNF-α Tumor necrosis factor alpha

Host response to the infection is often accompanied by the release of proinflammatory cytokines, such as interleukin 1 beta (IL-1B), IL-6, and tumor necrosis factor alpha (TNF-α), which alter the lipid metabolism and promote hyperlipidemia. In addition, common events in the evolution of the disease are influenced by risk factors or indicators. Genetic factors, environment, and other acquired habits differ in stage and form from one disease to another. Proinflammatory cytokines, such as IL-1B, TNF-α, and interferon Y (INF-Y), increase and induce the production of PGE2 and MMPS, molecules that promote the destruction of the extracellular matrix of gingival tissue and periodontal ligament as well as the reabsorption of alveolar bone [9]. Products originating from Gram-negative bacteria cell wall (LPS), the leading cause of periodontitis, trigger a host response, with the production and release of proinflammatory cytokines (IL-1B, IL-6, and TNF-α), which in turn induce a host response themselves, elevating the levels of C-reactive protein and fibrinogen [5]. Experimentally, the role played by the Porphyromonas gingivalis bacteria in atherosclerotic plaque formation proves that periodontitis causes fat accumulation in the aorta. Thus, chronic periodontitis alter the biochemical profile as well as the white cell count, evidenced by the altered immune response (20% higher). Clinical and laboratory evaluations of systemic diseases performed on healthy patients show a potential connection between periodontal diseases and their lipid and glycemic profiles [10]. Therefore, diagnosis and treatment of periodontal diseases are important not only to maintain good oral health, but also to help mitigate pathological changes such as atherosclerosis and, subsequently, acute myocardial infarction and strokes [7]. Periodontal diseases and their role in the etiology of acute ischemic syndromes have received growing attention in clarifying the possible mechanisms involved in both diseases [11]. Reports found in the literature document the association between acute ischemic syndromes and chronic infections by Gram-negative bacteria such as Chlamydia pneumoniae and Helicobacter pylori [12]. Hence, periodontal diseases and their possible interactions cannot be overlooked and their association with cardiovascular diseases should be investigated [13].

Periodontal bacterial DNA was observed in 10 out of the 17 samples of coronary arteries, representing approximately 59.9%, in which Porphyromonas gingivalis was present in 52.9%, Aggregatibacter actinomycetemcomitans, in 35.5%, Prevotella intermedia, in 23.5%, and Tannerella forsythia, in 11.7%. Chlamydia pneumoniae was seen in 35.3% of the coronary and internal thoracic arteries [1]. Thus, the presence of periodontal microorganisms in 10 out of the 17 coronary arteries studied supports the idea that those bacteria may be associated with the development and progression of atherosclerosis, as it has been observed in several epidemiological studies [1,14]. In light of this, we can say that the presence of periodontal microorganisms in the coronary and internal thoracic arteries may be associated with the development and progression of atherosclerosis as well as lesions in cardiac valves.

REFERENCES 1. Oliveira FJ, Vieira RW, Coelho OR, Petrucci O, Oliveira PPM, Antunes N, et al. Inflamação sistêmica causada pela periodontite crônica em pacientes vítimas de ataque cardíaco isquêmico agudo. Rev Bras Cir Cardiovasc. 2010;25(1):51-8. 2. Beltrán-Aguilar ED, Barker LK, Canto MT, Dye BA, Gooch BF, Griffin SO, et al. Surveillance for dental caries, dental sealants, tooth retention, edentulism, and enamel fluorosis: United States, 1988-1994 and 1999-2002. MMWR Surveill Summ. 2005;54(3):1-43. 3. Socranski S, Haffajee AD. Periodontal microbial ecology. Peridontol 2000. 2005;38:135-87. 4. Loos BG, Hunter J, Varoufaki A. Level of C-reactive protein in periodontitis patients and healthy controls. J Dent Res. 1988;77(special issue):666. 5. Loos BG, Craandijk J, Hoek FJ, Wertheim-van Dillen PM, van der Velden U. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol. 2000;71(10):1528-34. 6. Antunes N, Dragosavc D, Petrucci Junior O, Oliveira PPM, Kosour C, Blotta MHSL, et al. Ultrafiltração para remover mediadores inflamatórios durante circulação extracorpórea na revascularização do miocárdio. Rev Bras Cir Cardiovasc. 2008;23(2):175-82. 7. Graves DT, Jiang Y, Genco C. Periodontal disease: bacterial virulence factors, host response and impact on systemic health. Curr Opin Infect Dis. 2000;13(3):227-32.

VIII

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8. Meurman JH, Sanz M, Janket S. Oral health, atherosclerosis, and cardiovascular disease. Crit Rev Oral Biol Med. 2004;15(6):403-13.

al. Presence and severity of Chlamydia pneumoniae and Cytomegalovirus infection on coronary plaques are associated with acute coronary syndromes. Int Heart J. 2006;47(4):511-9.

9. Page RC. The pathobiology of periodontal disease may affect systemic diseases: inversion of a paradigm. Ann Periodontol. 1998;3(1):108-20.

13. Offenbacher S, Beck JD, Moss K, Mendoza L, Paquette DN, Barrow DA, et al. Results from Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. J Periodontol. 2009;80(2):190-201.

10. Salvi GE, Carollo-Bittel E, Lang NP. Effects the diabetes mellitus on periodontal and peri-implant conditions: update on associations and risks. J Clin Periodontol. 2008;35(8 Suppl):398-409. 11. Kinane DF, Lowe GD. How periodontal disease may contribute to cardiovascular disease. Periodontol. 2000;23:121-6.

14. Humphrey LL, Fu R, Buckley DI, Freeman M, Helfand M. Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis. J Gen Intern Med. 2008;23(12):2079-86.

12. Liu R, Moroi M, Yamamoto M, Kubota T, Ono T, Funatsu A, et

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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

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Rev Bras Cir Cardiovasc 2014;29(1):1-8

Lisboa LAF, ORIGINAL et al. - EuroSCORE II and the importance of a local model, ARTICLE InsCor and the future SP-SCORE

EuroSCORE II and the importance of a local model, InsCor and the future SP-SCORE EuroSCORE II e a importância de um modelo local, InsCor e o futuro SP-SCORE

Luiz Augusto Ferreira Lisboa1, MD, PhD; Omar Asdrubal Vilca Mejia1, MD, PhD; Luiz Felipe Pinho Moreira1, MD, PhD; Luís Alberto Oliveira Dallan1, MD, PhD; Pablo Maria Alberto Pomerantzeff1, MD, PhD; Luís Roberto Palma Dallan1, MD; Maria Raquel B. Massoti1, MD; Fabio B. Jatene1, MD, PhD

DOI: 10.5935/1678-9741.20140004

RBCCV 44205-1514

Abstract Introduction: The most widely used model for predicting mortality in cardiac surgery was recently remodeled, but the doubts regarding its methodology and development have been reported. Objective: The aim of this study was to assess the performance of the EuroSCORE II to predict mortality in patients undergoing coronary artery bypass grafts or valve surgery at our institution. Methods: One thousand consecutive patients operated on coronary artery bypass grafts or valve surgery, between October 2008 and July 2009, were analyzed. The outcome of interest was in-hospital mortality. Calibration was performed by correlation between observed and expected mortality by Hosmer Lemeshow. Discrimination was calculated by the area under the ROC curve. The performance of the EuroSCORE II was compared with the EuroSCORE and InsCor (local model).

Results: In calibration, the Hosmer Lemeshow test was inappropriate for the EuroSCORE II (P=0.0003) and good for the EuroSCORE (P=0.593) and InsCor (P=0.184). However, the discrimination, the area under the ROC curve for EuroSCORE II was 0.81 [95% CI (0.76 to 0.85), P<0.001], for the EuroSCORE was 0.81 [95% CI (0.77 to 0.86), P<0.001] and for InsCor was 0.79 [95% CI (0.74-0.83), P<0.001] showing up properly for all. Conclusion: The EuroSCORE II became more complex and resemblance to the international literature poorly calibrated to predict mortality in patients undergoing coronary artery bypass grafts or valve surgery at our institution. These data emphasize the importance of the local model.

1. Heart Institute of the Clinics Hospital at the Faculty of Medicine, University of São Paulo (InCor-HCFMUSP), São Paulo, SP, Brazil.

This study was carried out at the Clinics Hospital at the Faculty of Medicine, University of São Paulo (InCor-HCFMUSP), São Paulo, SP, Brazil.

Descriptors: Risk Factors. Cardiovascular Surgical Procedures. Coronary Artery Bypass. Myocardial Revascularization. Coronary Disease. Heart Valve Diseases.

Correspondence address: Luiz Augusto Ferreira Lisboa Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas de Carvalho Aguiar, 44 – 2º andar – sala 11 – Cerqueira César – São Paulo, SP, Brazil – Zip code: 05403-000 E-mail: luiz.lisboa@incor.usp.br

No financial support.

Article received on October 12th , 2013 Article accepted on November 17th, 2013

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Rev Bras Cir Cardiovasc 2014;29(1):1-8

Lisboa LAF, et al. - EuroSCORE II and the importance of a local model, InsCor and the future SP-SCORE

tra-hospitalar. A calibração foi realizada pela correlação entre mortalidade esperada e observada por meio do teste de Hosmer Lemeshow. A discriminação foi calculada pela área abaixo da curva ROC. O desempenho do EuroSCORE II foi comparado com os modelos EuroSCORE e InsCor (modelo local). Resultados: Na calibração, o teste de Hosmer Lemeshow foi inadequado para o EuroSCORE II (P=0,0003) e bom para os modelos EuroSCORE (P=0,593) e InsCor (P=0,184). No entanto, na discriminação, a área abaixo da curva ROC para o EuroSCORE II foi de 0,81 [IC 95% (0,76-0,85), P<0,001]; para o EuroSCORE foi de 0,81 [IC 95% (0,77-0,86), P<0,001] e para o InsCor foi de 0,79 [IC 95% (0,74-0,83), P<0,001], revelando-se adequada para todos. Conclusão: O EuroSCORE II se tornou mais complexo e, à semelhança com a literatura internacional, mal calibrado para predizer mortalidade nos pacientes operados de coronária e/ou valva em nosso meio. Esses dados reforçam a importância do modelo local.

Abbreviations, acronyms and symbols EuroSCORE InCor-HCFMUSP ROC SPSS STS score

European System for Cardiac Operative Risk Evaluation Clinics Hospital at the Faculty of Medicine, University of São Paulo Receiver Operating Characteristic Statistical Package for the Social Sciences Society of Thoracic Surgeons score

Resumo Introdução: O modelo mais utilizado para predição de mortalidade em cirurgia cardíaca foi recentemente remodelado, mas dúvidas referentes à sua metodologia e desenvolvimento têm sido relatadas. Objetivo: O objetivo deste estudo foi avaliar o desempenho do EuroSCORE II na predição de mortalidade em pacientes submetidos a cirurgia de coronária e/ou valva na instituição. Métodos: Mil pacientes, operados consecutivamente de coronária e/ou valva, entre outubro de 2008 e julho de 2009, foram analisados. O desfecho de interesse foi mortalidade in-

Descritores: Fatores de Risco. Procedimentos Cirúrgicos Cardiovasculares. Ponte de Artéria Coronária. Revascularização Miocárdica. Doença das Coronárias. Doenças das Valvas Cardíacas.

INTRODUCTION

power of discrimination. Still, we must not forget that “few variables as possible” prevails in a model in order to have a greater acceptance [12,13]. At the Heart Institute, Clinics Hospital of the Faculty of Medicine, University of São Paulo (Incor-HCFMUSP), the remodeling of EuroSCORE models and 2000 Bernstein-Parsonnet [8] together, using the bootstrap technique, gave rise to InsCor [14]. This model was similar to the first EuroSCORE and its performance was simpler than this and that the 2000 Bernstein-Parsonnet score to predict mortality in patients undergoing coronary and/or valve at Incor-HCFMUSP. This fact becomes more important when there is a need to assess the experience of treatment against the “casemix” location at a given time, as it has been done by several groups. The aim of this study was to validate the EuroSCORE II and compare it to InsCor and EuroSCORE models in patients undergoing coronary and/or valve on Incor-HCFMUSP.

In modern medicine, the use of risk scores as predictors of cardiovascular events is well established [1]. Efficient models should be derived from prospective, compulsory and complete records, be built upon bootstrap statistical techniques and demonstrate adequate internal validation, strictly following the scientific principles [2,3]. Clearly risk models derived and validated on a local, usually have lower performance when applied elsewhere and even in the same location over time [4]. However, the first EuroSCORE created in 1999 [5] in the European population, was suitable in a contemporary Brazilian population [6-8]. Undoubtedly, the incorporation of the EuroSCORE on key services in Europe brought to mind the “Hawthorne” effect, explaining that nothing much has improved outcomes in cardiac surgery at the beginning of the century, as monitoring by EuroSCORE [9]. Over time, the remodeling of the EuroSCORE for countries that joined its mandatory use would be justifiable. Thus, the EuroSCORE II has aroused [10], from a record with 22,381 consecutive patients undergoing cardiac surgery in 154 hospitals in 43 countries (inside and outside Europe), over a 12-week period (May to July 2010). This updated model has more variables than the first EuroSCORE, so in addition to the risk of having high discrimination power, it carries the risk of overfitting [11]. Thus, smaller models have good accuracy but unfortunately decrease the

METHODS Sample size, inclusion and exclusion criteria A retrospective analysis of prospectively collected data was performed at the Division of Cardiovascular Surgery, Incor - HCFMUSP. For validation of risk scores in a sample of at least 100 deaths, the study by Lisboa et al. [15] on the results of cardiovascular surgery at Incor-HCFMUSP of the past 23 years, was the basis for the study. For this, 1000 pa-

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Rev Bras Cir Cardiovasc 2014;29(1):1-8

tients operated sequentially for coronary bypass or associated and/or isolated or combined valve surgery, including reoperations and in elective, urgent or emergency procedures, from October 2008 to July 2009, were selected. Of these, all filled the variables contained in the InsCor EuroSCORE models, however, only 900 patients included all variables required by Euroscore II. Patients younger than 18 years or undergoing other types of surgery other than CABG and/or valve surgery were excluded from the study.

called area under the ROC (Receiver Operating Characteristic, sometimes called c-statistic or c-index). Statistical Analysis Statistical analysis was performed using the Statistical Package for Social Sciences software (SPSS) version 16.0 for Windows (IBM Corporation Armonk, New York). Continuous variables were expressed as mean±standard deviation and categorical variables as percentages. The logistic regression analysis for the outcome of in-hospital mortality was performed by using the value given to each patient by the InsCor, EuroSCORE and EuroSCORE II scores. Calibration and discrimination were measured for each score value in the patient population. The performance of the models was also measured by comparing mortality between observed and expected mortality in risk groups established by the models. The Fisher exact test was used for contingency tables. The P value <0.05 was considered significant.

Collection, definition and organization of data Data were collected from electronic medical records system of the Incor (SI3) and stored in spreadsheets. Each worksheet has been adapted to take account of all the variables, respecting their definitions as described by EuroSCORE [9], EuroSCORE II [10] and InsCor [14] models. Patients were sorted according to the risk groups established by the scores and placed in the database made in Excel. The outcome of interest was in-hospital mortality, defined as death that occurred in the time interval between surgery and discharge.

Ethics and written informed consent This study was approved by the Research Ethics Committee for Projects Analysis (CAPPesq) at Clinics Hospital of the University of São Paulo, with the number 1575.

Validation of InsCor, EuroSCORE and EuroSCORE II To assess the performance of InsCor, EuroSCORE and EuroSCORE II in predicting mortality, the predictive validity of the models was performed. The analysis was performed using calibration and discrimination test. Calibration assesses the accuracy of the model to predict risk in a group of patients. The force calibration was assessed by testing the goodness of fit by the Hosmer-Lemeshow test. P value> 0.05 indicates that the model fits the data and predicts mortality properly. Discrimination measures the ability of the model to distinguish between patients at low and high risk. Discrimination was measured by use of the statistical technique

RESULTS Calibration InsCor Calibration of InsCor was adequate, with P=0.184 in the Hosmer-Lemeshow test. The average value of InsCor for survivors was significantly lower than for deaths (3.64 ± 3.5 and 7.96 ± 4.6, P<0.001). In Table 1, the InsCor calibration by risk group is presented.

Table 1. InsCor calibration - Analysis by risk group. Risk

Mortality % observed (95% CI) % predicted (95% CI)

Number of cases

Low (0-3)

437

2.97 (1.38; 4.57)

4.35 (2.44; 6.26)

Mean (4-7)

317

10.09 (6.78; 13.41)

8.83 (5.71; 11.96)

High (≥8)

246

26.83 (21.29; 32.37)

26.02 (20.53; 31.50)

Hosmer-Lemeshow test (P=0.184)

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EuroSCORE The calibration of the EuroSCORE was also adequate, with P=0.593 in the Hosmer-Lemeshow test. In Table 2, the calibration of the EuroSCORE by risk groups is presented.

Discrimination InsCor and EuroSCORE On discrimination, the area under the ROC curve of the EuroSCORE was 0.81 [95% CI (0.77 to 0.86), P<0.001] and the InsCor was 0.79 [95% CI (0.74 to 0.83), P <0.001 ] (Figure 1).

EuroSCORE II The calibration of the EuroSCORE II was not appropriate, with P=0.0003 in the Hosmer-Lemeshow test. In Table 3, the calibration of the EuroSCORE II by risk group is presented.

EuroSCORE II On discrimination, the area under the ROC curve was 0.81 [95% CI (0.77 to 0.85) P<0.001] for the EuroSCORE II (Figure 2).

Table 2. EuroSCORE calibration - Analysis by risk group. Risk

Mortality % observed (95% CI) % predicted (95% CI)

Number of cases

Low (0-2)

333

2.10 (0.56; 3.64)

2.40 (0.76; 4.05)

Mean (3-5)

328

5.79 (3.26; 8.32)

High (â&#x2030;Ľ6)

339

25.07 (20.45; 29.69)

24.79 (20.18; 29.37)

Hosmer-Lemeshow test (P=0.593)

Table 3. EuroSCORE II calibration - Analysis by risk group. Risk

Mortality % observed (95% CI) % predicted (95% CI)

Number of cases

Low (0.17-0.80)

180

1.11 (-0.42; 2.64)

6.67 (3.02; 10.31)

Mean (0.81-1.22)

182

2.75 (0.37; 5.12)

6.59 (2.99; 10.20)

Mean-High (1.23-2.02)

181

6.08 (2.60; 9.56)

7.73 (3.84; 11.63)

High (2.03-4.11)

182

14.84 (9.67; 20.00)

9.34 (5.11; 13.57)

Very High (4.14-47.60)

175

31.43 (24.55; 38.31)

25.71 (19.24; 32.19)

Hosmer-Lemeshow test (P=0.0003)

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Fig. 1 - ROC curve for InsCor 0.79 [95% CI (0.74 to 0.83), P<0.001] and the EuroSCORE was 0.81 [95% CI (0.77 to 0.86), P<0.001] in the evaluation of the power of discrimination performed in 1,000 patients

Fig. 2 - ROC curve for EuroSCORE II 0.81 [95% CI (0.77 to 0.85), P<0.001] in the evaluation of the power of discrimination performed in 900 patients

DISCUSSION

consists of 10 variables and can be used for predicting mortality in cardiovascular procedures of adults. Over time, countries that have adopted strict monitoring by the EuroSCORE, in the past decade, had to adjust the model to their new â&#x20AC;&#x153;Hawthorne Effectâ&#x20AC;? results. Thus, in October 2011, Nashef et al. [10] presented in Lisbon, in 25th European Association for Cardio-Thoracic Surgery Annual Meeting, the EuroSCORE remoldeled, which came to be called EuroSCORE II. In this study, 23,000 patients underwent cardiac surgery in more than 150 hospitals in 43 countries between May and July 2010. In the internal model validation, on calibration, the observed mortality was 3.9% and the expected mortality by EuroSCORE II of 3.77%, compared to 4.6% of the EuroSCORE. The authors also reported that discrimination of the new model was very good, although the model was not described in the presentation. In our study, the discrimination of three models proved to be adequate, which means that qualitatively the variables included in the models are the same that have strong relationship with mortality. However, the calibration with respect to the amount or intensity of each predictor variable was adequate for InsCor and EuroSCORE and bad for the EuroSCORE II. Faced with these results, we were waiting for the complete version of the EuroSCORE II, held in January 2012 [10]. After careful analysis of this publication, we point out

Risk scores should be simplified formulas without the need for personal digital assistants or calculators to predict mortality or other adverse effects at the bedside. They are a valuable aid in therapeutic decisions and for informed consent [16]. However, to be incorporated into the risk models they must be validated. Validating a model means to investigate its calibration and discrimination of a population under certain conditions. Proper calibration and especially good discrimination are the most important factors of a model. Thus, in a model with high discrimination power, many variables are needed in general. In this situation, there is the risk of overfitting. An important feature for adherence of the model is that it is simple and comprehensive, so that the methodology is important [17]. In the history of cardiac surgery, the risk prediction model with greater impact was the EuroSCORE and was published in 1999 by Nashef et al. [5], with more than 108,000 references on Google search and some 1,300 formal citations in the medical literature. This model includes 17 risk factors, from 19,030 patients from 128 centers in Europe. In 2012, in Brazil, the remodeling of EuroSCORE and 2000 Bernstein-Parsonnet models together through the bootstrap technique, gave rise to InsCor [14]. This parsimonious model

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some problems in the internal validation of the EuroSCORE II, justifying inadequate external validation of the model. Our analysis is consistent and supported by several sequential international publications [18-20], being reinforced by editorial that demonstrated that, in fact, there are problems in the design of the EuroSCORE II [21,22]. In general, problems with randomly division into two groups for development and validation of the model and details such as the P=0.0505 (ideal >0.05) value in the Hosmer-Lemeshow test, stating a good calibration, are questionable [23]. It is doubtful, especially considering the association of this statistical value with some clinical significance. The term EuroSCORE was also inappropriate, since several non-European countries participated in the remodeling of the model. With this in mind, it would be better to calculate the mortality rate itself or the local risk-adjusted hospital, since the model was built to predict death in a wide variety of groups, making it difficult to forecast specific clinical scenarios. Another reason for poor calibration would be the large number of highly correlated risk factors, including confounding variables and over-adjusted to a certain types of procedures or specific subgroups of patients. Upon publication of the EuroSCORE II, it was not reported if analyzes of first order interaction and multicollinearity were performed, so many variables could overestimate the risk of certain categories of patients (e.g., intermediate risk or extreme risk). In the follow-up, there was inefficient management of patients with loss of data, where the bias arises due to significant differences between individuals with complete data and those with missing data. Thus, a regression coefficient calculated for a predictor may be influenced if missing data were associated with the outcome. In EuroSCORE II, the authors could have chosen otherwise imputation to preserve these cases. In general, the performance of the participating centers, with major failures in the supply of data, especially in the follow-up, was poor [21]. Furthermore, there should be more careful in order to not to increase the number of variables at all times, since models with only a few variables are very stable and, if robust they may achieve good calibration. The inclusion of many variables increases the risk of errors that can be caused by differences in interpretation of definitions, types, or conflicting information. The reduced number of variables without affecting its accuracy (“few variables as possible”) in comprehensive models is one of the most important aspects of the cost, popularity and applicability of risk scores [12,24]. Another concern with the EuroSCORE II is that the primary outcome was mortality at the base hospital, and we cannot forget that, in actual practice, it is common for patients to be transferred to other hospitals in accordance with clinical outcome. Recently, Kunt et al. [20] compared the EuroSCORE,

STS score and EuroSCORE II in a population of 428 patients who underwent isolated coronary surgery, between 2004 and 2012 in Turkey. The mortality rate was 7.9% and the predicted mortality was 6.4% for the additive EuroSCORE, 7.9% for the logistic EuroSCORE, 1.7% for the EuroSCORE II and 5.8% for STS score. The area under the ROC curve for the additive EuroSCORE, logistic EuroSCORE, STS score and EuroSCORE II was 0.7, 0.7, 0.72 and 0.62, respectively. In the modern evolution of risk assessment, it has been widespread the concept of applying external models and remold them to the characteristics of the region [25]. To apply a risk score, it must first be remolded (adaptation of the variables and their weights) or at least recalibrated (adjusting the weights of the variables) and never used form of ready-made (without adaptation of the variables and their weights) [24]. In Brazil, the adhesion of a model itself is of paramount importance, especially by differences in patient characteristics, clinical presentation due to socioeconomic, cultural and geographical reasons, the uneven distribution of medical facilities and the high endemicity of subclinical inflammation, infection and rheumatic disease [25]. Thus, the external validation InsCor is required. We are already in advanced work in collaboration with seven centers of large representation of the state of São Paulo, for the study and creation of the SP-SCORE [26]. Importantly, risk scores are based on the experience of the participating teams, patients with regional characteristics and certain infrastructure and time. A model cannot be transported to other locations or be included in the same location over time without performing preliminary validation tests, so it is important to know the limitations of these instruments. Limitations Although data were collected prospectively, this is a retrospective analysis. However, the collection within the electronic database was “blind”, or that is, we selected the first 1000 patients undergoing coronary and/or valve within the period studied without knowledge of clinical outcome. Another important factor is that, as the study was retrospective, only 900 patients had all the data to calculate the EuroSCORE II. To minimize this limitation, we performed an analysis with 100 unselected patients and observed that the mortality of these patients showed no statistical difference with the selected group to perform validation of the EuroSCORE II. CONCLUSION The InsCor and EuroSCORE were adequate in all phases of the validation. However, the errors found in the design of the EuroSCORE II were also manifest in the calibration of patients undergoing coronary and/or valve surgery on Incor-HCFMUSP. These data reinforce the importance of InsCor local model and future SP-SCORE.

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10. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44.

Author' roles and responsibilities LAFL OAVM LFPM LAOD PMAP LRPA MRBM FBJ

Study design, analysis of results and writing of the manuscript Study design, collection of data and writing of the manuscript Evaluation of results and statistics Evaluation of results and discussion Evaluation of results and discussion Medical records analysis and risk factors Medical records analysis and risk factors Study design and discussion

11. Altman DG, Royston P. What do we mean by validating a prognostic model? Stat Med. 2000;19(4):453-73. 12. Tu JV, Sykora K, Naylor CD. Assessing the outcomes of coronary artery bypass graft surgery: how many risk factors are enough? Steering Committee of the Cardiac Care Network of Ontario. J Am Coll Cardiol. 1997;30(5):1317-23. 13. Ranucci M, Castelvecchio S, Conte M, Megliola G, Speziale G, Fiore F, et al. The easier, the better: age, creatinine, ejection fraction score for operative mortality risk stratification in a series of 29,659 patients undergoing elective cardiac surgery. J Thorac Cardiovasc Surg. 2011;142(3):581-6.

14. Mejía OA, Lisboa LA, Puig LB, Moreira LF, Dallan LA, Pomerantzeff PM, et al. InsCor: a simple and accurate method for risk assessment in heart surgery. Arq Bras Cardiol. 2013;100(3):246-54.

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15. 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. Takkenberg JJ, Kappetein AP, Steyerberg EW. The role of EuroSCORE II in 21st century cardiac surgery practice. Eur J Cardiothorac Surg. 2013;43(1):32-3.

16. Hannan EL, Racz M, Culliford AT, Lahey SJ, Wechsler A, Jordan D, et al. Risk score for predicting in-hospital/30-day mortality for patients undergoing valve and valve/coronary artery bypass graft surgery. Ann Thorac Surg. 2013;95(4):1282-90.

3. Hannan EL, Cozzens K, King SB 3rd, Walford G, Shah NR. The New York State cardiac registries: history, contributions, limitations, and lessons for future efforts to assess and publicly report healthcare outcomes. J Am Coll Cardiol. 2012;59(25):2309-16.

17. Altman DG, Vergouwe Y, Royston P, Moons KG. Prognosis and prognostic research: validating a prognostic model. BMJ 2009;338:b605.

4. Shahian DM, Normand SL. Comparison of “risk-adjusted” hospital outcomes. Circulation. 2008;117(15):1955-63.

18. Carnero-Alcázar M, Silva Guisasola JA, Reguillo Lacruz FJ, Maroto Castellanos LC, Cobiella Carnicer J, Villagrán Medinilla E, et al. Validation of EuroSCORE II on a singlecentre 3800 patient cohort. Interact Cardiovasc Thorac Surg. 2013;16(3):293-300.

5. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9-13. 6. Moraes F, Duarte C, Cardoso E, Tenório E, Pereira V, Lampreia D, et al. Avaliação do EuroSCORE como preditor de mortalidade em cirurgia de revascularização miocárdica no Instituto do Coração de Pernambuco. Rev Bras Cir Cardiovasc. 2006;21(1):29-34.

19. Chalmers J, Pullan M, Fabri B, McShane J, Shaw M, Mediratta N, et al. Validation of EuroSCORE II in a modern cohort of patients undergoing cardiac surgery. Eur J Cardiothorac Surg. 2013;43(4):688-94.

7. 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.

20. Kunt AG, Kurtcephe M, Hidiroglu M, Cetin L, Kucuker A, Bakuy V, et al. Comparison of original EuroSCORE, EuroSCORE II and STS risk models in a Turkish cardiac surgical cohort. Interact Cardiovasc Thorac Surg. 2013;16(5):625-9.

8. Mejía OA, Lisboa LA, Dallan LA, Pomerantzeff PM, Moreira LF, Jatene FB, et al. Validation of the 2000 Bernstein-Parsonnet and EuroSCORE at the Heart Institute - USP. Rev Bras Cir Cardiovasc. 2012;27(2):187-94.

21. Sergeant P, Meuris B, Pettinari M. EuroSCORE II, illum qui est gravitates magni observe. Eur J Cardiothorac Surg. 2012;41(4):729-31.

9. Nashef SA; EuroSCORE Project team. The New EuroSCORE Project. Nowa skala EuroSCORE. Kardiol Pol. 2010;68(1):128-9.

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22. Collins GS, Altman DG. Design flaws in EuroSCORE II. Eur J Cardiothorac Surg. 2013;43(4):871.

25. Sá MP, Sá MV, Albuquerque AC, Silva BB, Siqueira JW, Brito PR, et al. GuaragnaSCORE satisfactorily predicts outcomes in heart valve surgery in a Brazilian hospital. Rev Bras Cir Cardiovasc. 2012;27(1):1-6.

23. Nezic D, Borzanovic M, Spasic T, Vukovic P. Calibration of the EuroSCORE II risk stratification model: is the HosmerLemeshow test acceptable any more? Eur J Cardiothorac Surg. 2013;43(1):206.

26. Mejía OA, Lisboa LA, Dallan LA, Pomerantzeff PM, Trindade EM, Jatene FB, et al. Heart surgery programs innovation using surgical risk stratification at the São Paulo State Public Healthcare System: SP-SCORE-SUS study. Rev Bras Cir Cardiovasc. 2013;28(2):263-9.

24. Mejía OA, Lisboa LA. The risk of risk scores and the dream of BraSCORE. Rev Bras Cir Cardiovasc. 2012;27(2):xii-xiii.

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Andrade ING,ORIGINAL et al. - Use of EuroSCORE as a predictor of morbidity after ARTICLE cardiac surgery

Use of EuroSCORE as a predictor of morbidity after cardiac surgery Uso do EuroSCORE como preditor de morbidade no pós-operatório de cirurgia cardíaca

Isaac Newton Guimarães Andrade1, MD; Fernando Ribeiro de Moraes Neto2, MD, PhD; Tamirys Guimarães Andrade2, MD

DOI: 10.5935/1678-9741.20140005

RBCCV 44205-1515

Abstract Objective: To evaluate the use of the EuroSCORE as a predictor of postoperative morbidity after cardiac surgery. Methods: We retrospectively analyzed the charts of 900 patients operated on and admitted to the intensive care unit postoperatively at the Royal Portuguese Hospital of Recife. We included all patients with complete medical records, excluding those who died during surgery, underwent transplantation or correction of congenital heart disease. We evaluated the development of respiratory infection, cerebrovascular accident, and dialysis-dependent renal failure, and the EuroSCORE was compared in terms of the three complications using the Mann-Whitney test. The calibration model for predicting the morbidities being studied was evaluated using the test set of Homer-Lemeshow goodness. The accuracy of the model was assessed using the area under the ROC curve (AUROC). Results: The model showed good calibration in predicting

respiratory infection, acute renal failure and stroke (P=0.285, P=0.789, P=0.45, respectively), with good accuracy for respiratory infection (AUROC=0.710 and P<0.001) and dialysis-dependent renal failure (AUROC=0.834 and P<0.001), but no accuracy to predict stroke (AUROC=0.519). The highrisk patients were more likely to develop respiratory infection (OR=9.05, P<0.001) and dialysis-dependent renal failure (OR=39.6, P<0.001). The probability of developing respiratory infection and dialysis-dependent renal failure was less than 10% with EuroSCORE up to 7 and more than 70% with EuroSCORE greater than 15. Conclusion: EuroSCORE proved to be a good predictor of major postoperative morbidity in cardiac surgery: respiratory and dialysis-dependent renal failure.

Institute of Cardiovascular Surgery of Paraíba, Campina Grande, PB, Brazil. Heart Institute of Pernambuco (INCOR-PE), Recife, PE, Brazil.

Correspondence address: Isaac Newton Guimaraes Andrade Rua Capitão João Alves de Lira, 1004 – ap. 1302 – Prata – Campina Grande, PB, Brazil – Zip Code: 58400-560 E-mail: isaacguimaraes@oi.com.br

Descriptors: Risk Assessment. Morbidity. Cardiovascular Surgical Procedures.

1 2

Work carried out at the Royal Portuguese Hospital of Recife, Recife, PE, Brazil.

Article received on May 16th, 2013 Article approved on September 10th, 2013

No financial support.

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Andrade ING, et al. - Use of EuroSCORE as a predictor of morbidity after cardiac surgery

sendo o EuroSCORE comparado em relação às três complicações, usando-se o teste de Mann-Whitney. A calibração do modelo para predição das morbidades estudadas foi avaliado com o teste de ajuste de bondade de Homer-Lemeshow. A acurácia do modelo foi avaliada utilizando-se a área sob a curva ROC (ASROC). Resultados: O modelo apresentou boa calibração na predição de infecção respiratória, insuficiência renal dialítica e acidente vascular cerebral (P=0,285; P=0,789; P=0,45, respectivamente), tendo boa acurácia para infecção respiratória (ASROC =0,710 e P<0,001) e insuficiência renal dialítica (ASROC=0,834 e P<0,001) e sem acurácia para acidente vascular cerebral (ASROC=0,519). Os pacientes de alto risco apresentaram maior chance de desenvolver infecção respiratória (OR=9,05; P<0,001) e insuficiência renal dialítica (OR=39,6; P<0,001). A probabilidade de desenvolver infecção respiratória e insuficiência renal dialítica foi de menos de 10% com EuroSCORE até 7 e de mais de 70% com EuroSCORE maior que 15. Conclusão: O EuroSCORE mostrou-se um bom preditor das principais morbidades pós-operatórias em cirurgia cardíaca: infecção respiratória e insuficiência renal dialítica.

Abbreviations, acronyms & symbols AUROC CVA EuroSCORE DDRF RTI ROC SPSS ITU

Area under the ROC curve Cerebrovascular accident European System for Cardiac Operative Risk Evaluation Dialysis-dependent renal failure Respiratory tract infection Receiver Operating Characteristic Statistical Package for the Social Sciences Intensive therapy unit

Resumo Objetivo: Avaliar o uso do EuroSCORE como preditor de morbidade no pós-operatório de cirurgia cardíaca. Métodos: Foram analisados, retrospectivamente, os prontuários de 900 pacientes operados no Real Hospital Português do Recife e admitidos na unidade de terapia intensiva pós-operatória. Foram incluídos todos os pacientes com prontuários completos, sendo excluídos aqueles que foram a óbito no transoperatório, submetidos a transplante ou a correção de cardiopatia congênita. Foi avaliado o desenvolvimento de infecção respiratória, acidente vascular cerebral e insuficiência renal dialítica,

Descritores: Medição de Risco. Morbidade. Procedimentos Cirúrgicos Cardiovasculares.

INTRODUCTION

ies, there are no specific scores derived from major studies capable of predicting the chances of developing such complications and, hence, capable of predicting morbidity. This study sets out to evaluate the EuroSCORE as a predictor of morbidity, since it is simple and practical, has a reduced number of variables, and is widely used throughout the world, having been validated several times, including in our midst, with good results [11,12].

Risk stratification has become more relevant in cardiac surgery practice with the use of specific scores, which are important tools to measure risk, analyze quality of care, and evaluate costs [1,2]. Thus, several scores have been developed and applied to predict mortality in cardiac surgery [3,4]. Calculating surgical risk, i.e., death, is relatively simple since the response variable “death” is an obvious excluding variable. However, studying causes of death is often a lot more complex as there are multiple variables, making it difficult to develop specific scores to predict mortality. In addition, the relationship between the development of a complication and death does not always hold true; nonetheless, it can prolong hospital stay and change patients’ quality of life [5]. In cardiac surgery, when the following three major events are present, there is greater risk of death: onset of respiratory tract infection (RTI), preoperative cerebrovascular accident (CVA), and dialysis-dependent renal failure (DDRF) [6-9]. Besides being associated with higher mortality rates, those events are the leading cause of readmission to the intensive care unit, increasing hospital costs [10]. Even though it is known that those adverse events can definitely contribute to unfavorable results in cardiac surger-

METHODS This cross-sectional observational study was developed at the Thoracic Surgery Recovery Unit of the Royal Portuguese Hospital of Recife. Medical records of 900 out of 1036 patients operated on from July 1, 2008 to July 30, 2009 were analyzed. Patients with complete medical records were included in the study and patients who died during surgery or who had undergone either cardiac transplant or correction of congenital heart disease were excluded. Data was collected from electronic medical records and inserted into an Excel spreadsheet containing all the variables included in the study. A specific calculator was used to obtain the EuroSCORE, classifying patients into the following three risk groups, according to additive score values: high, medium,

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and low. Variables studied were EuroSCORE values, death, and development of RTI, DDRF or CVA, the occurrence of the latter being considered in the period between surgery and hospital discharge. RTI was diagnosed according to clinical and radiological criteria, and it was confirmed by quantitative culture of tracheal aspirate containing colony counts above one million. Patients who developed the need to have compulsory renal replacement therapy after surgery were considered as having DDRF. Patients with CVA should have their diagnosis confirmed by recent findings of brain damage as evidenced by non-contrast computed tomography scan performed 72 hours after suspicion of the event. Continuous variables were expressed as means and/or medians and standard deviation. Categorical variables were expressed as their relative and absolute frequencies. The non-parametric Mann-Whitney test was applied to compare EuroSCORE in terms of death, CVA, RTI, and DDRF. Calibration of EuroSCORE was measured by the Hosmer-Lemeshow goodness of fit test for logistic regression models, in which response was hospital mortality or morbidities (CVA, RTI, and DDRF) and the independent variable was EuroSCORE. Accuracy was assessed by the area under the ROC curve (receiver operating characteristic curve), built based on sensitivity (correct prediction of death) and 1 – specificity (correct prediction of survival), which were calculated for every score value studied. The relationship between the risk groups classified by the score and the development of the aforementioned complications was measured by chi-square and Fischer’s exact test, as indicated. P-values of P<0.05 were considered statistically significant to reject the null hypothesis. The Statistical Package for the Social Sciences 16.0 (SPSS) was the software used for analysis. The project was approved by the Ethics Committee of the Royal Portuguese Hospital of Recife.

Analysis of the predictive ability of EuroSCORE for morbidities Respiratory tract infection A comparison of score values revealed higher values for patients who developed RTI than those who did not, as shown in Table 2. The predictive model for RTI showed good calibration, as presented in Table 3, and good accuracy, determined by analysis of the area under the ROC curve (Figure 2).

Fig.1 – Characteristics of the sample according to the surgery performed Tipo de cirurgia realizada = surgery performed Valvular isolada = isolated valve Cirurgia da Aorta = Aortic surgery CRM isolada = isolated coronary artery bypass grafting CRM associada = coronary artery bypass grafting associated with another cardiac surgery Outras cirurgias = Another surgeries

RESULTS The sample studied consisted of 900 patients, with a mean age of 57.6 ± 13.9 years, ranging from 11 to 86 years old, and 518 (57.6%) being male. Mean EuroSCORE was 2.76 ± 2.27. Most patients had undergone isolated coronary artery bypass grafting (67%), followed by isolated valve surgery (26%), and coronary artery bypass grafting associated with another cardiac surgery (4%) (Figure 1). Population distribution in the high, medium, and low EuroSCORE risk groups was 12.1%, 38.4%, and 49.4%, respectively. Prevalence of complications was 4.8% and sample mortality was 4.1%. In addition, EuroSCORE values were higher among patients who died. Mortality in the group with complications was significantly higher than in the group without complications (Table 1).

Table 1. Incidence of complications and mortality. Variable Comorbidities RTI DDRF CVA Complications General mortality Mortality in the group without complications Mortality in the group with complications

n (%) 30 (3.3%) 17 (1.9%) 15 (1.7%) 43 (4.8%) 37 (4.1%) 1.8% 47.7%*

* P<0.0001 chi-square. CVA = preoperative cerebrovascular accident; DDRF = dialysis-dependent renal failure; RTI = respiratory tract infection

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Table 2. Comparison of EuroSCORE according to RTI. Death N No 870 Yes 30 Total 900

Mean Median 2.68 2.00 5.13 4.50 2.76 3.00

Standard Deviation Minimum Maximum 2.17 0 15 3.59 0 13 2.27 0 15

P-value < 0.001 (Mann-Whitney test). RTI = respiratory tract infection

Fig. 3 – Graph of the ROC curve for RTI Table 4. Comparison of EuroSCORE according to DDRF. Death N 883 No 17 Yes Total 900

Mean 2.68 6.88 2.76

Median Standard Deviation Minimum Maximum 2.16 0 12 2.00 3.94 1 15 6.00 2.27 0 15 3.00

P-value = 0.001 (Mann-Whitney test). DDRF = dialysis-dependent renal failure Fig. 2 – Comparison of EuroSCORE in patients with and without RTI

Table 3. RTI observed and predicted using EuroSCORE as predicting variable in the groups defined according to the HosmerLemeshow test. Contingency table for the Homer-Lemeshow test

Step 1

1 2 3 4 5 6 7

RTI = no Observed Expected 148 150.583 171 169.740 121 119.746 144 144.162 131 131.065 107 107.205 48 47.499

RTI = yes Observed Expected 4 1.417 1 2.260 1 2.254 4 3.838 5 4.935 7 6.795 8 8.501

Total 152 172 122 148 136 114 56

Chi-square (5) = 6.221 (P-value = 0.285). RTI = respiratory tract infection

Fig. 4 – Comparative Box-plot of EuroSCORE according to DDRF

Dialysis-dependent renal failure Just like RTI, higher EuroSCORE values were found among patients who developed DDRF than in those who did

The area under the ROC curve was 0.710 (CL 95%, 0.600 – 0.821), with P-value<0.001. Results obtained show that EuroSCORE was good in discriminating between patients with and without RTI (Figure 3).

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not develop DDRF, as shown in Table 4 and Figure 4. The predictive model for DDRF showed good calibration, as presented in Table 5, and excellent accuracy, determined by analysis of the area under the ROC curve (Figure 2). The area under the ROC curve was 0.834 (CL 95%, 0.738 – 0.930), with P-value<0.001. Results show that EuroSCORE was good in discriminating between patients with and without DDRF (Figure 5).

accurate to discriminate between patients who did and did not develop CVA in the postoperative period (area under the ROC curve = 0.519), as shown in Figure 3. Analysis of the relationship between the risk group and the chance of developing postoperative complications It was observed that patients in the high-risk group, according to EuroSCORE values, had greater chances of developing RTI (OR: 9.05) and DDRF (OR: 39.96), as presented in Tables 6 and 7. However, the same association could not be said of the occurrence of CVA. Cut-off points for greater specificity and sensitivity for prediction of RTI and DDRF are listed in Table 8. The probability of developing RTI and DDRF based on EuroSCORE was determined, varying from less than 10% to more than 70% (Tables 9 and 10).

Cerebrovascular accident With regard to occurrence of CVA, there was no difference in EuroSCORE values between patients who developed this complication and those who did not (P=0.484; Mann-Whitney test). In terms of the predictive model for this morbidity, despite good calibration (P=0.45), it was not

Table 6. Crossing of EuroSCORE with RTI RTI Total OR Não Sim (CL 95%) Low N 439 6 445 1.0 % 98.7% 1.3% 100.0% 334 12 346 2.63 Risk Medium N Group % 96.5% 3.5% 100.0% (0.98 – 7.08) High N 97 12 109 9.05 % 89.0% 11.0% 100.0% (3.32 – 24.70) P-value < 0.001 (chi-square). RTI = respiratory tract infection

Table 5. DDRF observed and predicted using EuroSCORE as predicting variable in the groups defined according to the Hosmer-Lemeshow test. Contingency table for the Homer-Lemeshow test

Step 1

1 2 3 4 5 6 7

DDRF = no Observed Expected 152 151.723 171 171.467 122 121.358 146 146.681 133 133.951 110 110.209 49 47.611

DDRF = yes Observed Expected 0 0.277 1 0.533 0 0.642 2 1.319 3 2.049 4 3.791 7 8.389

Total 152 172 122 148 136 114 56

Chi-square (5) = 2.419 (P-value = 0.789). DDRF = dialysisdependent renal failure Table 7. Crossing of EuroSCORE and DDRF. RTI Total OR No Yes (CL 95%) Low N 444 1 445 1.0 % 99.8% 0.2% 100.0% Risk Medium N 339 7 346 9.17 Group % 98.0% 2.0% 100.0% (1.1 – 74.9) High N 100 9 109 39.96 % 91.7% 8.3% 100.0% (5.0 – 78.9) P< 0.001. DDRF = dialysis-dependent renal failure

Table 8. Cut-off points and sensitivity and specificity values. Variable Cut-off points Sensitivity Specificity RTI ≥ 3,5 66.7% 67.1% DDRF ≥ 3,5 82.4% 66.9% DDRF = dialysis-dependent renal failure; RTI = respiratory tract infection

Fig. 5 – Graph of the ROC curve for DDRF

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Andrade ING, et al. - Use of EuroSCORE as a predictor of morbidity after cardiac surgery

Table 9. Probability of developing RTI according to EuroSCORE.

Table 10. Probability of developing DDRF according to EuroSCORE.

EuroSCORE 0-7 8-9 10 11 - 12 13 14 15 >15

EuroSCORE 0-7 8-9 10 11 12 13 >14

RTI Probability < 10% 10% - 19% 20 – 29% 30 – 39% 40 – 49% 50 – 59% 60 – 69% ≥ 70%

DDRF Probability < 10% 10% - 19% 20 – 29% 30 – 39% 40 – 59% 60 – 69% ≥ 70%

DDRF = dialysis-dependent renal failure

RTI = respiratory tract infection

0.834, respectively, both statistically significant. In practice, these data translates into good ability to discriminate which patients will definitely develop complications among those with chances of developing them. Similar to the model calibration, the values for predictive ability were significant for both RTI and DDRF. However, the results of the DDRF group were more robust, probably because of better characterization of the patients belonging to that group, and since diagnostic criteria is exclusive, i.e., whether or not the patient developed DDRF, there are no confounding variables in the diagnosis of the complication. The opposite was observed when the score was used to predict CVA. The score was not successful, showing neither effective calibration nor effective predictive ability, probably due to the diagnostic method used: the computed tomography. Even though computed tomography was performed 72 hours after suspected clinical diagnosis, the scan might not show ischemic lesions and nuclear magnetic resonance is more accurate. However, due to the characteristics of the patients, such as hemodynamic instability at the time of the exam, the decision was made not to perform a longer exam that could put the patient at risk. Finally, it is interesting to observe the exponential growth in the chance of developing RTI and DDRF as the EuroSCORE values increase, with sensitivity and specificity cutoff points starting at score 3.5. In patients with EuroSCORE values above this cut-off point, it allows for the possibility of implementing protective measures, directing human and material resources, and defining the best surgical strategy so that the occurrence of complications with potential mortality can be reduced. The results and validations of the EuroSCORE II were published during this study [17-19]; however, we decided to continue using EuroSCORE I because of it has numerous validations, including in our midst, it is easy to use, and it is widely known to all professionals involved in the care of patients undergoing cardiac surgery, such as intensivists, surgeons, and cardiologists. The publication of studies showing the lack of superiority

DISCUSSION The use of risk scores in surgical practice is a valid strategy, not only to measure risk but also to analyze and compare results. Risk scores are related to factors inherent to the model itself, the population for which they were developed, and the characteristics of the population in which they will be applied. As a result, the majority of scores show conflicting results in the prediction of risks. In addition, the large number of variables of a score also reduces its effectiveness when applied to distinct populations [13,14]. On the other hand, scores that are validated in diverse populations, such as the EuroSCORE, tend to show better results. The prevalence of complications (RTI, DDRF, and CVA) was similar to what has been described in the literature. Likewise, general mortality in the sample studied was also similar to previous results, drawing attention to the high mortality rate, an important fact that indicates the importance of both early identification of patients at risk for developing those complications and aggressive intervention to reverse this situation [8,15,16]. Even though the prevalence of complications was similar to what has been described in the literature, the use of strict diagnostic criteria to characterize complications may have left patients who had only clinical diagnoses out of the RTI and CVA groups, which could lead to underdiagnosis of those complications. By using the score to predict RTI, it was observed that patients with higher EuroSCORE values had greater chances of developing a complication, which could be considered an obvious outcome, but the score tool now presents numeric data. The model showed good calibration to that end, especially in patients with medium to high EuroSCORE values. The same findings were obtained when predicting the development of DDRF, with higher values (P=0.789). In terms of discriminating power, assessed by the area under the ROC curve, the model was also deemed adequate, with predicting values for RTI and DDRF of 0.710 and

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of EuroSCORE II over EuroSCORE I [19,20] supports the decision to use EuroSCORE I and emphasizes the need for constant recalibration of risk scores, especially when used in populations other than the ones they were developed for.

8. Riera M, Ibañez J, Herrero J, Ignacio Sáez De Ibarra J, Enríquez F, Campillo C, et al. Respiratory tract infections after cardiac surgery: impact on hospital morbidity and mortality. J Cardiovasc Surg (Torino). 2010;51(6):907-14. 9. Carrascal Y, Guerrero AL. Neurological damage related to cardiac surgery: pathophysiology, diagnostic tools and prevention strategies. Using actual knowledge for planning the future. Neurologist. 2010;16(3):152-64.

CONCLUSION EuroSCORE proved to be a good predictor for major postoperative morbidities in cardiac surgery (RTI and DDRF). However, in this study, it could not predict the development of CVA. The chances of developing RTI and DDRF increase as additive EuroSCORE values increase, making it possible to identify high-risk patients and to start implementing preventive measures and early intervention.

10. Litmathe J, Kurt M, Feindt P, Gams E, Boeken U. Predictors and outcome of ICU readmission after cardiac surgery. Thorac Cardiovasc Surg. 2009;57(7):391-4. 11. Moraes F, Duarte C, Cardoso E, Tenório E, Pereira V, Lampreia D, et al. Avaliação do EuroSCORE, como preditor de mortalidade em cirurgia de revascularização miocárdica no Instituto do Coração de Pernambuco. Rev Bras Cir Cardiovasc. 2006;21(1):29-34.

Authors’ roles & responsibilities INGA FRMN TGA

Main author Coordination of data collection, data and bibliographic referencesorganization Tabulation and organization of data, partial drafting of the final text

12. Andrade ING, Moraes Neto FR, Oliveira JPSP, Silva ITC, Andrade TG, Moraes CRR. Avaliação do EuroSCORE como preditor de mortalidade em cirurgia cardíaca valvar no Instituto do Coração de Pernambuco. Rev Bras Cir Cardiovasc. 2010;25(1):11-8. 13. Geissler HJ, Hölzl P, Marohl S, Kuhn-Régnier F, Mehlhorn U, Südkamp M, et al. Risk stratification in heart surgery: comparison of six score systems. Eur J Cardiothorac Surg. 2000;17(4):400-6.

REFERENCES

14. Ivanov J, Borger MA, Rao V, David TE. The Toronto Risk Score for adverse events following cardiac surgery. Can J Cardiol. 2006;22(3):221-7.

1. Granton J, Cheng D. Risk stratification models for cardiac surgery. Semin Cardiothorac Vasc Anesth. 2008;12(3):167-74.

15. Hobson CE, Yavas S, Segal MS, Schold JD, Tribble CG, Layon AJ, et al. Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation. 2009;119(18):2444-53.

2. Litmathe J, Kurt M, Feindt P, Gams E, Boeken U. Predictors and outcome of ICU readmission after cardiac surgery. Thorac Cardiovasc Surg. 2009;57(7):391-4. 3. Geissler HJ, Hölzl P, Marohl S, Kuhn-RégnieR F, Mehlhorn U, Südkamp M, et al. Risk stratification in heart surgery: comparison of six score systems. Eur J Cardiothorac Surg. 2000;17(4):400-6.

16. Guaragna JCVC, Bolsi DC, Jaeger CP, Melchior R, Petracco JB, Facchi LM, et al. Preditores de disfunção neurológica maior após cirurgia de revascularização miocárdica isolada. Rev Bras Cir Cardiovasc. 2006;21(2):173-9.

4. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9-13.

17. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al. EuroSCORE II. Eur J Cardiothorac Surg. 2012;41(4):734-44.

5. Shroyer AL, Coombs LP, Peterson ED, Eiken MC, DeLong ER, Chen A, et al; Society of Thoracic Surgeons. The Society of Thoracic Surgeons: 30-day operative mortality and morbidity risk models. Ann Thorac Surg. 2003;75(6):1856-64.

6. Hobson CE, Yavas S, Segal MS, Schold JD, Tribble CG, Layon AJ, et al. Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation. 2009;119(18):2444-53.

19. Noyez L, Kievit PC, van Swieten HA, de Boer MJ Cardiac operative risk evaluation: The EuroSCORE II, does it make a real difference? Neth Heart J. 2012;20(12):494-8.

7. Ngaage DL, Cowen ME, Griffin S, Guvendik L, Cale AR. Early neurological complications after coronary artery bypass grafting and valve surgery in octogenarians. Eur J Cardiothorac Surg. 2008;33(4):653-9.

20. Poullis M, Fabri B, Pullan M, Chalmers J. Sampling time error in EuroSCORE II. Interact Cardiovasc Thorac Surg. 2012;14(5):640-1.

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Adademir T, etORIGINAL al. - SurgicalARTICLE treatment of aortic valve endocarditis: a 26-year experience

Surgical treatment of aortic valve endocarditis: a 26-year experience Tratamento cirúrgico da endocardite da válvula aórtica: 26 anos de experiência

Taylan Adademir1, MD; Eylem Yayla Tuncer1, MD; Serpil Tas1, MD; Arzu Antal Donmez1, MD; Ebru Bal Polat2, MD; Altug Tuncer1, MD

DOI: 10.5935/1678-9741.20140006

RBCCV 44205-1516

Abstract Objective: We have retrospectively analyzed the results of the operations made for aortic valve endocarditis in a single center in 26 years. Methods: From June 1985 to January 2011, 174 patients were operated for aortic valve endocarditis. One hundred and thirty-eight (79.3%) patients were male and the mean age was 39.3±14.4 (9-77) years. Twenty-seven (15.5%) patients had prosthetic valve endocarditis. The mean duration of follow-up was 7.3±4.2 years (0.1-18.2) adding up to a total of 1030.8 patient/ years. Results: Two hundred and eighty-two procedures were performed. The most frequently performed procedure was aortic valve replacement with mechanical prosthesis (81.6%). In-hospital mortality occurred in 27 (15.5%) cases. Postoperatively, 25 (14.4%) patients had low cardiac output and 17 (9.8%) heart block. The actuarial survival rates for 10 and 15 years were 74.6±3.7% and 61.1±10.3%, respectively. In-hospital mortality was found to be associated with female gender, emergency

operation, postoperative renal failure and low cardiac output. The long term mortality was significantly associated with mitral valve involvement. Male gender was found to be a significant risk factor for recurrence in the follow-up. Conclusion: Surgery for aortic valve endocarditis has significant mortality. Emergency operation, female gender, postoperative renal failure and low cardiac output are significant risk factors. Risk for recurrence and need for reoperation is low.

Kartal Kosuyolu Heart and Research Hospital, Department of Cardiovascular Surgery, Istanbul, Turkey. 2 Bakirkoy Dr Sadi Konuk Training and Research Hospital, Department of Cardiovascular Surgery, Istanbul, Turkey.

Correspondence address: Taylan Adademir Kartal Kosuyolu Heart and Research Hospital Denizer Caddesi Cevizli Kavşağı, 2 – Cevizli/Kartal – İstanbul, Turkey – Zip code: 34000 E-mail: taylanadademir@gmail.com

Descriptors: Treatment Outcome. Aortic Valve. Endocarditis. Resumo Objetivo: Analisamos, retrospectivamente, os resultados das operações realizadas para endocardite valvar aórtica em um único centro em 26 anos. Métodos: De junho de 1985 a janeiro de 2011, 174 pacientes foram operados por endocardite da válvula aórtica. Cento e trinta e oito (79,3%) pacientes eram do sexo masculino e a

This study carried out at Kartal Kosuyolu Heart and Research Hospital, Department of Cardiovascular Surgery, Istanbul, Turkey.

Article received on June 29th, 2013 Article accepted on September 10th, 2013

No financial support.

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Adademir T, et al. - Surgical treatment of aortic valve endocarditis: a 26-year experience

intra-hospitalar ocorreu em 27 (15,5%) casos. No pósoperatório, 25 (14,4% ) pacientes apresentaram baixo débito cardíaco e 17 (9,8%) bloqueio cardíaco . As taxas de sobrevida atuarial para 10 e 15 anos foram 74,6±3,7% e 61,1±10,3%, respectivamente. A mortalidade intra-hospitalar foi encontrada esteve associada com o sexo feminino, operação de emergência, insuficiência renal pós-operatória e baixo débito cardíaco. A mortalidade a longo prazo foi significativamente associada com o envolvimento da válvula mitral. O sexo masculino encontrado mostrou-se um fator de risco para a recorrência no seguimento. Conclusão: A cirurgia para tratamento da endocardite da válvula aórtica apresenta mortalidade. Operação de emergência, o sexo feminino, insuficiência renal pós-operatória e baixo débito cardíaco são fatores de risco significativos. O risco de recorrência e necessidade de reoperação são baixos.

Abbreviations, acronyms & symbols CI IE LCO NVE OR PPL PVE SPSS

Confidence interval Infective endocarditis Low cardiac output Native valve endocarditis Odds ratio Periprosthetic leakage Prosthetic valve endocarditis Statistical Package for the Social Sciences

média de idade foi de 39,3 ± 14,4 (9-77) anos. Vinte e sete (15,5%) pacientes apresentavam endocardite na prótese valvar. O tempo médio de acompanhamento foi de 7,3 ± 4,2 anos (0,118,2) totalizando 1.030,8 paciente/ano . Resultados: Duzentos e oitenta e dois procedimentos foram realizados. O procedimento mais realizado foi a substituição da valva aórtica por prótese mecânica (81,6 %). A mortalidade

Descritores: Resultado de Tratamento. Valva Aórtica. Endocardite.

INTRODUCTION

METHODS

Microbial infection of the endothelial lining of any part of the heart, infective endocarditis (IE), is an uncommon but life threatening condition. Despite advances in diagnosis, antimicrobial therapy, surgical techniques, and management of complications, the incidence has not decreased in the past 30 years and patients with IE still have high morbidity and mortality rates related to this condition [1]. Its management aims to eradicate the infecting organism as soon as possible mainly with antibioticotherapy but clinical complications and treatment failure suggest surgery up to 60% of the cases [2]. IE effecting aortic valve accounts about 40-67% of all cases and about 60-70% of these cases undergo surgery in the acute phase [3]. In spite of the high mortality and morbidity it carries, surgical therapy is still the mainstay in the treatment of aortic valve IE. Numerous studies have assessed different risk factors for mortality and morbidities in the treatment of IE but risk factors for surgical treatment of aortic valve IE patients need to be clarified. In this study, we have retrospectively assessed the results of the surgical treatment of patients with aortic valve endocarditis over a period of 26 years in an attempt to address these issues.

The study was approved by the local hospital ethics committee. The patient data were collected from the hospital records retrospectively. From June 1985 to January 2011, 174 consecutive patients with aortic valve endocarditis underwent surgery at our institution. For the definitions of active, healed, native, and prosthetic and culture negative endocarditis, modified Aranki criteria have been used [4]. The presence of acute or chronic inflammatory changes at microscopy confirmed the diagnosis of endocarditis. There were 138 (79.3%) male and 36 (20.7%) female patients aged 39.3±14.4 (9-77) years in average. One hundred and forty-seven (84.5%) patients were presented with native valve endocarditis (NVE) and 27 (15.5%) with prosthetic valve endocarditis (PVE). Vegetations on the mitral valve were detected in 38 (21.8%) cases and peri-prosthetic leakage (PPL) was present in 13 patients. Thirty-two (18.4%) patients had a history of previous cardiac surgery and four of them had two cardiac operations previously. Coronary angiography was rarely performed in order to avoid any embolic complications. Of the 27 patients with septic emboli, one of them had both peripheral and central emboli preoperatively. The preoperative characteristics are summarized in Table 1.

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Adademir T, et al. - Surgical treatment of aortic valve endocarditis: a 26-year experience

Table 1. Preoperative characteristics. Preoperative characteristic Age Male / Female Fever Septic emboli Central Peripheral NYHA Class Class I Class II Class III Class IV Congestive heart failure Renal dysfunction Periprosthetic leakage Previous cardiac surgery Mitral valve involvement Aortic annulus involvement Prosthetic valve endocarditis Operation in the active phase Culture positive endocarditis LVD (EF<40%) Emergency operation ECG Sinus rhythm AF AV block LBBB RBBB

n (%) or mean±SD 39.3±14.4 138 (79.3%) / 36 (20.7%) 97 (55.7%) 27 (15.5%) 14 (8.0%) 14 (8.0%) 15 (8.6%) 64 (36.8%) 74 (42.5%) 21 (12.1%) 97 (55.7%) 15 (8.6%) 13 (7.5%) 32 (18.4%) 72 (41.4%) 42 (24.1%) 27 (15.5%) 84 (48.3%) 92 (52.9%) 11 (6.3%) 26 (14.9%)

P1 ns 0.022 ns ns

P2 ns 0.034 ns ns

P3 ns ns ns ns

P4 ns ns

ns ns ns ns ns ns ns ns ns

ns ns

0.003

ns 0.009 ns ns ns ns ns ns

154 (88.5%) 13 (7.5%) 4 (2.3%) 2 (1.1%) 1 (0.6%)

AF= Atrial fibrillation; AV= Atrioventricular; ECG= Electrocardiography; LBBB= Left bundle branch block; LVD= Left ventricular dysfunction; NYHA= New York Heart Association; RBBB= Right bundle branch block; SD= Standard deviation; ns= Not Significant. P1: Statistical significance for in-hospital mortality in logistic regression analysis. P2: Statistical significance for recurrence in logistic regression analysis. P3: Statistical significance for reoperation in logistic regression analysis. P4: Statistical significance for late mortality in logistic regression analysis

of the microbiologic studies can be seen in Table 2. The diagnosis of IE was performed according to the Duke criteria [5]. All patients were examined by transthoracic or transesophageal echocardiography. Valvular destruction was evident in 120 (69.0%) cases and aortic annular involvement was present in 42 (24.1%) cases. Gross vegetations on aortic valves were detected in 25 (14.4%) patients and vegetations on mitral valve in 38 (21.8%) cases preoperatively. Operations were performed during the active phase of infection in 84 (48.3%) patients. The indications for emergency surgery were high as well as mobile vegetations on the aortic valve, acute leaflet rupture and cardiac decompensation, periannular extensive abscess with intracardiac fistula and prosthetic valve dysfunction.

Table 2. Culture results. Microorganism Culture negative Streptococcus Staphylococcus Brucella MRSA Acinetobacter E. Coli Enterobacter

n (%) 82 (47.1%) 51 (29.3%) 23 (13.2%) 11 (6.3%) 4 (2.3%) 1 (0.6%) 1 (0.6%) 1 (0.6%)

MRSA: Methicillin resistant Staphylococcus aureus; E. coli: Escherichia coli

Culture-negative endocarditis was present when no microorganism could be identified either on serial blood cultures or on cultures from the explanted valvular tissue in patients presenting with the clinical picture of endocarditis. The results

Operative technique All patients underwent moderate (28°C) hypothermic cardiopulmonary bypass by means of bicaval cannulation with cannulation of either the ascending aorta (169 patients) or

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the femoral artery (5 patients). The left ventricle was vented through the right superior pulmonary vein. Isothermic blood cardioplegic solution was administered via antegrade and retrograde route during aortic cross-clamping. For eradication of the aortic valve endocarditis, radical debridement of all the necrotic and infected tissues was performed. In cases with annular involvement, aortic annulus was skeletonized. All infected and necrotic tissue around the annulus and when present, within the abscess and fistula between the ventriculoarterial junction and the sinotubular junction were resected. All vegetations were removed. When the aortic valve was not extensively dam-

aged, vegetectomy and reconstruction either primary or by using pericardial patch was preferred as described before [6]. Before cardiopulmonary bypass, a patch was harvested from the pericardium, stabilized with 0.62% glutaraldehyde solution for 5 minutes, and rinsed thoroughly with 0.9% saline solution. When necessary, the pericardial strip trimmed to an appropriate length and was sutured continuously with 5-0 polypropylene according to the area to be patched. The completely resected annular area was covered with the glutaraldehyde-treated autologous pericardial patch sutured to firm, fibrous tissue for a secure anastomosis or valve implantation [6,7].

Table 3. Procedures. Procedures Aortic valve replacement Redo AVR AVR with bioprosthesis Aortic reconstruction Primary repair of periprosthetic leak Aortic root replacement Bentall de Bono procedure Xenograft implantation Homograft implantation Cabrol procedure Aortic root enlargement Fistula repair Patch repair of a sinus Valsalva aneurysm repair Subaortic discrete membrane resection Aortic vegetectomy Drainage of subaortic abscess and patch repair Septal vegetectomy Patch repair of an ascending aortic pseudoaneurysm Graft interposition in the ascending aorta Patch repair of a ventricular septal defect Mitral valve procedures Mitral valve replacement Redo mitral valve replacement Mitral reconstruction Primary repair of periprosthetic leak Vegetectomy of mitral leaflets Tricuspid De Vega annuloplasty Coronary artery bypass grafting Primary repair of atrial septal defect Closure of patent ductus arteriosus Femoral embolectomy Pericardiectomy Concomitant procedure

n (%)* 142 (81.6%) 13 (7.5%) 2 (1.1%) 3 (1.7%) 4 (2.3%) 22 (12.6%) 10 (5.7%) 6 (3.4%) 5 (2.9%) 1 (0.6%) 1 (0.6%) 6 (3.4%) 4 (2.3%) 4 (2.3%) 3 (1.7%) 2 (1.1%) 1 (0.6%) 1 (0.6%) 1 (0.6%) 6 (3.4%) 72 (41.4%) 55 (31.6%) 4 (2.3%) 14 (8.0%) 2 (1.1%) 1 (0.6%) 3 (1.7%) 2 (1.1%) 2 (1.1%) 1 (0.6%) 1 (0.6%) 1 (0.6%) 81 (46.6%)

0.971

0.205

0.237

*Percentages are the ratio to the number of patients. AVR: Aortic valve replacement. P1: Statistical significance for in-hospital mortality in logistic regression analysis. P2: Statistical significance for recurrence in logistic regression analysis. P3: Statistical significance for reoperation in logistic regression analysis. P4: Statistical significance for late mortality in logistic regression analysis

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Mitral valve involvement was present in 72 (41.4%) cases. Two hundred and eighty-two procedures were performed on 174 patients. The list of procedures can be seen in Table 3. In the cases with aortic PPL, all prostheses were replaced except for four patients that had a primary repair of the periprosthetic leak. Primary repair of the mitral PPL was preferred in two cases.

involvement, valvular destruction, emergency operation, postoperative heart block, postoperative renal dysfunction, postoperative fever and low cardiac output (LCO). The independent variables for late mortality were previous cardiac surgery, septic emboli, preoperative renal dysfunction, congestive heart failure, culture-negative endocarditis, and left ventricular dysfunction, operation during active phase of infection, aortic annular involvement, mitral valve involvement, emergency operation, postoperative heart block, postoperative fever, PVE, recurrence and reoperation. Age and gender adjustments were made. The survival comparisons were made with log-rank test. P values less than 0.05 were accepted as statistically significant differences.

Follow-up All patients received at least four weeks of antibiotherapy postoperatively. Broad range antibiotics (vancomycin and aminoglycosides) were preferred in culture-negative cases. Antibiotics were arranged according to the antibiograms results in culture-positive patients. After the patients were discharged from the hospital, they were involved in a follow-up program in the outpatient clinic. Follow-up was complete in 95.2% of the patients. Seven patients were lost to follow-up. The mean duration of follow-up was 7.3Âą4.2 years (0.1-18.2) adding up to a total of 1030.8 patient/years.

RESULTS Mortality Twenty-seven (15.5%) patients had in-hospital mortality. Fourteen were female and 11 had PVE. The reasons for mortality are outlined in Table 4. Emergency operation (OR=4.40; 95% CI: 1.68-11.51; P=0.003), postoperative LCO (OR=1.19; 95% CI: 1.78-76.92; P=0.011), postoperative renal failure (OR=7.52; 95% CI: 1.22-45.45; P=0.030) and female gender (OR=5.62; 95% CI: 1.28-25.00; P=0.022) were associated with in hospital mortality in regression analysis.

Statistical analysis The statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) 16.0 statistical software package. All continuous variables were expressed as mean Âą standard deviation with the ranges and discrete variables as frequencies and percentages. Comparisons of the discrete variables were made by chi-square test or Fisherâ&#x20AC;&#x2122;s Exact test where appropriate. The survival, freedom from recurrence and reoperation analyses was made with Kaplan Meier analysis. Logistic regression analyses were performed for the factors affecting early and late mortality, recurrence and reoperation. The independent variables for in hospital mortality, recurrence and reoperation were concomitant non-aortic procedure, previous cardiac surgery, septic emboli, preoperative fever, preoperative renal dysfunction, congestive heart failure, PPL, culture-negative endocarditis, operation during active phase, PVE, aortic annular involvement, mitral valve

Morbidity Postoperative fever was found in 45 (25.9%) patients. Twenty-five (14.4%) patients had LCO and 18 cases in this group died in the postoperative follow-up. Complete heart block was present in 17 (9.8%) patients, but only four (2.3%) patients required permanent pacemaker implantation. Four of these patients had complete heart block preoperatively. Three of these patients had PVE and 6 had aortic annular involvement. Five patients with postoperative heart block died in the early postoperative period. Renal dysfunction was

Table 4. Operative variables and postoperative morbidity. Perioperative characteristic Postoperative fever Postoperative atrioventricular block Low cardiac output Renal failure Need for dialysis Valvular destruction Recurrence during follow-up Reoperation during follow-up

n (%) 45 (25.9%) 17 (9.8%) 25 (14.4%) 34 (19.5%) 12 (6.9%) 120 (69.0%) 10 (5.7%) 8 (4.6%)

P1 ns ns 0.011 0.030

P2 ns ns ns ns

P3 ns ns ns ns

P4 ns ns

ns ns

ns: Not Significant. P1: Statistical significance for in-hospital mortality in logistic regression analysis. P2: Statistical significance for recurrence in logistic regression analysis. P3: Statistical significance for reoperation in logistic regression analysis. P4: Statistical significance for late mortality in logistic regression analysis

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present in 34 (19.5%) patients and 12 (6.9%) required dialysis. Pulmonary morbidity was present in 24 (13.8%) patients. Cerebrovascular events occurred in 8 (4.6%) patients. Seven of these cases underwent surgery in the active phase of infection. Septic central emboli were present in two cases preoperatively. Seventy-three (42%) patients had ≥2 morbidity postoperatively. Postoperative morbidity has been outlined in Table 5. Follow-up Follow-up was complete in 140 (95.2%) cases. Seven patients were lost to follow-up. Fourteen (8%) patients had mortality after discharge. Three of them were female. The data of the patients with early and late mortality have been summarized in Table 5. Table 5. Patients with mortality. Etiology for mortality Hospital mortality Low cardiac output Low cardiac output + sepsis Sepsis Pulmonary complication Sudden death Late mortality Cardiac Extracardiac

Fig. 1 – Actuarial survival curve

n (%) 27 15 (55.6%) 7 (25.9%) 3 (11.1%) 1 (3.7%) 1 (3.7%) 14 8 (57.1%) 6 (42.9%)

The actuarial survival rates for 1, 5, 10 and 15 years were 80.8%±3%, 77.4%±3.3%, 74.6±3.7% and 61.1±10.3%, respectively (Figure 1). The logistic regression analysis showed that mitral valve involvement (OR=45.45; 95% CI: 2.56-1000.00; P=0.009) was associated with long term mortality and the significance persisted after adjustment for sex and age. The difference in the actuarial survival rates in patients with and without mitral valve involvement were also statistically significant (P=0.0001). The 1, 5, 10 and 15 years survival rates for patients with mitral valve involvement were 96.6%±2.4%, 84.6%±5%, 77.5%±6.7% and 51.7%±16.7%, respectively. The 1 and 5 years survival rates for patients without mitral valve involvement were 98.8%±1.2% and 97.4%±1.8% and remained stable for the following term (Figure 2). Recurrence of infection occurred in 10 (5.7%) cases and reoperations were performed in 8 (4.6%). The rates of freedom from recurrence from infection at 1 and 5 years were 94.7%±1.8% and 93.1%±2.1% (Figure 3). The rates of freedom from reoperation at 1 and 5 years were 96.1%±1.6% and 94.5%±1.9%, respectively (Figure 4). Male gender was significantly associated with recurrence (OR=9.35; 95% CI: 1.41-16.85; P=0.034), however, none of the factors were found to be associated with reoperation.

Fig. 2 – Actuarial survival curve for patients with and without mitral valve involvement

Fig. 3 – Survival free from recurrence

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poor outcomes were also reported by Revilla et al. [18]. They found that the poor outcomes were associated with persistent infection and renal failure but not with heart failure. More recently, Koeda et al. [12] reported even mild renal dysfunction at the time of admission as an important predictor of early mortality. However, we did not detect any association of renal failure and mortality. Female gender was significantly associated with in-hospital mortality in our analysis like others [19,20]. LCO and postoperative renal dysfunction were found to be associated with in-hospital mortality which suggests that cardiorenal interaction may play an important role in the deterioration of IE. Their associations with postoperative mortality were similar to a recent reports [9,10,21]. Operation in the active phase was not a significant factor for any dependent variable in our analyses (Table 1). Although the relation is not so obvious, it may still be a risk factor for in-hospital mortality. The high rate of active phase operations (almost 50%) in this cohort could be understood this way. The primary aim of surgery is the eradication of infective tissue and the reconstruction of cardiac morphology. Mode of surgery (replacement/repair) or the type of prosthesis (mechanical/ biologic) was reported to have no influence on mortality [19,22]. Although biological solution is recommended especially for aortic root involvement [23], biological prostheses, especially allografts were reported to have a significant reoperation rate which increases with time [24]. We used mechanical prosthesis in the majority of the patients. The low recurrence and reoperation rates in this study confirm our preference for the valve substitute. The long-term survival given in this report is compatible with recent reports [9,11]. One of the most interesting results of our analysis was the significant lower survival in patients with mitral valve involvement. The regression analysis revealed that presence of mitral valve involvement was significantly associated with long-term mortality (Table 1) and this association was confirmed by the Kaplan Meier analysis results (Figure 2). Multivalve involvement association with higher mortality was reported before [10], but the lower survival was not mentioned. The most possible explanation may be the extent of the destruction by the infectious process. In the analysis of patients with double valve endocarditis, Gillinov et al. [25] report that increasing age was significantly associated with lower long term survival. Age was not a significant predictor in our analysis. One of the most important aspects of surgery for IE is the recurrence. The recurrence was 5.7% in our patient group (Table 4). The rate of recurrence is similar to others [26] and the recurrence-free survival is very satisfactory (Figure 3). The only significant association with recurrence was male gender (Table 1). The reoperation-free survival rates were also satisfactory. These satisfactory results were due to the high rate of mechanical valve utilization according to our

Fig. 4 â&#x20AC;&#x201C; Survival free from reoperation

DISCUSSION Aortic valve endocarditis is mainly managed surgically since 1965 [8]. The disease is highly fatal for the potential consequences of sepsis and cardiac dysfunction. This study is a report of a single institution experience for aortic valve endocarditis over 26 years. The majority of the cases were operated for aortic valve replacement with mechanical prosthesis. Despite the advances in the operative and postoperative techniques, surgery is still associated with a significant mortality rate. The latest study about the results of surgery for IE in America reports 17% overall mortality [9]. There is a wide range of variation in mortality rates ranging from 6% to 33% [2,10-14]. We have previously reported 12% mortality for active IE [15]. The slight increase (15.5%) was mainly because of the patient profile. In our previous report, congestive heart failure was present in less than 40% of the cases, however, in this group, more than 55% of the cases had congestive heart failure. Another striking difference is the lack of PVE cases in the previous report. In fact, regression analysis did not give PVE as a risk factor for in-hospital mortality. Delay et al. [16] did not observe significant differences as well. A recent study from Sweden reported 30-days mortality for surgically treated native and PVE as 5.2% and 14.7% respectively, but did not mention PVE as a risk factor [13]. However, it may affect the overall mortality in many different ways. Especially the preoperative status is an important factor. Another important determinant was emergency operation. The significant association of emergency operation and in-hospital mortality was not unexpected. Kirali et al. [15] reported significant association of urgent operations in NVE before. The indications for emergency operation in IE were documented with high level of evidence [17]. The

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point of view. This fact was also discussed by others [19,24]. Fedoruk and colleagues reported that type of prosthesis did not affect survival and recurrence rates were primarily associated with human immunodeficiency virus infection and intravenous drug usage [27]. None of the patients in our cohort had such history. Most important feature in preventing recurrence is complete debridement [28]. The low rates of recurrence and reoperation confirm the completeness of the debridement. The most important drawback of our study is the high rate of culture negative cases. Although no associations with mortality and morbidity were revealed (Table 1), this high negative culture results necessitates further attention. The most frequently growing bacteria was streptococcus (Table 2) in this group, however, we could not reach to further conclusions due to the high rate of negative cultures. In the literature, 20% to 60% incidence of negative culture results have been reported [14,29]. Even United States reported 69.4% positive culture rates using Nationwide Inpatent Sample. High rate of unknown cultures (30.6%) was explained by coding error [30]. Several factors may cause the lack of isolation of microorganisms from the blood like healed endocarditis, broad range antibiotic therapy, low-virulence germs and poor blood sampling [8]. Also, we did not make serological testing for some rare bacteria which could further lower the culture negative rates. Another important limitation is the retrospective nature of the study. We tried to neutralize this fact by detailed multivariable analyses.

REFERENCES 1. Bashore TM, Cabell C, Fowler V Jr. Update on infective endocarditis. Curr Probl Cardiol. 2006;31(4):274-352. 2. Nakatani S, Mitsutake K, Ohara T, Kokubo Y, Yamamoto H, Hanai S; CADRE Investigators. Recent picture of infective endocarditis in Japan: lessons from Cardiac Disease Registration (CADREIE). Circ J. 2013;77(6):1558-64. 3. Nguyen DT, Delahaye F, Obadia JF, Duval X, Selton-Suty C, Carteaux JP, et al; AEPEI study group. Aortic valve replacement for active infective endocarditis: 5-year survival comparison of bioprostheses, homografts and mechanical prostheses. Eur J Cardiothorac Surg. 2010;37(5):1025-32. 4. Aranki SF, Santini F, Adams DH, Rizzo RJ, Couper GS, Kinchla NM, et al. Aortic valve endocarditis. Determinants of early survival and late morbidity. Circulation. 1994;90(5 Pt 2): II175-82. 5. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med. 1994;96(3):200-9. 6. Bozbuga N, Erentug V, Erdogan HB, Kirali K, Ardal H, Tas S, et al. Surgical treatment of aortic abscess and fistula. Tex Heart Inst J. 2004;31(4):382-6. 7. Kirali K, Omeroglu SN, Mansuroglu D, Ipek G, Yakut C. Aortic root abscess with fistula formation into right ventricular myocardium. Türk Kardiyol Dern Arş. 2000;28:647-9.

CONCLUSION

8. Wallace AG, Young WG Jr, Osterhout S. Treatment of acute bacterial endocarditis by valve excision and replacement. Circulation. 1965;31:450-3.

In conclusion, surgery for aortic valve endocarditis was associated with significant mortality. Emergency operation, female gender, postoperative renal failure and LCO are significant risk factors for in-hospital mortality. Operation in the active phase of infection was a risk factor for in-hospital mortality as it constitutes a significant risk factor for postoperative LCO. Male gender was a predictor for recurrence but no risk factors were found to be significant for reoperation. In the surviving patients, risk for recurrence and need for reoperation was low. Long term survival was lower in patients who had mitral valve involvement.

9. Machado MN, Nakazone MA, Murad-Júnior JA, Maia LN. Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center. Rev Bras Cir Cardiovasc. 2013;28(1):2935. 10. Gaca JG, Sheng S, Daneshmand MA, O’Brien S, Rankin JS, Brennan JM, et al. Outcomes for endocarditis surgery in North America: a simplified risk scoring system. J Thorac Cardiovasc Surg. 2011;141(1):98-106.e1-2. 11. Prendergast BD, Tornos P. Surgery for infective endocarditis: who and when? Circulation. 2010;121(9):1141-52. 12. Koeda C, Tashiro A, Itoh T, Okabayashi H, Nakamura M. Mild renal dysfunction on admission is an important prognostic predictor in patients with infective endocarditis: a retrospective single-center study. Intern Med. 2013;52(10):1013-8.

Authors’ roles & responsibilities TA Writer EYT Co-writer ST Collecting and Analyzing Data AAD Collecting and Analyzing Data EBP Analyzing Data AT Final control of the study

13. Ternhag A, Cederström A, Törner A, Westling K. A nationwide cohort study of mortality risk and long-term prognosis in infective endocarditis in Sweden. PLoS One. 2013;8(7):e67519.

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14. Elbey MA, Akdag S, Kalkan ME, Kaya MG, Sayin MR, Karapınar H, et al. A multicenter study on experience of 13 tertiary hospitals in Turkey in patients with infective endocarditis. Anadolu Kardiyol Derg. 2013;13(6):523-7.

Cardiothorac Surg. 1998;14(2):156-64. 23. Dossche K, Brutel de la Rivière A, Morshuis W, Schepens M, Ernst J. Aortic root replacement with human tissue valves in aortic valve endocarditis. Eur J Cardiothorac Surg. 1997;12(1):47-55.

15. Kirali K, Guler M, Yakut N. Combined medical and surgical treatment for active native valve infective endocarditis: ten-year experience. Turk Kardiyol Dern Arş. 2001;29:543-8.

24. Klieverik LM, Yacoub MH, Edwards S, Bekkers JA, RoosHesselink JW, Kappetein AP, et al. Surgical treatment of active native aortic valve endocarditis with allografts and mechanical prostheses. Ann Thorac Surg. 2009;88(6):1814-21.

16. Delay D, Pellerin M, Carrier M, Marchand R, Auger P, Perrault LP, et al. Immediate and long-term results of valve replacement for native and prosthetic valve endocarditis. Ann Thorac Surg. 2000;70(4):1219-23.

25. Gillinov AM, Diaz R, Blackstone EH, Pettersson GB, Sabik JF, Lytle BW, et al. Double valve endocarditis. Ann Thorac Surg. 2001;71(6):1874-9.

17. Delahaye F, Célard M, Roth O, de Gevigney G. Indications and optimal timing for surgery in infective endocarditis. Heart. 2004;90(6):618-20.

26. Heiro M, Helenius H, Mäkilä S, Hohenthal U, Savunen T, Engblom E, et al. Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980-2004. Heart. 2006;92(10):1457-62.

18. Revilla A, López J, Vilacosta I, Villacorta E, Rollán MJ, Echevarría JR, et al. Clinical and prognostic profile of patients with infective endocarditis who need urgent surgery. Eur Heart J. 2007;28(1):65-71.

27. Fedoruk LM, Jamieson WR, Ling H, Macnab JS, Germann E, Karim SS, et al. Predictors of recurrence and reoperation for prosthetic valve endocarditis after valve replacement surgery for native valve endocarditis. J Thorac Cardiovasc Surg. 2009;137(2):326-33.

19. Avierinos JF, Thuny F, Chalvignac V, Giorgi R, Tafanelli L, Casalta JP, et al. Surgical treatment of active aortic endocarditis: homografts are not the cornerstone of outcome. Ann Thorac Surg. 2007;84(6):1935-42. 20. Wallace SM, Walton BI, Kharbanda RK, Hardy R, Wilson AP, Swanton RH. Mortality from infective endocarditis: clinical predictors of outcome. Heart. 2002;88(1):53-60.

28. Renzulli A, Carozza A, Romano G, De Feo M, Della Corte A, Gregorio R, et al. Recurrent infective endocarditis: a multivariate analysis of 21 years of experience. Ann Thorac Surg. 2001;72(1):39-43.

21. Costa MA, Wollmann DR Jr, Campos AC, Cunha CL, Carvalho RG, Andrade DF, et al. Risk index for death by infective endocarditis: a multivariate logistic model. Rev Bras Cir Cardiovasc. 2007;22(2):192-200.

29. Renzulli A, Carozza A, Marra C, Romano GP, Ismeno G, De Feo M, et al. Are blood and valve cultures predictive for long-term outcome following surgery for infective endocarditis? Eur J Cardiothorac Surg. 2000;17(3):228-33.

22. Edwards MB, Ratnatunga CP, Dore CJ, Taylor KM. Thirty-day mortality and long-term survival following surgery for prosthetic endocarditis: a study from the UK heart valve registry. Eur J

30. Bor DH, Woolhandler S, Nardin R, Brusch J, Himmelstein DU. Infective endocarditis in th U.S., 1998-2009: a nationwide study. PLoS One. 2013;8(3):e60033.

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Leão SC, et al.ORIGINAL - IL-10 and ET-1 as biomarkers of rheumatic valve disease ARTICLE

IL-10 and ET-1 as biomarkers of rheumatic valve disease IL-10 e ET-1 como biomarcadores de doença valvar reumática

Sydney Correia Leão1, MD; Maria Regina Menezes Lima1, MSc; Hertaline Menezes do Nascimento1, MSc; Shirlei Octacilio-Silva1, MSc, PhD; Tania Maria de Andrade Rodrigues1, MD, MSc, PhD

DOI: 10.5935/1678-9741.20140007

RBCCV 44205-1517

Abstract Objective: To evaluate the immunological profile and gene expression of endothelin-1 (ET-1) in mitral valves of patients with rheumatic fever originated from a reference service in cardiovascular surgery. Methods: This was a quantitative, observational and cross-sectional study. Thirty-five subjects (divided into four groups) participated in the study, 25 patients with chronic rheumatic heart disease and ten control subjects. The mean age of the sample studied was 34.5 years. Seventeen of them (48.58%) were male and 18 (51.42%) were female. Inflammatory cytokines (TNF-α, IL-4 and IL-10) were measured and ten mitral valves of patients who underwent first valve replacement were collected for determination of gene expression of endothelin-1 by real time PCR. Results: Among the groups studied (patients vs. controls), there was a statistically significant difference in IL-10 levels (P=0.002), and no differences in other cytokines. Expression of endothelin-1 was observed in 70% of samples. Quantitatively, average of ET-1 expression was 62.85±25.63%. Conclusion: Inflammatory cytokine IL-10 participates in the maintenance of chronicity of rheumatic fever in patients who underwent valve replacement and those who are undergoing medical treatment. The expression of endothelin-1 in heart valve lesions in patients undergoing mitral valve re-

placement confirms its association with inflammatory activity in rheumatic fever.

1. Federal University of Sergipe (UFS), São Cristóvão, SE, Brazil.

Federal University of Sergipe Marechal Rondon Avenue b.b – Rosa Elze Neighborhood – São Cristóvão, SE, Brazil – Zip code: 49100-000 E-mail: sydneyleao@hotmail.com

Descriptors: Interleukin-10. Interleukin-4. Receptors, Tumor Necrosis Factor. Endothelin-1. Mitral Valve Stenosis. Resumo Objetivo: Avaliar o perfil imunológico e a expressão gênica de endotelina-1 em valvas mitrais de pacientes com febre reumática, originados de um serviço de referência em cirurgia cardiovascular. Métodos: Este foi um estudo quantitativo, observacional e transversal. Trinta e cinco indivíduos (divididos em quatro grupos) participaram do estudo, 25 deles com doença cardíaca reumática crônica, além de 10 controles. A média de idade da amostra estudada foi de 34,5 anos. Dezessete (48,58%) dos indivíduos eram homens, e 18 (51,42%) eram mulheres. Foram medidas algumas citocinas inflamatórias (TNF-α, IL-4 e IL-10) e coletadas 10 valvas mitrais de pacientes que se submeteram a primeira troca valvar para determinação da expressão gênica de endotelina-1 pelo PCR real-time. Resultados: Entre os grupos estudados (pacientes e controles), observou-se diferença estatisticamente significante em rela-

Work carried out at the Molecular Anatomy Group (GAM), Department of Morphology, Federal University of Sergipe, São Cristóvão, SE, Brazil. Financial support: CNPq and Fapitec. Correspondence address: Sydney Correia Leao

Article received on April 4th, 2013 Article accepted on January 6th, 2014

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Conclusão: A citocina inflamatória IL-10 participa da manutenção da cronicidade da febre reumática em pacientes que se submeteram a troca valvar e naqueles que estão em tratamento médico. A expressão de endotelina-1 nas lesões em valvas cardíacas de pacientes que foram submetidos à troca valvar mitral confirma sua relação com a atividade inflamatória na febre reumática.

Abbreviations, acronyms & symbols RF Rheumatic fever CRHD Chronic rheumatic heart disease ET-1 Endothelin-1 ET-2 Endothelin-2 ET-3 Endothelin-3

ção aos níveis de IL-10 (P=0,002), sem diferenças nas outras citocinas. Em relação à endotelina-1, foi observada sua expressão em 70% das amostras. Quantitativamente, a expressão média de endotelina-1 foi de 62,85±25,63%.

Descritores: Interleucina-10. Interleucina-4. Receptores do Fator de Necrose Tumoral. Endotelina-1. Estenose da Valva Mitral.

INTRODUCTION

Cardiac involvement in acute RF characterizes the most serious and most important of all manifestations of the disease because of the possibility of progressing to chronic rheumatic valvular disease or death. The most common rheumatic mitral valvulopathy is a dual unbalanced dysfunction, i.e, insufficiency and stenosis in different stages of development, which may lead to an indication of surgical repair or replacement of the damaged valve in children and young people in productive age [17,18]. The aim of this study was to compare the levels of some interleukins (TNF-alpha, IL-4 and IL-10) among different patients with RF. In addition, we sought to assess gene expression of endothelin-1 in native replaced mitral valves.

Rheumatic fever (RF) represents a serious public health problem. It is a rheumatic and inflammatory disease of autoimmune origin, which occurs in response to an infection by group A streptococcus (Streptococcus pyogenes). On a global scale, this agent is responsible for approximately 15.6 million annual cases of rheumatic heart disease, with 282,000 new cases and 233,000 deaths each year. From this perspective, health systems face higher expenses with clinical exams, surgeries and frequent hospitalizations due to congestive heart failure [1-4]. The pathogenesis of RF involves a complex network of genetic, environmental and immunological interactions. Genetic factors predispose individuals to developing autoimmune reactions [5]. Cytokines are proteic molecules, glycosylated or not, that send a range of stimulatory, modulatory or inhibitory signals to the various cells of the immune system. Studies indicate that the inflammatory response in acute RF on cardiac tissues is generated by antigenic mimicry of the protein M leading to an abundant infiltration of CD4+ T cells [5-7]. This leads to production of inflammatory cytokines (e.g., TNF-α, IL-2, and IL-10), which have a decisive influence on the immune response of patients with rheumatic fever. It is also known that increased levels of Th1 inflammatory cytokines (TNF-α and IFN-γ) and lower levels of Th2 and regulatory cytokine IL-4 lead to maintenance and progression of rheumatic valvulopathy [8-12]. Endothelin is a highly potent vasoconstrictor peptide. This peptide is composed of 21 amino acids and has three isoforms. The three isoforms are called endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3) [13,14]. Endothelin-1 is the subtype predominantly produced by cardiac endothelium. Some studies show gene expression of endothelin in heart valves of patients who underwent surgical valve replacement [15,16].

METHODS A quantitative, field, observational and cross-sectional study was performed after obtaining approval by the Ethics Committee for Human Research of the Federal University of Sergipe (CAAE 2344.0.000.107.10) and written informed consent from participants. Socio-epidemiological data and peripheral venous blood of 35 individuals, 25 patients with RF and chronic rheumatic heart disease (CRHD) originated from a cardiovascular surgery service in the city of Aracaju and 10 control subjects were collected. The different groups of RF patients were divided as follows: G1 (ten patients with RF /CRHD who underwent first valve replacement); G2 (five patients with CRHD who underwent second valve replacement); G3 (ten patients with RF in clinical treatment and regular medical monitoring, without indication of valve replacement). The control group (G4) consisted of healthy individuals without evidence of any autoimmune disease and who did not use antibiotics at the time of data collection. The exclusion criteria were adults aged over 65 years or older, pregnant women and patients with autoimmune disease. All participants answered a clinical and socio-epidemiological questionnaire.

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The sample size was determined from the amount of surgeries performed where this research was conducted: 107 surgical valve replacements in 2009 (75 native valve replacements and 32 second valve replacements). Using a confidence level of 95% and a level of heterogeneity of 99%, we arrived at 13 patients for the first group and 11 patients for the second group. There were difficulties related to the composition of group 2 (second valve replacement) due to the natural progression of disease (death before the second valve replacement).

on Nanodrop® (Thermo ScientificTM). cDNA Control 1 (CT1) was used to generate a calibration curve for efficiency ET1 and GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) primers. The cDNA sample was diluted in 5x and 10x dilutions, and PCR reactions in real time were subsequently performed using the primers for ET-1 and GAPDH. By using the results of the slope and the number of cycles required to increase the amount of molecules 10x, we can calculate the efficiency of reactions for both primers with the formula: efficiency = 10 (-1/slope) - 1. The expression of the mRNA of target genes of ET-1 and GAPDH primers was quantified with real-time PCR using QuantiTect Primer Assay 10x (QIAGEN®). Reactions were carried out with 15 µl of QuantiFast SYBR Green PCR kit (Qiagen®). After that, a dissociation curve was run to verify the specificity of each pair of primers. Data from real-time PCR were tabulated and analyzed by the CFX96 Real Time System (BIORAD®) device and calculations of relative expression were performed by the Delta Ct method (Pfaffl, 2001) [19], according to the formula:

Epidemiological profile Of the total number of subjects, 17 (48.57%) were male and 18 (51.43%) were female. Of the 25 patients with RF/ CRHD, 13 (52%) were female and 12 (48%) were male. Mean age was 34.5±2.56 years. Among the different groups, G1 had a mean age of 43.7± .85 years, G2 had a mean age of 40 ± 8.91 years, and the average age of patients with RF/ CRHD without indication of surgical replacement (G3) was 33.70±2.56 years. The control group (G4) had an average age of 21.6±0.52 years (P=0.0005). Regarding the frequency of symptoms, dyspnea was the most prevalent symptom (68%), followed by chest pain (16%), palpitations (8%) and edema in the legs (8%). Echocardiographic data showed mitral valve involvement in 64% of the patients, followed by the aortic and mitral double lesion in 24% of the patients. There was no involvement of the pulmonary and tricuspid valves. Regarding the type of valvular involvement, we observed reflux in 80% of the sample, followed by stenosis (68%), calcification (40%), and prolapse of the chordae (4%).

ratio= (Etarget) ∆Ct target (control-treated) (Eref) ∆Ctref (control-treated) Cytokines We collected 10 ml of peripheral blood, which was centrifuged and stored at -80ºC, to determine TNF-alpha, IL-4 and IL-10 by sandwich ELISA immunoenzymatic assays (eBioscience). Measurements of these cytokines followed the instructions provided by the manufacturer. Wells of polystyrene distributed into strips were used in the adsorption of specific monoclonal antibodies for each cytokine (100 μL/ well) at the appropriate concentration. This step for sensitization was performed overnight at 4ºC and completed after five washes of the wells with the wash solution provided by the manufacturer. Subsequently, blockade of residual free sites was done with 200 μL/ well of diluent for one hour at room temperature. The wells were again washed five times and then incubated overnight at 4ºC with 100 μL/ well of patterns and samples corresponding to each cytokine. A new washing cycle was processed, followed by the addition of 100 μL/well of biotin-conjugated antibody for detection, and incubation for one hour at room temperature. Following new washes, the wells were incubated with 100 μL/ well of conjugate formed by peroxidase-labeled streptavidin for 30 minutes at room temperature. After a new round of washes, the reactions were developed with 100 μL/ well of substrate (tetramethylbenzidine solution containing hydrogen peroxide) for 15 minutes at room temperature. After stopping the reaction with 2N of HCl, the absorbance was read at 450 nm-570 nm in an ELISA reader. Cytokine concentrations were determined in serum pg/ml, using the previously established pattern curves with known quantities of cytokines.

Determination of endothelin-1 by real-time PCR We collected ten mitral valves of patients that underwent first valve replacement surgery (G1). These valves were stored in RNA stabilization solution at -20ºC. For the extraction of total RNA from the valves, we used 30-40 µg of valve tissue, manually macerated in the presence of liquid nitrogen, in accordance with the protocol recommended by Mini Kit RNeasy Fibrous (QIAGEN®). Total RNA was quantified by spectrophotometry in Nanodrop® (Thermo ScientificTM). The quantification was performed in duplicate, obtaining the average RNA concentration in ng/ µL. Absorbance values obtained were analyzed according to the following formula: [RNA (µg/ml)] = 40 x A260 x diluition/ 1000 (Maniatis). Purity was assessed by the ratio of absorbance values obtained at 260 nm and 280 nm (A260/ A280), and samples with between 1.8 and 2.0 were considered viable. cDNA from the valves was obtained by reverse transcriptase reaction (RT). To obtain cDNA, we used 38.4 to 82.5 ng of total RNA from each sample in accordance with the protocol recommended by QuantiTect Reverse Transcription Kit (QIAGEN®). The cDNAs were quantified

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Statistical analysis For distribution of continuous variables, we used D’Agostino, Pearson and Kruskal-Wallis tests. We considered statistically significant the results of the analysis with P<0.05. Statistical analyzes were performed using Graph Pad Prism 5.0 (GraphPad Software Inc., USA). RESULTS Determination of endothelin-1 by real-time PCR The average amount of RNA in the samples was 65.75±19.72 ng/ul (Table 1). The mean concentrations of nucleic acid (total RNA), and cDNA were 20.60±26.84 ng/μl and 615.31±77.20 ng /μl, respectively (Table 1). Mean values of absorbance at 260 nm and 280 nm were 0.51±0.66 UA (A260) and 0.25±0.31 UA (A280), respectively. The A260/ A280 ratio was 1.79±0.26 (Table 1). In the real-time PCR reactions, it was observed that the slope for ET-1 appeared in -3.272 (R2=0.944), resulting in an efficiency of 102.1%; and the slope of GAPDH was in -3.286 (R2=0.996), resulting in an efficiency of 101.5%. According to these calculations, reactions with both primers have adequate efficiency. After generating the calibration curve and calculating the efficiency of the reactions, we plotted dissociation curves for both primers, showing that both have specificity. Based on standardized protocol for the calibration curve, we performed amplifications for the reactions with ET-1 and GAPDH primers. We observed the expression of ET-1 in seven of the ten samples collected. Quantitatively, the average gene expression relative to ET-1 was 62.85± 25.63% (Figure 1).

Fig. 1 – Graph showing the relative expression of endothelin 1 (ET-1) in mitral valves samples 2, 4, 5, 6, 7, 8 and 10

Cytokines Patients submitted to the first (G1) and second valve replacement (G2) had an average concentration of cytokine IL-4 of 2.39±4.37 pg/ml and 15.71±34.66 pg/ml, respectively, whereas in RF patients (G3) and in the control group, the values were 16.66±51.81 pg/ml and 0.32±0.64 pg/ml (P=0.56), respectively (Figure 2A). Regarding the levels of IL-10, there was a mean concentration of 7.30±8 pg/ml in the first group, 8.07±2.26 pg/ml in the second group, 6.97±1.68 pg/ml in the third group (RF patients) and 0.77±1.68 pg/ml in the control group (P=0.002) (Figure 2B). The dosage of TNF-alpha in the first and second groups was 4.25±11.87 pg/ ml and 2.67±5.09 pg/ml, respectively. In RF patients group and in the control group, levels of TNF-alpha were, respectively, 1.43±4.54 pg/ml and 4.04±12.61 pg/ml (P=0.91) (Figure 2C).

Table 1. Quantification of total RNA, cDNA and spectophotometry from heart valves. Samples GAM01 GAM02 GAM03 GAM04 GAM05 GAM06 GAM07 GAM08 GAM09 GAM10 Mean Std Dev

Mean Nucleic Acid Conc. (ng/ml) 7.5 66 4.5 75 18 11 3.2 3.3 3.5 14 20.6 26.84995345

Total cDNA 724.8 659.3 573.9 565.4 594 760.5 617 547.1 588.6 522.5 615.31 77.20521643

A260 0.178 1.686 0.123 1.805 0.435 0.253 0.076 0.111 0.115 0.349 0.5131 0.6600568

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A280 0.097 0.82 0.087 0.878 0.212 0.139 0.05 0.072 0.072 0.167 0.2594 0,3148898

A260/A280 1.835 2.056 1.413 2.055 2.051 1.82 1.52 1.54 1.597 2.089 1.7976 0,26153997

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LeĂŁo SC, et al. - IL-10 and ET-1 as biomarkers of rheumatic valve disease

Fig. 2 â&#x20AC;&#x201C; Graph showing the mean expression for different interleukins (A: TNF-alpha; B: IL-4 and C: IL-10). LegendsTNF-alpha: Tumor necrosis factor alpha; IL-4: Interleukin-4; IL-10: Interleukin-10

DISCUSSION

cal treatment. Their levels were decreased in the control group, as expected. Since the IL-10 is an anti-inflammatory cytokine, results show the immune response to control the inflammatory process that triggers valvular lesions [12]. Situating endothelin-1 in rheumatic fever, several studies have reported high serum levels of this peptide in patients with rheumatic disease, associated with mitogenesis, fibrosis and inflammatory activity [14]. Chen et al. [21] reported increased serum levels of endothelin-1 in patients with rheumatic mitral stenosis. In our study, there is gene expression of endothelin-1 in damaged heart valves in patients that underwent mitral valve replacement, resembling those seen in other samples of the Brazilian population. In this sense, Moura et al. [1] found that 40.7% of mitral valves (fibrosed and stenosed) replaced in patients with RF presented gene expression of ET-1 and, in our previous study [22], we observed expression of both endothelin receptors (ETrA and ETrB) in replaced rheumatic mitral valves. Chang [12] showed that TNF-alpha induces the increase of ET-1mRNA expression. In another study, Patel et al. [23] reported that TNF stimulates the release of endothelin-1 and its vasoconstrictor activity. This finding was confirmed by Wagner [24], who exposed endothelial cell cultures to high concentrations of TNF, finding a considerable increase of the secretion of ET-1 accompanied by a correspondingly increase in the levels of the pre-pro-ET-1 mRNA transcription. Despite the connection between production of TNF-alpha and endothelin-1, in this study, we did not find a difference between the levels of TNF-alpha in the different groups. Moreover, a limitation of this study was the small sample

From the results presented, serum levels of TNF-alpha as well as the levels of IL-4 and IL-10 were shown to be reduced when compared to a previous study [20]. When analyzing the group of patients with RF/ CHRD (compared to the control group), we identified lower serum concentrations of TNF-alpha as well as elevated serum levels of IL-4 and IL-10. Considering that the patients with RF/CRHD had had rheumatic disease for over a decade and they had not been submitted to surgical replacement of the mitral valve, it suggests that decreased levels of TNF-alpha (which is a pro-inflammatory cytokine) can correspond to a possible immunological control of disease in this group [6,8,12]. In addition, serum levels of TNF-alpha were similar in patients who had replaced the native heart valve and in the control group indicating pro-inflammatory immune response. There were high levels of IL-4 in patients who have replaced the bioprosthetic valve and in patients with RF in clinical treatment. In patients that underwent native valve replacement, there were low levels of IL-4, and in the control group, production of this interleukin was insignificant, as expected. There were large variations in the data concerning IL-4, leading to a non-significant P-value. Guilherme et al. [6,9] showed that lower production of IL-4 by the infiltrating cells of valvular tissue can lead to persistence and progression of rheumatic valvular disease. There are more cells producing IL-4 in the myocardium, hence, rheumatic myocarditis healing occurs after a few weeks [9]. There were higher levels of IL-10 in patients who have replaced the native mitral valve and in patients with RF without surgi-

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size, which may have been responsible for the lack of statistical significance in some comparisons. We conclude that inflammatory cytokine IL-10 participates in maintaining the process of chronicity of RF in patients that underwent valve replacement and in those who are undergoing medical treatment. Additionally, the presence of gene expression of endothelin-1 was observed in most of the valvular fragments studied.

9. Guilherme L, Ramasawmy R, Kalil J. Rheumatic fever and rheumatic heart disease: genetics and pathogenesis. Scand J Immunol. 2007;66(2-3):199-207. 10. Guilherme L, Faé KC, Kalil J. Rheumatic heart disease: molecular basis of autoimmune reactions leading to valvular lesions. New York: Springer Science Business Media; 2005. p.115-25. 11. Spina GS. Rheumatic disease: neglected but still present and deadly. Rev Med São Paulo. 2008;87(2):128-41. 12. Chang C. Cutting edge issues in rheumatic fever. Clin Rev Allergy Immunol. 2012;42(2):213-37.

Authors’ roles & responsibilities SCL MRML HMN SOS TMAR

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

Translation and editing of the article Data collection; original writing of the article and final revision of the article Data analysis Data collection and analysis Original writing and final revision of the manuscript

14. Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum. 2003;48(5):1190-9. 15. Porto CC. Doenças do coração: prevenção e tratamento. 2ª ed. Rio de Janeiro: Guanabara Koogan; 2005. 16. Veinot JP. Pathology of inflammatory native valvular heart disease. Cardiovasc Pathol. 2006;15(5):243-51.

REFERENCES 1. 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.

17. Terreri MTRA, Caldas AM, Len CA, Ultchak F, Hilário MOE. Características clínicas e demográficas de 193 pacientes com febre reumática. Rev Bras Reumatol. 2006;46(6): 385-90.

2. Seckeler DM, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol. 2011;3:67-84.

18. Tarasoutchi F, Montera MW, Grinberg M, Barbosa MR, Piñeiro DJ, Sánchez CRM, et al. Diretriz Brasileira de Valvopatias - SBC 2011- I Diretriz Interamericana de Valvopatias - SIAC 2011. Arq Bras Cardiol. 2011;97(5 supl. 1):1-67.

3. Meneghelo ZM, Ramos AIO. Lesões das valvas cardíacas: diagnóstico e tratamento. São Paulo: Atheneu; 2007.

19. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45.

4. Barbosa PJB, Muller RE, Latado AL, Achutti AC, Ramos AIO, Weksler C, et al. Diretrizes brasileiras para diagnóstico, tratamento e prevenção da febre reumática da Sociedade Brasileira de Cardiologia, da Sociedade Brasileira de Pediatria e da Sociedade Brasileira de Reumatologia. Arq Bras Cardiol. 2009;93(3 supl.4):1-18.

20. Yeğin O, Coşkun M, Ertuğ H. Cytokines in acute rheumatic fever. Eur J Pediatr. 1997;156(1):25-9. 21. Chen MC, Wu CJ, Yip HK, Chang HW, Chen CJ, Yu TH, et al. Increased circulating endothelin-1 in rheumatic mitral stenosis: irrelevance to left atrial and pulmonary artery pressures. Chest. 2004;125(2):390-6.

5. Guilherme L, Kalil J. Rheumatic fever and rheumatic heart disease: cellular mechanisms leading autoimmune reactivity and disease. J Clin Immunol. 2010;30(1):17-23.

22. Leão SC, Souto FM, Costa RV, Rocha TF, Pacheco YG, Rodrigues TM. Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves. Rev Bras Cir Cardiovasc. 2012;27(4):512-9.

6. Guilherme L, Köhler KF, Postol E, Kalil J. Genes, autoimmunity and pathogenesis of rheumatic heart disease. Ann Pediatr Cardiol. 2011;4(1):13-21. 7. Varella PPV, Forte WCN. Citokines: a review. Rev Bras Imunopatol. 2005;24(4):146-54.

23. Patel JN, Jager A, Schalkwijk C, Corder R, Douthwaite JA, Yudkin JS, et al. Effects of tumour necrosis factor-alpha in the human forearm: blood flow and endothelin-1 release. Clin Sci. 2002;103(4):409-15.

8. Artola RT, Mihos CG, Santana O. The immunology of mitral valve stenosis. Dovepress. 2011;(3):1-8.

24. Wagner EM. TNF-alpha induced bronchial vasoconstriction. Am J Physiol Heart Circ Physiol. 2000;279(3):H946-51.

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Araújo EF, et ORIGINAL al. - Cardiac resynchronization therapy in patients with chronic ARTICLE Chagas cardiomyopathy: long-term follow up

Cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy: long-term follow up Terapia de ressincronização cardíaca em pacientes com cardiomiopatia chagásica crônica: seguimento de longo prazo

Edgard Ferreira de Araújo1, MD; Eduardo Gregório Chamlian2, MD; Alexey Pomares Peroni2, MD; Wilson Lopes Pereira2, MD; Sylvio Matheus de Aquino Gandra2, MD; Luiz Antonio Rivetti2, MD

DOI: 10.5935/1678-9741.20140008

RBCCV 44205-1518

Abstract Introduction: Chagas disease is a major cause of cardiomyopathy and sudden death in our country. It has a high mortality when their patients develop New York Heart Association (NYHA) class IV. Objective: The objective of this study is to analyze the clinical outcome of patients with Chagas’ cardiomyopathy with congestive heart failure with optimized pharmacological therapy, undergoing cardiac resynchronization therapy. Methods: Between January 2004 and February 2009, 72 patients with Chagas’ cardiomyopathy in NYHA class III and IV underwent cardiac resynchronization therapy and were monitored to assess their clinical evolution. We used the t test or the Wilcoxon test to compare the same variable in two different times. A P value < 0.05 was established as statistically significant. Results: The average clinical follow-up was 46.6 months (range 4-79 months). At the end of the evaluation, 87.4% of patients were in NYHA class I or II (P<0.001). There was response to therapy in 65.3% of patients (P<0.001), with an overall mortality of 34.7%.

Conclusion: In patients with chronic Chagas cardiomyopathy undergoing cardiac resynchronization therapy, we found the following statistically significant changes: improvement in NYHA class and increase of left ventricle ejection fraction, a decrease of the systolic final diameter and systolic final left ventricle volume and improvement of patient survival.

1. Cardiologic Unit of Salinas, Salinas, MG, Brazil. 2. Faculty of Medical Sciences of Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

This study was carried out at Faculty of Medical Sciences of Santa Casa de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

Descriptors: Chagas disease. Chagas cardiomyopathy. Myocarditis. Cardiomyopathy, dilated. Death, sudden, cardiac. Resumo Introdução: A doença de Chagas é a maior causa de miocardiopatia e morte súbita em nosso país. Apresenta alta mortalidade quando seus portadores evoluem para classe funcional IV da New York Heart Association (NYHA). Objetivo: O objetivo deste trabalho é analisar a evolução clínica dos pacientes portadores de cardiomiopatia chagásica com insuficiência cardíaca avançada e terapia farmacológica otimizada submetido a terapia de ressincronização cardíaca.

Correspondence address: Edgard Ferreira de Araújo Faculdade de Ciências Médicas da Santa Casa de São Paulo Departamento de Cirurgia – Disciplina de Cirurgia Cardiovascular Rua Dr. Cesário Mota Júnior, 112 – Vila Buarque – São Paulo, SP, Brazil – Zip code: 01221-020 E-mail: edgard.ferreira.araujo@gmail.com

No financial support.

Article received on May 22th, 2013 Article accepted on November 24th, 2013

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Araújo EF, et al. - Cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy: long-term follow up

meses (variando de 4 a 79 meses). Ao final do seguimento, 87,4% dos pacientes estavam em classe funcional I ou II da NYHA (P<0,001). Houve resposta à terapia em 65,3% dos pacientes (P<0,001), com mortalidade total de 34,7%. Conclusão: Nos pacientes com cardiomiopatia chagásica crônica submetidos à terapia de ressincronização cardíaca, encontramos as seguintes alterações estatisticamente significativas: melhora da classe funcional segundo NYHA; melhora da fração de ejeção do ventrículo esquerdo; diminuição do diâmetro sistólico final e volume sistólico final do ventrículo esquerdo e maior sobrevida destes pacientes.

Abbreviations, acronyms and symbols LVEF NYHA

Left ventricular ejection fraction New York Heart Association

Métodos: Entre janeiro de 2004 e fevereiro de 2009, 72 pacientes com cardiomiopatia chagásica em classe funcional III e IV da NYHA foram submetidos à terapia de ressincronização cardíaca e acompanhados para avaliar sua evolução clínica. Para comparar a mesma variável em dois momentos diferentes utilizamos o Teste t pareado ou o Teste de Wilcoxon. Um valor de P<0,05 foi estabelecido como estatisticamente significante. Resultados: O acompanhamento clínico médio foi de 46,6

Descritores: Doença de Chagas. Cardiomiopatia chagásica. Miocardite. Cardiomiopatia dilatada. Morte súbita cardíaca.

INTRODUCTION

treatment in functional class IV (NYHA) and LVEF less than 35% have only 16% survival at 36 months [5]. In a systematic review of observational studies, Rassi et al. [5] claim that chagasic patients with impaired ventricular function, cardiomegaly, functional class III and IV (NYHA) and episodes of non-sustained ventricular tachycardia have a poor prognosis in 12 months. The potential hemodynamic benefit of biventricular pacing in humans was first demonstrated in 1983, but its clinical application occurred only in 1994, when Cazeau et al. [6] reported the case of a 54 year old patient with congestive heart failure functional class IV (NYHA), with electrocardiogram showing left bundle branch block with a QRS interval of 200 ms. The authors believe that the ventricular dyssynchrony was treated, and it was caused by the delay of the electrical impulse in left bundle branch block, and that the stimulation of the four chambers promotes a sequence of ventricular activation close to normal. In 2000, Cazeau et al. [7], in an editorial of the journal Heart, assessed the concept of cardiac dyssynchrony, defined as a heterogeneous spread of electrical activity of the heart that occurs as a consequence of myocardial progressive focal or global degradation. Such a change in heart electrical propagation provides levels of atrioventricular asynchrony, interventricular and intraventricular [7,8]. Also in 2000, Leclercq et al. [9] present a pilot experience with biventricular pacemaker to treat advanced heart failure, mentioning the indications for the procedure: delayed dilated cardiomyopathy, NYHA functional class III or IV (NYHA) intraventricular conduction delay of the electrical stimulus.

Chagas disease is a neglected disease in the world, and in Latin America there are nearly 10 million patients infected with Trypanosoma cruzi [1]. In 2005, it was estimated that, in Brazil, there were approximately 2 million infected [2]. Approximately 30% of these individuals will develop Chagas cardiomyopathy in a period between 10 and 30 years of disease [3]. Chronic Chagas cardiomyopathy is caused by the invasion of Trypanosoma cruzi in the muscular structures and electrical conduction of the heart tissue, leading to destruction of it and replacement by fibrous tissue [3]. It is estimated approximately 3,000 deaths occur each year related to Chagas disease in Brazil [2]. It is the most common cardiomyopathy in Central and South America and, in endemic areas, is the leading cause of cardiovascular death in patients aged between 30 and 50 years old. The fundamental determinant in the evolution of patients infected by Trypanosoma cruzi is cardiac involvement, due to the occurrence of arrhythmias, cardiac insufficiency in its varying degrees, and thromboembolic phenomena. Currently, heart failure is the main cause of deaths related to Chagas disease in Brazil [4]. Serious ventricular arrhythmias, especially when associated with severe impairment of ventricular function, are important risk factors for sudden death [4]. In Chagas cardiomyopathy, NYHA functional class (the New York Heart Association - NYHA) and left ventricular systolic dysfunction assessed by ejection fraction (LVEF) are predictors of mortality, and patients with optimal medical

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From these original studies by Cazeau and Leclercq, several randomized clinical trials on cardiac resynchronization therapy [10-15] emerged. Since then, studies have shown benefit in morbidity and mortality of non-chagasic patients with chronic systolic heart failure undergoing cardiac resynchronization therapy. However, few studies related to cardiac resynchronization therapy were performed in patients with chronic systolic heart failure due to Chagas’ cardiomyopathy. These studies led the Brazilian Society of Cardiology to publish, in 2007, together with the Department of Cardiac Pacing and Brazilian Society of Cardiac Arrhythmias, the Brazilian Guidelines for Cardiac Implantable Electronic Devices, normalizing the recommendations for cardiac resynchronization therapy. In the literature, it is observed that these studies that supported the creation of the Brazilian guideline were performed in patients with dilated cardiomyopathy of ischemic or idiopathic etiology. Against the scenario of the large number of patients with Chagas cardiomyopathy and advanced heart failure in our country and the excellent results obtained mainly in Europe in the treatment of terminal dilated cardiomyopathy by cardiac resynchronization therapy, the Department of Cardiovascular Surgery and Electrophysiology Service of Santa Casa de São Paulo, together with the Department of Cardiology of Salinas, Minas Gerais, resolved in 2003, to initiate the study of cardiac resynchronization therapy in patients with Chagas’ disease. The aim of this study is to assess the clinical long-term outcome of patients with Chagas cardiomyopathy with advanced heart failure undergoing cardiac resynchronization therapy by assessing the functional class and echocardiographic parameters in 5 years.

Patients with the following conditions were excluded: atrial arrhythmias, neoplastic disease, acquired valvular heart disease other than mitral regurgitation secondary to Chagas cardiomyopathy, thoracic aortic aneurysm and cerebral vascular disease. Once filled the criteria, patients who agreed to participate in this study signed a written informed consent. Patients were referred to the Irmandade da Santa Casa de São Paulo, at the Cardiovascular Surgery Unit and, after surveying the clinical history, laboratory tests, medications, and complementary tests (blood count, thrombin time, activated partial thromboplastin time, serum sodium, potassium, urea and creatinine) underwent implantation of cardiac resynchronization device, placing an electrode in the right atrium and an electrode in the right ventricle (both intravenous), and an electrode in the lateral side of the left ventricle through a left anterior mini-thoracotomy in the 4th intercostal space, with placement of an epicardial lead. When possible, the electrode placement of the left ventricle was performed through the coronary venous sinus, moving the endocardial electrode on the left side of the left ventricular coronary vein. Preoperative clinical parameters were: Functional class: 60 (83.8%) patients were in functional class III and 12 (16.2%), functional class IV; Medication used: 59 (81.9%) patients used amiodarone, 39 (54.1%), captopril, 72 (100%), carvedilol, 16 (22.2%), digoxin, 71 (98.6%), spironolactone, 68 (94.4%), furosemide and 11 (15.2%), losartan; Electrocardiographic parameters: 34 (47.2%) patients had left bundle branch block, 11 (15.3%), pacemaker-induced left bundle branch block, 26 (36.2%), right bundle branch block + left anterior hemiblock and 1 (1.3%), complete atrioventricular block. The average width of the QRS interval was 148.1 ± 17.5 ms; Doppler echocardiographic parameters: mean LVEF calculated by Teicholz method was 27.3 ± 7.7%, the average left ventricular end systolic diameter was 57.5 ± 7.2 mm, the end left ventricular diastolic diameter was 66.2 ± 7.6 mm, the mean left ventricular end-systolic volume was 167.8 ± 50.6ml and end-diastolic volume of the left ventricle average was 230±63.3ml; Average dose of carvedilol 20±16.2mg; Mean QRS interval before cardiac resynchronization: 140±38.2ms. From January 2004 to November 2010, when the study was completed, patients underwent clinical and quarterly electrocardiographic control and echocardiographical control; also, assessment of cardiac resynchronization semiannually was performed, observing the command analysis and sensitivity and statistical biventricular command. In clinical management, in addition to the adequacy of

METHODS This study was approved by its Research Ethics Committee in Human Beings of the Irmandade da Santa Casa de Misericórdia de São Paulo, protocol No. 026/2011, on 28/01/2011. In the period between January 2004 and February 2009, were selected by the same cardiologist in Salinas, Minas Gerais, 72 patients with positive serology for Chagas cardiomyopathy and heart failure, receiving optimal dose of the following drugs, according to the characteristics of their disease and specific indications: furosemide, spironolactone, hydrochlorothiazide, captopril, losartan, carvedilol, digoxin, warfarin, aspirin and amiodarone. The inclusion criteria for the study were patients with the following characteristics: age over 18 years, positive serology for Chagas’ disease, severe heart failure despite optimal medical therapy, electrocardiogram with QRS interval greater than 120 ms, LVEF less than 35% and left ventricle end-diastolic diameter greater than 55 mm assessed by Doppler echocardiography.

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medication treatment, we assessed the functional class according to the NYHA classification. The electrocardiogram assessed the rhythm and biventricular command. Doppler echocardiography assessed: LVEF, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular end-systolic volume and left ventricular end-diastolic volume. Performance assessment of resynchronization was performed at the Irmandade da Santa Casa de S達o Paulo, and the other exams in Salinas, Minas Gerais. The criteria used for patients considered to be responders to cardiac ressincronization therapy were: being in functional class I or II (NYHA) or alive at the end of follow-up. In statistical analysis and the construction of the graphs we used the GraphPad Prism software version 6.00 (GraphPad Software, San Diego, California, USA, www.graphpad.com), to make graphical comparisons of samples used in the study. For analysis of the same variable of the same individual at two different times, we used the t test for paired samples (variable of parametric distribution) and Wilcoxon test (non-parametric variable distribution). In all tests, we used a significance level of 5% (P<0.05).

The end-systolic left ventricular volume decreased from 167.8 ml to 130.9 ml on average after implantation of the cardiac resynchronization device (P<0.0001) (Figure 3). The left ventricular end-diastolic volume decreased from 230.0 ml to 224.5 ml on average after implantation of cardiac resynchronization device (P=0.206).

RESULTS The follow-up after implantation of resynchronization device occurred until November 2010, ranging from 4 to 79 months (mean follow-up of 46.6 months). The implantation of resynchronization was performed through mini-thoracotomy in 48 (66.7%) patients and via venous sinus in 24 (33.3%). At the final follow-up, 45.8% of patients were in functional class I, 41.6% in functional class II, 7% in functional class III and 5.6% in functional class IV (NYHA). Regarding the response to cardiac resynchronization therapy, it was observed that 47 (65.3%) patients responded to cardiac resynchronization therapy and 24 (33.3%) did not respond with loss to follow-up of 1 (1.4%) patient. The overall mortality was 34.7 % (25 patients), and the causes of death were worsening heart failure in 15 (60%) cases, ischemic stroke in 1 (4%), sudden death in 2 (8%), endocarditis in 1 (4%), chronic obstructive pulmonary disease in 1 (4%), pneumonia in 1 (4%) and 4 (16%) patients had unknown cause of death. LVEF ranged from 27.3% to 44.2%, on average, after implantation of the cardiac resynchronization device (P<0.0001) (Figure 1). The left ventricular end-systolic diameter decreased from 57.5 mm to 50.8 mm on average after implantation of cardiac resynchronization therapy (P < 0.0001 ) ( Figure 2 ). The left ventricular end-diastolic diameter decreased from 66.2 mm to 65.4 mm on average after implantation of cardiac resynchronization device (P=0.295).

Fig. 1 - Changes in ejection fraction in patients undergoing cardiac resynchronization therapy, Santa Casa de S達o Paulo, 2013

Fig. 2 - Variation of left ventricular end-systolic diameter of patients undergoing cardiac resynchronization therapy, Santa Casa de S達o Paulo, 2013

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volume of more than 10% after cardiac resynchronization therapy was associated with lower mortality in an observational study [17]. At the molecular level, there is a reduction in interstitial fibrosis in the proinflammatory cytokine tumor necrosis factor-alpha and decreased cellular apoptosis [18]. The improvement in ventricular function after cardiac resynchronization therapy is also associated with favorable changes in genes that regulate the contractile apparatus and pathological myocardial hypertrophy [19]. CONCLUSION In patients with chronic Chagas cardiomyopathy undergoing cardiac resynchronization therapy, we found the following statistically significant changes: the functional class; improvement in LVEF, decrease in left end-systolic diameter and end-systolic volume on Doppler echocardiography.

Fig. 3 - Change in left ventricular end-systolic volume of patients undergoing cardiac resynchronization therapy, Santa Casa de São Paulo, 2013

DISCUSSION Authors’ roles and responsibilities

Dilated cardiomyopathy combines primary abnormalities in the heart muscle, with alterations in filling its chambers, neurohormonal activation and molecular adaptations triggered by increasing stress and the endocardial hypertrophy. In conjunction with these changes, affecting the myocardium diffusely, changes in electrical conduction can change the range of atrioventricular conduction or delay in the portions of the left ventricle relative to each other, generating a contractile dyssynchrony. This dyssynchrony is frequently observed in patients with a widened QRS complex and left bundle branch block - the standard of intraventricular conduction disturbance. In the present study, performed in an uncontrolled way and not randomized, we observed that 87.4% of patients were in functional class I or II at the end of follow-up, and we found only 12.6% in functional class III or IV. We found 33% of patients who did not respond to cardiac resynchronization therapy, given that this is slightly higher than that found in patients with heart failure of ischemic or idiopathic etiology. The observed increase in LVEF was 61.9 % on average between the beginning and end of follow-up, with a percentage reduction of 11.4% in left ventricular end-systolic diameter and 21.9% in left ventricular end-systolic volume. A number of randomized studies have demonstrated that cardiac resynchronization therapy leads to reduced dimensions and internal volume of the left ventricle and increased LVEF when compared to drug therapy. Although most of the remodeling occurs between 3 and 9 months after cardiac resynchronization therapy, remodeling still occurs up to 18 months [16]. A decrease of the end-systolic left ventricular

EFA EGC APP WLP SMAG LAR

Design and conduct of the study; writing of the manuscript Preparation of graphics Review and text orientation Review and drafting of the text Review and drafting of the text Final review of the text

REFERENCES 1. Kirchhoff LV. Changing epidemiology and approaches to therapy for Chagas disease. Cur Infect Dis Rep. 2003;5(1):59-65. 2. Braz SC, Melo MF, Lorena VM, Souza WV, Gomes YM. Chagas disease in the state of Pernambuco, Brazil: analysis of admissions and mortality time series. Rev Soc Med Trop. 2011;44(3):318-23. 3. Dias E, Laranja FS, Miranda A, Nobrega G. Chagas’ disease; a clinical, epidemiologic, and pathologic study. Circulation. 1956;14(6):1035-60. 4. Theodoropoulos TA, Bestetti RB, Otaviano AP, Cordeiro JA, Rodrigues VC, Silva AC. Predictors of all-cause mortality in chronic Chagas’ heart disease in the current era of heart failure therapy. Int J Cardiol. 2008;128(1):22-9. 5. Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation. 2007;115(9):1101-8.

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AraĂşjo EF, et al. - Cardiac resynchronization therapy in patients with chronic Chagas cardiomyopathy: long-term follow up

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6. Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, et al. Four chamber pacing in dilated cardiomyopathy. Pacing Clin Electrophysiol. 1994;17(11 Pt 2):1974-9.

heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003;42(8):1454-9.

7. Cazeau S, Gras D, Lazarus A, Ritter P, Mugica J. Multisite stimulation for correction of cardiac asynchrony. Heart. 2000;84(6):579-81.

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8. Leclercq C, Cazeau S, Le Breton H, Ritter P, Mabo P, Gras D, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol. 1998;32(7):1825-31.

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9. Leclercq C, Cazeau S, Ritter P, Alonso C, Gras D, Mabo P, et al. A pilot experience with permanent biventricular pacing to treat advanced heart failure. Am Heart J. 2000;140(6):862-70. 10. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation. 1999;99(23):2993-3001.

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11. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al.; Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873-80.

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19. Vanderheyden M, Mullens W, Delrue L, Goethals M, Bruyne B, Wijns W, et al. Myocardial gene expression in heart failure patients treated with cardiac resynchronization therapy responders versus nonresponders. J Am Coll Cardiol. 2008;51(2):129-36.

13. Higgins SL, Hummel JD, Niazi IK, Giudici MC, Worley SJ, Saxon LA, et al. Cardiac resynchronization therapy for the treatment of

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Barros RT, et ORIGINAL al. - Evaluation of patients' quality of life aspects after cardiac ARTICLE pacemaker implantation

Evaluation of patients' quality of life aspects after cardiac pacemaker implantation Avaliação de aspectos da qualidade de vida em pacientes pós-implante de marca-passo cardíaco

Rubens Tofano de Barros1, MD, PhD; Sebastião Marcos Ribeiro de Carvalho2, MD, PhD; Marcos Augusto de Moraes Silva1, MD, PhD; Juliana Bassalobre Carvalho Borges3, PhD

DOI: 10.5935/1678-9741.20140009

RBCCV 44205-1519

Abstract Objective: To evaluate patients’ quality of life aspects after pacemaker implantation, relating it to gender, age, and implantation timespan. Methods: A total of 107 clinically stable patients of both genders (49.5% women and 50.5% men) over 18 years old (average 69.3±12.6 years) and presenting an implantation timespan of three to 12 months (average 6.36±2.99 months) were evaluated. The evaluation included personal, clinical, and implant data as well as quality of life questionnaires (AQUAREL and SF-36). Statistical analysis was conducted using the t test and Pearson correlation. with a 5% significance level. Results: The lowest SF-36 score referred to physical aspects, and the highest score referred to social aspects. In AQUAREL. the lowest score referred to dyspnea, and the highest referred to discomfort. There was a significant association between gender and quality of life in SF-36 (physical functioning and emotional aspects) and in AQUAREL (dyspnea). A negative correlation was observed between age and quality of life (functional capacity in SF-36, and discomfort in AQUAREL) in relation to implantation timespan, a correlation with vitality from SF-36.

Conclusion: Lower quality of life scores were found in physical aspects and dyspnea; and higher scores in social aspects and discomfort. Men presented higher quality of life scores related to physical functioning, emotional aspects and dyspnea. As age increases, quality of life worsens regarding functional capacity and discomfort; and the longer the pacemaker implantation timespan, the worse quality of life when it comes to vitality. Gender, age, and implantation timespan influence quality of life; thus, these variables must be considered in strategies for improving quality of life of patients with pacemakers.

1. Universidade Estadual Paulista, Botucatu Medical School (FMB-UNESP). Botucatu, SP, Brazil. 2. Universidade Estadual Paulista. College of Philosophy and Sciences (FFC), Marília Campus, Marília, SP, Brazil. 3. Universidade Federal de Alfenas (UNIFAL), Nursing School, Physiotherapy Course. Alfenas, MG, Brazil.

E-mail: jubassalobre@ig.com.br

Correspondence address: Juliana Bassalobre Carvalho Borges Rua Professor Carvalho Júnior, 53/201 – Centro – Alfenas, MG, Brazil – Zip Code: 37130-000

No financial support.

Descriptors: Quality of Life. Indicators of Quality of Life. Pacemaker. Artificial. Resumo Objetivo: Avaliar aspectos da qualidade de vida em pacientes pós-implante de marca-passo e relacionar com gênero, idade e tempo de implante. Métodos: Foram estudados 107 indivíduos de ambos os gêneros (49,5% do sexo feminino e 50,5% do sexo masculino),

Work carried out at Universidade Estadual Paulista. Botucatu Medical School. Graduate Program, Doctorate in General Surgery, Botucatu, SP, Brazil.

Article received on September 18th, 2013 Article approved on January 6th, 2014

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Barros RT, et al. - Evaluation of patients' quality of life aspects after cardiac pacemaker implantation

vida no SF-36 (capacidade funcional e aspectos emocionais) e no AQUAREL (dispneia). Observaram-se correlações negativas entre idade e qualidade de vida (capacidade funcional do SF-36 e em desconforto do AQUAREL) em relação ao tempo de implante, correlação com vitalidade do SF-36. Conclusão: Menores escores de qualidade de vida foram encontrados em aspectos físicos e dispneia; maiores em aspectos sociais e desconforto. Homens apresentaram maiores escores de qualidade de vida em capacidade funcional, aspectos emocionais e dispneia. Conforme aumenta a idade, pior é a qualidade de vida em capacidade funcional e desconforto, e, quanto maior o tempo de implante de marca-passo, pior a qualidade de vida em vitalidade. Gênero, idade e tempo de implante influenciam na qualidade de vida, dessa forma. essas variáveis devem ser consideradas nas estratégias para melhora da qualidade de vida em portadores de marca-passo.

Abbreviations. acronyms & symbols AQUAREL Assessment of QUality of life And RELated events PM Pacemaker QoL Quality of life SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey SUS Unified Health System

tempo de implante três a 12 meses (média de 6,36±2,99 meses), estáveis clinicamente com idade acima de 18 anos (média de 69.3±12.6 anos). A avaliação constou de: dados pessoais, clínicos, do implante e questionários de qualidade de vida (AQUAREL e SF-36). Análise estatística empregou teste t e correlação de Pearson, com significância de 5%. Resultados: No SF-36, o menor escore ocorreu no domínio aspectos físicos e, o maior, em aspectos sociais. No AQUARE, o menor escore foi em dispneia e o maior em desconforto. Verificou-se associação significante entre gênero e qualidade de

Descritores: Qualidade de Vida. Marca-Passo Artificial. Indicadores de Qualidade de Vida.

INTRODUCTION

Organization defines QoL as “individuals’ perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations,standards and concerns” [10]. Several instruments have been suggested to assess health-related QoL. There are generic instruments, non-specific to a single disease and better suited for epidemiological studies, and instruments for specific diseases, which are clinically more sensitive to detect alterations related to the disease [9]. For patients with PM, literature recommends the use of a specific questionnaire coupled with general questions about health from a generic questionnaire [11]. Stofmeel et al. [11-13] developed and presented a questionnaire specifically for patients with PM, the Assessment of QUality of Life And RELated Events (AQUAREL), which should be used as an extension of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) questionnaire [7]. A number of studies have used those instruments in assessing QoL of patients with PM. However, they have proved insufficient to determine how PM therapy interferes in the patient’s life. Their effectiveness in improving survival is clearly seen, yet there is still concern about evaluating and monitoring the clinical and psychological consequences of the therapy. Patients undergoing PM therapy can suffer changes in different aspects of their lives: physical, social, emotional, and psychological [14]. Investigating the patient

The use of artificial heart stimulation as treatment for cardiac conduction disorders is a challenge that seeks to add quality to the change in prognosis of patients with heart disease. The technology of current devices provides several resources, which can be adapted to the needs of every patient, making it possible to improve quality of life (QoL) [1-3]. The pacemaker (PM) is a resource for artificial cardiac stimulation that favors many patients with heart disease who have atrioventricular blocks in correcting heart rhythm disorders and atrioventricular synchrony [4]. There have been many PM implantations worldwide, and records from the 11th World Survey of Cardiac Pacing and Implantable Cardioverter-Defibrillators: Calendar Year 2009 show that there were 136 PM implantations per million inhabitants in Brazil [5]. Following the advances and the performance of the medical field. several studies have been carried out in order to assess QoL as well as recognize the importance of the patient’s point of view on his disease and the importance of monitoring the quality of therapeutic measures [6-9]. Thus, assessment of QoL associated with health refers to the patient’s subjective viewpoint on his health, which can be in conflict with physiological evaluations, interpretations of his well-being, and physical functioning, but it can also broaden the clinical parameters [6,9]. In this sense, the World Health

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with PM’s perception of his QoL can help direct the interpretations and analysis of the treatment’s effectiveness, which justifies the importance of this study. Given the above, this study set out to assess the perception of QoL of patients with definitive PM and its association with gender, age, and implantation time span.

The scores of the three domains of the AQUAREL QoL questionnaire (chest discomfort: questions 1 to 6, 11 and 12; dyspnea: questions 7 to 10, 18 to 20; arrhythmia: questions 13 to 17) were calculated using Oliveira’s [16] Formula (1), where equivalence between the letters of the answers for items of every question in the AQUAREL questionnaire and the 5-point Likert scale was: a)=5; b)=4; c)=3; d)=2 e e)=1. Formula (1): Score = 100 – {[ ( ΣN - n°N ) / (n°N X 5) – n°N ]} X 100 Where: ΣN = sum of points from questions that comprise the score n° N = number of questions that comprise the score SF-36 consists of questions divided into eight domains: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health [17]. The AQUAREL and SF-36 questionnaires were applied in the form of interviews by a previously trained interviewer. Sum of the points was done according to what has been described in the literature for each of the questionnaires and the domains were graded by a specific calculation ranging from 0 to 100. A low numeric score reflects poor health perception, loss of function, and presence of pain whereas a high numeric score reflects good health perception, preserved function, and absence of pain [16,19]. Therefore, a cut-off point of 50 (mean score) was established to determine the best and worst domains. Domains with scores lower than 50 represent worse QoL and those with scores 50 or over represent better QoL [20,21].

METHODS A descriptive, quantitative, cross-sectional, observational study was carried out in patients with PM during follow-up at the Cardiac Surgery and Pacemaker Department at Santa Casa de Misericórdia in Marília, SP. Data was collected from August 2009 to June 2010. Minimum sample was estimated at n=85, considering a significance level of 5% (α=0.05), a type II error of 20% (β=0.20), and effect size ǀ r ǀ =0.30 [15]. The study had been previously approved by the Ethics Committee of the Marília Medical School (FAMEMA), protocol nº442/08. All volunteers provided written informed consent. Clinically stable patients of both genders aged 18 and older, within three and 12 months of PM implantation, and who provided written informed consent, were included in the study. Patients excluded were the ones who did not understand the test sequence; were speech, hearing or mentally impaired; or did not wish to participate in the study. Volunteers were assessed using a protocol developed by the researchers according to the literature [16,17], which included: personal data, vital signs, background, and questions related to the PM. In addition, specific tests were also performed, such as functional class according to Goldman’s Specific Activity Scale [18,19] and QoL questionnaire. The assessment of QoL was made by applying AQUAREL, a QoL questionnaire specifically designed for patients with PM, which must be used with the SF-36 generic questionnaire [11,13]. Both instruments. AQUAREL and SF36, have been translated and adapted to Portuguese, validated, and had their reliability and reproducibility well-established in the Brazilian population [7,17]. AQUAREL consists of 20 questions divided into three domains: chest discomfort (corresponding to questions 1 to 6, about chest pain, and questions 11 and 12, about dyspnea at rest), arrhythmia (corresponding to questions 13 to 17), and dyspnea on exertion (corresponding to questions 7 to 10, about dyspnea on exertion, and questions 18 to 20, about fatigue) [16]. Every domain has specific items with five response categories, with values ranging from 1 to 5. Individual scores obtained for each of the domains were added up and computed using the formula shown in Formula (1). Final scores can range from zero (all complaints) to 100 (no complaints), where a score of 100 represents perfect QoL [7,12].

Statistical analysis Data were summarized using tables. absolute frequency, percentages, means, standard deviation, and minimum and maximum values. In order to assess the relationship between gender and the SF-36 and AQUAREL domains, the following tests were used: t test for independent samples and one-way ANOVA for three or more independent groups complemented by Tukey’s HSD multiple comparison test for statistically significant results as indicated by the ANOVA test, Pearson correlation coefficient (r) was used to analyze the correlations between quantitative variables [22]. A 5% level of probability of rejecting the null hypothesis was set for all tests. RESULTS A total of 107 patients of both genders participated in the study, where 49.5% were female and 50.5% were male ranging from 29 to 90 years old. Mean period after PM implantation was 6.36±2.99 months and mean age was 69.3±12.6 years. In terms of profession. most were retired citizens (43%), followed by 31.8% of homemakers. There were 12.1% of the patients with Chagas disease; 64.5% with systemic arterial hypertension; 24.3% with diabetes mellitus;

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48.6% of non-smokers; and 38.3% with some kind of sleep disorder. Patient characteristics and type of intervention are summarized in Table 1. One-way ANOVA (significance level of 5%) showed significant differences between perceptions of the respondents (AQUAREL and SF-36) in terms of implantation time span. according to the following groups: G1 – implantation time span of three months or less; G2 to G10 – implantation time span of 4, 5, 6, 7, 8, 9, 10, 11, and 12/13 months, respectively. All of the results were non-significant (P>0.05), i.e., there were no significant differences between at least two of the groups, which allowed for the creation of one single group in terms of implantation time span for the assessment of respondents’ perception using the AQUAREL and SF-36 questionnaires. Table 2 shows the scores of the AQUAREL QoL questionnaire obtained from the total sample and comparison according to gender. A significant result was observed in the dyspnea domain. Table 3 shows data from the evaluation of the SF-36 QoL questionnaire obtained from the total sample and comparison according to gender. Significant results were observed in the physical functioning and role-emotional domains. The results of the study indicate a significant positive correlation between AQUAREL chest discomfort domain and age. There was no significant correlation between age and the remaining domains. In terms of implantation time span, there was no correlation with QoL according to AQUAREL (Table 4).

Table 1. General and clinical characteristics of the 107 patients included in the study. Variables Gender Female Male Education Illiterate Basic education – incomplete Secondary education – incomplete Secondary education – complete Tertiary education Chagas disease Yes No Indication for implantation Atrioventricular block Sinus node syndrome Other Type of stimulation Bicameral Unicameral Implantation time span (months) Mean (standard deviation) Minimum – Maximum Functional class Class I Class II Class III Class IV

53 54

49.5 50.5

33 59 2 8 4

30.8 55.1 1.9 7.5 3.7

13 94

12.1 87.8

62 30 15

57.9 28.0 14.1

93 14

86.9 13.1

6.4±3.0 1 - 13 74 8 23 2

69.2 7.5 21.5 1.9

Table 2. Mean values for quality of life from the AQUAREL questionnaire for full sample and comparison of domains according to gender (t test). Gender Full sample Male Female t test (P value)

Chest Discomfort 90.8 ± 14.9 90.6 ± 13.2 91.0 ± 16.6 P=0.887

Dyspnea 75.0 ± 21.3 79.1 ± 18.3 70.8 ± 23.3 P=0.044*

Arrhythmia 89.0 ± 14.1 90.4 ± 13.6 87.6 ± 14.6 P=0.306

Total AQUAREL 84.9 ± 13.9 86.7 ± 13.1 83.1 ± 14.6 P=0.187

* Significant (P<0.05)

Table 3. Mean values for quality of life from the SF-36 questionnaire for full sample and comparison of domains according to gender (t test). Gender Full sample Male Female t test (P value)

Physical Functioning 69.2 ± 24.9 75.8 ± 20.9 62.5 ± 27.0 P=0.005*

RolePhysical 58.4 ± 37.6 60.6 ± 36.5 56.1 ± 38.8 P=0.537

Bodily Pain 63.5 ± 27.0 66.5 ± 28.5 60.5 ± 25.2 P=0.255

General Health 72.4 ± 23.6 74.5 ± 20.4 70.2 ± 24.0 P=0.352

Vitality 74.2 ± 20.6 75.7 ± 20.3 72.7 ± 20.9 P=0.454

* Significant (P<0.05)

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Social Functioning 89.1 ± 21.8 91.8 ± 20.4 86.3 ± 23.0 P=0.189

RoleEmotional 62.6 ± 43.1 71.6 ± 37.9 53.4 ± 46.3 P=0.029*

Mental Health 74.0 ± 23.0 77.6 ± 21.5 70.3 ± 24.2 P=0.103

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Barros RT, et al. - Evaluation of patients' quality of life aspects after cardiac pacemaker implantation

Table 4. Pearson correlation coefficient and P value between score values of AQUAREL questionnaire domains and age and implantation time span. Chest Discomfort r=0.197* P=0.042 r=-0.016 P=0.872

Age Implantantion time span

Dyspnea r=0.013 P=0.895 r=-0.103 P=0.289

Arrhythmia r=0.024 P=0.807 r=0.039 P=0.663

Total AQUAREL r=0.085 P=0.385 r=-0.045 P=0.645

* Significant (P<0.05)

Table 5. Pearson correlation coefficient and P value between score values of SF-36 questionnaire domains and the variables: age and implantation time span.

Age Implantantion time span

Physical Functioning r =- 0.338 P<0.001* r=-0.095 P= 0.330

RolePhysical r=0.074 P=0.447 r=-0.098 P=0.315

Bodily Pain r=-0.118 P=0.226 r=0.040 P=0.679

General Health r=-0.094 P=0.337 r=-0.095 P=0.328

Vitality r=-0.014 P=0.886 r=- 0.193 P=0.046*

Social Functioning r=-0.078 P=0.422 r=0.089 P=0.362

RoleEmotional r=-0.022 P=0.821 r=0.118 P=0.226

Mental Health r=0.073 P=0.456 r=-0.049 P=0.615

* Significant (P<0.05)

In addition, there was negative correlation between the SF-36 physical functioning domain and age. In terms of implantation time span, a negative correlation was observed with the SF-36 vitality domain. There was no significant correlation between age and implantation time span across the remaining domains (Table 5).

the impossibility of immediate transfer to our Department. Under these circumstances, we chose to assess QoL of our population of patients as well as their perception of this condition at a specific time after implantation. The importance of assessing QoL in health-related outcomes is now well known and accepted. Most of the studies aimed at evaluating the results of treatments evaluate QoL from the patient’s perspective as well [6,14,17]. The patient’s perception of his own health and QoL have emerged as references for learning how the patient perceives the treatment being received. It is important to consider that advances in the medical field often allow interferences in the natural progression of diseases and, in some cases, in the complex patient-disease relationship. The question is whether we are adding life to the years or just prolonging an unsolvable medical condition. In the words of Nobre [24], “QoL has become increasingly more valued than extending life under limited or disabled conditions”. Concepts of dysthanasia and orthotanasia, now regulated by decree from the Federal Council of Medicine, make us ponder the use of techniques to prolong life of patients with incurable diseases. Indication of artificial stimulation cannot be a matter of artificial life support without expectation of cure neither of controlling morbid conditions

DISCUSSION Data for this study was collected in a single interview within a mean time span of six months after implantation. The lack of a preoperative evaluation as a control group may be questioned; however, recent data, such as those published by Gomes et al. [23], have systematically shown that preoperative QoL evaluation is lower than the postoperative one. Another point worth mentioning is the characteristics of the Department where the study was carried out. The Department is a reference for the Unified Health System (SUS) of the Regional Health Division IX, based in Marília and comprising 62 municipalities in the state of São Paulo. Thus, a large number of these patients are referred for emergency treatment, with stimulation being provided by a temporary PM and in need of immediate surgery, due to the difficulty of finding vacant beds in the system and, at times,

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[25]. In the past 25 years, artificial cardiac stimulation has gone through a fast and striking modernization process of its equipment (hardware and software). The miniaturization of generators achieved by the incorporation of circuits that use computer-derived language and technology coupled with increasingly efficient and reliable electrodes have allowed any patient to be artificially stimulated. whether temporarily or permanently. As a result, we are able to change the natural history of patients with heart conduction disorders [14]. The application of QoL questionnaires in patients with PM has proved to be of great use in evaluating the results of this type of treatment [8,11,12]. In terms of QoL assessment using the AQUAREL and SF-36 questionnaires, they both have final scores ranging from 0 to 100, thus, a cut-off point of 50 (average score) was established to determine the best and worst domains [20]. Domains with scores lower than 50 were classified as having lower QoL and those with scores of 50 or over as having good QoL [16,20]. In this sense, none of the domains obtained scores lower than 50, indicating that QoL of patients after implantation is above average. Therefore, we can state that, overall, the QoL perceived by these patients was good. corroborating the findings of Brasil [3] and Gomes et al. [23]. Analyzing the highest and lowest scores across the domains assessed by the SF-36 questionnaire, we found the worst result in physical functioning (58.4), followed by role-emotional (62.6), and the best result in social functioning (89.1). Since the lowest scores show poor health perception. we can say that, in the evaluation made by SF-36, our population has a poor assessment in terms of physical functioning, similar to the findings of [26], however, above those of Oliveira [16], which showed the worst QoL for role-emotional (46.7), followed by physical functioning (51.4), and the best quality in social functioning (74.3). In terms of social functioning. which reflects the ability to have relationships in addition to a few emotional aspects, we found perception of improvement, confirmed by the high score. According to SF-36, our patients showed better perceptions in the mental functioning domain compared to physical functioning. contrary to the findings of Gomes et al. [23], which stated a reduction in scores of the social functioning and role-emotional domains after PM implantation. The same correlation is seen when the results of physical and social functioning are confronted with the findings published by van Eck et al. [27], comparing the scores in patients waiting for PM implantation with a control population (no indication for PM) belonging to the same age group. There is no change in the components of the physical functioning domain before and after implantation; however, in the mental functioning domain, the difference is significant, presenting better scores after implantation.

We applied the AQUAREL questionnaire to the same population and results showed the lowest score for dyspnea (75.0) and the highest for discomfort (90.8). These findings corroborate with the study performed by Oliveira [16], who assessed QoL (AQUAREL and SF-36) in 139 patients with PM and observed lower QoL according to AQUAREL for dyspnea (75.3) and better for discomfort (85.3). Cesarino et al. [28] studied QoL in 50 patients with implantable cardioverter-defibrillator (ICD) using the SF-36 questionnaire. The social functioning domain had the highest score (80.5) and physical functioning. the lowest (40.5), in agreement with our study. When analyzing gender, significant results were found in the physical functioning and role-emotional domains. using SF-36, with women at a disadvantage. Nowak et al. [29] suggest that there is a delay in the indication of PM in women compared to men. The prevalence of atrioventricular blocks in male patients means that indication of artificial stimulation is more commonplace and it happens earlier for these patients. According to the authors, the same is seen in European records, leading to differences in the age of patients at the time of first implantation as well. This late indication in female patients might account for the difference observed in the QoL evaluation across gender. Women who undergo the surgery are already at a more advanced stage of the disease. As far as AQUAREL, significant results were also found in the dyspnea domain, which is related to symptoms associated with physical capacity, with women at a disadvantage. Brasil [3] observed non-significant results when comparing QoL (using the QoL index) in terms of gender, both before and after permanent PM implantation. Furthermore, we attempted to correlate the QoL variables obtained from applying both questionnaires with age and PM implantation time span. According to Cunha et al. [18], the literature shows controversial results concerning the correlation between age and QoL in different populations [13,23,30]. Nevertheless, the literature also indicates that age is related mainly to variables associated with the physical condition of patients [17,30,31]. In our study. in accordance with van Eck et al. [27], one of the most important predictors of QoL after implantation is age, which is inversely related to QoL, findings that are similar to those of Cunha [18] and Gomes et al. [23]. Our population is older (69.3 years) than others, as evaluated by Oliveira et al. [32] with a mean age of 60 years. In the population evaluated by Oliveira et al. [32], the worsening in functional class was the determining factor in lower QoL. When we performed this analysis using SF-36, we observed a negative correlation between age and physical functioning. This domain indicates how much health affects routine activities. Older patients per se show more difficulty performing the activities evaluated in this domain. Similar to

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Barros RT, et al. - Evaluation of patients' quality of life aspects after cardiac pacemaker implantation

our findings, Cunha et al. [18] observed a negative correlation between age and SF-36 physical functioning domain. On the other hand, they also found correlation between age and role-emotional, adding to the controversial question of the relationship between age and QoL. However, Cesarino et al. [28], in a study about QoL perception (SF-36) in patients with ICD, found no statistically significant difference between QoL and age. Two studies developed in the countryside of Goiás also found no significant association between QoL scores and age: Gomes et al. [23] assessed QoL (AQUAREL and SF-36) after PM implantation in 23 patients and Antônio et al. [33] evaluated QoL (SF-36) in 25 patients with heart disease who were eligible for PM implantation at a hospital. Age is one of the factors we cannot interfere with when we find more frequent and more severe cardiovascular diseases since it is part of a non-modifiable risk factor (ageing). Even though it is known that PM implantation can benefit QoL, at times, this cannot be measured in elderly populations because of other coexisting diseases and lower life expectancy [3,26]. There was also negative correlation between implantation time span and vitality when evaluated by SF-36. The vitality domain is included in the mental functioning dimension of SF 36. It evaluates daily situations that involve physical capacity characteristics related to anxiety and depression. In our findings, time span after implantation is associated with lower vitality. Studies about this association could not be found and we credit this association to the average age of the patients evaluated, as discussed in terms of physical functioning. These results enable us to evaluate our population of patients with PM and contribute to further increase indications of this technique so that the results can truly benefit patients. Patients had adequate perceptions of their QoL with the use of the AQUAREL and SF-36 questionnaires. The use of the AQUAREL and SF-36 questionnaires is feasible, being a good complement to patients with PM.

Authors’ roles & responsibilities RTB SMRC MAMS JBCB

Data collection. analysis. and interpretation; writing of the manuscript Study design; data analysis and interpretation Writing of the manuscript Data collection. analysis. and interpretation; writing of the manuscript

REFERENCES 1. Alt E, Heinz M, Hirgstetter C, Emslander HP, Daum S, Blomer H. Control of pacemaker rate by impedance-based respiratory minute ventilation. Chest. 1987;92(2):247-52. 2. Tse HF, Lau CP. Sensors for implantable devices: ideal characteristics, sensors combinations and automaticity. In: Ellenbogen KA, Kay GN, Lau CP, Wilkoff BL, eds. Clinical cardiac pacing, defibrillation and resynchronization therapy. 3rd ed. Philadelphia: W.B. Saunders; 2006. 3. Brasil VV. Qualidade de vida do portador de marca-passo cardíaco definitivo: antes e após implante [Tese de Doutorado]. São Paulo: Escola de Enfermagem da Universidade de São Paulo; 2001. 4. Aredes AF, Lucianeli JG, Dias MF, Bragada UCA, Dumbra APP, Pompeo DA. Conhecimento dos pacientes a serem submetidos ao implante de marca-passo cardíaco definitivo sobre os principais cuidados domiciliares. Relampa. 2010:23(1):28-35. 5. Pachón-Mateos JC, Pereira WL, Batista Jr. WD, Mateos. JCP. Mateo EIP. Vargas RNA. et al. RBM-Registro Brasileiro de Marcapassos, Ressincronizadores e Desfibriladores. Relampa. 2013;26(1):39-49. 6. Favarato MECS, Favarato D, Hueb WA, Aldrighi JM. Qualidade de vida em portadores de doença arterial coronária: comparação entre gêneros. Rev Assoc Med Bras. 2006;52(4):236-4.

CONCLUSION According to the results. we can conclude that QoL of patients with PM is worse in terms of physical capacity and dyspnea and better in terms of social functioning and discomfort. Male patients showed better QoL in the physical functioning, role-emotional, and dyspnea domains, when compared to female patients. As age increases, QoL becomes worse in terms of physical functioning and discomfort, and the longer the PM implantation time span. the worst QoL in terms of vitality. Gender, age, and implantation time span exert influence on QoL, thus, these variables should be considered in the strategies used to improve QoL of patients with PM.

7. Oliveira BG, Melendez JG, Ciconelli RM, Rincón LG, Torres AA, Sousa LA, et al. The Portuguese version, cross-cultural adaptation and validation of specific quality-of-life questionnaire - AQUAREL - for pacemaker patients. Arq Bras Cardiol. 2006;87(2):75-83. 8. van Hemel NM, Holwerda KJ, Slegers PC, Spierenburg HA. Timmermans AA, Meeder JG, et al. The contribution of rate adaptive pacing with single or dual sensors to health related quality of life. Europace. 2007;9(4):233-8. 9. Monteiro R, Braile DM, Brandau R, Jatene FB. Qualidade de vida em foco. Rev Bras Cir Cardiovasc. 2010;25(4):568-74.

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10. The World Health Organization Quality of Life Assessment (WHOQOL): development and general psychometric properties. Soc Sci Med. 1998;46(12):1569-85.

Russomano F. Qualidade de vida em usuárias e não usuárias de terapia de reposição hormonal. Rev Assoc Med Bras. 2005;51(3):133-8.

11. Stofmeel MA, Post MW, Kelder JC, Grobbee DE, van Hemel NM. Quality-of-life of pacemaker patients: a reappraisal of current instruments. Pacing Clin Electrophysiol. 2000;23(6):946-52.

22. Norman G. Likert scales, levels of measurement and the ‘‘laws’’ of statistics. Adv Health Sci Educ Theory Pract. 2010;15(5):625-32. 23. Gomes TB, Gomes LS, Antônio IHF, Barroso TL, Cavalcante AMRZ, Stiva MM, et al. Avaliação da qualidade de vida pósimplante de marca-passo cardíaco artificial. Rev Eletrôn Enferm. 2011;13(4):735-42.

12. Stofmeel MA, Post MW, Kelder JC, Grobbee DE, van Hemel NM. Psychometric properties of Aquarel. A disease-specific quality of life questionnaire for pacemaker patients. J Clin Epidemiol. 2001;54(2):157-65.

24. Nobre M. Qualidade de vida. Arq Bras Cardiol. 1995;64(4):299-300.

13. Stofmeel MA, Post MW, Kelder JC, Grobbee DE, van Hemel NM. Changes in quality-of-life after pacemaker implantation: responsiveness of the Aquarel questionnaire. Pacing Clin Electrophysiol. 2001;24(3):288-95.

25. Siqueira JE, Zoboli E, Kipper DJ (orgs.). Bioética clínica. São Paulo: Gaia; 2008. 26. Zatta LT. Avaliação da qualidade de vida de portadores de marcapasso cardíaco artificial em Goiânia. Goiás [Dissertação de Mestrado]. Goiânia: Faculdade de Enfermagem. Universidade Federal de Goiás; 2010.

14. Lamas GA, Orav EJ, Stambler BS, Ellenbogen KA, Sgarbossa EB, Huang SK, et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med. 1998;338(16):1097-104.

27. van Eck JW, van Hemel NM, Kelder JC, van den Bos A, Taks W, Grobbee DE, et al; FOLLOWPACE Investigators. Poor health-related quality of life of patients with indication for chronic cardiac pacemaker therapy. Pacing Clin Electrophysiol. 2008;31(4):480-6.

15. Hulley SB, Cumming SR, Browner WS, Grady DG, Hearst NB, Newman TB. Delineando a pesquisa clínica: uma abordagem epidemiológica. Porto Alegre: Artmed; 2003. 16. Oliveira BG. Medida da qualidade de vida em portadores de marca-passo: tradução e validação de instrumento específico [Dissertação de Mestrado]. Belo Horizonte: Escola de Enfermagem. Universidade Federal de Minas Gerais; 2003. 116p.

28. Cesarino CB, Beccaria LM, Aroni MM, Rodrigues LCC, Pacheco SS. Qualidade de vida em pacientes com cardioversor desfibrilador implantável: utilização do questionário SF-36. Rev Bras Cir Cardiovasc. 2011;26(2):238-43. 29. Nowak B, Misselwitz B; Expert Committee Pacemaker. Institute of Quality Assurance Hessen. Effects of increasing age onto procedural parameters in pacemaker implantation: results of an obligatory external quality control program. Europace. 2009;11(1):75-9.

17. Ciconelli RM, Ferraz MB, Santos W, Meinão I, Quaresma MR. Tradução para a língua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF-36). Rev Bras Reumatol. 1999;39(3):143-50.

30. Santos PR. Relação do sexo e da idade com nível de qualidade de vida em renais crônicos hemodialisados. Rev Assoc Med Bras. 2006;52(5):356-9.

18. Cunha TMB, Cota RMA, Souza BK, Oliveira BO, Ribeiro ALP, Sousa LAP. Correlação entre classe funcional e qualidade de vida em usuários de marcapasso cardíaco. Rev Bras Fisioter. 2007;11(5):341-5.

31. Castro M, Caiuby AVS, Draibe AS, Canziani MEF. Qualidade de vida de pacientes com insuficiência renal crônica em hemodiálise avaliada através do instrumento genérico SF-36. Rev Assoc Med Bras. 2003;49(3):245-9.

19. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation. 1981;64(6):1227-34.

32. Oliveira BG, Velasquez-Melendez G, Rincón LG, Ciconelli RM, Souza LA, et al. Health-related quality of life in Brazilian pacemaker patients. Pacing Clin Electrophysiol. 2008;31(9):1178-83.

20. Servelhere KR, Fernandes YB, Ramina R, Borges G. Aplicação da escala SF-36 em pacientes operados de tumores da base do crânio. Arq Bras Neurocir. 2011;30(2):69-75.

33. Antônio IHF, Barroso TL, Cavalcante AMRZ, Lima LR. Qualidade de vida dos cardiopatas elegíveis à implantação de marca-passo cardíaco. Rev Enferm UFPE on line. 2010;4(2):647-57.

21. Zahar SEV, Aldrighi JM, Pinto Neto AM, Conde DM, Zahar LO,

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Pivatto JúniorORIGINAL F, et al. - Advanced age and incidence of atrial fibrillation in ARTICLE the postoperative period of aortic valve replacement

Advanced age and incidence of atrial fibrillation in the postoperative period of aortic valve replacement Idade avançada e incidência de fibrilação atrial em pós-operatório de troca valvar aórtica

Fernando Pivatto Júnior1, MD; Guaracy Fernandes Teixeira Filho1, MD; João Ricardo Michelin Sant’anna1, MD, PhD; Pablo Mondim Py1, MD; Paulo Roberto Prates1, MD; Ivo Abrahão Nesralla1, MD, PhD; Renato Abdala Karam Kalil1, MD, PhD

DOI: 10.5935/1678-9741.20140010

RBCCV 44205-1520

Abstract Objective: This study aims to describe the correlation between age and occurrence of atrial fibrillation after aortic stenosis surgery in the elderly as well as evaluate the influence of atrial fibrillation on the incidence of strokes, hospital length of stay, and hospital mortality. Methods: Cross-sectional retrospective study of ≥ 70 yearold patients who underwent isolated aortic valve replacement. Results: 348 patients were included in the study (mean age 76.8±4.6 years). Overall, post-operative atrial fibrillation was 32.8% (n=114), but it was higher in patients aged 80 years and older (42.9% versus 28.8% in patients aged 70-79 years, P=0.017). There was borderline significance for linear correlation between age and atrial fibrillation (P=0.055). Intensive Care Unit and hospital lengths of stay were significantly increased in atrial fibrillation (P<0.001), but there was no increase in mortality or stroke associated with atrial fibrillation. Conclusion: Post-operative atrial fibrillation incidence in aortic valve replacement is high and correlates with age in patients aged 70 years and older and significantly more pro-

nounced in patients aged 80 years. There was increased length of stay at Intensive Care Unit and hospital, but there was no increase in mortality or stroke. These data are important for planning prophylaxis and early treatment for this subgroup.

1. Cardiology Institute/University Foundation of Cardiology (IC/FUC), Cardiovascular Surgery Service, Porto Alegre, RS, Brazil.

Work carried out at the Cardiology Institute/University Foundation of Cardiology (IC/FUC), Cardiovascular Surgery Service and Graduate Program, and at the Federal University of Health Sciences of Porto Alegre (UFCSPA), Surgical Clinic Department, Porto Alegre, RS, Brazil.

Descriptors: Aged. Atrial Fibrillation. Aortic Valve Stenosis. Postoperative Period. Resumo Objetivo: Descrever, em idosos, a correlação entre faixa etária e ocorrência de fibrilação atrial após cirurgia por estenose aórtica, além de avaliar a influência da ocorrência de fibrilação atrial na incidência de acidente vascular cerebral, tempo de internação e mortalidade hospitalar. Métodos: Estudo transversal retrospectivo incluindo pacientes com idade ≥ 70 anos submetidos à cirurgia de troca valvar aórtica isolada. Resultados: Foram estudados 348 pacientes com idade média de 76,8±4,6 anos. A incidência de fibrilação atrial no

Correspondence address: Renato Abdala Karam Kalil Instituto de Cardiologia /Fundação Universitária de Cardiologia (IC/FUC). Avenida Princesa Isabel, 395 – Santana – Porto Alegre, RS, Brazil – Zip Code: 90620-000 E-mail: kalil.pesquisa@gmail.com

No financial support. Article received on September 26th, 2013 Article approved on December 9th, 2013

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Pivatto Júnior F, et al. - Advanced age and incidence of atrial fibrillation in the postoperative period of aortic valve replacement

Verificou-se significativo maior tempo de internação na Unidade de Terapia Intensiva e hospitalar total, porém, não se observou maior taxa de acidente vascular cerebral ou de mortalidade hospitalar decorrente da fibrilação atrial. Conclusão: A incidência de fibrilação atrial no pós-operatório de cirurgia para estenose valvar aórtica em pacientes idosos com ≥ 70 anos foi elevada e linearmente correlacionada ao avanço da idade, especialmente após 80 anos, causando aumento dos tempos de internação total e em Unidade de Terapia Intensiva, sem aumento significativo da morbimortalidade. O conhecimento desses dados é importante para evidenciar a necessidade de medidas profiláticas e de tratamento precoce dessa arritmia nesse subgrupo.

Abbreviations, acronyms & symbols CVA CCS CABG AF LVEF HF NYHA SPSS ICU

Cerebrovascular accident Canadian Cardiovascular Society Coronary artery bypass grafting Atrial fibrillation Left ventricular ejection fraction heart failure New York Heart Association Statistical Package for Social Sciences Intensive care unit

pós-operatório foi 32,8% (n=114), sendo superior nos pacientes ≥ 80 anos (42,9 vs. 28,8% 70-79 anos, P=0,017) e havendo significância estatística limítrofe (P=0,055) para tendência linear na correlação idade e incidência de fibrilação atrial.

Descritores: Idoso. Fibrilação Atrial. Estenose da Valva Aórtica. Período Pós-Operatório.

INTRODUCTION

the incidence of postoperative CVA, hospital length of stay, and hospital mortality.

Postoperative atrial fibrillation (AF) is the most common complication after cardiac surgery [1] and is associated with higher risks of cerebrovascular accident (CVA), hospital expenses and mortality as well as longer hospital and Intensive Care Unit (ICU) stay [2]. In most cases, it spontaneously reverts to sinus rhythm, without the need for pharmacological intervention [3]. Postoperative AF occurs in approximately 30% to 40% of patients who undergo coronary artery bypass grafting (CABG) and in up to about 60% of patients who undergo concomitant valve surgery [4]. The incidence of this arrhythmia depends on the definitions adopted, the characteristics of the patients, the type of surgery performed, and the monitoring method [5]. AF incidence has been increasing for the past few decades thanks to the higher percentage of elderly patients undergoing cardiac surgery [1]. This arrhythmia occurs typically on the second or third postoperative day, with 70% of the events occurring by the fourth day. However, it can happen at any time after surgery, including after hospital discharge. In fact, AF is the leading cause of early hospital readmission after cardiac surgery [6]. Indications for aortic valve surgery have been increasing due to an increase in population longevity. Even though AF is expected to be more frequent, there are few data on the prevalence of this condition in individuals aged 80 years or older and on its correlation to morbidity and mortality to offer guidance on the possible need for more aggressive prophylaxis during the preoperative period of more elderly patients. The aim of this study was to analyze a sample of elderly patients and describe the correlation between age and occurrence of acute postoperative AF after aortic valve stenosis surgery. Secondly, it set out to assess the influence of AF in

METHODS This was a cross-sectional retrospective study of patients aged 70 years and older who underwent isolated aortic valve replacement, from 2000 to 2011, due to aortic stenosis or double aortic lesion with predominant stenosis, including reoperations. Patients who underwent associated surgical procedures, including aortoplasty or aortic annular enlargement, and patients with preoperative endocarditis or AF were excluded. Heart rate was assessed by continuous cardiac monitoring in all patients for a minimum of 72 hours (postoperative ICU) and by daily electrocardiographic examinations until hospital discharge. Additional electrocardiograms were performed when patients suffered palpitations, tachycardia or angina. For the purposes of this study, AF consisted of any episode of supraventricular arrhythmia whose electrocardiography tracing showed “f” waves with varying morphology and amplitude as well as irregular ventricular rhythm. Angina and heart failure (HF) were classified according to the criteria established by the Canadian Cardiovascular Society (CCS) and New York Heart Association (NYHA), respectively. Current smoking was defined as smoking one or more cigarettes a day in the past month. Occurrence of CVA was determined in the presence of focal neurological signs or alterations in level of consciousness for > 24 hours. Hospital mortality was defined as death during hospital stay, regardless of length of stay. Data were collected directly from patients’ medical records, then inserted and analyzed by the Statistical Package for Social Sciences (SPSS) 21.0 software. Descriptive analysis was done through absolute and relative frequencies for

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qualitative variables and through average/median and standard deviation/interquartile range for quantitative variables. Comparison of groups was assessed by Student’s t-test for normally distributed quantitative variables, by Mann-Whitney U test for quantitative variables not normally distributed, and by Chi-square test for categorical variables. For low frequencies, Fisher’s exact test was used. Multivariate analysis was performed by using multiple logistic regression, where the variables included were the ones with P<0.20 in the univariate analysis. For multivariate analysis of not normally distributed continuous variables, logarithmic transformation was carried out, followed by multiple linear regression analysis with the aforementioned inclusion criteria. The relationship between age and incidence of acute postoperative AF was assessed by chi-square test for linear trends after assigning patients to 5-year age groups. A significance level of 5% was adopted for every test performed. This is a subanalysis of a previous study [7], submitted to and approved by the IC/ FUC Research Ethics Committee.

(42.9%) compared to those aged 70-79 years (28.8%), even when adjusted for chronic obstructive pulmonary disease, previous smoking, peripheral vascular disease, and left ventricular ejection fraction (FEVE) < 40% in the multivariate analysis (P=0.012) (Figure 1). The relationship between age group and occurrence of AF can be seen in Figure 2, which shows borderline statistical significance for linear trend (P=0.055).

RESULTS Fig. 1 – Incidence of postoperative atrial fibrilation after aortic stenosis surgery, total and according to age. *Adjusted for chronic obstructive pulmonary disease, previous smoking, peripheral vascular disease, and LVEF < 40% . Incidência fibrilação atrial = Incidence of atrial fibrillation; total = total; anos = years.

The sample was comprised of 348 patients, who fit the inclusion criteria established for the study. Demographic characteristics of the studied population are described in Table 1. Incidence of postoperative AF was 32.8% (n=114). It was significantly higher (P=0.017) in patients aged ≥ 80 years

Table 1. Demographic characteristics of the studied population. Variable Average age (years) Male patients (%) SAH (%) Diabetes (%) BMI ≥ 30 kg/m2 (%) COPD (%) Previous smoking (%) Current smoking (%) Heart failure III/IV (%) LVEF < 40% (%) Angina III/IV (%) Unstable angina (%) Syncope (%) Previous CVA (%) Peripheral vascular disease (%) Previous cardiac surgery (%) Previous AMI (%) Urgency/emergency surgery (%) Ischemia time (min) CPB time (min)

Total (n=348) 76.8 ± 4.6 195 (56.0) 251 (72.1) 77 (22.2) 62 (17.8) 38 (10.9) 147 (42.2) 10 (2.9) 132 (37.9) 28 (8.0) 23 (6.6) 25 (7.2) 96 (27.6) 24 (6.9) 35 (10.1) 45 (12.9) 17 (4.9) 7 (2.0) 57.1 ± 17.4 73.9 ± 21.6

70-79 years (n=250) 74.5 ± 2.8 143 (57.2) 178 (71.2) 57 (22.8) 42 (16.8) 33 (13.2) 118 (47.2) 9 (3.6) 91 (36.4) 16 (6.4) 18 (7.2) 21 (8.4) 71 (28.4) 17 (6.8) 30 (12.0) 33 (13.2) 12 (4.8) 5 (2.0) 57.0 ± 17.8 73.6 ± 20.9

≥ 80 years (n=98) 82.7 ± 2.7 52 (53.1) 73 (74.5) 20 (20.4) 20 (20.4) 5 (5.1) 29 (29.6) 1 (1.0) 41 (41.8) 12 (12.2) 5 (5.1) 4 (4.1) 25 (25.5) 7 (7.1) 5 (5.1) 12 (12.2) 5 (5.1) 2 (2.0) 57.2 ± 16.3 74.9 ± 23.5

P <0.001 0.562 0.629 0.734 0.525 0.047 0.004 0.293 0.414 0.113 0.639 0.241 0.682 1.000 0.084 0.951 1.000 1.000 0.934 0.598

SAH = Systemic arterial hypertension; BMI = body mass index; COPD = chronic obstructive pulmonary disease; LVEF = left ventricular ejection fraction; CVA = cerebrovascular accident; AMI = acute myocardial infarction; CPB = cardiopulmonary bypass

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The analysis of patients who did and those who did not suffer from postoperative AF did not identify characteristics or risk factors with statistically significant differences between those two groups (Table 2). In patients with acute AF, there was a slightly higher, but statistically insignificant, incidence of postoperative CVA. On the other hand, patients with this arrhythmia had a sig-

nificantly longer Intensive Care Unit and total hospital stay, even in the multivariate analysis. There was no statistically significant difference in terms of hospital mortality. Those analyses are described in Table 3. DISCUSSION By evaluating elderly patients who underwent aortic valve replacement, this study observed an almost linear trend of age and incidence of postoperative AF, with individuals aged ≥ 86 years presenting a 55% rate of this arrhythmia. In addition, hospital length of stay was longer for this population, both total and in the ICU, but incidences of CVA and hospital mortality were not higher. Postoperative arrhythmias have multifactorial etiology, but it has been suggested that, in the postoperative period, they are mainly a result of incomplete myocardial protection. Oxygen-derived free radicals and calcium overload resulting from reperfusion of ischemic areas are important arrhythmogenic mechanisms that lead to transmural reentry [8]. Some studies have found advanced age, male gender, previous AF, HF, and beta blocker withdrawal as being preoperative factors associated with higher incidence of AF. Even though a number of studies have shown risk factors

Fig. 2 – Relationship between age and acute postoperative AF after aortic stenosis surgery. Borderline statistical significance for linear trend (P=0.055). Incidência fibrilação atrial = Incidence of atrial fibrillation. Faixas etárias (anos) = Age

Table 2. Demographic characteristics of patients with acute postoperative AF. Variable Average age (years) Male patients (%) SAH (%) Diabetes (%) BMI ≥ 30 kg/m2 (%) COPD (%) Previous smoking (%) Current smoking (%) Heart failure III/IV (%) LVEF < 40% (%) Angina III/IV (%) Unstable angina (%) Syncope (%) Previous CVA (%) Peripheral vascular disease (%) Previous cardiac surgery (%) Previous AMI (%) Urgency/emergency surgery (%) Ischemia time (min) CPB time (min)

AF (n=114) 77.4 ± 5.2 59 (51.8) 84 (73.7) 23 (20.2) 24 (21.1) 14 (12.3) 44 (38.6) 3 (2.6) 48 (42.1) 7 (6.1) 7 (6.1) 7 (6.1) 35 (30.7) 8 (7.0) 10 (8.8) 11 (9.6) 4 (3.5) 2 (1.8) 58.5 ± 14.8 74.8 ± 16.5

no AF (n=234) 76.5 ± 4.3 136 (58.1) 167 (71.4) 54 (23.1) 38 (16.2) 24 (10.3) 103 (44.0) 7 (3.0) 84 (35.9) 21 (9.0) 16 (6.8) 18 (7.7) 61 (26.1) 16 (6.8) 25 (10.7) 34 (14.5) 13 (5.6) 5 (2.1) 56.3 ±18.5 73.5 ± 23.8

P 0.101 0.314 0.745 0.635 0.341 0.700 0.398 1.000 0.316 0.483 0.987 0.760 0.435 1.000 0.714 0.270 0.571 1.000 0.273 0.622

AF = atrial fibrillation; SAH = Systemic arterial hypertension; BMI = body mass index; COPD = chronic obstructive pulmonary disease; LVEF = left ventricular ejection fraction; CVA = cerebrovascular accident; AMI = acute myocardial infarction; CPB = cardiopulmonary bypass

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Pivatto JĂşnior F, et al. - Advanced age and incidence of atrial fibrillation in the postoperative period of aortic valve replacement

Table 3. Incidence of CVA, hospital length of stay, and hospital mortality according to the incidence of postoperative AF. Complication CVA (%) Hospital length of stay Median days of ICU stay (25-75%) Median days of total stay (25-75%) Outcome Mortality (%)

Total (n=348) 7 (2.0)

AF (n=114) 3 (2.6)

no AF (n=234) 4 (1.7)

0.687

3 (2-5) 8 (7-13)

5 (3-7) 10 (8-15)

3 (2-4) 8 (7-10)

< 0.001 < 0.001

<0.001 <0.001

25 (7.2)

5 (4.4)

20 (8.5)

0.234

AF = atrial fibrillation; CVA = cerebrovascular accident; ICU = Intensive Care Unit. (25-75%) = 25-75% interquartile range. *Adjusted for age

for postoperative AF following cardiac surgery, an effective prediction model has yet to be developed [9]. A Brazilian study conducted by Silva et al. [4] analyzed the occurrence of AF in 452 patients who underwent cardiac surgery and developed a score to predict this arrhythmia. Factors most associated with AF included patients aged 75 years and older, mitral valve disease, no use of beta blocker, beta blocker withdrawal, and positive fluid balance. The absence of risk factors reflected a 4.6% chance of postoperative AF and for one, two, and three or more risk factors, the chance was 16.6%, 25.9%, and 46.3%. A previous study that analyzed only patients who underwent aortic valve replacement found that age, previous history of paroxysmal AF, supraventricular heart rate of > 300 bpm in 24 hours, and supraventricular tachycardia on the day before surgery were independent predictors of postoperative paroxysmal AF [10]. In this study, only patients with aortic stenosis were included, without correlating with either beta blockers or fluid balance; however, age was confirmed as an independent risk factor. Likewise, in other series, advanced age is considered an independent predictor for postoperative AF following cardiac surgery. It has been described that this arrhythmia affects more than 18% of individuals over 60 years old and about 50% of those over 80 years old who underwent CABG [3]. The literature reports any patient over 70 years old who underwent CABG as being at a high risk for developing AF. Furthermore, it is known that for every 10-year increase in patientâ&#x20AC;&#x2122;s age, the risk of developing postoperative AF following cardiac surgery increases 75% [8,11,12]. This association is because these individuals have more comorbidities related to age as well as structural changes in the atrial myocardium, such as distension and fibrosis, which are secondary to changes typical of old age [3]. In this study, which included only patients aged â&#x2030;Ľ 70 years, besides a high overall occur-

rence rate of AF (32.8%), there was also a linear increase with age, as described above; however, the increase was not statistically significant. Despite being often considered a harmless temporary problem, postoperative AF is associated with an increase in early and late mortality [13], as it has been shown in meta-analysis [14]. High incidence of postoperative AF after cardiac surgery warns of the importance of identifying patients at high risk of developing this arrhythmia [8]. Even though risk factors for postoperative AF are known in a substantial number of patients, when analyzed individually no single risk factor could be identified. That justifies the importance of establishing prophylaxis in order to reduce the incidence of this arrhythmia and consequently its clinical implications to patients who underwent cardiac surgery [3]. Several studies have evaluated the effectiveness of pharmacological and non-pharmacological prophylactic interventions in the prevention of postoperative AF. Meta-analysis was used to assess the impact of those interventions, including amiodarone, beta blockers, sotalol, magnesium, atrial stimulation, and posterior pericardiotomy. All of those significantly reduced the rate of postoperative AF after cardiac surgery. The prophylactic interventions reduced hospital length of stay by about 16 hours and hospital expenses by approximately USD 1,250. In addition, they reduced the occurrence of postoperative CVA, though this reduction was not statistically significant (OR 0.69; CL 95% 0.47-1.01), and they did not affect mortality, neither cardiovascular nor by any other cause [2]. The administration of beta-blocking agents is the most effective measure in AF prophylaxis [3], significantly reducing its incidence after cardiac surgery (OR 0.33; CL 95% 0.26-0.43) [2]. As part of the routine at our institution, every patient starts to receive this class of drugs on the first

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postoperative day, unless there are contraindications such as hemodynamic instability. Limitations of this study include its retrospective nature, which could have influenced the quality and uniformity of the data collected; being performed at one single institution, which makes it difficult to make generalizations from the data presented; and the relatively small sample, which could have impacted, for example, the failure to observe a relationship between AF and incidence of CVA and mortality.

2. Ferro CR, Oliveira DC, Nunes FP, Piegas LS. Postoperative atrial fibrillation after cardiac surgery. Arq Bras Cardiol. 2009;93(1):59-63. 3. Valle FH, Costa AR, Pereira EM, Santos EZ, Pivatto Júnior F, Bender LP, et al. Morbidity and mortality in patients aged over 75 years undergoing surgery for aortic valve replacement. Arq Bras Cardiol. 2010;94(6):720-5. 4. Silva RG, Lima GG, Guerra N, Bigolin AV, Petersen LC. Risk index proposal to predict atrial fibrillation after cardiac surgery. Rev Bras Cir Cardiovasc. 2010;25(2):183-9.

CONCLUSION

5. Geovanini GR, Alves RJ, Brito G, Miguel GA, Glauser VA, Nakiri K. Postoperative atrial fibrillation after cardiac surgery: who should receive chemoprophylaxis? Arq Bras Cardiol. 2009;92(4):326-30.

In conclusion, incidence of postoperative AF after aortic valve stenosis surgery in patients aged ≥ 70 years proved high and linearly correlated with advanced age, reaching 55% in patients aged 85 years and older. As a result, there was an increase in ICU and total hospital length of stay; however, there was no increase in morbidity and mortality of affected patients. Knowledge of those data is important to show the need for prophylactic measures and early treatment of this arrhythmia in this subgroup in order to minimize morbidity and postoperative length of stay.

6. Aranki SF, Shaw DP, Adams DH, Rizzo RJ, Couper GS, VanderVliet M, et al. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation. 1996;94(3):390-7. 7. Zaman AG, Archbold RA, Helft G, Paul EA, Curzen NP, Mills PG. Atrial fibrillation after coronary artery bypass surgery: a model for preoperative risk stratification. Circulation. 2000;101(12):1403-8. 8. Hogue CW Jr, Hyder ML. Atrial fibrillation after cardiac operation: risks, mechanisms, and treatment. Ann Thorac Surg. 2000;69(1):300-6. 9. Rho RW. The management of atrial fibrillation after cardiac surgery. Heart. 2009;95(5):422-9.

Authors’ roles & responsibilities FPJ GFTF JRMS PMP PRP IAN RAKK

Research plan and design; data collection; data analysis and interpretation; statistical analysis; writing of the manuscript Data analysis and interpretation; critical review of the manuscript Data analysis and interpretation; critical review of the manuscript Data analysis and interpretation; critical review of the manuscript Data analysis and interpretation; critical review of the manuscript Data analysis and interpretation; critical review of the manuscript Research plan and design; data analysis and interpretation; statistical analysis; writing of the manuscript

10. Kaw R, Hernandez AV, Masood I, Gillinov AM, Saliba W, Blackstone EH. Short- and long-term mortality associated with new-onset atrial fibrillation after coronary artery bypass grafting: a systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2011;141(5):1305-12. 11. Orlowska-Baranowska E, Baranowski R, Michalek P, Hoffman P, Rywik T, Rawczylska-Englert I. Prediction of paroxysmal atrial fibrillation after aortic valve replacement in patients with aortic stenosis: identification of potential risk factors. J Heart Valve Dis. 2003;12(2):136-41. 12. Hogue CW Jr, Creswell LL, Gutterman DD, Fleisher LA; American College of Chest Physicians. Epidemiology, mechanisms, and risks: American College of Chest Physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest. 2005;128(2 Suppl):9S-16S.

13. Mariscalco G, Engström KG. Atrial fibrillation after cardiac surgery: risk factors and their temporal relationship in prophylactic drug strategy decision. Int J Cardiol. 2008;129(3):354-62.

REFERENCES

1. Arsenault KA, Yusuf AM, Crystal E, Healey JS, Morillo CA, Nair GM, et al. Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery. Cochrane Database Syst Rev. 2013;1:CD003611.

14. Echahidi N, Pibarot P, O’Hara G, Mathieu P. Mechanisms, prevention, and treatment of atrial fibrillation after cardiac surgery. J Am Coll Cardiol. 2008;51(8):793-801.

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Ikeoka DT, etORIGINAL al. - Evaluation of the Society of Thoracic Surgeons score ARTICLE system for isolated coronary bypass graft surgery in a Brazilian population

Evaluation of the Society of Thoracic Surgeons score system for isolated coronary bypass graft surgery in a Brazilian population Avaliação dos escores da Society of Thoracic Surgeons para cirurgia de revascularização miocárdica isolada em uma população brasileira

Dimas Tadahiro Ikeoka1, MD, PhD; Viviane Aparecida Fernandes1; Otávio Gebara1, MD, PhD; José Carlos Teixeira Garcia1, MD; Pedro Gabriel Melo de Barros e Silva1, MD; Marcelo Jamus Rodrigues1, MD; Valter Furlan1, MD; Antônio Cláudio do Amaral Baruzzi, MD, PhD1

DOI: 10.5935/1678-9741.20140011

RBCCV 44205-1495

Abstract Objective: Report the experience with the Society of Thoracic Surgeons scoring system in a Brazilian population submitted to isolated coronary artery bypass graft surgery. Methods: Data were collected from January-2010 to December-2011, and analyzed to determine the performance of the Society of Thoracic Surgeons scoring system on the determination of postoperative mortality and morbidity, using the method of the receiver operating characteristic curve as well as the Hosmer-Lemeshow and the Chi-square goodness of fit tests. From the 1083 cardiac surgeries performed during the study period 659 represented coronary artery bypass graft procedures which are included in the present analysis. Mean age was 61.4 years and 77% were men. Results: Goodness of fit tests have shown good calibration indexes both for mortality (X2=6.78, P=0.56) and general morbidity (X2=6.69, P=0.57). Analysis of area under the ROCcurve (AUC) demonstrated a good performance to detect

the risk of death (AUC 0.76; P<0.001), renal failure (AUC 0.79; P<0.001), prolonged ventilation (AUC 0.80; P<0.001), reoperation (AUC 0.76; P<0.001) and major morbidity (AUC 0.75; P<0.001) which represents the combination of the assessed postoperative complications. STS scoring system did not present comparable results for short term hospital stay, prolonged length of hospital stay and could not be properly tested for stroke and wound infection. Conclusion: Society of Thoracic Surgeons scoring system presented a good calibration and discrimination in our population to predict postoperative mortality and the majority of the harmful events following coronary artery bypass graft surgery. Analysis of larger samples might be needed to further validate the use of the score system in Brazilian populations.

1. Hospital TotalCor, São Paulo, SP, Brazil.

Work carried out at Hospital TotalCor, São Paulo, SP, Brazil.

Correspondence address: Dimas Tadahiro Ikeoka Hospital TotalCor Alameda Santos, 764 – Cerqueira César – São Paulo, SP, Brazil – Zip code: 01418-100 E-mail: dimas.ikeoka@hotmail.com

No financial support.

Descriptors: Risk Management. Cardiovascular Surgical Procedures. Myocardial Revascularization. Postoperative Complications. ROC Curve.

Article received on June 29th, 2013 Article accepted on November 17th, 2013

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Ikeoka DT, et al. - Evaluation of the Society of Thoracic Surgeons score system for isolated coronary bypass graft surgery in a Brazilian population

são aqui analisadas. A idade média foi de 61,4 anos e 77% dos pacientes eram homens. Resultados: Testes de bondade de ajustamento demonstraram boa calibração tanto para mortalidade (X2=6,78, P=0,56) quanto para morbidade geral (X2=6,69, P=0,57). A análise da área sob a curva ROC (AUC) demonstrou bom desempenho para detectar o risco de morte (AUC 0,76; P<0,001), insuficiência renal (AUC 0,79; P<0,001), ventilação prolongada (AUC 0,80; P<0,001), reoperação (AUC 0,76; P<0,001) e morbidade maior (AUC 0,75; P<0.001) que representa a combinação das complicações avaliadas. O escore Society of Thoracic Surgeons não apresentou resultados comparáveis para internação de curta duração, internação hospitalar prolongada e não pôde ser adequadamente testado para acidente vascular cerebral e infecção de ferida operatória. Conclusão: O sistema de escore Society of Thoracic Surgeons apresentou boa calibração e discriminação em nossa população para a predição de mortalidade pós-operatória e para a maioria dos eventos adversos após cirurgia de revascularização miocárdica isolada. Análises de maiores amostras podem ser necessárias para validar o método na população brasileira.

Abbreviations, acronyms & symbols AUC CABG CAD EuroSCORE LOS PLOS ROC STS

Area under the curve Coronary artery bypass graft Coronary artery disease European System for Cardiac Operative Risk Evaluation Length of stay Prolonged postoperative length of stay Receiver operating characteristic Society of Thoracic Surgeons

Resumo Objetivo: Relatar a experiência com o “Society of Thoracic Surgeons scoring system” em uma amostra de pacientes da população brasileira submetida a cirurgia de revascularização miocárdica isolada. Métodos: Foram coletados dados de janeiro de 2010 até dezembro de 2011 e analisados para determinar o desempenho do “Society of Thoracic Surgeons scoring system” na determinação de mortalidade e morbidade pós-operatória, utilizando o método da característica de operação do receptor (ROC-curve) e testes Chi-quadrado e Hosmer-Lemeshow para qualidade de ajuste. Das 1083 cirurgias cardíacas realizadas durante o período de estudo, 659 foram cirurgias de revascularização miocárdica que

Descritores: Controle de Risco. Procedimentos Cirúrgicos Cardiovasculares. Revascularização Miocárdica. Complicações Pós-Operatórias. Curva ROC.

INTRODUCTION

tion recorded in that bank, accurate risk scores for morbidity and mortality were developed with help of multiple logistic regression models [5,6]. For the North-American hospitals and surgical facilities who take part at the STS databank, uploading their detailed results is compensated by three-monthly structured performance reports produced and sent back by the society, along with a comprehensive comparison of their results with the entire databank [6]. For those medical professionals around the world who are not STS associated, an online calculator is available at their institutional website [7]. This internet tool enables cardiologists and surgeons all over the world to determine the risk scores for individual patients and prompts their teams for better control of risk factors leading to improved postoperative results. The present report aims to determine how finely the STS score system could predict complications and mortality in a set of consecutive patients of a private hospital in Brazil, considering that ethnic and socioeconomic characteristics might substantially differ from that of the North-American databank. This is therefore a preliminary analysis of adequacy and calibration of the STS methodology in a South-American population.

Coronary artery bypass graft (CABG) surgery has been a widely used modality of treatment for coronary artery disease (CAD) for the last few decades. Postoperative outcomes of CABG have progressively improved as a consequence of new technologies, surgical techniques, postoperative care, but also because of better control of specific risk factors, before, during and after surgery [1]. The burden of publications describing risk factors for a worse outcome evolved with the use of large sets of data collected from patients submitted to surgery over distinct periods of time. One important example to be cited is the European System for Cardiac Operative Risk Evaluation (EuroSCORE), a method largely used by many surgeons and clinicians around the world, to assess the risk of death following cardiac surgery [2]. In the late eighties, the Society of Thoracic Surgeons (STS) also started a visionary effort of collecting data from patients submitted to cardiothoracic surgery all over the United States of America which culminated with the development of the STS National Adult Cardiac Surgery Database, a databank that accounts for more than four and a half millions of surgically treated patients [3,4]. Using the informa-

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METHODS

the mathematical models and to calculate the risk rates were previously published in detail elsewhere [6]. We did not register any loss to follow-up.

Study design This is a single center and observational study, performed on consecutive patients who underwent coronary artery bypass surgery at the TotalCor Hospital, located in São Paulo, Brazil. The study was submitted to the local ethics committee that works in consonance with the Declaration of Helsinki, and approved as presented herein. Written and signed informed consent was waived, since the protocol consisted in a retrospective analysis of an institutional databank, ethical principles for medical research were entirely assured and no risks were added to that associated with the surgical treatment, as acknowledged by the Ethics Committee (protocol number: 461, approved at December, 28th 2011).

Statistics Continuous variables are shown as mean (standard deviation) if normally distributed or median (25-75 percentile) in the cases they don’t fit normality; categorical variables are displayed as absolute number and percentages. The accuracy (sensitivity and specificity) of the STS scores was tested in our population for each individual endpoint using the method of receiver operating characteristic (ROC) curve as described elsewhere [8]. In brief, sensitivity is plotted against “one minus specificity” (1 – specificity) for each value of a specific prognostic score. Area under the curve (AUC) is than calculated and statistically compared with a baseline AUC of 0.50 that indicates prediction no better than chance, and is represented by a diagonal line crossing the graphic area. The larger is the AUC (closer to 1.0), the higher is considered the capability of the method to predict outcomes. We considered AUC above 0.70 as the limit for adequate discrimination in our analysis. Endpoints that reached a low number of events (5 or less) were excluded from the analysis given the significantly high probability of methodological errors with low number of events. Adequacy between expected and observed endpoints for distinct quintiles of risk was additionally assessed using goodness of fit Chi-square test and the Hosmer-Lemeshow by logistic regression method. Both methods are based on the comparison of expected versus observed events using a Chi-square distribution and considering significance when the descriptive values of P are above the specified value, being in this case 0.05. For the remaining statistics, descriptive levels of P below 0.05 were considered as significant for any two-tailed tests.

Data management About two hundred distinct parameters of demographic, clinical and laboratorial nature are routinely collected for each patient who had undergone cardiac surgery in our hospital by a team of quality managers that feed an institutional databank of cardiac surgery on a daily basis. Data collection is performed ahead of the procedure, but also along the hospital stay and after hospital discharge, by telephone in the late postoperative period. Information from this institutional databank is routinely used to detect possible flaws on the treatment and to plan strategies to improve medical practice. Based on these data, STS scores are calculated online in the website as previously cited for each patient and stored as well in the databank. For the purpose of the present investigation, an electronic data-sheet with the relevant variables as extracted from the databank was generated and assessed using the methods described below. Table 1 shows a summary of the baseline clinical variables that were considered relevant for the study. The website calculator returns a list of estimated risk rates for nine distinct endpoints during the postoperative period, which are defined as follows: 1) operative mortality: death during the in-hospital stay following surgery, regardless of timing, or within 30 days of surgery; 2) permanent stroke (cerebrovascular accident): a central neurologic deficit persisting longer than 72 hours; 3) renal failure: requirement for dialysis or an increase of the serum creatinine to more than 2.0 mg/dL or double the most recent preoperative creatinine level; 4) prolonged mechanical ventilation (longer than 24 hours); 5) deep sternal wound infection (mediastinitis); 6) reoperation for any cause; 7) major morbidity or mortality that include any of the above mentioned events; 8) prolonged postoperative length of stay (PLOS): length of stay (LOS) longer than 14 days; and 9) short postoperative LOS (SLOS): LOS shorter than 6 days with patient alive at discharge. We assessed all nine endpoints as cited for the studied population. A detailed description of the methods used to develop

RESULTS From January 2010 to December 2011, one thousand eighty three (1083) patients underwent cardiothoracic surgery in the TotalCor Hospital. The mean age of that population was 61.4 years and 77% were men. Six hundred fifty nine (659) patients underwent isolated CABG surgery. The remaining subjects underwent valve replacement surgery (221 patients), aortic dissection surgery (30 patients), combined – aortic replacement plus CABG – procedures (133 patients), distinct procedures for congenital heart diseases and other cardiac interventions (40 patients). Overall mortality rate was 4.3% (47/1083), whereas in the isolated CABG group the observed mortality was 2.3% (15/659). Overall clinical and demographic characteristics of the CABG population are presented in Table 1. For those patients in this population where a concomitant cardiac illness (e.g.: mitral regurgitation and aortic stenosis) was diagnosed, it was con-

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sidered mild or of low risk and therefore not treated, at the discretion of the assistant surgeon. Analysis of sensitivity and specificity – Figure 1 shows the observed mortality in comparison to the mean expected mortality rate as calculated by the STS scoring system. Population was distributed by quintiles of expected events and according to the NCD definitions. General morbidity is displayed similarly in Figure 2. Goodness of fit Chi-Square

tests were performed for the end points total mortality and general morbidity and have shown no differences between the expected and the observed mortality (X2=6.78, P=0.56) or morbidity (X2=6.69, P=0.57). In addition, Hosmer-Lemeshow goodness of fit tests were performed and contingency tables for respectively mortality and morbidity are presented (Tables 2 and 3).

Fig. 2 – Observed (black columns) and expected (mean, white columns) general morbidity rates distributed according to the quintiles of expected mortality, as calculated by the STS scoring system. Goodness of fit Chi-square test has shown that the pattern of distribution of expected and observed morbidity rates did not significantly differ in the study population (X2=6.77, P=0.15)

Fig. 1 – Observed and expected (mean) mortality rates divided by quintiles of expected mortality, as calculated by the STS scoring system. Goodness of fit Chi-square test has shown that the pattern of distribution of expected and observed mortality did not significantly differ in the study population (X2=1.06, P=0.90)

Table 1. Baseline demographic and clinical characteristics of the studied population submitted to CABG procedures (659 patients) at TotalCor Hospital, between January, 2010 and December, 2011. Variable Patient age (years) Female Race (percent Caucasian) Obese or morbid obesity Diabetes Last creatinine level preoperatively (median; 25 - 75 percentile – mg/dL) Previous cardiac surgery Cerebrovascular disease Myocardial infarction (< 21 days prior to surgery) ST elevation or NST elevation on admission Arrhythmia Coronary vessels (three) Left main disease > or = 50% Ejection fraction < 40% Aortic stenosis Mitral insufficiency (mild) Status of the procedure (urgent or emergent)

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Frequency 61.2 24% 95% 26% 42% 1.0; 0.9 – 1.2 2.4% 1.8% 45% 43.3% 3.0% 91.5% 14.6% 4.2% 10% 30% 40%

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Table 2. Hosmer-Lemeshow contingence table for goodness of fit as determined for mortality in isolated CABG patients. Calculated Chi-square = 6.89 P=0.55. Survival Death Deciles of risk Total 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th

Observed 40 42 56 46 46 48 47 46 45 61

Expected 40.4 41.3 55.0 45.2 46.1 47.1 48.0 45.9 46.5 61.4

Observed 1 0 0 0 1 0 2 1 3 6

Expected 0.65 0.71 0.97 0.83 0.88 0.93 1.02 1.10 1.32 5.62

41 42 56 46 47 48 49 47 48 67

Table 3. Hosmer-Lemeshow contingence table for goodness of fit as determined for general morbidity in isolated CABG patients. Calculated Chi-square = 6.69 P=0.57. Deciles of risk 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th

Observed 47 48 44 47 44 44 40 40 38 23

Event free Expected 46.9 46.8 45.3 43.7 45.8 42.2 41.9 41.2 36.1 25.2

Any event Expected Observed 2.11 2 3.23 2 3.68 5 4.30 1 5.23 7 5.79 4 7.10 9 8.84 10 12.94 11 22.78 25

Total 49 50 49 48 51 48 49 50 49 48

Fig. 3 â&#x20AC;&#x201C; ROC-curves showing relation between sensitivity and 1-specificity for STS scoring system for seven postoperative outcomes measured: A) mortality; B) morbidity; C) renal failure; D) prolonged length of hospital stay; E) reoperation; F) prolonged mechanical ventilation and G) short length of hospital stay

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ROC-curves describing relation between sensitivity versus 1-specificity for seven, out of nine investigated endpoints, and the calculated area under the curve (AUC) for each measured complication are displayed in Figure 3. The estimated scores of risk have shown to accurately predict the occurrence of renal failure (AUC 0.79; P<0.001), prolonged ventilation (AUC 0.80; P<0.001), reoperation (AUC 0.76; P<0.001), total morbidity (AUC 0.75; P<0.001) and mortality (AUC 0.76; P<0.001). The use of calculated scores could not appropriately predict the occurrence of shortened length of stay (AUC 0.57; P=0.47), whereas permanent stroke and deep wound infection were not analyzed due to a low number of occurrences in the studied population. Although considered significant by the hypothesis test, prolonged length of hospital stay (AUC 0.68; P<0.001) cannot be considered as well predicted by the score due to an AUC bellow the pre-specified limit of 0.70.

profiles. Additionally, such tools can be used in order to assess and improve the quality of medical services, as well as to compare risk profiles amongst distinct populations [16,17]. Although risk prediction models are not specifically designed to calculate the risk of complications for individual patients, they have been largely used to help physicians on decision making, especially in the context of cardiothoracic surgery [10]. For all these possible applications, it is advisable to take into account the differences in the population features before using the models at sites far from that of the original cohort. It is acknowledged that differences in baseline variables, ethnic (or more specifically, genetically determined) characteristics, as well as environmental influences, might result in significant diversions in comparison to the original source cohort. As an example, Yap and colleagues assessed the use or the EuroSCORE in an Australian cohort different from the derivation cohort, and the calibration of the model in these new patients was considered poor [18]. Ideally, scores for risk estimation should be developed at each specific location, considering all the local genetic and environmental issues. Previous studies have investigated locally developed risk indexes in Brazilian populations, with variable success rates that are worth to be mentioned. Almeida et al. [19] have investigated distinct parameters as determinants of elevated risk after isolated CABG, but no prediction rule was proposed. Guaragna et al. [20] proposed a risk score for patients submitted to surgery for valve replacement and the model has shown to be very sensitive to detect the risk of death. Gomes et al. [21] also proposed in 2007 a score system based on information collected before surgery and in the first postoperative day, coming up with eight variables that have shown useful to predict mortality. However, none of these prediction models have been disseminated to use in clinical practice so far. The alternative approach might be to define the appropriateness of the scoring system of a previously developed model as described in this article. This means more specifically, to verify whether it can adequately fit to the clinical, demographic and environmental reality of the local population where it is intended to be used. Previously, a comparable approach was applied to assess the EuroSCORE in Brazilian population, showing satisfactory capability to predict death after CABG surgeries [22]. As we could observe after applying a similar methodology in our study the ROC curve has shown a highly significant area under the curve that represents a good discrimination for risk prediction for mortality and most of the studied endpoints. Additionally, the goodness of fit test has indicated that progressively increasing levels of risk as estimated by STSscore was associated with comparable and also increasing mortality rates, reinforcing the appropriateness of the method in terms of calibration for the studied population. Similar results could be as well observed for general morbidity which represents a summary of all nine adverse outcomes. For the majority of the individual endpoints we could also observe

DISCUSSION The use of the STS methodology is currently disseminated throughout the North-American hospitals, helping to improve the quality of cardiac surgery, as demonstrated by distinct publications [9-11]. Recently, STS databank subscription was opened for candidates outside the USA, and the first institution to participate as an international member was the TotalCor Hospital, a one-hundred beds facility, dedicated to the management of patients with cardiovascular diseases, located in Sao Paulo, Brazil. A couple of years before the agreement with STS Databank the hospital staff started to routinely use the online calculator at the STS-website for the determinations of the risk for a panel of possible complications for each individual patient. In parallel, risk scores and clinical, surgical and postoperative information were systematically recorded in an institutional database. Our study assessed these data and indicated that STS scoring system could be able to detect the risk of postoperative complications in our population. From the best of our knowledge it is the first time that the complete set of risk prediction scores is tested in a Brazilian sample and, considering the presented data, it is likely that STS methodology is useful as a tool to safely predict postoperative outcomes after CABG, although further evaluation on larger population samples are needed. Previously, other initiatives have tested individual aspects of the method for one single complication, namely wound sternal infection [12,13], but never in a similar number of subjects. Risk assessment of adverse outcomes using prediction models has been used in many distinct clinical situations in recent years, with remarkable applications in the prevention of postoperative complications [14-16]. Development these models involves gathering of data in large multicentric databanks and meticulous mathematical analysis with help of multiple logistic regression statistics [5,6]. The resulting score systems are useful to determine the risk of complications in populations that share similar risk

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good performance for the calculated scores, with large and statistically significant areas under the ROC curves.

REFERENCES 1. Greason KL, Schaff HV. Myocardial revascularization by coronary arterial bypass graft: past, present, and future. Curr Probl Cardiol. 2011;36(9):325-68.

Study limitations A few limitations of this study must be declared. First of all, our sample is not representative of the whole Brazilian population, as expected for a unicentric study. Second, the number of events for each endpoint is too small to unequivocally indicate the precision of the methods in our population. Additionally, for the endpoints stroke and mediastinitis, we were not able to calculate the accuracy using ROC curves, due to a low number of accounted events. Furthermore, our analysis has shown a low capability to predict short length of hospital stay that is likely to be explained by the current use in our institution to discharge patients in the sixth or seventh post-operative day, meaning that almost none of the patients in the sample left the hospital prior to that time point. Presently, however, in view of the current international trends and the understanding that such practice could possibly impact short and long term morbidity, efforts have been made in order to shorten the hospital length of stay to below six days in our institution. This single action represents well how the use of the STS scoring system might impact clinical practice in terms of postoperative care, and additionally, contribute to reduction of complications.

2. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9-13. 3. Anderson RP. First publications from the Society of Thoracic Surgeons National Database. Ann Thorac Surg. 1994;57(1):6-7. 4. Clark RE. The STS Cardiac Surgery National Database: an update. Ann Thorac Surg. 1995;59(6):1376-80. 5. O’Brien SM, Shahian DM, Filardo G, Ferraris VA, Haan CK, Rich JB, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2- isolated valve surgery. Ann Thorac Surg. 2009;88(1 Suppl):S23-42. 6. Shahian DM, O’Brien SM, Filardo G, Ferraris VA, Haan CK, Rich JB, et al. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1--coronary artery bypass grafting surgery. Ann Thorac Surg. 2009;88(1 Suppl):S2-22. 7. http://209.220.160.181/STSWebRiskCalc261/. STS Calculator. 2011.

CONCLUSION Concluding, we have shown that STS scoring system is well calibrated to be used in the studied population that was submitted to CABG procedures, being able detect mortality and the majority of the investigated outcomes. In addition, the statistical methods used in our analysis cannot substitute an accurate and long term observation of our own population, using appropriate databanks to develop mathematical methods that will represent local genetic and environmental characteristics.

8. Chambless LE, Diao G. Estimation of time-dependent area under the ROC curve for long-term risk prediction. Stat Med. 2006;25(20):3474-86. 9. Anderson RJ, O’Brien M, MaWhinney S, VillaNueva CB, Moritz TE, Sethi GK, et al. Renal failure predisposes patients to adverse outcome after coronary artery bypass surgery. VA Cooperative Study #5. Kidney Int. 1999;55(3):1057-62. 10. Ferguson TB Jr, Hammill BG, Peterson ED, DeLong ER, Grover FL; STS National Database Committee. A decade of change: risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: a report from the STS National Database Committee and the Duke Clinical Research Institute. Society of Thoracic Surgeons. Ann Thorac Surg. 2002;73(2):480-9.

Authors’ roles & responsibilities DTI VAF OG JCTG PGMBS MJR VF ACAB

Idealization of study, methodology defining, data analysis, writing of the manuscript, final approval Data collection, discussion of methodology, discussion and presentation of results, final approval Discussion of methodology and results, discussion and assistance in drafting the manuscript, final approval Data collection, methodology and discussion of results, discussion of the manuscript, final approval Review of manuscript, final approval Discussion of methodology and results, discussion and assistance in the composition of the manuscript, final approval Discussion of methodology and results, aid in the composition of the manuscript, final approval Idealization of work, methodology and discussion of results, discussion of the manuscript, final approval

11. Grover FL, Shroyer AL, Hammermeister K, Edwards FH, Ferguson TB Jr, Dziuban SW Jr, et al. A decade’s experience with quality improvement in cardiac surgery using the Veterans Affairs and Society of Thoracic Surgeons national databases. Ann Surg. 2001;234(4):464-72. 12. Farsky PS, Graner H, Duccini P, Zandonadi EC, Amato VL, Anger J, et al. Risk factors for sternal wound infections and application of the STS score in coronary artery bypass graft surgery. Rev Bras Cir Cardiovasc. 2011;26(4):624-9. 13. Strabelli TM, Stolf NA, Uip DE. Practical use of a risk assessment

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model for complications after cardiac surgery. Arq Bras Cardiol. 2008;91(5):342-7.

PD, et al. Validation of the EuroSCORE model in Australia. Eur J Cardiothorac Surg. 2006;29(4):441-6.

14. Ad N, Barnett SD, Speir AM. The performance of the EuroSCORE and the Society of Thoracic Surgeons mortality risk score: the gender factor. Interact Cardiovasc Thorac Surg. 2007;6(2):192-5.

19. Almeida FF, Barreto SM, Couto BR, Starling CE. Predictive factors of in-hospital mortality and of severe perioperative complications in myocardial revascularization surgery. Arq Bras Cardiol. 2003;80(1):51-60, 41-50.

15. Tzoulaki I, Liberopoulos G, Ioannidis JP. Assessment of claims of improved prediction beyond the Framingham risk score. JAMA. 2009;302(21):2345-52.

20. 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.

16. van Dieren S, Beulens JW, Kengne AP, Peelen LM, Rutten GE, Woodward M, et al. Prediction models for the risk of cardiovascular disease in patients with type 2 diabetes: a systematic review. Heart. 2012;98(5):360-9.

21. Gomes RV, Tura B, Mendonรงa Filho HT, Almeida Campos LA, Rouge A, Matos Nogueira PM, et al. A first postoperative day predictive score of mortality for cardiac surgery. Ann Thorac Cardiovasc Surg. 2007;13(3):159-64.

17. Braile DM, Monteiro R, Brandau R, Jatene FB. Risk prediction models: are they really necessary? Arq Bras Cardiol. 2010;95(6):677-8.

22. 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.

18. Yap CH, Reid C, Yii M, Rowland MA, Mohajeri M, Skillington

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Campos NLKL - Comparison of the occurrence of thromboembolic and ORIGINAL ARTICLE bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position

Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position Comparação da ocorrência de complicações tromboembólicas e hemorrágicas em pacientes portadores de prótese valvares cardíacas mecânicas com um e dois folhetos na posição mitral

Nelson Leonardo Kerdahi Leite de Campos1 MD

DOI: 10.5935/1678-9741.20140012

RBCCV 44205-1522

Abstract Introduction: Patients with mechanical heart valve prostheses must continuously be treated with oral anticoagulants to prevent thromboembolic events related to prosthetesis. These patients should be continually evaluated for the control of oral anticoagulation. Objective: To compare the occurrence of thromboembolic and hemorragic complications in patients with mechanical heart valve prosthesis with one (mono) and two (bi) leaflets in the mitral position in anticoagulant therapy. Methods: We studied the 10-year interval, 117 patients with prosthesis in the mitral position, 48 with prosthetic single leaflet and 69 with two leaflets. We evaluated the occurrence of thromboembolic and hemorrhagic major and minor degree under gravity. The results are presented in an actuarial study and the frequency of occurrence of linear events. Results: The actuarial survival curves showed that over

time, patients with prosthetic heart valve with one leaflet were less free of thromboembolic complications than patients with two leaflet prosthetic valve, while the latter (two leaflet) were less free of hemorrhagic accidents. The linearized frequency of occurrence of thromboembolism were higher in patients with mono leaflet prosthesis. Bleeding rates were higher for patients with bi leaflet prosthetic valve. Conclusion: Patients with mono leaflet prosthetic heart valve showed that they are more prone to the occurrence of serious thromboembolic events compared to those with bi leaflet prosthetic valve. Patients with bi leaflet prosthetic valve had more bleeding than patients with mono leaflet prosthetic valve, however this difference was restricted to the bleeding of minor nature.

1 – Faculty of Medicine of Botucatu, Paulista State University (FMB/UNESP), Botucatu, SP, Brazil.

This study was carried out at Faculty of Medicine of Botucatu, Paulista State University (FMB/UNESP), Botucatu, SP, Brazil

Descriptors: Anticoagulants. Embolism and Thrombosis. Hemorrhage. Heart Valve Prosthesis.

Correspondence address: Nelson Leonardo Kerdahi Leite de Campos Faculdade de Medicina de Botucatu - UNESP Avenida Prof. Montenegro, s/n - Distrito de Rubião Júnior Botucatu, SP, Brazil - Zip code: 18618-970 E-mail: ncampos@fmb.unesp.br

No financial support. Article received on September 19th, 2013 Article accepted on December 9th, 2013

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Campos NLKL - Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position

cardíacas mecânicas de um (mono) e de dois (bi) folhetos na posição mitral em terapêutica anticoagulante. Métodos: Foram estudados, no intervalo de 10 anos, 117 pacientes portadores de prótese na posição mitral, sendo 48 com próteses de folheto único e 69 de folheto duplo. Avaliou-se a ocorrência de complicações tromboembólicas e hemorrágicas de grau maior e menor de acordo com a gravidade. Os resultados estão apresentados sob forma de estudo atuarial e de frequência linearizada de ocorrência de eventos. Resultados: As curvas atuariais mostraram que, ao longo do tempo, os pacientes portadores de próteses valvares monofolheto estiveram menos livres de complicações tromboembólicas que os pacientes com próteses bifolheto, enquanto que, estes últimos (bifolheto) estiveram menos livres de acidentes hemorrágicos. As frequências linearizadas de ocorrência para tromboembolismo foram maiores nos pacientes com próteses monofolheto. Nos episódios hemorrágicos as taxas foram maiores para os portadores de próteses bifolheto. Conclusão: Os portadores de próteses valvares cardíacas monofolheto mostraram-se mais propensos à ocorrência de acidentes tromboembólicos graves em relação aos com próteses bi folheto. Os pacientes com prótese bifolheto apresentaram maior sangramento que os pacientes com prótese monofolheto, no entanto, esta diferença se restringiu aos sangramentos de pouca gravidade.

Abbreviations, acronyms & symbols ICVA Bi EP FHE FHM FHm LLCI95% FAE ULCI95% FTE FTM FTm Mo FPH INR

Ischemic cerebrovascular ischemic Bi-leaflet Prosthesis Standard error Patients free of hemorrhagic and potentially hemorrhagic events Patients free of major hemorrhagic events Patients free of minor bleeding events Lower limit of 95% Confidence interval Patients free of any type of event Lower limit of 95% Confidence interval Patients free of thromboembolic events Patients free of major thromboembolic events Patients free of minor thromboembolic events Mono-leaflet Prostheses Patients free of potentially hemorrhagic events International Normalization Ratio

Resumo Introdução: Pacientes portadores de próteses valvares cardíacas mecânicas devem medicados continuamente com anticoagulantes orais para evitar acidentes tromboembólicos. Estes pacientes são avaliados continuamente para o controle da anticoagulação oral. Objetivo: Comparar a ocorrência de complicações tromboembólicas e hemorrágicas em portadores de próteses valvares

Descritores: Anticoagulantes. Embolia e Trombose. Hemorragia. Próteses Valvulares Cardíacas.

INTRODUCTION

tion between the previous two. However, in patients with adequate anticoagulation, the incidence of thrombosis is similar for the three types of mechanical [3] prostheses. For Lavitola et al. [4] in certain situations, in patients with mitral bioprosthesis in the presence of atrial fibrillation, where is commonly indicated prophylaxis with oral anticoagulants, the replacement of the anticoagulant by aspirin could be considered. However, for mechanical prostheses, continuous oral administration of antivitamin K would always be indispensable, with or without concomitant atrial fibrillation. Bussey [5] states that many studies do not consider some factors that influence the thrombogenicity, among them, the prosthesis structure (type). Currently, the use of mechanical heart valve prostheses is performed almost in its entirety with bileaflet prostheses. The mono-leaflet prostheses were out of use in cardiac surgery for valve performance problems and other complications in some models more than other types of prostheses. In 1986, for example, the convexo-concave Bjork-Shiley

The implantation of mechanical heart valve prosthesis requires the need for continuous use of oral anticoagulants for its potential thrombogenicity and thromboembolism [1]. An individualized approach in the monitoring of patients with mechanical heart valve prosthesis receiving oral anticoagulation is essential to obtain satisfactory results in the control of oral anticoagulation. Besides the type of prosthesis used, the risks inherent in each patient to thromboembolism, bleeding, and the anatomical position of the prosthesis are also important [2]. The mechanical heart valve prostheses have been produced since the 1950s and are primarily made of metal and carbon alloy after being classified as prosthetic cage- balltype, single disc (or mono-leaflet or uni-leaflet) and double disc (or bi-leaflet). Those with higher thrombogenic potential are the cage-ball and those with lower thrombogenicity are the bi-leaflet, and the bi-leaflet valve prostheses are in posi-

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Campos NLKL - Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position

prosthesis stopped being used due to reports of the fracture ring, and embolization resulting in displacement of the plate [3]. For many years, the mechanical mono-leaflet prosthesis has not been used in our cardiovascular surgery service, which made gradually decrease the number of patients with this type of prosthesis with respect to bi-leaflet prostheses. However, many of the patients followed for control of anticoagulation carries prosthesis with single disc and will continue this behavior permanently. Several studies have assessed the occurrence of thromboembolic and bleeding complications in patients with mechanical mono-leaflet heart valve prostheses [6-9] and double bi-leaflet [10,11], however, without comparing the two types of prosthesis. Then, we perform a particular study comparing patients with mono- and bi-leaflet prosthesis in the mitral position, given that patients have no cage-ball in this position. We question whether a prosthesis of different model, supposedly developed with most advanced technology could indeed cause less thromboembolic and bleeding complications than other older models.

Chart 1. Models of mechanical heart valve prostheses implanted. Model Bicarbon St Jude Medical Omnicarbon Omniscience Sorin-mono Lilliehi-Kaster Edwards Hall-Kaster TOTAL

Mitral 46 23 17 15 13 1 1 1 117

Age and gender As the study performed follow-up of patients over a period of time, it was considered the standard for each patient his age at the time of implant surgery prosthesis. The mean age of patients was 40.97 years. 84 women and 33 men participated. Mean age of 41.12 years for women and 40.58 years for men.

METHODS

Patients excluded from the study Patients in whom it has not been possible to obtain sufficient or reliable data for the study were excluded from the study.

Outpatient data and hospital records of patients with mechanical heart valve prostheses in the mitral position were obtained, followed-up in the Outpatient Anticoagulation Control Unit, Clinics Hospital, Faculty of Medicine of Botucatu, UNESP. Due to the fall into disuse in our service, the mono-leaflet mechanical prostheses (or uni-leaflet or single disc) in 1995, the interval between January 1, 1993 to December 31 (ten years) 2002 was established because it is a period in which the number of patients with the two types of prostheses, with regular visits at the clinic, allows a better comparison of the data. After the above mentioned period, only came into monitoring patients with double leaflet prostheses (or bi-leaflet), which limited the entry of new patients and the expansion of the observation period. All data were collected and organized by the same researcher. This study was approved by the Research Ethics Committee of the Faculty of Medicine of Botucatu - SĂŁo Paulo State University - UNESP, under CEP registry OF605/2006. The patients signed a written informed consent for the use of their records and service forms before the beginning of data collection, as required by the Ethics and Research Committee.

The outpatient anticoagulation control During the consultations,the guidance on care and importance of anticoagulation are strengthened, trying to leave no doubt in understanding the dose of anticoagulant to be used. Patients should be cautioned about signs of bleeding, and if it occurs, they should seek the Emergency Room of the Clinics Hospital immediately. Patients with significant complaints or signs related to anticoagulation, as well as greatly increased INR (even without bleeding), hospitalized in Cardiovascular Surgery Nursery. When hospitalization is necessary, but there are complaints of minor bleeding or other less significant changes, a return is scheduled as soon as possible, as the case requires. When the patientâ&#x20AC;&#x2122;s INR is well controlled, a monthly return is scheduled. Deviations of INR require returns in smaller spaces of time. In general, patients who have about four returns with satisfactory INR (four months), will have returns every two months. Patients who, for some reason, come in search of care are met, even if they are not scheduled for that day. We considered the ranges of INR desired at each visit for patients with prosthetic valves in the mitral position at INR 2.50-3.50.

Patients Number of Patients In this study, 117 patients with prosthesis in the mitral position, of which 48 prostheses were mono-leaflet and 69 bi-leaflet (Chart 1) were included. During the study period, patients made use of two types of anticoagulants: warfarin and phenprocoumon.

Groups Those with mechanical prosthetic valve in the mitral po-

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sition were divided into two groups: 1 ) Mono: patients with mono-leaflet prosthesis (or single leaflet), and 2) Bi: patients with bi-leaflet prostheses or two leaflets (or double-leaflet).

used the Statistical Calculations For Windows V. 1.8 software developed by Dr. Domingo Marcolino Braile and Dr. Moacir Fernandes de Godoy and implemented in Power Builder 6.5 by M. S. Djalma Domingos da Silva. For construction of actuarial curves, the Microsoft Excel program was used.

Complications Complications type Complications were divided into thromboembolic complications (major and minor) and bleeding (major and minor).

Division of patients according to the occurrence of complications for the actuarial study For actuarial study, patients were divided according to the occurrence of complications as follows: Patients free of any event: free of bleeding thromboembolic events and potentially bleeding. Patients free of thromboembolic events: free of major or minor thromboembolic complications events. Patients free of major thromboembolic events: free of major thromboembolic complications events. Patients free of minor thromboembolic events: free of minor thromboembolic complications events. Patients free of bleeding or potentially bleeding events: free of major or minor bleeding complications events. It is noteworthy that in the patients who despite not having found effective bleeding, the occurrence of episodes with INR greater than or equal to 7.0 in consultation in the Ambulatory of Anticoagulation Control was considered as a complication. In actuarial study, due to the use of “event-free” terms, we preferred herein to call these episodes as “episodes or potentially bleeding events”. Patients free of major bleeding events: free of major bleeding complications events. Patients free of minor bleeding events or potentially bleeding events: considering here the increase of PT equal to or greater than 7.0 a minor complication compared to major bleeding; then the patients free of this type of event were grouped to patients free of minor bleeding events. Patients free of minor bleeding events: patients who effectively had no minor bleeding events.

Thromboembolic Complication: Any kind of complication in which the patient’s records showed evidence on the occurrence of thromboembolic episodes. Major thromboembolic complications: severe episodes requiring hospital treatment, and may or may not have left sequelae. Event types: ischemic stroke, acute arterial occlusion in limbs, prosthetic heart valve thrombosis. Minor thromboembolic complications: Episodes of low gravity, which allowed treatment and outpatient. Event type: transient ischemic attack. Hemorrhagic Complication: Any kind of complication in which the patient’s records showed evidence on the occurrence of bleeding episode. Major hemorrhagic complications: severe episodes requiring hospital treatment, and may or may not have left sequelae. Event types: severe vascular hematuria, muscle bleeding in LL (bruising), vaginal bleeding (uterine), hemoperitoneum, hemopericardium, upper gastrointestinal bleeding, hemorrhagic stroke, intestinal bleeding, retroperitoneal hematoma and severe bleeding in tongue. Minor hemorrhagic complications: Minor episodes that usually allowed treatment and outpatient. Event types: purple spots on skin, epistaxis, hematuria, vaginal bleeding, minor bleeding in stools, mild ocular bleeding, mild hemoptysis, gingival bleeding, hematoma in post-surgical pacemaker incision, mild stomach bleeding, outpatient visits on which INR greater than or equal to 7.0 were observed without effective bleeding.

Actuarial calculations For actuarial studies, the following calculations, presented in tables, were made together with the curves: Proportion of free event (PFE%); standard error (SE%), lower limit of 95% confidence interval (LLCI95%) and upper limit of 95 % confidence interval (ULCI95%).

Potentially hemorrhagic complications: The outpatient visits in which INR greater than or equal to 7.0 were observed were considered potentially bleeding episode, though there was no effective bleeding.

Complications – Linearized index of occurrence of events - calculations of the number of patient-years event In calculating the complications patient-year, we consider the number of events. We emphasize that the same patient may have contributed to more than one event. Each patient contributed with different time intervals in the study. The sum of years of follow-up for each patient was 505.77 years, with 129 events in total.

Complications - Calculations and Actuarial curves In the study on the occurrence of complications calculations and actuarial curves were also used, which show the percentage of patients free of events throughout the study. To aid in the actuarial calculations, we

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The Linearized rates of occurrence of events were calculated:

Notes - The definitions of the events are the same as those found in relation to curves and actuarial calculations. - For the calculations of Events Patient/Year, we included one more subdivision of bleeding complications, “potentially bleeding events” alone, or that is, outpatient visits in which INR equal to or greater than 7.0 were observed without effective bleeding.

Bleeding events Major bleeding events Minor events Bleeding or potentially bleeding events Major bleeding events Minor bleeding events or potentially bleeding Minor bleeding events Potentially bleeding events

RESULTS

To compare mono- and bi-leaflet prostheses for number of events per 100 patients/year a linear generalized model was adjusted with Poisson distribution, considering the effects of hemorrhage thromboembolism with its subdivisions, according to Wald ‘s multiple comparison test.

Figure 1 shows the curves and actuarial calculations to patients free of any type of event to allow comparison between patients with mono- and bi-leaflet prostheses. In Figures 2, 3 and 4 we found the curves and actuarial calculations for patients free of any thromboembolic events, minor and major thromboembolic events, respectively for patients with monoand bi-leaflet prostheses.

Fig. 1 - Curves and actuarial data showing the percentage of patients free from any type of event FAE (ordinate) with time - years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

Fig. 2 - Curves and actuarial data showing the percentage of patients free of thromboembolic events FT (ordinate) with time - years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

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Fig. 3 - Curves and actuarial data showing the percentage of patients free of major thromboembolic events FMT (ordinate) with time - years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

Fig. 4 - Curves and actuarial data showing the percentage of patients free of minor thromboembolic events mTE (ordinate) with time-years ( abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

Table 1. Number of events per year patients/year. Data obtained by the inclusion of all patients in the study.

per 100 patients/year for patients with mono- and bi-leaflet prostheses.

Number of events per 100 patients/year Mono-leaflet prostesis Bi-leaflet prosthesis TNE 20.95 30.42 Total 2.67 1.23 T Major 1.90 0.82 Minor 0.7 0.41 Total 18.22 29.19 Major 3.05 3.29 H Minor or Ph 15.24 25.90 Minor 5.71 11.51 Ph 9.25 14.39

DISCUSSION

P 0.1890 0.4769 0.5248 0.7856 0.1144 0.9241 0.1005 0.1708 0.2944

According to â&#x20AC;&#x153;2008 focused update incorpored into the ACC/AHA 2006 - Guidelines for the manegament of Patientes with valvar heart diseaseâ&#x20AC;? [ 1 ] in patients with mechanical prosthesis in the mitral position is recommended higher level of anticoagulation than in patients with aortic prostheses based at greater risk of thrombogenicity in this location, and in any type of mechanical prosthetic mitral valve the PT (INR) should remain between 2.5 and 3.5, and this was the behavior adopted in our clinic. We have been studying the results of oral anticoagulation in Outpatient Oral Anticoagulation Control of the Faculty of Medicine of Botucatu - UNESP for a period of 10 years on several aspects, among which, we found that only about one third of patients remain with Time prothrombin time (PT) and International Normalized ratio (INR) within the desired range in at least half of their behaviors, and that these patients were more free of occurrence of thromboembolic and bleeding complications, with a smaller number of these events in relation to the other [12].

NTE: number of total events; B: bleeding events, H: hemorrhagic events, PHE: potentially hemorrhagic event (INR greater than or equal to 7.0). P = significance (P <0.05)

The results of the actuarial study with the curves and actuarial calculations from bleeding and potentially bleeding events and their subdivisions in major, minor and potentially bleeding and minor events, for both types of prostheses studied are shown in Figures 5, 6, 7 and 8. Table 1 shows the linearized occurrence rates of events for complications and their subdivisions in number of events

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Fig. 5 - Curves and actuarial data showing the percentage of patients free of bleeding and potentially bleeding PB (ordinate) with time - years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval.

Fig. 6 - Curves and actuarial data showing the percentage of patients free of major bleeding events MBE (ordinate) with time-years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

The occurrence of temporary fluctuations in the levels of prophylactic anticoagulation in patients with mechanical heart valve prosthesis leads to increased risk of embolism, since the thrombus forms more easily. When the subtherapeutic anticoagulation levels decrease, followed by increases to the desired levels occur, the thrombus becomes less adherent to the surface of the valve, so it can embolize more readily [13]. Oral anticoagulation in patients with mechanical heart valve prostheses aiming to antithrombotic prophylaxis requires differential control of prothrombin time (PT - INR or International Normalization Ratio) according to the position of the prosthesis. In the aortic position, the flow through the valve is comparatively faster and causes more stress when compared to the mitral position, especially in cases of mitral stenosis with increase of pre-existing left atrium implant. In the case of flow with marked acceleration of the blood (aortic position), platelets are activated and that the erythrocyte membranes are damaged, affecting the release of ADP-enhanced platelet activation and aggregation, with a secondary

role to involvement of coagulation factors in the thrombotic potential. In the prosthesis in the mitral position, where the flow through the valve is comparatively slow, higher stasis and prolonged contact of coagulation factors with the surface of the prosthesis occurs, and in this case with the minor contribution of platelets in relation to coagulation factors in thrombogenic potential [14]. In heart valve prostheses, thrombi, mostly are formed in the suture ring, at the site of greatest tissue growth, toward the valve opening, which can result in embolism. In prosthetic cage, the thrombus may also be formed in the apex of the cage. With repeated ball impact, pieces of the thrombus may become loose, causing embolic episodes of repetition, and in this type of prosthesis thrombosis with immobilization of the ball is less common. In single and double disc prosthesis, however, the thrombus may extend to local support and joints, causing their locking and embolism is the less frequent [15-17]. In the literature, assessments of the occurrence of complications by oral anticoagulation in patients with prosthetic

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Campos NLKL - Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position

Fig. 7 - Curves and actuarial data showing the percentage of patients free of minor bleeding or potentially bleeding events mBE or PB (ordinate) with time - years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

Fig. 8 - Curves and actuarial data showing the percentage of patients free from minor bleeding events mBE (ordinate) with time - years (abscissa) for both types of prostheses studied. Mo = Mono-leaflet prosthesis; Bi = Bi-leaflet prosthesis; SE = standard error range; LLCI95% = lower limit of 95% Confidence Interval and ULCI95 % = Upper Limit of 95% Confidence Interval

heart valves are mostly retrospective due to ethics and compliance time for the occurrence of complications. In the case of the involvement of single disc prosthesis, often collections of data from earlier periods were done well, or that is, closer to the time of implantation of the prosthesis periods, as shown in the case in the study by Florez et al. [6] with Omnicarbon prostheses (mono-leaflet) in aortic, mitral and mitral-aortic positions between April 1985 and May 1995 (10 years ). Similarly, in our study we had to choose a period in which there was greater availability of patients with mono-leaflet prostheses with regular controls of anticoagulation, which allowed better comparison with bi-leaflet prostheses (from January 1, 1993 to December 31 2002), this time that also corresponds most closely to routine implants of uni-leaflet prostheses. We ponder the significance of this comparison between the two types of prostheses lies mainly in the fact that many patients with single-disk prostheses continue and will continue to attend our clinic. In this study, when comparing the actuarial curves of mitral mechanical prostheses and mono-leaflet (Figure 1) we observed that patients with mono-leaflet prostheses (FAE Mo)

were more free from any kind of event with the passage of time, than patients with bileaflet prostheses (FAE Bi). When we assess only the total bleeding events (T) ( Figure 2 ), the position of the curves is reversed, leaving those with bi-leaflet prostheses freer from these events. The same presentation can be found for curves that consider only the major bleeding events (MBE) ( Figure 3). In the case of minor bleeding events (mBE) ( Figure 4 ), the curves are very close and the small number of patients should be considered here, which may have affected this analysis. When assessing these curves we found that patients with bi-leaflet prostheses were most affected by complications in total, but were more free of bleeding complications. In Figure 5, we observe that the actuarial curve of bi-leaflet prosthesis is positioned below the curve of mono-leaflet, indicating less involvement of the latter in total bleeding complications or potentially bleeding (PB). In the most serious bleeding complications, or that is, higher bleeding, there was an alternation of positions of the two curves, both positioned next and at the upper portion of the graph showing that fewer patients has been achieved in this type of complications. The

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major differences between the two groups of prostheses in relation to bleeding cases, become more restricted to the minor bleeding or potentially bleeding (mB or PB) (Figure 7) and the minor bleedings (min) alone (Figure 8), and the patients with bi-leaflet valvular prostheses were more subject to these minor bleeding complications. The results found help us to reinforce the assertion by Vongpatanasin et. al. [3] on the single-disk mechanical heart valve prostheses would present more thrombogenic potential than those of double-disc. Misawa et al. [7] assessing the experience of 14 years of use of 57 Omnicarbon prostheses (mono-leaflet) found at the end of 10 years, 80% of patients with prosthesis in the mitral position free of bleeding events. Butchart et al. [8] presented a report of 20 years experience with Meditronic Hall prosthetic valve (mono-leaflet) in the mitral position in 796 cases. At the end of 10 years, 77% of patients remained free of bleeding events. At the end of 10 years, Misawa et al. [8] found 92% of patients with mitral prosthesis free of severe bleeding (major). In the study with mono-leaflet prostheses (Meditronic Hall) Butchart et al. [9] the percentage of patients free of major bleeding events after 10 years was 87% in the mitral position. In the study by Florez et. al. [6] with Omnicarbon mono-leaflet prosthetic valves in aortic, mitral and mitral-aortic positions over a period of ten years, curiously, only bleeding complications in patients with mitro-aortic prostheses are mentioned, not occurring with prostheses in mitral and aortic position alone. 97.6% of mitral-aortic patients were free of bleeding events in 10 years, with no prosthetic thrombosis. Patients with prosthesis in the mitral position also showed no bleeding complications, and 94.2% of the aortic group and 92.3% of mitral-aortic valves were free of significant bleeding after 10 years. Ikonomidis et al. [10] published results of implantation of St. Jude Medical cardiac valve prostheses (bi-leaflet) between January 1979 and December 2000. Actuarial calculations showed that, after 10 years, 80% of mitral were free of any bleeding event, and after 20 years of follow-up, 71%. 86% of mitral were free of bleeding episodes (not specified if totals, higher or lower) after 10 years and, after 20 years, 65%. Then, we can compare our actuarial data with some others in the literature, but in the studies cited there is no comparison between the two types of mechanical prostheses, as it was done in this study. In the series by Misawa et al. [7], with mono-leaflet prostheses, linearized incidence rates for events in the first 5 years for any bleeding event was 2.28 per 100 patient -years in the mitral position. In major bleeding events showed 1.02 per 100 patient-years in the mitral position. Butchart et al. [8] in the study also with mono-leaflet

prostheses showed linearized incidence rates for bleeding events in 20 years from 4.0 per 100 patient-years in the mitral position. The major bleeding events were classified as ischemic strokes (ischemic stroke), and therefore shows the incidence rates of ischemic stroke of 0.8 per 100 patient-years; minor bleeding events: 3.2 per 100 patient-years and major bleeding events were 1.4 per 100 patient-years. Florez et al. [6] assessing mono-leaflet prostheses show linearized incidence rates for events from 0 for bleeding events in patients with prostheses in mitral and aortic positions alone and 0.4 per 100 patient-years in mitral-aortic. From bleeding, the rates were 0 for mitral, 0.6 for aortic and 0.8 per 100 patient-year for mitral-aortic. In the study of Ikonomidis et al. [10] with bi-leaflet prostheses, the linearized incidence rates for bleeding events after 20 years was 3.4 per 100 patient-year for mitral. In bleeding events (not specified whether minor or major) at the end of 10 years of 2.2 per 100 patient-years for mitral, and after 20 years: 1.8 per 100 patient-years. Braile et al. [9], in Brazil, studied complications in 126 mitral mono-leaflet mechanical prostheses of some types (Bjรถrk-Shiley 49, 71 Liliehei-Kaster, 6 Hall-Kaster), with all patients receiving oral anticoagulants. The incidence of thrombosis and thromboembolism was 7.7 per 100 patient-years for patients with Bjรถrk-Shiley, 5.6 and 6.7 per 100 patient-years for those with Liliehei-Kaster and Hall-Kaster prostheses, respectively. The linearized incidence rates for events found in the literature did not compare mono- and bi-leaflet prostheses. In our assessment on the number of occurrences per 100 patients/year, according to Table 1, despite the numerical differences in the P value, no statistically significant differences between the two types of prostheses studied were observed, considering thromboembolic and bleeding effects and their subdivisions, after Poisson statistical adjustment. We should consider some limitations in this study because it was a retrospective study, in which part of the patients carries a type of heart valve prosthesis that virtually is no longer in use, and that the most important or serious complications can take a long time to occur (sometimes years), which makes difficult a prospective study in the area. CONCLUSION According the actuarial study we found that patients with mono-leaflet prosthetic heart valves in the mitral position were more prone to serious thromboembolic events compared to those with bi-leaflet prostheses. Patients with bi-leaflet mechanical heart valve prostheses in the mitral position were less free from bleeding accidents than patients with single-disc prosthetic valves. These differences, however, were more significant in minor bleeding episodes, without significant clinical signs.

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Campos NLKL - Comparison of the occurrence of thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis with one and two leaflets in the mitral position

8. Butchart EG, LI HH, Payne N, Buchan K, Grunkemeier GL. Twenty years’ experience with the Medtronic Hall valve. J Throrac Cardiovasc. Surg. 2001;121(6):1090-100.

Author’s role and responsibilities NLKLC

Data survey and writing

9. Braile DM, Ardito RV, Zaiantchick M, Santos JLV, Campos NLK, Jacob JLB, et al. Estudo comparativo entre válvulas biológicas e válvulas mecânicas nas posições mitral ou aórtica até 14 anos. Rev Bras Cir Cardiovasc. 1988;3(3):141-58.

REFERENCES

10. Ikonomidis JS, Kratz JM, Crumb AJ 3rd, Stroud MR, Bradley SM, Sade RM, et al. Twenty-year experience with the St Jude Medical mechanical valve prosthesis. J Thorac Cardiovasc Surg. 2003;126(6):2022-31.

1. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, et al.; 2006 Writing Committee Members; American College of Cardiology/American Heart Association Task Force. 2008 Focused update incorporated into the ACC/ AHA 2006 guidelines for the management of patients with valvar 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): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118(15):e523-e661.

11. Brandão CMA, Pomerantzeff PMA, Cunha CR, Morales JIE, Puig LB, Grinberg M, et al. Substituição valvar com próteses mecânicas de duplo folheto. Rev Bras Cir Cardiovasc. 2000;15(3):227-33. 12. Campos NLKL, Andrade RR, Silva MAM. Anticoagulação oral em portadores de próteses valvares cardíacas mecânicas. Experiência de 10 anos. Rev Bras Cir Cardiovasc. 2010;25(4):457-65.

2. Emery RW, Emery AM, Raikar GV, Shake JG. Anticoagulation for mechanical heart valves: a role for patient based therapy. J Thromb Thrombolysis. 2008;25(1):18-25.

13. Madras PN, Thomson CL, Johnson WR. The effect of Coumadin upon thrombus forming on foreign surfaces. Artif Organs. 1980;4(3):192-8.

3. Vongpatanasin W, Hills LD, Lange RA. Prosthetic Heart Valves. N Engl J Med. 1996;335(6):407-16.

14. Becker RC, Eisenberg P, Turpie AG. Pathobiologic features and prevention of thrombotic complications associated with prosthetic heart valves: fundamental principles and the contribution of platelets and thrombin. Am Heart J. 2001;141(6):1025-37.

4. Lavitola PL, Sampaio RO, Oliveira WA, Bôer BN, Tarasouchtchi F, Spina GS, et al. Varfarina ou aspirina na prevenção de fenômenos embólicos na valvopatia mitral com fibrilação atrial. Arq Bras Cardiol . 2010;95(6):749-55.

15. Acar J, Enriquez-Sarano M, Farah E, Kassab R, Tubiana P, Roger V. Recurrent systemic embolic events with valve prosthesis. Eur Heart J. 1984;5Suppl D:35-8.

5. Bussey H. Better delivery of standard antithrombotic care. Am Heart J. 2001;141(6):1038-42.

16. Metzdorff MT, Grunkemeier GL, Pinson CW, Starr A. Thrombosis of mechanical cardiac valves: a qualitative comparison of the silastic ball valve and tilting disc valve. J Am Coll Cardiol. 1984;4(1):50-3.

6. Florez S, Di Stefano S, Carracal Y, Buatamante J, Fulquet E, Echevarria JR, et al. Valve replacement with the Omnicarbon valve prosthesis: a 10-year follow-up. Arq Bras Cardiol. 2005;84(5):371-5.

17. Björk VO, Wilson GJ, Sternlieb JJ, Kaminsky DB. The porous metal-surfaced heart valve. Long-term study without long-term anticoagulation in mitral position in goats. J Thorac Cardiovasc Surg. 1988;95(6):1067-82.

7. Misawa Y, Fuse K, Saito T, Konishi H, Oki SI. Fourteen year experience with the omnicarbon prosthetic heart valve. ASAIO J. 2001;47(6):677-82.

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Leite ACE, etORIGINAL al. - Effects of periodontal therapy on C-reactive protein and ARTICLE HDL in serum of subjects with periodontitis

Effects of periodontal therapy on C-reactive protein and HDL in serum of subjects with periodontitis Efeitos da terapia periodontal sobre proteína C-reativa e HDL no soro de indivíduos com periodontite

Anne Carolina Eleutério Leite1, MsC; Valéria Martins de Araújo Carneiro1, PhD; Maria do Carmo Machado Guimarães1, PhD

DOI: 10.5935/1678-9741.20140013

RBCCV 44205-1523

Abstract Objective: To investigate the effects of nonsurgical periodontal therapy on levels of high-sensitivity C-reactive protein in the sera and its association with body mass index and high density lipoprotein in subjects with severe periodontitis. Methods: Sera from 28 subjects (mean age: 34.36±6.24; 32% men) with severe periodontitis and 27 healthy controls (mean age: 33.18±6.42; 33% men) were collected prior to periodontal therapy. Blood samples were obtained from 23 subjects who completed therapy (9-12 months). Oral and systemic parameters such as the number of blood cells, glucose examination, lipid profile, and high-sensitivity C-reactive protein levels accessed by high-sensitivity immunonephelometry assay, were included. Results: Before therapy, in the periodontitis group, the ratio of subjects with high-sensitivity C-reactive protein <0.3 mg/ dL was statistically lower than in the control group (P<0.0216).

After therapy, the ratio of subjects with high-sensitivity C-reactive protein <0.3 mg/dL was significantly higher (65.22%) (P<0.0339). The mean value for body mass index was statistically lower in subjects with high-sensitivity C-reactive protein <0.3 mg/dL (24.63±4.19), compared with those with high-sensitivity C-reactive protein ≥0.3 mg/dL (28.91±6.03) (P<0.0411). High density lipoprotein presented a mean value statistically higher after therapy (P<0.0027). Conclusion: In systemically healthy subjects with periodontitis, periodontal therapy was associated with decreased levels of circulating high-sensitivity C-reactive protein and increase of high density lipoprotein in serum. The clinical trial was registered at http://www.clinicaltrials.gov.br/, No. RBR-24T799.

1. Brasília University (UnB-DF), Brasília, DF, Brazil.

This study was carried out at Universidade de Brasília (UnB-DF), Faculdade de Ciências da Saúde (FS), Brasília, DF, Brazil.

Descriptors: C-Reactive Protein. Periodontal Diseases. Cardiovascular Diseases.

Correspondence address: Anne Carolina Eleutério Leite Brasília Shopping Torre Norte – Sala 825 – Asa Norte – Brasília, DF, Brazil – Zip code: 70715-000 E-mail: annecarolinaleite@gmail.com

No financial support. Article received on November 14th, 2013 Article accepted on January 6th, 2014

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Leite ACE, et al. - Effects of periodontal therapy on C-reactive protein and HDL in serum of subjects with periodontitis

(idade média: 33,18±6,42; 33% homens) foi coletado antes da terapia periodontal. Novas amostras de sangue foram obtidas dos 23 indivíduos que completaram o tratamento periodontal (entre 9-12 meses após). Parâmetros bucais e sistêmicos, tais como contagem do número de células do sangue, exame complementar de glicose, lipidograma e níveis de proteína C-reativa ultrassensível, acessados pelo método de nefelometria (imunonefelometria ultrassensível) foram incluídos. Resultados: Antes da terapia, a proporção de indivíduos com proteína C-reativa ultrassensível <0,3 mg/dL no grupo periodontite foi estatisticamente menor que a proporção de indivíduos com proteína C-reativa ultrassensível <0,3 mg/ dL nos controles (P<0,0216). Após a terapia, a proporção de indivíduos com proteína C-reativa ultrassensível <0,3 mg/dL foi estatisticamente maior (65,22%) (P<0,0339). O valor médio para índice de massa corporal foi estatisticamente menor nos indivíduos com proteína C-reativa ultrassensível <0,3 mg/ dL (24,63±4,19), comparados àqueles com proteína C-reativa ultrassensível ≥0,3 mg/dL (28,91±6,03) (P<0,0411). O colesterol lipoproteína de alta densidade pós-terapia apresentou valor médio estatisticamente maior (P<0,0027). Conclusão: Em indivíduos com periodontite e saudáveis sistemicamente, a terapia periodontal foi associada com o decréscimo dos níveis de proteína C-reativa ultrassensível circulante no soro e aumento de lipoproteína de alta densidade. O ensaio clínico foi registrado no http://www.clinicaltrials.gov. br/, No. RBR-24T799.

Abbreviations, acronyms & symbols Aa BMI BOP CAL CG CRP CVD HDL hs-CRP LDL NSPT NT PD PG Pg PI Pi PT SPT Tf

Aggregatibacter actinomycetemcomitans Body mass index Bleeding on probing Clinical attachment level Control group C-reactive protein Cardiovascular disease High density lipoprotein High-sensitivity C-reactive protein Low-density lipoprotein Nonsurgical periodontal therapy Number of teeth Probing depths Periodontitis group Porphyromonas gingivalis Plaque index Prevotella intermedia Periodontal therapy Supportive periodontal therapy Tannerella forsythia

Resumo Objetivo: Investigar os efeitos da terapia periodontal não cirúrgica sobre níveis de proteína C-reativa ultrassensível no soro e associação dessa com o índice de massa corporal e lipoproteína de alta densidade em indivíduos com periodontite grave. Métodos: O soro de 28 indivíduos (idade média: 34,36±6,24; 32% homens) com periodontite grave e 27 controles saudáveis

Descritores: Proteína C-Reativa. Doenças Periodontais. Doenças Cardiovasculares.

INTRODUCTION

Such damage compromises the function of the periodontal tissues and may result in tooth loss [1]. The chronic and cyclical nature of the periodontal disease provides an opportunity for continuous hematogenous dissemination of periodontal pathogens and, consequently, a direct exposure of blood vessels to these microorganisms and their endotoxins [4]. Hence, the invasion and proliferation of pathogens in specific sites of the host organism, as in periodontitis, may produce tissue damage and subsequent progression of other diseases through a variety of cellular mechanisms [1]. C-reactive protein (CRP), an acute phase protein, is a marker of systemic inflammation in response to infectious, inflammatory and/or traumatic stimulation [5]. Although produced primarily in the liver in response to proinflammatory cytokines (IL-1, IL-6, TNF-α), recently, extrahepatic synthesis of CRP has been reported in gingival biopsies [6]. Furthermore, it was also found in saliva and gingival crevicular fluid [7]. The potential role of CRP in cardiovascular pathogenesis is not fully understood. However, it has been suggested that it can directly damage blood vessels via activation of the complement

Periodontal diseases are characterized as the pathological manifestation of the host immune response to the bacterial infection at the tooth/gingival interface. These are mainly caused by Gram-negative bacteria, including Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Aggregatibacter actinomycetemcomitans (Aa), and Tannerella forsythia (Tf) [1]. Severe periodontitis affects up to 15% of most populations [2]. In Brazil, the most recent National Survey of Oral Health reported that the distribution of the most severe forms of periodontal disease are more significant in adults between 35-44 years of age, with a prevalence of 19.4% [3]. The term periodontitis comprises, generally, chronic forms of periodontal disease, which are the result of a polymicrobial infection and are characterized by the loss of collagen fibers and insertion in the cementum surface (mineralized tissue that covers the root surface), apical migration of junctional epithelium (epithelium continuous with the oral epithelium that promotes the insertion of the gum to the tooth), periodontal pocket formation (cementum surface devoid of periodontal fibers) and alveolar bone reabsorption.

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cascade, enhancing the formation of atherosclerotic lesions, and it is associated with endothelial dysfunction [8]. In healthy subjects, CRP levels are found in trace amounts with values <0.3 mg/L [9]. It is also known that levels below 1.0 mg/L indicate low risk for cardiovascular disease (CVD). Levels between 1.0 and 3.0 mg/L and above 3.0 mg/L indicate medium and high risk, respectively [10]. Chronic bacterial infections such as periodontitis, are one of the well-established risk factors for moderately elevated CRP level [7]. In otherwise, in healthy subjects with periodontitis, especially in severe forms, high systemic levels of IL-6 [11], dyslipidemia [12], and moderate leukocytosis [11] have been observed. Experimental and clinical trials have been performed in order to investigate the biological mechanisms of association between periodontal disease and atherosclerosis, which are not yet completely understood [4,7,11]. The ability of the periodontal pathogen to induce platelet aggregation, formation of foam cells, and development of the atheroma has been demonstrated [4]. Evidence supports at least two mechanisms that are biologically plausible: increased levels of systemic inflammation in patients with periodontitis, and the frequent migration of Gram-negative bacteria from periodontal pockets into the bloodstream (bacteremia and endotoxemia) [4,13]. The treatment of periodontal disease, in both systemically healthy patients and those with history of cardiovascular events, has been shown to reduce systemic inflammation [1416]. Recently, a systematic review and meta-analysis reported a reduction of 0.231 (P=0.000) in mean levels of CRP after nonsurgical periodontal therapy (NSPT) [15]. This study aimed to investigate the effect of severe periodontal disease on the systemic inflammatory response related to the elevation of CRP levels in serum and to determine the influence of NSPT on these levels. Furthermore, the correlation between systemic levels of hs-CRP and demographic characteristics of the population study (gender and age), body mass index (BMI), high-density lipoprotein (HDL), and clinical oral parameters before and after NSPT were assessed.

loss. Exclusion criteria were history of smoking, pregnancy or lactation, periodontal therapy (PT), antimicrobial therapy for systemic conditions or use of topical oral antibiotics in the last twelve months, diabetes, autoimmune disease, acute infections, severe allergies, gastrointestinal and renal diseases, cancer, morbid obesity (BMI >40 kg/m2) or underweight (malnourished BMI <18.5 kg/m2) [18], and use of medications that alter the levels of inflammatory mediators. The study protocol was approved by the Ethics Committee of the Faculty of Health Sciences - University of Brasilia, Brazil (045/2008). All subjects were informed about the purpose of the study, both orally and written, and a written informed consent document prior to participation was also signed. Clinical examination The clinical examination performed at baseline and after six months of supportive periodontal therapy (SPT) included detection of visible plaque accumulation described as plaque index (PI), BOP, PD and CAL. Measurements were assessed at four sites around each tooth, buccal, lingual and both proximal sites using a manual probe (probe Michigan O with Williams markings), excluding third molars. Treatment protocol/Retention and Laboratory analysis PG subjects were treated in three stages: mechanical periodontal therapy, sites reinstrumentation, and SPT. The first stage was performed in ≤ 14 days. One month later, in stage 2, new mechanical instrumentation was performed in patients who persisted with deep pockets, BOP and calculus. At this stage, meticulous scaling and root planning were performed until reaching the following periodontal conditions: PD above 4 mm in at least three or fewer sites, PD above 5 mm in two places at most, PI ≤15% and BOP ≤10%. In Stage 3, subjects were scheduled biweekly or monthly, according to the need to control biofilm formation. SPT was performed for six months. Out of the 28 subjects in PG, five did not complete the treatment. Twenty-three completed the three stages of periodontal protocol. Among these, ten (43%) subjects completed the treatment in nine months, ten (43%) subjects in ten months, and three (14%) subjects in 12 months. Blood samples were collected for biochemical analysis at baseline for all 28 PG subjects and 27 CG subjects. New blood samples were collected from 23 PG subjects who completed treatment. The fasting venous blood was collected in gel separator tubes. Each EDTA tube was assessed within three hours in order to perform blood counts with standard measurements for the number of neutrophils, lymphocytes, monocytes, basophils and eosinophils. Additionally, glucose examination was performed. Plasma and serum samples were immediately placed on ice and stored at -80°C. Lipid profile included serum levels of triglycerides, total cholesterol, HDL cholesterol and low-density lipoprotein

METHODS Subjects and study groups The total sample (convenience sampling) consisted of 55 systemically healthy subjects. The periodontitis group (PG) consisted of 19 women (68%) and nine men (age range 20-45; mean age: 34.36±6.24 years old), with ≥18 teeth. The classification of periodontal disease was according to Armitage & Cullinan [17]. The control group (CG) consisted of 18 women (67%) and nine men (age range 21-44; mean age: 33.18±6.42 years old), with clinical probing depths (PD) ≤3 mm and clinical attachment level (CAL) ≤3 mm, ≤10% of sites with bleeding on probing (BOP), and no radiographic evidence of bone

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(LDL) obtained by the esterase-oxidase method, homogeneous direct method, oxidase-peroxidase method, and Friedevald formula. The hs-CRP levels in serum were accessed by the nephelometry method (ultrasensitive immunonephelometry assay) with the lowest detection limit of 0.1 mg/dL. This method is characterized as highly sensitive [14].

were assessed by SAS 9.2 for Windows. For purposes of analysis, a significance level of 5% was used (P<0.05). Finally, hs-CRP levels were divided into two groups: hsCRP <0.3 and ≥0.3 mg/dL. To compare means between these groups before and after treatment, and between the other variables mentioned above (gender, age, BMI, HDL, BOP, PD and CAL), the Student’s t-test was used for variables that showed a Gaussian distribution for both groups. When normality was not observed for both groups, the nonparametric Mann-Whitney test was used. To compare the ratio of clinical cases with hs-CRP <0.3 and ≥0.3 mg/dL, Fisher’s exact test was used. McNemar’s test was performed to verify whether the ratio of PG patients that exhibited hs-CRP between 0.3 and 3 mg/dL was different before and after the PT. The reduction of the mean levels of hs-CRP after SPT was calculated by paired Student’s t-test.

Statistical analysis The clinical oral parameters and the demographic and hematological characteristics (lipids, glucose, and blood cells) before and post-SPT for both groups (PG and CG) were presented as mean ± standard deviation. The clinical periodontal parameters PI, PD ≤3, 5 and 6 mm and BOP before and post-therapy in the PG were compared by paired Student’s t-test, as well as lymphocytes, monocytes, neutrophils, total white blood cell and blood glucose. In both periods evaluated for this group, a nonparametric Wilcoxon test was used for the following variables: number of teeth (NT), PD=4 and ≥7 mm, BMI, systolic and diastolic blood pressure (SBP and DBP, respectively), triglycerides, total cholesterol, HDL and LDL, eosinophils and basophils. The measurements NT, BMI, SBP, DBP, PI, BOP and hematological characteristics, except hs-CRP, were compared between both groups before and after therapy by Student’s t-test for variables that showed the Gaussian distribution. In cases where normality was not observed for both groups, the nonparametric Mann-Whitney test was used. Results for hs-CRP were expressed as percentages. For the analysis of hs-CRP in the PG before and post-therapy McNemar’s test was used and, when compared to the CG, the chi-square test was used. Data

RESULTS Demographic and hematological characteristics, BMI, and clinical oral parameters of the study population before and after NSPT Initially, 28 patients with periodontal disease were involved in this study (32% men; mean age: 34.36±6.24 years old) and 27 healthy controls (33% men; mean age: 33.18±6.42 years old). There was no difference between PG and CG for age (P=0.4955) and gender (P=0.9251). Of all the patients in the PG, 23 were followed until remission of periodontal disease. Clinical oral parameters and characteristics before and post-SPT are shown in Table 1.

Table 1. Characteristics and clinical oral parameters before and after supportive periodontal therapy Characteristics / Parameters* NT BMI (kg/m2) SBP (mmHg) DBP (mmHg) PI (%) BOP (%) PD (mm) ≤3 mm 4 mm 5-6 mm ≥7 mm CAL (mm) ≤3 mm 4 mm 5-6 mm ≥7 mm

Control (n=27) 28.78±2.01 22.23±2.32 120.85±4.75 80.44±2.47 4.74±2.30 2.67±1.49

Pre-therapy (n=28) 27.25±4.84 26.92±5.60 120.74±13.60 79.95±12.16 63.61±33.64 44.46±29.35

Post-therapy (n=23) 24.70±5.79 26.95±6.29 117.33±10.87 76.47±7.91 4.83±6.73 1.63±3.35

P value pre x post 0.00011 0.09231 0.10551 0.42301 < 0.00012 < 0.00012

P value control x pre 0.53173 0.00024 0.85843 0.05133 <0.00013 <0.00013

P value control x post 0.02943 0.00214 0.16893 0.00043 0.06793 <0.00013

100.00±0.00 0 0 0

68.71±14.38 4.02±4.02 17.08±8.85 10.45±8.89

98.32±1.79 0.63±0.96 0.85±1.22 0.17±0.61

< 0.00012 < 0.00011 < 0.00012 < 0.00011

NA NA NA NA

100.00±0.00 0 0 0

62.56±18.20 4.97±4.77 18.74±8.96 13.73±11.49

NA NA NA NA

*Results shown as mean ± standard deviation. 1 Wilcoxon test; 2 pair T test; 3 Mann-Whitney test; 4 T test; NA = not applicable. BMI = body mass index, PI = plaque index, NT = number of teeth, CAL = clinical attachment level, DBP = diastolic blood pressure, SBP = systolic blood pressure, PD = probing depth, BOP = bleeding on probing

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In the PG, PT led to a significant decrease in all clinical periodontal parameters (P<0.0001). The mean values for BMI, SBP and DBP after SPT did not differ statistically from the mean values of the same measurements before therapy. At baseline, the CG was significantly different from the PG for PI and BOP (P<0.0001). The mean values for PI and BOP in the PG were greatly reduced after the therapy. As shown in Table 2, there were no statistical differences in hematological and biochemical parameters between the PG and the CG before and after therapy, except for hs-CRP levels. This reflects the systemic health of both groups and shows that PT did not modify other hematological and biochemical parameters. For comparisons between the CG and the PG before therapy, the ratio of patients with hs-CRP <0.3 mg/dL was statistically lower in PG than in CG (P<0.0216). Therefore, among systemically healthy patients, those with severe periodontitis had higher levels of CRP. In addition, for comparisons between the PG and the CG after therapy, the ratio of patients in the PG with hs-CRP <0.3mg/dL did not differ statistically from that observed in CG patients. In the PG, the mean values of triglycerides, total cholesterol, LDL cholesterol, glucose, and total leukocytes did not differ statistically before and after treatment. However, HDL cholesterol was statistically higher after treatment (P<0.0027). Moreover, the ratio of patients in the PG with hs-CRP <0.3mg/dL was statistically higher after than before treatment (P<0.0339). This result suggests that NSPT led to reduce levels of hs-CRP in the PG and reduced levels below 0.3mg/dL in 65.22% of patients with severe periodontitis.

≥0.3 mg/dL did not differ between males and females, among PG 28 subjects (P<0.6891). The mean BMI was statistically lower in subjects with hs-CRP <0.3 mg/dL than in those with ≥0.3 mg/dL (P<0.0411). As for HDL cholesterol, patients with hs-CRP <0.3 mg/dL had statistically higher mean value than those with ≥0.3 mg/dL (P<0.0171). The mean value for all the clinical oral parameters suggested that patients with lower levels of CRP (<0.3 mg/dl) have less severe periodontal disease, even though, for this sample, the mean value for the measurements BOP, PD ≥7 mm and CAL ≥7 mm contradicted this suggestion (Table 3). After treatment, the mean value of all variables did not differ statistically among 23 PG subjects with hs-CRP <0.3 and ≥0.3 mg/dL. However, the mean value for HDL cholesterol was slightly higher in patients with hs-CRP <0.3 mg/dL (Table 4). NSPT effect on levels of hs-CRP In this study, the PG was found to be within the range of low or medium risk for CVD (CRP levels <1mg/L and between 1-3 mg/L, respectively). No subject with periodontitis exhibited CRP levels ≥3 mg/L (high risk for CVD). The frequency of the levels of hs-CRP in the PG before and after therapy is given in Table 5 and Figure 1. The ratio of subjects in the PG with high levels of hs-CRP (≥0.3 to 3 mg/dL) and low levels as considered for healthy subjects (<0.3 mg/dL) was different before and after SPT. The percentage of subjects with hs-CRP <0.3 mg/dL was statistically lower before (39.13%) than after SPT (65.22%, P<0.0339). Thus, hs-CRP levels from ≥0.3-3 mg/dL were observed in a higher percentage of subjects before treatment (60.87%) than after SPT (34.78%). Regarding two subgroups of levels of hs-CRP (<0.3 and from ≥0.3-3 mg/dL), it was observed that, out of nine patients with hs-CRP level <0.3 mg/dL before treatment, eight

Relationship between high-sensitivity C-reactive protein (hs-CRP) and demographic/hematological characteristics, BMI, and clinical oral parameters At baseline, the ratio of patients with hs-CRP <0.3 and

Table 2. Hematologic and biochemical parameters before and after supportive periodontal therapy. Characteristics / Parameters* Triglycerides (mg/dL) Total Cholesterol (mg/dL) HDL Cholesterol (mg/dL) LDL Cholesterol (mg/dL) Glucose (mg/dL) Eosinophils Basophils Lymphocytes Monocytes Neutrophils Total Leukocytes hs-CRP (<0,3 mg/dL) †

Control (n=27) 87.22±35.24 172.70±30.93 47.56±12.28 107.17±24.59 85.07±6.63 143.74±102.00 14.19±31.35 2238.52±520.45 428.22±141.26 3208.56±865.86 6171.48±1260.51 76.92

Pre-therapy (n=28) 101.32±46.86 176.21±30.07 42.82±12.60 112.94±27.09 90.96±14.51 227.96±179.80 8.71±21.97 2136.75±508.12 368.75±128.59 3548.64±1279.78 6297.50±1515.88 39.13

Post-therapy (n=23) 106.26±43.34 182.78±38.15 49.17±20.07 112.36±31.14 88.83±11.21 178.26±95.26 13.30±21.30 2075.22±550.65 366.65±138.50 3104.59±1496.55 5970.00±1734.72 65.22

P value pre x post 0.70121 0.09751 0.00271 0.97651 0.75282 0.16661 0.21881 0.30182 0.51872 0.08712 0.18082 0.03395

P value control x pre 0.22543 0.67134 0.16414 0.41284 0.05894 0.05493 0.57653 0.46634 0.10824 0.32794 0.73934 0.02166

P value control x post 0.08483 0.30744 0.61943 0.51384 0.16794 0.25483 0.60333 0.28704 0.12774 0.80494 0.63734 0.36546

* Results shown as mean ± standard deviation. 1 Wilcoxon test; 2 pair T test; 3 Mann-Whitney test; 4 T test; 5 Mc Nemar test; 6 X-square test. HDL = high-density lipoprotein, LDL = low-density lipoprotein, hs-CRP = high-sensitivity C-reactive protein

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Table 3. Comparison between levels of hs-CRP and demographic/hematological characteristics, BMI, and clinical oral parameters at baseline. Variable* Gender† Female Male Age (years) BMI (kg/m2) HDL Cholesterol (mg/dL) BOP (%) PD <3 mm PD 4 mm PD 5-6 mm PD ≥7 mm‡ CAL <3 mm CAL 4 mm CAL 5-6 mm CAL ≥7 mm

hs-CRP <0.3 mg/dL

hs-CRP ≥0.3 mg/dL

8 (42.11) 5 (55.56) 34.62 ± 6.19 24.63 ± 4.19 49.08 ± 14.19 49.08 ± 33.23 69.63 ± 12.92 2.63 ± 1.92 15.90 ± 5.79 11.83 ± 9.12 64.68 ± 19.81 3.03 ± 2.25 17.12 ± 6.99 15.18 ± 13.58

11 (57.89) 4 (44.44) 34.13 ± 6.50 28.91 ± 6.03 37.40 ± 8.10 40.47 ± 26.04 67.91 ± 15.95 5.22 ± 4.97 18.11 ± 10.95 9.25 ± 8.82 60.72 ± 17.17 6.65 ± 5.75 20.15 ± 10.41 12.48 ± 9.64

P-value# 0.6891§ 0.8430 0.0411 0.0171 0.4492 0.7587 0.0779 0.5025 0.4067 0.5765 0.0369 0.3825 0.5462

* Values expressed as mean ± standard deviation. † Values expressed as frequency (percentage). # P-values are results of Student's t-test. ‡ P-values are results of Mann-Whitney test. § P-value is result of Fisher's test. HDL = high-density lipoprotein, BMI = body mass index, CAL = clinical attachment level, hs-CRP = high-sensitive C-reactive protein, PD = probing depth, BOP = bleeding on probing Table 4. Comparison between levels of hs-CRP and demographic/hematological characteristics, BMI, and clinical oral parameters after supportive periodontal therapy. Variable* Gender† Female Male Age (years) BMI (kg/m2) HDL Cholesterol (mg/dL) ‡ BOP (%)‡ PD <3 mm PD 4 mm‡ PD 5-6 mm‡ PD ≥7 mm‡

hs-CRP <0.3 mg/dL

hs-CRP ≥0.3 mg/dL

9 (56.25) 6 (85.71) 34.47 ± 6.40 26.20 ± 5.86 50.53 ± 22.06 1.47 ± 3.48 98.09 ± 1.97 0.83 ± 1.02 0.86 ± 1.34 0.18 ± 0.68

7 (43.75) 1 (14.29) 33.88 ± 6.29 28.35 ± 7.23 46.63 ± 16.74 1.94 ± 3.30 98.75 ± 1.42 0.26 ± 0.74 0.84 ± 1.06 0.17 ± 0.49

P-value# 0.3452§ 0.8339 0.4472 0.7712 0.0659 0.4135 0.1490 0.6867 0.7414

Table 5. Frequency of hs-CRP in periodontitis group before and after supportive periodontal therapy. hs-CRP (before therapy) <0.3 mg/dL ≥0.3 to 3 mg/dL Total

hs-CRP (after therapy) <0.3 mg/dL ≥0.3 to 3 mg/dL 8 (88.89) 1 (11.11) 7 (50.00) 7 (50.00) 15 (65.22) 8 (34.78)

(88.89%) maintained this level, and only one (11.11%) had a hs-CRP level ≥0.3-3 mg/dL post-therapy. Out of 14 patients with hs-CRP levels from ≥0.3-3 mg/dL before therapy, seven (50%) maintained this level, and seven had hs-CRP level <0.3 mg/dL after treatment. Therefore, 26.09% of 23 PG patients showed a decrease in hs-CRP levels: between ≥0.3 and 3 mg/dL to levels <0.3 mg/dL after therapy. The reduction of hs-CRP levels was 0.1487±0.6290 after SPT, which was considered not statistically significant (P=0.2691).

Total 9 (39.13) 14 (60.87) 23 (100.00)

Values expressed as frequency (percentage); McNemar test. hs-CRP = high-sensitive C-reactive protein

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Leite ACE, et al. - Effects of periodontal therapy on C-reactive protein and HDL in serum of subjects with periodontitis

DISCUSSION This study included a homogeneous group of patients with severe periodontitis. The ratio of patients in the PG with hs-CRP levels >0.3 mg/dL was higher than in the CG (60.87 versus 23.08, respectively; P=0.0216). These results are consistent with previous reports [11,12], in that higher levels of hs-CRP were observed in the serum of patients with severe periodontitis. The levels of serum IL-6 and CRP have been reported to increase with age [14]. However, in this study, there was no difference in the ratio of patients with levels of hs-CRP <0.3 and ≥0.3 mg/dL, with a mean age in the PG of 34.36±6.24. Also, increased levels of CRP have been reported in women due to hormonal changes [19]. Interestingly, the ratio of patients in the PG with hs-CRP <0.3 and ≥0.3 mg/dL did not differ between female and male subjects (P<0.6891), although, before NSPT, the ratio of subjects with hs-CRP≥0.3 mg/dL was higher for women than men. Race/ethnicity has been described to affect CRP levels [20]. Asian populations have a lower range of systemic levels of CRP than black populations [21]. Since the Brazilian population presents miscegenation of browns, whites, blacks and Indians, race/ethnicity may have influenced the levels of CRP in this population study. Here, subjects with severe periodontitis were at “low risk” (<1 mg/L) or “medium risk” (1 to 3 mg/L) for CVD, as shown in previous studies [20,21]. There is a strong link between CRP levels in the blood and future development of high blood pressure [19]. This association is stronger for SBP than for DBP [22]. In this study, no difference was found between the mean values of SBP and DBP in the PG before and after therapy. White blood cell count also has been associated with significant prediction of future cardiovascular events and glucose intolerance in different populations [22]. In this study, the non-observation of leucocytosis indicated that patients with severe periodontitis exhibited less pronounced systemic inflammation due to periodontal disease. A positive relationship between the severity of periodontitis and initial systemic levels of hs-CRP has been observed [11]. Also, in this study, the clinical periodontal parameters before and after SPT suggested that patients with lower levels of CRP (<0.3 mg/dl) had less severe periodontal disease. NSPT led to a significant decrease of all clinical periodontal parameters (P<0.0001). It should be noted that there was a significant reduction of PI from 63.61±33.64 to 4.83±6.73 and of BOP from 44.46±29.35 to 1.63±3.35. After therapy, the NT was statistically fewer due to the extraction of periodontally condemned teeth (P=0.0001). Regarding the levels of hs-CRP, the ratio of PG subjects with hs-CRP <0.3 mg/dL was statistically higher after therapy (P<0.0339). This result indicates that NSPT led to reduced levels of hs-CRP in the PG and demonstrated levels <0.3 mg/dL in most subjects

Fig. 1 – Frequency of the hs-CRP in the periodontitis group before and after periodontal therapy. hs-CRP - high-sensitivity C-reactive protein; BT - before therapy; AR - after therapy

with severe periodontitis (65.22%). It should be emphasized that for 26.09% of the 23 subjects that completed treatment, changes in the risk stratification for CVD was detected. These patients, prior to therapy, had hs-CRP levels from ≥0.3 to 3 mg/dL and, after therapy, levels were <0.3 mg/ dL, i.e., considered as normal levels for subjects. Although the reduction in levels of hs-CRP was 0.1487±0.6290, i.e., moderate and not statistically significant (P=0.2691), the ratio of subjects in PG with hs-CRP <0.3mg/dL did not differ statistically from that observed in subjects in CG after SPT. There are reports of significant reductions in CRP levels, especially for subjects with high levels of CRP at baseline [23]. However, it is known that among systemically healthy patients, NSPT may decrease levels of CRP that were initially below 3 mg/dL [23]. It is known that anti-inflammatory and non-steroidal drugs (aspirin and ibuprofen), oral drugs of synergistic combinations of cardiovascular agents, and low doses of steroids can potentially decrease the serum CRP levels [19]. In this study, the use of any medication was prohibited because it could affect the immunoinflammatory response and directly interfere with clinical outcomes. Since smoking has been reported as an independent risk factor for periodontitis and elevated serum CRP levels, patients with history of smoking and obesity were excluded in order to avoid adjustments to their potential effects on CPR response to the periodontal treatment [23]. NSPT employed with the reinstrumentation of residual periodontal pockets with BOP and calculus, reassessment, and SPT for 6 months indicate that maintaining a healthy periodontium without signs of periodontal inflammation had a positive impact on the reduction of serum CRP levels. This supports previous results showing that a greater reduction in CRP levels occurs among those with better clinical responses to PT [23]. In contrast, other studies found no significant reduction in serum CRP levels after NSPT, despite

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Leite ACE, et al. - Effects of periodontal therapy on C-reactive protein and HDL in serum of subjects with periodontitis

improvement in clinical periodontal parameters [21]. A systematic review and meta-analysis justified that these differences are due to the fact that the authors have not studied the same type or severity of periodontal disease [24]. Another explanation refers to the medical follow-up and the methodology proposed by each study (for example, the assay used to detect CRP). Furthermore, our results showed no association between periodontitis and BMI. However, subjects with BMI >27 kg/ m2 were not included in this study. There is evidence that increase of BMI also increases risk for periodontitis [12,23]. However, our data showed a significant increase in HDL (P=0.0027) and no significant change in other serum lipids in the PG after therapy. The concentration of CRP has also been correlated with the levels of lipids (e.g., triglycerides and HDL) and an inverse relationship between CRP and HDL levels has been observed [19]. In this study, PG subjects with hs-CRP <0.3 mg/dL presented a mean value of HDL statistically higher than those with hs-CRP ≥0.3 mg/dL (P<0.0171) before treatment. Furthermore, the mean value for BMI was lower in patients with hs-CRP <0.3 mg/dL compared with those with hs-CRP ≥0.3 mg/dL (P<0.0411). However, between patients with hs-CRP <0.3 and ≥0.3 mg/dL the mean values of HDL and BMI were not statistically different after therapy. Therefore, these results demonstrate the significant association between periodontitis and decrease in HDL cholesterol. This association has been related to local production of inflammatory cytokines (IL-1, TNF-α) due to periodontal infection and its effect on other systemic mediators (IL-6) that can induce changes in lipid metabolism [25], such as increased LDL and triglycerides. This is due to increased hepatic lipogenesis, lipolysis of adipose tissue or reduced clearance of blood. Bacterial toxins (LPS) may also induce changes in cholesterol levels (reduced HDL and increase LDL), or to target the metabolism of glucose and produce a state of insulin resistance [22]. Hence, our results showed that periodontitis significantly increases the levels of serum CRP, and therefore might be related with moderate risk of atherosclerosis and its consequences. Nevertheless, to better understand the association between periodontal disease and atherosclerosis, additional studies with larger samples are required in order to statistically compensate the other various covariates such as age, adiposity, smoking, and insulin resistance. A higher number of subjects certainly contains a sample with a broader variation of systemic CRP levels, that would help to clarify whether PT has a significant impact on CVD, i.e., if the control of periodontal infections leads to decreased risk of future cardiovascular events. Additionally, a longitudinal follow-up of patients with periodontal risk would evaluate the duration of the therapeutic effects of the SPT on systemic biomarkers.

CONCLUSION This study showed that severe periodontitis is associated with increased levels of hs-CRP in serum, and NSPT is able to reduce these levels to values close to that of healthy subjects, and therefore reduce the category of inflammatory risk for CVD. Moreover, a significant increase in HDL cholesterol also was shown after the periodontal treatment. The results emphasize the importance of NSPT and the maintenance of periodontal health to avoid high levels of hs-CRP, which are also increased in other systemic inflammatory diseases such as arthritis, diabetes mellitus, and obesity. ACKNOWLEDGEMENTS We are grateful to Prof. Dr. Eduardo Freitas da Silva from the Department of Statistics of the Universidade de Brasília (UnB-DF); to the laboratory technicians of the Laboratory of hematological exams of the HUB-DF and to the dental surgeons D’Angela Marise G. de Alencar and Mariah Bastos B. de Azevedo. Authors’ roles & responsibilities ACEL Main author VMAC Coauthor MCMG Coauthor

REFERENCES 1. Sanz M, van Winkelhoff AJ; Working Group 1 of Seventh European Workshop on Periodontology. Periodontal infections: understanding the complexity: consensus of the Seventh European Workshop on Periodontology. J Clin Periodontol. 2011;38(Suppl 11):3-6. 2. Papapanou PN. Epidemiology of periodontal diseases: an update. J Int Acad Periodontol. 1999;1(4):110-6. 3. Brasil. Ministério da Saúde. Secretaria de Atenção à Saúde/ Secretaria de Vigilância em Saúde. Departamento de Atenção Básica. Coordenação Geral de Saúde Bucal. Projeto SBBrasil 2010: Pesquisa Nacional de Saúde Bucal - resultados principais. Brasília: Ministério da Saúde; 2011. 92p. 4. Offenbacher S, Elter JR, Lin D, Beck JD. Evidence for periodontitis as a tertiary vascular infection. J Int Acad Periodontol. 2005;7(2):39-48. 5. Loos BG. Systemic effects of periodontitis. Int J Dent Hygiene. 2006;4(Suppl 1):34-8. 6. Lu Q, Jin L. Human gingiva is another site of C-reactive protein formation. J Clin Periodontol. 2010;37(9):789-96.

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7. Tüter G, Kurtis B, Serdar M. Evaluation of gingival crevicular fluid and serum levels of high-sensitivity C-reactive protein in chronic periodontitis patients with or without coronary artery disease. J Periodontol. 2007;78(12):2319-24.

16. D’Aiuto F, Orlandi M, Gunsolley JC. Evidence that periodontal treatment improves biomarkers and CVD outcomes. J Clin Periodontol. 2013;40(Suppl 14):S85-105. 17. Armitage GC, Cullinan MP. Comparison of the clinical features of chronic and aggressive periodontitis. Periodontol 2000. 2010;53:12-27.

8. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285(19):2481-5.

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21. Yamazaki K, Honda T, Oda T, Ueki-Maruyama K, Nakajima T, Yoshie H, et al. Effect of periodontal treatment on the C-reactive protein and proinflammatory cytokine levels in Japanese periodontitis patients. J Periodont Res. 2005;40(1):53-8.

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12. Liu J, Wu Y, Ding Y, Meng S, Ge S, Deng H. Evaluation of serum levels of C-reactive protein and lipid profiles in patients with chronic periodontitis and/or coronary heart disease in an ethnic Han population. Quintessence Int. 2010;41(3):239-47.

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Molinari GJDP,SPECIAL et al. - Proposal of renal artery's ostial projection under virtual ARTICLE geometric correction in infrarenal aneurysms: initial results of a pilot study

Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study Proposta de correção virtual geométrica da projeção ostial da artéria renal no estudo operatório de aneurismas infrarrenais: resultados iniciais de um estudo piloto

Giovani José Dal Poggetto Molinari1; Andreia Marques de Oliveira Dalbem1; Fabio Hüsemann Menezes1, MD; Ana Terezinha Guillaumon1, PhD

DOI: 10.5935/1678-9741.20140014

RBCCV 44205-1524

Abstract Introduction: Endovascular aneurysm repair requires the precise deployment of the graft. In order to achieve accurate positioning, the anatomical and morphological characteristics of the aorta and its branches is mandatory. Software that perform three dimensional reformatting of multislice tomographic images, allow for the study of the whole aorto-iliac axis and the perpendicular visualization of the origin of the renal arteries. The correct length of the proximal neck can be evaluated and adequate graft fixation and sealing may be foreseen. A technique is presented, using an software, for the orthogonal correction of the position of the renal arteries in relation to the proximal neck, which may guide the radioscopic orientation intraoperatively. Methods: Within a multiplanar tomographic image reconstruction, virtual triangulation allows for the three dimensional orthogonal correction of the renal arteries' ostia position. The predetermined best angulations for visualization are annotated and used for the positioning of the surgical C-arm.

Results/Discussion: Some authors discuss that the anatomic position of the renal vessels seen on the tomographic scan can change during the surgical procedure. It is known that the renal arterys' angular positioning does not alter, even after insertion of stiff guidewires, introducers, and the endograft itself. Therefore, it is possible, using concepts of spacial geometry and orthogonal correction, to predict the ideal bidimensional intraoperative positioning of the radioscopy device in order to reproduce the optimized renal artery ostial projection, ensuring the best accuracy during endograft deployment. Conclusion: As closer to the tomographic reproduction was the radioscopic correction, more careful is the visualization of the ostium of the renal artery, better is the exploitation of the lap for fixing and sealing and the endoprosthesis deployment is more accurate. Descriptors: Endovascular Procedures. Aortic Aneurysm, Abdominal. Multidetector Computed Tomography. Renal Artery. User-Computer Interface. Pilot Projects.

See the video by clicking: http://rbccv.org.br/video/2221/Proposal_of_renal_artery_s_ostial_projection_under_virtual_geometric_correction_in_infrarenal_aneurysms__initial_results_ of_a_pilot_study

1. State University of Campinas (HC-Unicamp), Campinas, SP, Brazil.

E-mail: drgiovani.molinari@uol.com.br

Correspondence address: Giovani José Dal Poggetto Molinari Universidade Estadual de Campinas – Unicamp/Cidade Universitária Zeferino Vaz Rua Vital Brasil, 251 - Barão Geraldo – Campinas, SP, Brazil Zip code: 13083-888 Post office box: 6142

This study was carried out at Clinics Hospital of the State University of Campinas (HC-Unicamp), Campinas, SP, Brazil. No financial support.

Rev Bras Cir Cardiovasc | Braz J Cardiovasc Surg

Article received on August 30th, 2013 Article accepted on January 20th, 2014

Rev Bras Cir Cardiovasc 2014;29(1):78-82

Molinari GJDP, et al. - Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study

Métodos: Por meio de reconstrução multiplanar de imagens tomográficas em software obtém-se um corte axial em ângulo reto. Conceitos geométricos de triangulação virtual promovem a correção ortogonal em três dimensões da visualização ostial da artéria renal, que pode ser reproduzida intraoperatoriamente, através do reposicionamento do arco cirúrgico. Resultados/Discussão: Embora alguns autores argumentem que a anatomia do vaso observada na tomografia possa mudar durante o intraoperatório, sabe-se que o posicionamento angular das artérias renais não se modifica, mesmo após a inserção dos fios guia rígidos, introdutores e da própria endoprótese. Assim, acreditamos ser possível, por meio de conceitos de geometria espacial e correção ortogonal (por meio da manipulação das imagens em software), predizer o posicionamento ideal do aparelho de radioscopia de maneira a reproduzir o mesmo ângulo de projeção ostial da artéria renal em imagem bidimensional intraoperatória (angiografia), assegurando maior precisão na liberação da endoprótese. Conclusão: Quanto mais próxima da reprodução tomográfica for essa correção radioscópica, mais cuidadosa é a visualização do óstio da artéria renal, melhor é o aproveitamento do colo para a fixação e selamento e mais precisa é a liberação da endoprótese.

Abbreviations, acronyms and symbols 3D Three Dimensions AAA Abdominal aortic aneurysm DICOM Digital Imaging and Communications in Medicine h Height MIP Maximum intensity projection MPR Multiplanar reconstruction r Radius CT Computed Tomography

Resumo Introdução: Para o preparo pré-operatório endovascular dos aneurismas infrarrenais é necessária a mensuração acurada de suas características anatômicas e morfológicas, alcançada com o uso de softwares avançados em manipulação de imagens de tomografias multicanais. Este processo permite também o estudo acurado das relações anatômicas das demais artérias do eixo aorto-ilíaco. Uma visualização perpendicular à origem da artéria renal mais baixa possibilita o uso de toda a extensão do colo para fixação da endoprótese e selamento proximal, o que pode ser previsto durante o estudo da tomografia, impedindo um posicionamento subótimo e a sobreposição das estruturas vasculares no intraoperatório. Expõem-se aqui os resultados iniciais de um projeto piloto, envolvendo manipulação de imagens tomográficas, na correção ortogonal da artéria renal aplicada à orientação radioscópica no intraoperatório.

Descritores: Procedimentos Endovasculares. Aneurisma da Aorta Abdominal. Tomografia Computadorizada Multidetectores. Artéria Renal. Interface Usuário-Computador. Projetos Piloto.

INTRODUCTION

ning of the type of stent to be used. This is achieved with the use of reconstruction methods available in software such as multiplanar reconstruction (MPR and MPR - Curved), maximum intensity projection (MIP) and 3D image reconstruction volume. At this stage, performed in the preoperative period, we obtain the necessary information for surgical planning. Thus, it is possible the acquisition of final images that offer not only better accuracy of measurements and morphological features of the aneurysm as well as the study of their anatomical relationship with the other arteries of the aortoiliac axis [1]. An important aspect of planning is determining the best intraoperative placement of fluoroscopy, with a perfectly perpendicular view to the origin of the lowest renal artery visualization. A suboptimal positioning can cause overlapping of vascular structures, preventing the use of the entire length of the colon to the fixation of the stent graft and proximal sealing [4]. The initial results of a pilot project are set herein, performed by examining the feasibility of manipulation of CT images in software, the visualization and determination of radioscopic angulation of the aneurysm neck, through the use of a new technique. It is believed that this technique is quite simple, of immediate practical significance and can be easily incorporated into routine planning of endovascular treatment

It is known that for the preoperative preparation of endovascular infrarenal abdominal aortic aneurysms (AAA) accurate measurement of morphological and anatomical characteristics of the aneurysm is required, such as diameters, lengths and angles, essential strategy for their exclusion, the final result endovascular procedure [1]. With the enhancement of information technology, the study of helical biplane CT scans associated with complementary marked catheter aortography was replaced by the use of computed tomography (CT) multichannel (multislice), with cuts in smaller thicknesses and with greater detail that, when associated with three dimensions (3D) reconstruction software, allow the scanned virtual reproduction of the patient and his anatomy [2]. CT and angiography (angioTC) have an essential role in preinterventional planning and control of the procedure and is considered the test of choice in assessing the candidate patient to envodascular treatment and for his monitoring in search of complications [3]. These reconstructions allow rapid assessment of the extent of the aneurysm, visceral involvement, presence of angulation, tortuosity and access difficult. An accurate analysis of the axial, coronal and sagittal sections enables the plan-

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Molinari GJDP, et al. - Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study

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with stents. So far, we have collected a series of cases of about 14 studies with encouraging results. For purposes of illustration of the technique used, the steps developed in one case in our series are following described.

amid at the beginning of the construction of the triangle. Therefore, we reproduced two additional marks guided by the height of the triangle placed subsequently in order to form an equilateral triangle (Figure 2C). To calculate the markup, we used the concepts of geometric construction, where the height (h) of an equilateral triangle in a circle corresponds to ¾ diameter, or 1 ½ time the radius of the circle [6] (r) (Figure 2D). Starting with the geometric concept that three points are always coplanar, we proceeded to the three-dimensional reconstruction of CT. By means of rotational manipulation of the image if the three aligned points along a single axis, equidistant (Figure 3). The projection angles of the image display were provided automatically by the software (highlighted). The images and angles achieved during the 3D reconstruction software were reproduced during surgery - with correction of angular positioning of the fluoroscopy unit – and were considered equivalent (Figures 4A , B and C). We can also mention that for prostheses that have above two radiopaque markers at the same level at the proximal portion, it could be observed after the release of the stent, a placement in a straight position to these markings [ 4 ] which reinforces the idea of perpendicular view of the cervix (Figure 4D).

METHODS Multichannel CT scans of patients undergoing endovascular repair of infrarenal AAA at the Center for Highly Complex Endovascular Surgery, State University of Campinas, from August to December 2013 were assessed. We used three-dimensional multiplanar reconstruction through DICOM - Digital Imaging and Communications in Medicine image manipulation software (OsiriX MD), in analysis of aneurysms in serial CT images with fine cuts of 1 to 3mm, through intravenous iodinated contrast in the arterial phase. We chose the lowest renal artery as a reference for the treatment of images because the proximal colon constituted its thread until the start of the AAA [5]. The aim was to achieve a perfectly perpendicular image to its source, or that is, its ostial projection, to correct anteroposterior angulation inherent to its morphology and any rotational effects caused by tortuosity of AAA. For this, a linear axis of the aorta (at the level of the emergence of the lowest renal artery) cut was achieved in axial image, provided by the right-angle correction of the sagittal and coronal MPR projections (Figure 1). Upon analysis of the axial image, we then proceeded to construct a circumscribed equilateral triangle. Was traced a centerline axis of the aorta and parallel to the tangent of the arterial wall in the renal ostium where a first mark made in the anterior wall of the aorta was performed (Figs. 2A and 2B). This vertex is assumed to be the apex of the pyr-

DISCUSSION Early in the last decade, the study of helical CT combined with complementary biplanar aortography with marked catheters was recommended to all candidates for endovascular repair of AAA, by presenting themselves as complementary examinations values: while the first provided very accurate information about the diameters, the last allowed an accurate assessment of the length [7].

Fig. 1 - Multiplanar reconstruction (MPR), with repair of sagittal and coronal projections and axial cut at right angles (below left)

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Molinari GJDP, et al. - Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study

Fig. 2 - Above: - Tangent drawn from the projection of the right renal artery. B - Intraluminal positioning for beginning of space marking. Below : C - Construction of the equilateral triangle on axial CT at right angles. D - Geometric representation of an equilateral triangle in a circle (in the case described)

Due to the high technological development of the CT since the introduction of helical acquisition to multichannel detectors equipment with efficient systems of transmission, processing and storage of data - it was possible to reduce the time of image acquisition and the development of more sensitive and accurate algorithms, with better performance and spatial resolution [2] reconstruction. Currently, through angioTC the morphometry is performed, based on the assessment of the configuration, lengths and diameters of the aorta and iliac arteries and related to the lesion of interest as to the technique of performing the endovascular procedure. It allows even assess relevant anatomical variations when choosing the stent and the related surgical technique [2]. However, the intraoperative assessment of the release of the stent is usually guided by angiography, which provides two dimensional image. Therefore, it is known that the proximal neck of AAA and/or too angulated iliac arteries may hinder accurate visualization of the ostium of the renal artery.

Fig. 3 - Three-dimensional tomographic reconstruction. Note that the points are equally spaced and aligned, allowing a view at the right angle of the renal artery studied (right). The viewing angles to be used in the correction of intraoperative fluoroscopy were provided by the software itself (below right, highlighted - in this case, craniocaudal 13,6o and left-anterior-oblique - 30,6o). The values used for surgical arch are approximate

Fig. 4 - A - Tomographic image by 3D reconstruction. B - Intraoperative position of fluoroscopy unit, respecting the angles identified. C - Intraoperative arteriography. D - Final positioning of the endoprosthesis

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Molinari GJDP, et al. - Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study

The ideal positioning of the fluoroscopy unit during the surgical procedure may be different than expected during the preoperative study, in that the aneurysm possibly shorten or lengthen higher than expected [4]. Thus, some authors argue that the anatomy of the vessel can change due to the insertion of rigid guidewires, introducers and the delivery system itself. They believe that the image of the preoperative CT may be different from intraoperative angiography [6]. Van Keulen et. al. [4] discuss about the necessity of determining the intraoperative disposition of surgical arch arguing that a suboptimal positioning would lead the surgeon to underestimate the total length of the aneurysm neck and not using in its entirety for release and fixation of the endoprosthesis. This interpretation could be caused by an apparent overlap of vascular structures in the conventional biplane angiographic image. They recommend that the ideal angulation and positioning are determined taking into account the anteroposterior angulation of the neck and the clockwise orientation of the renal arteries. They also report that although the angulation of the neck of the aneurysm can be changed, the angular position of the renal arteries is not changed even under the influence of the inserted guide wire or the stent itself [4,8]. Our aim was to simplify this calculation, with simultaneous attainment of oblique and craniocaudais angles using concepts of three-dimensional geometry and spatial triangulation with the aid of software. That said, although the results are result from a pilot project underway, these proved to be very encouraging. Therefore, we believe that it is possible, by means of concepts of geometric correction and through manipulation of DICOM images in software, to trace the same angle of ostial projection of the renal artery on intraoperative two-dimensional image (angiography). When playing a tomographic cross section at right angles (or that is, perpendicular to the axis of the aorta), with rotation and orthogonal exposure of the renal artery, it is possible to predict the need for intraoperative correction of the fluoroscopy projection in obtaining two-dimensional angiographic image. Utilizing the application of concepts of spatial geometry to achieve the best angle of ostial exposure of the renal artery systematically, it may reduce the variations between study observers and allows the reproducibility of the technique, reducing errors of interpersonal interpretation. The closer this radioscopic correction of the tomographic reproduction, the more careful the visualization of the ostium of the renal artery, and the better the exploitation of the neck for fastening and sealing and the more accurate the endoprosthesis deployment.

Authors' roles and responsibilities GJDPM

AMOD FHM ATG

Lead author, creator of the technique described. Principal investigator for the manipulation of images used, writing of the Pilot Project and Research Project and bibliographic survey. Coauthor. Collaborative development and application of this technique, assistant researcher in the development of the Research Project. Coauthor. Reviewer of writing Technical Note, correction and preparation of the Abstract. Reviewer of references. Coauthor. Guidance. Final reviewer of Technical Note, Pilot Project and Research Project.

REFERENCES 1. Oderich GS, Malgor RD. Aneurisma da Aorta toracoabdominal. In: Lobato AC (org). Cirurgia Endovascular. 2nd ed. São Paulo: Instituto de Cirurgia Vascular e Endovascular de São Paulo; 2010. p.695-742. 2. Pitoulias GA, Donas KP, Schulte S, Aslanidou EA, Papadimitriou DK. Two-dimensional versus three-dimensional CT angiography in analysis of anatomical suitability for stentgraft repair of abdominal aortic aneurysms. Acta Radiol. 2011;52(3):317-23. 3. Kuroki IR, Magalhães FV, Rizzi P, Coreixas IMH. Angiotomografia. In: Brito CJ. Cirurgia Vascular: cirurgia endovascular, angiologia. 3a ed. Rio de Janeiro: Revinter; 2014. p.437-96. 4. van Keulen JW, Moll FL, van Herwaarden JA. Tips and techniques for optimal stent graft placement in angulated aneurysm necks. J Vasc Surg. 2010;52(4):1081-6. 5. Lobato AC. Aneurisma da Aorta Infrarrenal. In: Lobato AC (org). Cirurgia Endovascular. 2nd ed. São Paulo: Instituto de Cirurgia Vascular e Endovascular de São Paulo; 2010. p.743-96. 6. Rigonatto M. Triângulo equilátero inscrito numa circunferência. [cited 2013 Mai 22]. Available from: http://www.mundoeducacao. com/matematica/triangulo-equilatero-inscrito-numacircunferencia.htm 7. Espinosa G, Marchiori E. Araújo AP, Caramalho MF, Barzola P. Abdominal aorta orphometric study for endovascular treatment of aortic aneurysms: comparison between spiral CT and angiography. Rev Bras Cir Cardiovasc. 2002;17(4):323-30. 8. van Keulen JW, Moll FL, Tolenaar JL, Verhagen HJM, van Herwaarden JA. Validation of a new standardized method to measure proximal aneurysm neck angulation. J Vasc Surg. 2010;51(4):821-8.

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Oliveira MAB,SPECIAL et al. - Comparison of the solution of histidine-tryptophanARTICLE alfacetoglutarate with histidine-tryptophan-glutamate as cardioplegic agents in isolated rat hearts: an immunohistochemical study

Comparison of the solution of histidinetryptophan-alfacetoglutarate with histidinetryptophan-glutamate as cardioplegic agents in isolated rat hearts: an immunohistochemical study Comparação da solução de histidina-triptofano-alfacetoglutarato com histidina-triptofano-glutamato como agentes cardioplégicos em corações isolados de ratos: estudo imuno-histoquímico

Marcos Aurélio Barboza de Oliveira1, MD; Lívia Carvalho Ferreira1; Débora Aparecida Pires de Campos Zuccari1; Antônio Carlos Brandi2, MD; Carlos Alberto dos Santos2, MD; Paulo Henrique Husseni Botelho2, MD; Orlando Petrucci3, MD, PhD; Domingo Marcolino Braile1, MD, PhD

DOI: 10.5935/1678-9741.20140015

RBCCV 44205-1525

Abstract Introduction: Cardiac arrest during heart surgery is a common procedure and allows the surgeon to perform surgical procedures in an environment free of blood and movement. Using a model of isolated rat heart, the authors compare a new cardioplegic solution containing histidine-tryptophan-glutamate (group 2) with the histidine-tryptophan-alphacetoglutarate (group 1) routinely used by some cardiac surgeons. Objective: To assess caspase, IL-8 and KI-67 in isolated rat hearts using immunohistochemistry. Methods: 20 Wistar male rats were anesthetized and heparinized. The chest was opened, cardioctomy was performed and 40 ml/kg of the appropriate cardioplegic solution was infused. The hearts were kept for 2 hours at 4°C in the same solution, and thereafter, placed in the Langendorff apparatus for

30 minutes with Ringer-Locke solution. Immunohistochemistry analysis of caspase, IL-8, and KI-67 were performed. Results: The concentration of caspase was lower in group 2 and Ki-67 was higher in group 2, both P<0.05. There was no statistical difference between the values of IL-8 between the groups. Conclusion: Histidine-tryptophan-glutamate solution was better than histidine-tryptophan-alphacetoglutarate solution because it reduced caspase (apoptosis), increased KI-67 (cell proliferation), and showed no difference in IL-8 levels compared to group 1. This suggests that the histidine-tryptophan-glutamate solution was more efficient than the histidine-tryptophanalphacetoglutarate for the preservation of hearts of rat cardiomyocytes.

1. São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, SP, Brazil. 2. Hospital de Base (HB), São José do Rio Preto, SP, Brazil. 3. State University of Campinas (UNICAMP), Faculty of Medical Sciences, Campinas, SP, Brazil.

Zip code: 15092-500 E-mail: m_aurelio@sbccv.org.br

Correspondence address: Marcos Aurélio Barboza de Oliveira Av. República do Líbano, 2700 – casa 80 – Jardim Tarraf II – São José do Rio Preto, SP, Brazil

No financial support.

Descriptors: Heart Arrest, Induced. Myocardial Ischemia. Heart.

This study was carried out at São José do Rio Preto Medical School (FAMERP), São José do Rio Preto, SP, Brazil.

Article received on October 17th, 2013 Article accepted on November 21st , 2014

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Oliveira MAB, et al. - Comparison of the solution of histidine-tryptophanalfacetoglutarate with histidine-tryptophan-glutamate as cardioplegic agents in isolated rat hearts: an immunohistochemical study

Métodos: 20 ratos machos de raça Wistar foram anestesiados e heparinizados. O tórax foi aberto, realizado cardiectomia e infundido 40 ml/kg de solução cardioplégica apropriada. Os corações foram mantidos por 2 horas na mesma solução a 4oC e, após esse período, colocados em aparato de Langendorff por 30 minutos com solução de Ringer Locke. Foram feitas análises imuno-histoquímicas para caspase, IL-8 e KI-67. Resultados: A concentração de caspase estava menor no grupo 2 e da KI-67 estava mais elevada no grupo 2, ambos com P<0,05. Não houve diferença estatística entre os valores de IL-8 entre os grupos. Conclusão: A solução com histidina-triptofano-glutamato foi melhor que a com histidina-triptofano-cetoglutarato, pois reduziu a caspase (apoptose), aumentou o KI-67 (proliferação celular) e não apresentou valores diferentes de IL-8 (inflamação e necrose) que no grupo 1. Isso sugere que a solução histidinatriptofano-glutamato foi mais eficiente que a histidinatriptofano-cetoglutarato na preservação dos cardiomiócitos dos corações de ratos.

Abbreviations, acronyms and symbols ATP Adenosine triphosphate BSA bovine serum albumin MOD mean optical density HTG histidine-tryptophan-glutamate HTK histidine-tryptophan-ketoglutarate IL Interleukin IP Intraperitoneal AU Arbitrary units

Resumo Introdução: A parada do coração durante a cirurgia cardíaca é procedimento comum e permite que o cirurgião realize os procedimentos cirúrgicos em ambiente isento de sangue e movimento. Os autores comparam, em modelo de coração isolado de rato, uma nova solução cardioplégica com histidina-triptofano-glutamato (grupo 2) com a histidinatriptofano-alfacetoglutarato (grupo 1) já utilizada de rotina por alguns cirurgiões cardíacos. Objetivo: Avaliar por análise imuno-histoquímica a caspase, a IL-8 e KI-67 em corações isolados de ratos.

Descritores: Parada Cardíaca Induzida. Isquemia Miocárdica. Coração.

INTRODUCTION

to myocyte: the decrease in lactate and raising the pH in the mitochondrial matrix, even in ischaemia, avoiding intracellular acidosis and edema, and contributing to the maintenance of intracellular adenosine triphosphate (ATP), protecting the myocyte of ischemia - reperfusion lesion. In turn, the reduction of reperfusion injury cause decrease of caspase [10-12] and IL- 8, due to the reduction in cellular apoptosis and necrosis, respectively [13,14]. Nevertheless, the reduction of reperfusion injury may not be acting alone on behalf myocyte. Proliferative proteins such as KI- 67, could be re-coded, thus contributing to the reduction of the cell death and formation of new myocardial fibers [15,16]. This study assess HTG solution as a cardioplegic agent in isolated rat heart, considering immunohistochemical analysis of caspase markers, IL-8 and KI-67.

Induction of temporary arrest of the heart during cardiac surgery is a relatively common procedure that allows the surgeon to perform procedures in an environment free of blood and movement [1-3]. One of the cardioplegic agents is histidine-tryptophan-ketoglutarate (HTK) solution. The HTK was tested by Bretschneider et al. [ 4] in Germany, 1975. Its mechanism of action comes from the absence of calcium, which prevents its influx into the cell by type “L” calcium channel in the plateau phase of the potential action, inhibiting the release of calcium from the sarcoplasmic reticulum over the myocyte, resulting in inactivation of myofilaments [5,6]. This mechanism is complemented by cellular protection given by the constituents of this solution, whose main functions include: 1 - histidine: temperature-dependent buffer system, inhibitor of matrix metalloproteinases and cell impermeant [7] 2 – tryptophan: acts in maintaining the integrity of cell membrane [8], and 3 - ketoglutarate: improves maximum developed pressure and prevents increased creatine kinase MB fraction [8]. According Pisarenko et al. [9], the substitution of alpha-Ketoglutaric acid by glutamate bring some advantages

METHODS After approval by the Ethics Committee on Animal Experimentation of the Faculty of Medicine of São José do Rio Preto (autorization number 015/2012), 20 male Wistar rats (10 in each group) were used, weighing 280±29 grams. All animals received care according to the recommendations of the Committee on Care and Use of Laboratory An-

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imals - Institute of Laboratory Animal Resources (ILAR) National Research Council, United States [17].

Histological and immunohistochemical technique preparation Initially, the material was embedded in paraffin, a procedure that provides resistance allow for cutting thickness of 3m and placed on silanized slides. The silanization of the blades consisted in preparing these with an adhesive that fixes the fragment to the blades, preventing their detachment during the immunohistochemical procedure. For this, they were immersed in acetone P.a. (2 minutes), 4% silane solution diluted with acetone (2 minutes) and again in acetone P.a. (4 to 5 dips). The drying of the slides was performed in an oven at 60ºC. The block was attached to the microtome, the slice thickness was set to 3 µm and the cuts placed on silanized identified and left in an oven at 60°C for 24 hours. The blade went through the process of deparaffinization in xylene, followed by hydration in absolute alcohol I, II and III, finishing with six dives in tap water, incubated with 3% hydrogen peroxide for 30 minutes to block endogenous peroxidase. Antigen retrieval was performed in the steamer with specific buffer for each antibody for 30 minutes (Table 2). Then the slides were covered up with a solution containing fetal bovine serum (BSA) and incubated with the primary antibody.

Experimental Protocol The animals were anesthetized with an injection of 65 mg/kg intraperitoneal sodium pentobarbital and received IP systemic heparin (500 IU/kg). After opening the chest, cardiectomy was performed . Hearts received Ringer’s lactate solution to “wash” the coronary tree and then cardioplegic solution according to the corresponding group. The hearts in this phase of the experiment were divided into 2 groups. In group 1, was used HTK solution at 4°C and in Group 2, solution of histidine-tryptophan-glutamate (HTG) at 4°C. Table 1 shows the composition of each solution. In all cases, the infusion of cardioplegia was performed as a single dose 40 ml/kg at the aortic root, followed by immersion of the organ in the same solution for 2 hours at 4°C. After this time, the hearts were placed in a Langendorff system and perfused with oxygenated Locke Ringer buffer under normothermy and constant pressure of 100 cm H2O for gravitational method for 30 minutes. The drainage of the right ventricle was performed by opening the pulmonary artery, and the right atrium was maintained intact in order to preserve the sinus node [18]. Three threads of epicardial pacemaker were inserted at equidistant points of the ventricles for electrocardiographic documentation of cardiac events. The time of onset of ventricular fibrillation and the first heartbeat counted from the start of infusion of Ringer Locke solution was noted. After 30 minutes of infusion of Ringer Locke, the experiment was discontinued. The hearts were removed from the Langendorff system and fragments of the cardiac apex, which were stored in sterile Falcon type tubes containing 10% formalin for subsequent histological and immunohistochemical preparation.

Table 2. List of antibodies used. Antibody anti-Ki-67 anti-Caspase 3 anti-IL-8

Dilution Buffer Lab 1:200 Citrato pH6 Biocare Medical 1:1000 Citrato pH6 Abcam 1:50 Citrato pH6 Santa Cruz

After this step, the slides were washed in PBS solution and incubated for 15 minutes with Starr Trek Universal HRP Detection kit (Biocare Medical®), which consisted in secondary antibody biotinylated for 1 hour and streptavidin-peroxidase complex for 30 minutes, followed by washing with PBS for 15 minutes. The revelation was performed with substrate chromogen (DAB Betazoidchromogen) of the Starr Trek Universal HRP Detection kit (Biocare Medical®) for 2 to 5 minutes, and counterstained with Harrys hematoxylin for 40 seconds. The tissues were dehydrated in alcohol in ascending degree and bathed in xylene before mounting the slides on ERV-MOUNT amid (Erviegas®). Negative control reactions were obtained by omitting the primary antibody. Tonsil tissue was used for Ki-67 reactions and Caspase 3 and as positive control breast tissue for IL-8 reaction.

Table 1. Composition of solutions used. Substance HTK (g/L) Sodium chloride 0.8766 Potassium chloride 0.671 0.8132 Magnesium chloride Calcium chloride 0.0022 Potassium-hydrogen-2-ketoglutarate 0.1842 Glutamate --Histidine 27.9289 Histidine chloride, H2O 3.7733 Tryptophan 0.4085 Mannitol 5.4651 Water for injection a 1000 ml

Specificity Monoclonal Polyclonal Monoclonal

HTG (g/L) 0.8766 0.671 0.8132 0.0022 --0.1842 27.9289 3.7733 0.4085 5.4651 a 1000 ml

Quantification of immunohistochemical staining Slides were photographed and quantified by enzyme AxioVision software on X40 magnification microscope Zeiss Axioskop 2. For each sample, three regions of cardiac tissue and 20 points of myocardial cell were marked in each region were selected. Thus, 60 different points on each sample were assessed by obtaining the average relative intensity of immunoreactivity. The values were obtained in arbitrary units

HTK: Histidine-tryptophan ketoglutarate; HTG: histidinetryptophan-glutamate

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(AU). The average optical density (AOD) was obtained with the aid of the following formula: AOD = 255 – AU This formula showed the intensity of immunostaining specifically in immunoreactive areas. Statistical Analysis The data were subjected to the Kolmogorov-Smirnov test and subsequently the parametric analysis by unpaired Student’s t test or non-parametric by Mann-Whitney test when appropriate, and Fisher’s exact test for categorical data. Results were expressed only in mean ± standard deviation due to the fact all variables behave as continuous quantitative with Gaussian distribution. P values were presented, and those who were less than 0.05 were considered significant. The GraphPad Instat and Prism 6.0 softwares of statistical analysis, both for Windows® were used.

Fig. 1 - Histograms showing mean optical densities of: (A) caspase, (B) KI67 and (C) IL-8. Group 1: solution with histidine-tryptophan-ketoglutarate, Group 2: solution with histidine-tryptophan-glutamate

RESULTS The average weight of the animals was 277.4 ± 24.6 g (group 1) and 288 ± 34.5 g (group 2 ), respectively, with no significant difference between groups (P=0.4396). Regarding the average volume of Ringer Locke collected from coronary sinus after 30 minutes (363.1 ± 177.3 ml and 277.4 ± 33.7 ml, respectively), there was no significant difference between groups (P=0.1923).

creases contraction, and glutamate and aspartate; increases lactate, pyruvate, alanine and succinate [9]. According Pisarenko et al. [9] the addition of glutamate in the perfusate keeps the intracellular ATP and decreases both lactate and pyruvate as that contribute to acidosis. These effects contribute to improve cardiac function recovery after ischemia. Our results show similar behavior in the two solutions studied concerning the time and duration of ventricular fibrillation first beat, however, it was better for group 2 concerning heart rate, which was lower, which can be correlated with lower acidosis, probably myocyte . Another process that is intrinsically related to ischemia-reperfusion injury is apoptosis [10,11], characterized by morphological changes such as chromatin condensation, fragmentation of nuclei and formation of “apoptotic bodies”. These changes are made by a family of proteases called caspases [12]. The degree of caspase activation is directly related to the degree of apoptosis, which plays a critical factor in the recovery of cardiac function [13]. Our results demonstrate less caspase activity in group 2, suggesting a potential protective for myocardial function. In contrast to apoptosis, necrosis is an irreversible process of cell death due to the breakdown in cellular homeostasis. There is disruption of the cell membrane, with leakage from the cytosol to the extracellular medium, leukocyte margination and activation of the inflammatory cascade [13,14]. Anselmi et al. [14] have described IL-8 peak at 35 minutes of reperfusion and IL-6 in 75 minutes. Lee et al. [13] stated that the HTK solution inhibits increase of interleukin. Thus, as in this study there was no significant difference in IL-8 between groups 1 and 2, and we can infer that the anti-inflammatory

Findings during perfusion with cardioplegic solution and Ringer Locke All hearts showed adequate perfusion of cardioplegia and Ringer Locke, evidenced by clear staining in the ventricular wall. The average heart rate after 5 minutes of perfusion (233±36 and 188±53.4 beats per minute, respectively), showed a significant difference (P=0.0086). The time of onset of ventricular fibrillation (49 ± 28.2 and 45 ± 17 seconds, respectively) and time to first heartbeat (153 ± 78 and 117 ± 96.8 seconds respectively) showed no significant difference (P=0.5869 and P=0.187, respectively). Immunohistochemical findings After 2 hours of ischemia and 30 minutes of reperfusion, caspase activity was significantly lower in group 2 (P<0.0001), the activity of KI-67 was higher in group 2 (P<0.0001) and IL-8 was not different between groups (Figure 1). DISCUSSION Myocardial ischemia causes various cardiac effects, such as decreases force of contraction; increases diastolic pressure, indicating contraction of myofibrils in isovolumic conditions, causes a decline in phosphocreatine and ATP; de-

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protection provided by HTG solution was not different from that given by the HTK solution. Mammalian hearts have low proliferative capacity after birth. One of the markers used to assess cell proliferation is the Ki-67 [15]. With this marker, Walsh et al . [16] demonstrated that 12% to 23% of fetal rat cardiomyocytes exhibit proliferative activity, from 1% to 8% up to the 7th day and virtually undetectable from the 14th day. In our study, there was a significant increase of the KI-67 in group 2, demonstrating early proliferative activity of HTG solution guaranteed with 2 hours of ischemia. Associated with this, Walsh et al. [16] also draw the attention to the KI-67 activity also be inversely related to apoptosis, which is also confirmed in our study, in which caspase is lower in group 2 than in 1. However, the increased activity of this marker is worrisome because it has been associated with myxomas [19,20] and cardiac sarcomas [21]. Although the results obtained here are consistent with the literature, they are not definitive regarding the replacement of alpha-Ketoglutaric acid by glutamate. Quantitative analysis with ATP and other nuclear markers for cell proliferation should be used to target a more comprehensive and safe conclusion. Another relevant aspect is the concentration of glutamate. Would have the same protective effect on the heart if we change its concentration? Further studies are needed to answer these questions.

REFERENCES 1. Chambers DJ. Mechanisms and alternative methods of achieving cardiac arrest. Ann Thorac Surg. 2003;75(2):S661-6. 2. Fannelop T, Dahle GO, Matre K, Moen CA, Mongstad A, Eliassen F, et al. Esmolol before 80 min of cardiac arrest with oxygenated cold blood cardioplegia alleviates systolic dysfunction. An experimental study in pigs. Eur J Cardiothorac Surg. 2008;33(1):9-17. 3. Braile DM, Ardito RV, Zaiantchick M, Santos JLV, Soares MJF. Cardioplegia sanguínea contínua normotérmica. Rev Bras Cir Cardiovasc. 1989;4(2):109-38. 4. 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. 5. Fallouh HB, Kentish JC, Chambers DJ. Targeting for cardioplegia: arresting agents and their safety. Curr Opin Pharmacol. 2009;9(2):220-6. 6. Chambers DJ, Hearse DJ. Developments in cardioprotection: “polarized” arrest as an alternative to “depolarized” arrest. Ann Thorac Surg. 1999;68(5):1960-6. 7. Antunovic M, Aleksic D. Preparation and testing of solutions for organ perfusion and preservation in transplantation. Vojnosanit Pregl. 2008;65(8):596-600.

CONCLUSION

8. Hachida M, Ookado A, Nonoyama M, Koyanagi H. Effect of HTK solution for myocardial preservation. J Cardiovasc Surg (Torino). 1996;37(3):269-74.

Immunohistochemical analysis of replacement of alpha-Ketoglutaric by glutamate in cardioplegia with histidine and tryptophan showed that heart muscle cells showed no greater incidence of necrosis, since when measuring IL-8 they presented a lower incidence of apoptosis, confirmed by the lower values of in group 1 and caspase best proliferative activity, with higher values of Ki-67 compared to group 1. This suggests that HTG solution was more efficient than the HTK in preserving cardiomyocytes of rat hearts.

9. Pisarenko OI, Solomatina ES, Ivanov VE, Studneva IM, Kapelko VI, Smirnov VN. On the mechanism of enhanced ATP formation in hypoxic myocardium caused by glutamic acid. Basic Res Cardiol. 1985;80(2):126-34. 10. Xu YJ, Saini HK, Zhang M, Elimban V, Dhalla NS. MAPK activation and apoptotic alterations in hearts subjected to calcium paradox are attenuated by taurine. Cardiovasc Res. 2006;72(1):163-74. 11. Fischer UM, Cox CS Jr, Laine GA, Mehlhorn U, Bloch W, Allen SJ. Induction of cardioplegic arrest immediately activates the myocardial apoptosis signal pathway. Am J Physiol Heart Circ Physiol. 2007;292(3):H1630-3.

Authors’ roles and responsibilities MABO LCF DAPCZ ACB CAS PHHB OP DMB

Study design, execution of experiments, analysis of results and writing of the manuscript Assistance in immunohistochemical techniques Assistance in immunohistochemical techniques Participation in the preparation of the final text Participation in the preparation of the final text Participation in drafting the final text Review of the version Study design, analysis of results and writing of the manuscript

12. Pirnia F, Schneider E, Betticher DC, Borner MM. Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway. Cell Death Differ. 2002;9(9):905-14. 13. Lee S, Huang CS, Kawamura T, Shigemura N, Stolz DB, Billiar TR, et al. Superior myocardial preservation with HTK solution over Celsior in rat hearts with prolonged cold ischemia. Surgery. 2010;148(2):463-73.

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14. Anselmi A, Abbate A, Girola F, Nasso G, Biondi-Zoccai GG, Possati G, et al. Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence. Eur J Cardiothorac Surg. 2004;25(3):304-11.

18. Lahaye Sle D, Gratas-Delamarche A, Malardé L, Vincent S, Zguira MS, Morel SL, et al. Intense exercise training induces adaptation in expression and responsiveness of cardiac β-adrenoceptors in diabetic rats. Cardiovasc Diabetol. 2010;9:72.

15. Lee Y. To proliferate or not to proliferate. Cardiovasc Res. 2010;86(3):347-8.

19. Kusumi T, Minakawa M, Fukui K, Saito S, Ohashi M, Sato F, et al. Cardiac tumor comprising two components including typical myxoma and atypical hypercellularity suggesting a malignant change. Cardiovasc Pathol. 2009;18(6):369-74.

16. Walsh S, Pontén A, Fleischmann BK, Jovinge S. Cardiomyocyte cell cycle control and growth estimation in vivo: an analysis based on cardiomyocyte nuclei. Cardiovasc Res. 2010;86(3):365-73.

20. Suvarna SK, Royds JA. The nature of the cardiac myxoma. Int J Cardiol. 1996;57(3):211-6.

17. Committee on Care and Use of Laboratory Animals - Institute of Laboratory Animal Resources - Commission on Life Sciences National Research Council. Guide for the care and use of laboratory animals. 8th ed. Washington: National Academies Press; 2010. 211p.

21. Brunner-La Rocca HP, Vogt PR, Burke AP, Schneider J, Jenni R, Turina MI. A primary cardiac sarcoma with unusual histology and clinical course. Ann Thorac Surg. 2001;71(5):1675-7.

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Sciarra AMP, etSPECIAL al. - Information technology implementing globalization on ARTICLE strategies for quality care provided to children submitted to cardiac surgery: International Quality Improvement Collaborative Program – IQIC

Information technology implementing globalization on strategies for quality care provided to children submitted to cardiac surgery: International Quality Improvement Collaborative Program – IQIC A tecnologia da informação implementando a globalização nas estratégias de qualidade para o atendimento às crianças submetidas à cirurgia cardíaca: o Programa de Colaboração Internacional – IQIC

Adilia Maria Pires Sciarra1, MD, MSc; Ulisses Alexandre Croti1, MD, PhD; Fernando Batigália1, MD, PhD

DOI: 10.5935/1678-9741.20140016

RBCCV 44205-1526

Abstract Introduction: Congenital heart diseases are the world’s most common major birth defect, affecting one in every 120 children. Ninety percent of these children are born in areas where appropriate medical care is inadequate or unavailable. Objective: To share knowledge and experience between an international center of excellence in pediatric cardiac surgery and a related program in Brazil. Methods: The strategy used by the program was based on long-term technological and educational support models used in that center, contributing to the creation and implementation of new programs. The Telemedicine platform was used for real-time monthly broadcast of themes. A chat software was used

for interaction between participating members and the group from the center of excellence. Results: Professionals specialized in care provided to the mentioned population had the opportunity to share to the knowledge conveyed. Conclusion: It was possible to observe that the technological resources that implement the globalization of human knowledge were effective in the dissemination and improvement of the team regarding the care provided to children with congenital heart diseases.

1. Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil

Work carried out at Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil; Fundação Faculdade Regional de Medicina de São José do Rio Preto (FUNFARME), São José do Rio Preto, SP, Brazil and Hospital de Base-(HB), São José do Rio Preto, SP, Brazil.

Descriptors: Heart Defects, Congenital. Cardiovascular Surgical Procedures. Telemedicine.

Correspondence address: Adilia Maria Pires Sciarra Faculdade de Medicina de São José do Rio Preto (FAMERP) Av. Brigadeiro Faria Lima, 5416 – Vila São Pedro- São José do Rio Preto, SP, Brazil - Zip code: 15090-000 E-mail: adilia@famerp.br

Financial support: Pro-Ensino na Saúde – CAPES. Article received on October 13th, 2013 Article accepted on December 11th, 2013

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Sciarra AMP, et al. - Information technology implementing globalization on strategies for quality care provided to children submitted to cardiac surgery: International Quality Improvement Collaborative Program – IQIC

em modelos de suporte tecnológico e educacional a longo termo advinda daquele centro, contribuindo para criação e efetivação de novos programas. Foi utilizada plataforma de Telemedicina para transmissão mensal em tempo real dos temas. Um programa de chat foi utilizado para a interação entre os membros participantes e o grupo do centro de excelência. Resultados: Os profissionais especializados no cuidado dessa população tiveram a oportunidade de participar do conhecimento transmitido. Conclusão: Pode-se observar que os recursos tecnológicos que implementam a globalização do conhecimento humano foram efetivos na disseminação e aprimoramento da equipe no que diz respeito ao cuidado às crianças com cardiopatias congênitas.

Abbreviations, acronyms & symbols CHL IQIC RACHS-1

Children’s HeartLink International Quality Improvement Collaborative Risk Adjustment in Congenital Heart Surgery

Resumo Introdução: Doenças cardíacas congênitas são consideradas o maior defeito ao nascimento, afetando uma em cada 120 crianças. Noventa por cento destes recém-nascidos encontram-se em áreas onde os cuidados médicos são inadequados ou indisponíveis. Objetivo: Compartilhar o conhecimento e a experiência entre um centro de excelência internacional em cirurgia cardíaca pediátrica e um programa correlato no Brasil. Métodos: Estratégia utilizada pelo programa foi baseada

Descritores: Cardiopatias Congênitas. Procedimentos Cirúrgicos Cardiovasculares. Telemedicina.

INTRODUCTION

genital heart surgery in developing world programs. The mission of the IQIC is to reduce mortality and major complications for children undergoing congenital heart surgery in developing world programs. To achieve the goals, the collaborative program aims to create strategies for quality improvement in order to reduce mortality and major complications for these programs in developing countries [1,2]. IQIC was divided in two phases: • Phase 1 included data collection and analysis. After the first year, participating sites continue assessing the data and start Phase 2 to implement quality improvement strategies targeted at drivers of mortality; • Phase 2 includes participating in monthly educational modules and webcasts broadcast from Boston Children’s Hospital in a telemedicine platform. The webcasts are focused on improving team-based practice through nurse “empowerment”, training, infection prevention and implementing safe operative practices [1,2].

The establishment of surgical programs for children with congenital heart disease in developing countries is a major step to improve surgical outcomes, since most of them are deprived of appropriated medical care [1]. Although congenital heart surgery in developing countries offers access to children who would otherwise die, surgery when required is particularly challenging and associated with high mortality [2]. In 2007, clinical leaders providing surgical cardiac care to children around the world congregated at the Global Forum on Humanitarian Medicine in Cardiology and Cardiac Surgery in Geneva. The existence of potential contributing factors to mortality that may be specific to children receiving cardiac surgery in developing countries was discussed. and it became evident that there are few benchmarks to identify specific risk factors and assess the performance of these surgical programs. In an effort to address these gaps, the International Quality Improvement Collaborative Program (IQIC) was launched. In 2008, Children’s HeartLink (CHL), a nongovernmental and nonprofit organization; the Boston Children’s Hospital in Boston, USA; the Humanitarian Association Coeurs pour Tous in Geneva, Switzerland; the Dr. K. M. Cherian Heart Foundation in Chennai, India; and the International Children’s Heart Foundation in Memphis, USA, established the foundations of the International Quality Improvement Collaborative for Congenital Heart Surgery in Developing World Countries (IQIC), with the hope of fostering collaboration between programs of developed and developing countries (twinning programs) [1]. The IQIC is managed by Boston Children’s Hospital of Harvard Medical School. The program’s vision is to facilitate the collaboration of health teams from around the world working to create a culture of patient safety and quality improvement of the infrastructure for children receiving con-

Phase 1: IQIC Database (Benchmarking Data) Data collection and analysis Data collection began in 2008 and the first participant sites were: the Cardiovascular Surgery Unit of Guatemala (Guatemala), the Armed Forces Institute of Cardiology (Pakistan), the Frontier Lifeline Hospital (India), the National Children’s Cardiac Surgical Center (Belarus), and the Shanghai Children’s Medical Center (China). Teams of doctors and nurses from each location supervised data collection and the management of the project. They submit diagnoses, procedures and clinical information to a centralized repository using Web tools. Assessment of surgical outcomes and risk-adjusted mortality rates are used as benchmarking for comparison between the participating sites. Detailed information about the data collection process on the web portal and completion of the forms are found in the Database Reference Guide.

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The Boston Children’s Hospital maintains the project database. Data are sent to generate semi-annual confidential reports for each site. Benchmarking data can be used to assess the performance of programs and the improvement of quality in the driver of each participating institution (Chart 1).

ability of a collaborative model for quality improvement. It aims to identify mortality drivers and create strategies focused on quality improvement for obtaining satisfactory outcomes. Since January 2010, the Boston Children’s Hospital has conducted monthly Webinars to facilitate dialogue and disseminate learning for quality knowledge. The modules are based on three mortality drivers: teambased practice; reduction of infection at the surgical site; and perioperative safe practice (Chart 2). Each module includes a series of three educational sessions developed from elementary to advanced levels. The main goal of the seminars is to provide a collaborative learning experience that is flexible enough to be adapted according to the needs of each site. The Boston Children’s Hospital develops modules and provides assistance to sites for the implementation of interventions on quality improvement. The modules include: an overview of the problem; learning objectives; implementation and problem solving based on case studies; and tools for assessment (Chart 2).

Risk adjustment in congenital heart surgery (RACHS-1) Risk-adjusted mortality rates are obtained using the Risk Adjustment in Congenital Heart Surgery (RACHS-1) method. Each surgical procedure is classified into one of six predefined risk categories based on the RACHS-1 method. Risk 1 category represents low mortality risk whereas risk 6 category represents high risk. Additional clinical factors integrated into RACHS-1 include age, prematurity and major non-cardiac structural abnormalities. The RACHS-1 method has been validated and applied in databases in the United States and Europe [3]. Phase 2: Implementation of strategies for quality improvement: modules for learning – Web seminars The goal of this implementation is to assess the sustain-

Chart 1. IQIC database: benchmarking data. Data Collection and Analysis Registration and procedure Registration must be completed with the following items: 1. Demographic information 2. Preoperative status 3. Patient’s diagnosis 4. Surgical procedure 5. Outcome/Complications

Follow-up Patients’ registration to be completed 30 days after the procedure 6. 30-day follow-up

Chart 2. Key driver diagram. Objective

Reduction of 30-day mortality rates associated with congenital heart surgery

Key drivers Safe perioperatory practice

Strategy changes Use a checklist for surgical safety to record immediate measures in a process based on evidence (i.e., antibiotics administered within 60 min after surgical incision)

Reduction of surgical site infection

Focus on hand hygiene of all members dealing with patients’ care

Team-based practice

Train nurses with nursing practice based on evidence Guidance for nurses in infirmaries and ICUs on how to carry out reports Total 24 h of entry and exit Accurate daily records of patients’ weight

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Core Curriculum Outline Module 1: Team-based practice: effective communication and team work • Elementary: Clear communication and efficient team work; • Intermediate: Care in the postoperative after pediatric cardiac surgery: important considerations in nursing; • Advanced: Resources management during crises at the intensive care unit.

to the data sent to date, but also due to the webinars, which are broadcast monthly throughout the year via a telemedicine platform. Prior to the scheduled broadcast, each lesson is submitted for translation (Brazilian Portuguese) and contextualization. On the scheduled day and time, the local team meets and the translated and contextualized lessons are attended at the same time the lessons are being broadcast by the IQIC team directly from Boston. Synchronous interaction is accomplished through the use of chat rooms for questions and answers between the local team and the IQIC team. Thus, this joint participation between the two programs with the goal of putting into practice the quality improvement of care provided to children with congenital heart diseases has only been possible through technological resources implementing globalization on this knowledge.

Module 2: Reducing surgical site infections and bacterial sepsis • Elementary: Prevention of healthcare - Associated infections: creating a hand hygiene culture; • Intermediate: Prevention of bacterial sepsis - bloodstream infections; • Advanced: Prevention of bacterial sepsis - Surgical site infections. Module 3: Safe perioperative practice • Elementary: Implementation of a checklist for surgical safety in congenital heart surgery (Session I); • Intermediate: Implementation of a checklist for surgical safety in congenital heart surgery (Session II) [4].

Authors’ roles & responsibilities AMPS UAC FB

Advanced Modules: Modules with advanced content that expanded on the mortality drivers were also created. The themes are as follows: • Heart embryology; • Arrhythmias; • Congenital heart defects; • Pain and nutrition management; • Respiratory management in the postoperative period and prevention of pneumonia; • Fetal circulation; • Hypoplastic left heart syndrome, anatomy and physiology. Partnership and participation of the Cardiology and Pediatric Cardiovascular Surgery Service of São José do Rio Preto (SECCAP) and the Base Hospital of the Medical School of São José do Rio Preto (FAMERP) in the IQIC program started in 2009, at the suggestion and request of the American organization CHL. Its primary objective was a suitable control of data to enable effective actions to improve the care provided to children with heart diseases in Brazil [5]. At that time, our service began the collection of data and improvement of this methodology and after June 2010 all Brazilian data from the service were included in the world database, alongside numerous centers in developing countries. This integration has advanced considerably, not only due

Main author, text drafting, content expert, review of the text development Specialist in the area Checking of text development, spelling and layout

REFERENCES 1. IQIC International Quality Improvement Collaborative, IQIC | Children’s HeartLink. Acessed 05/02/2013. Available at: http:// www.childrensheartlink.org/iqic. 2. International Quality Improvement Collaborative for Congenital Heart Surgery. Orientation manual. Version 5.0, Revised January 2012. 3. Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg. 2002;123(1):110-8. 4. Croti UA, Jenkins KJ, Braile DM. Checklist in pediatric cardiac surgery in Brazil: an useful and necessary adaptation of the Quality Improvement Collaborative International Congenital Heart Surgery in Developing Countries. Rev Bras Cir Cardiovasc. 2011;26(3):511-5. 5. Croti UA, Braile DM. International cooperation in Brazil: Children´s HeartLink. Rev Bras Cir Cardiovasc. 2010;25(1):VIII-IX.

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Liguori GR, et al. - Managing the inflammatory response after cardiopulmonary REVIEW ARTICLE bypass: review of the studies in animal models

Managing the inflammatory response after cardiopulmonary bypass: review of the studies in animal models Manejo da resposta inflamatória pós-circulação extracorpórea: revisão dos estudos em modelos animais

Gabriel Romero Liguori1; Alexandre Fligelman Kanas1; Luiz Felipe Pinho Moreira1, MD, PhD

DOI: 10.5935/1678-9741.20140017

RBCCV 44205-1527

Abstract Objective: To review studies performed in animal models that evaluated therapeutic interventions to inflammatory response and microcirculatory changes after cardiopulmonary bypass. Methods: It was used the search strategy (“Cardiopulmonary Bypass” [MeSH]) and (“Microcirculation” [MeSH] or “Inflammation” [MeSH] or “Inflammation Mediators” [MeSH]). Repeated results, human studies, non-English language articles, reviews and studies without control were excluded. Results: Blood filters, system miniaturization, specific primers regional perfusion, adequate flow and temperature and pharmacological therapies with anticoagulants, vasoactive drugs and anti-inflammatories reduced changes in microcirculation and inflammatory response. Conclusion: Demonstrated efficacy in animal models establishes a perspective for evaluating these interventions in clinical practice.

Resumo Objetivo: Revisar estudos realizados em modelos animais avaliando intervenções terapêuticas e resposta inflamatória e alterações da microcirculação após instalação de circulação extracorpórea. Métodos: Utilizada a estratégia de busca (“Cardiopulmonary Bypass”[MeSH]) AND (“Microcirculation”[MeSH] OR “Inflammation”[MeSH] OR “Inflammation Mediators”[MeSH]). Resultados repetidos, estudos humanos, artigos em língua não inglesa, revisões e estudos sem controle foram excluídos. Resultados: Filtros sanguíneos, miniaturização do sistema, perfusatos específicos, perfusão regional, fluxo e temperatura adequados e terapias farmacológicas com fármacos anticoagulantes, vasoativos e anti-inflamatórios reduziram alterações em microcirculação e resposta inflamatória. Conclusão: A eficácia demonstrada em modelos animais estabelece uma perspectiva para avaliação dessas intervenções na prática clínica.

Descriptors: Extracorporeal Circulation. Inflammation. Models, Animal. Microcirculation.

Descritores: Circulação Extracorpórea. Inflamação. Modelos Animais. Microcirculação.

1. Heart Institute at the Clinics Hospital of the Faculty of Medicine, University of São Paulo (InCor –FMUSP), São Paulo, SP, Brazil.

Correspondence address: Gabriel Romero Liguori Instituto do Coração (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Av. Dr. Enéas de Carvalho Aguiar, 44 – 2º andar – bloco II – sala 13 – Cerqueira César – São Paulo, SP, Brazil – Zip code: 05403-000 E-mail: gabriel.liguori@usp.br

This study was carried out at the Clinics Hospital of the Faculty of Medicine, University of São Paulo (InCor –FMUSP), São Paulo, SP, Brazil.

Article received on April 23rd , 2013 Article accepted on September 24th, 2013

No financial support.

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Liguori GR, et al. - Managing the inflammatory response after cardiopulmonary bypass: review of the studies in animal models

mune system, leading to changes that, at first, are manifested by an exaggerated inflammatory response, but which then lead to a temporary immunodeficiency presentation. The development of strategies to control the damage caused by CPB in the body is therefore essential in order to reduce these complications and has been the focus of several experimental research and clinical studies. The therapeutic possibilities targeting to reduce the inflammatory process are based on two main pillars: non-pharmacological interventions in the CPB system and administration of drugs in the peri- or intraoperative period. Although clinical trials may indicate possible routes and general aspects of aggression caused by CPB in the body, new therapies may not be initially assessed by means of this type of study, since they need to be tested on animals to ensure their safety and only then be investigated in clinical studies. Thus, animal models are essential for developing strategies against the inflammatory response to CPB. Furthermore, the use of animal models allows analysis in which the only variable of the study is the studied intervention, since the animals used can be genetically identical, thus reducing possible biases. The aim of this literature review is therefore to understand how animal models have been used to study the inflammatory response and changes in microcirculation after CPB and possible control strategies, presenting results and prospects for improving CPB systems in its clinical use.

Abbreviations, acronyms and symbols ANP CPB CO CO2 DXS MUF NO PaO2 PFOB PGE1 PHC PO2

atrial natriuretic peptide cardiopulmonary bypass Carbon Monoxide Carbon dioxide Dextran Sulfate Modified ultrafiltration Nitric oxide Arterial partial pressure of oxygen Bromide perfluoroctil Prostaglandin 1 Hydrochloride penehyclidine Partial pressure of oxygen

INTRODUCTION The history of cardiovascular surgery began concretely only in the 1940s, with some procedures that could be performed without cardiopulmonary bypass (CPB). Complex cardiac conditions, however, could not be corrected with the heart beating, or even stopped, during the short time provided by hypothermia. Thus, many surgeons began attempts to put into operation a machine that was able to replace the patient heart and lungs during surgery, allowing more prolonged handling of the arrested heart [1]. After a series of unsuccessful attempts of many scholars, Gibbon successfully performed in 1953, the first cardiac surgery under CPB [2]. Since then, the CPB has become perhaps the most important component of modern cardiac surgery. In these nearly 60 years, the technique has undergone several improvements, coming to current models, which, in essence, does not much differ from the initially proposed by Gibbon. The CPB devices currently consist in a circuit with a pump, which may be centrifugal or roller, an oxygenator, usually membrane, cannulas, tubes and a cardioplegia circuit. Despite the significant changes and improvements in CPB systems, complications related to tissue damage affecting postoperative morbidity and mortality still persist [3]. The CPB exposes the body to a series of non-physiological conditions, leading to complex changes in normal physiology of the circulatory system. The contact of blood with the artificial surface of the circuit, the phenomenon of ischemia-reperfusion, tissue hypoperfusion and hemolysis may initiate and exacerbate the inflammatory response. CPB induces both humoral and the cellular constituent of the im-

METHODS Search Strategy For this review, search in the PubMed databases (MEDLINE, scientific journals and online books) was performed, being used terms from the “Medical Subject Headings” (MeSH), comprising terms controlled by the “National Library of Medicine” of the United States and that is used for indexing articles in PubMed. Initially, the term (“Cardiopulmonary Bypass” [MeSH]) was used, and from this search the results published in the last ten years, until May 2012 were selected, yielding 7,099 articles. Subsequently, in addition to the aforementioned term, the search was restricted to results that also contained the terms (“Microcirculation”[MeSH]) or (“Inflammation”[MeSH]) or (“Inflammation Mediators”[MeSH]), being found respectively 69, 455 and 304 results totaling 828. Of these, repeated results were excluded, leading to a total of 717 articles. Excluding items that were not in English or did not represent experimental studies in animals, 110 results were obtained. These articles received a more detailed analysis, being excluded literature reviews and studies that did not have control group. Thus, in the end, 72 articles were selected for this review (Figure 1).

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Fig. 1 - Chart showing the search strategy of the articles until reaching the final number

Studied data The specific objectives of each study were raised and, after analysis, we determined the main thematic groups that would embrace such goals. In each study the main intervention (independent variable) and the main consequences of

them (dependent variables) were highlighted. Thus, it was possible to compare, within each thematic group, the interventions and the results of the selected studies. It was also determined the number of times that each dependent variable appeared, and for the analysis were selected

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those that were found in at least three studies. Thus, both for presentation of results and for the sake of argument, only the parameters showing certain frequency have been included.

modified ultrafiltration (MUF) technique studied by Atkins et al. [17], in which it keeps filtering the blood for some time after the end of CPB, in addition to reduce pulmonary vascular resistance, reduced levels of IL-6 and IL-8, although it has not changed the values of TNF-α.

RESULTS

Flow One of the concerns frequently raised by the use of CPB systems is the attempt to bring them closer to the maximum of the physiological functioning of the body, being the characterization of the blood flow a great representative of this concern. Two studies have attempted to assess the effects of different flow regimes on inflammatory response and microcirculation. Voss et al. [18] compared the plasma levels of IL-6 and IL-1 receptor between pulsatile and non-pulsatile flow regimes, but found no significant differences between these two patterns. Anttila et al. [19], in turn, sought to determine the lowest safe performance of CPB flow, assessing the potential adverse changes if CPB was performed under conventional blood flow, and demonstrated that the flow reductions also reduce tissue PO2. Schears et al. [20] showed that even in the presence of a persistent arterial duct, the more dimished the flow, the lower the tissue PO2.

The studies assessed in this review attempted to assess three main topics: 1) the effects of CPB on the inflammatory response and microcirculation, 2) non-pharmacological interventions in the CPB system and 3) the administration of drugs in the peri- or intraoperative period. Effects of CPB on inflammatory response and the microcirculation Nine studies seek to better understand the consequences of the CPB in microcirculation and inflammatory response, and all showed induction of inflammatory response and microcirculatory changes by CPB. The amount of activated leukocytes adhered to tissues and water in the extracellular space proved to be increased in the groups where CPB was performed, showing, respectively, activation of the inflammatory cascade and increased vascular permeability [4-6]. Moreover, it was found a significant reduction in blood flow and arteriolar endothelium-dependent relaxation [4,5,7-9]. Furthermore, we found increased NF-κB expression and caspase-3 activity [10,11]. With respect to cytokines, both those typically inflammatory, such as TNF-α, IL-6, IL-8 and IL-1β, as anti- inflammatory, such as IL-10, presented increased [4,7,11,12].

Miniaturization The miniaturization of CPB systems is very useful for pediatric cardiac surgery, especially in neonates and infants, allowing the reduction of the amount of priming and hence hemodilution. Two studies have attempted to assess the use of miniaturization of the CPB system in order to reduce the inflammatory response and changes in microcirculation. Schnoering et al. [21], using the MiniHLM, a miniaturized heart-lung machine created by the authors, found no significant differences compared to the control group. Ugaki et al. [22], on the other hand, showed a reduction in IL-8, thrombin-antithrombin complex, water content in the extracellular space and pulmonary vascular resistance with the use of TinyPump, an ultra-miniaturized centrifugal pump developed by the group.

Non-pharmacological interventions in the CPB system Filtration The use of four different types of filters in the CPB circuit was proposed in five of the studies assessed, with the aim of reducing the deleterious effects of CPB. Darling et al. [13] used zero balance ultrafiltration (Z-BUF), a technique that aims to fix the water balance generated by CPB through infusion of saline solution simultaneously to filtration, demonstrating increased arterial partial pressure of oxygen (PaO2), decreased tissue edema and reduced histologic injury. Alaoja et al. [14] studied the filtration of leukocytes, demonstrating reduction in activated leukocytes adhered to tissues. The leukocyte depletion was also studied by Tao et al. [15], which showed good results on the inflammatory response and microcirculation, such as decreased neutrophils, IL-8, plasma elastase and myeloperoxidase, in addition to lower pulmonary vascular resistance. The third filter, studied by Ohki et al. [16], was the hemoperfusion with polymyxin B-immobilized cartridge (MPX), which acts as an endotoxin scavenger filter and has demonstrated increased tissue partial pressure of oxygen (PO2), reduction of tissue lesions and diminished IL-8. Finally, the use of the

Perfusate One of the most important variables of CPB is the type of perfusate used in the filling of the heart-lung machine circuits. Two studies sought to investigate whether changes in priming would lead to changes in the inflammatory response and the microcirculation after the use of CPB. Ugaki et al. [23] demonstrated that the filtration of blood perfusate prior to the commencement of CPB reduces the formation of IL-8 and thrombin-antithrombin complex, in addition to increase the PaO2. Farstad et al. [24], in turn, investigated the use of iso-oncotic solutions of hetastarch and albumin as perfusate, demonstrating that both significantly reduce tissue edema when compared to commonly used perfusate solution.

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Temperature The effects of hypothermia on the inflammatory response during CPB were assessed in three studies. Qing et al. [25] studying the effects of CPB in liver of pigs, showed decreased production of TNF-α and NF-κB and increased IL10, confirming the anti-inflammatory effect of hypothermia. Lower leukocyte counts and lower histologic lesions were described by Antilla et al. [26,27] when studying the effects of hypothermia on cerebral territory of pigs on CPB.

by Isaka et al. [38], but no significant differences in the traditional perfusate were found. Administration of drugs in peri- or intraoperative period The drugs assessed by the studies reviewed herein could be divided into 3 main classes, according to their actions: 1) drugs with effects on coagulation, 2) vasoactive drugs and 3) drugs with anti-inflammatory activity. Drugs with effects on coagulation The bivalirudin, a direct thrombin inhibitor, was investigated by Welsby et al. [39] and proved to reduce the thrombin-antithrombin complex as well as IL-6 and IL-10. Another drug that showed a decrease in thrombin-antithrombin complex was dextran sulfate (DXS), an antithrombotic studied by Banz et al. [40], that also reduced neutrophil adherence, extravasation of fluid into the extracellular medium and pulmonary arterial pressure. The DXS also reduced the expression of IL-1β, IL-6, IL-8 and TNF-α cytokines. Finally, the effects of antiplatelet eptifibatide, an inhibitor of IIb/IIIa glycoprotein were studied in cerebral territory by Ben Mime et al. [41], demonstrating reduction of histological lesions and increased tissue PO2, effects possibly related to decreased formation of microbubbles.

Regional perfusion The use of regional infusion regimes, parallel to the main CPB circuit allows prioritizing the perfusion of vital organs and thus increases the time on cardiac arrest, providing greater freedom to the surgeon. The use of these regimens was assessed in four different studies. In cerebral territory, the techniques used were selective cerebral perfusion, achieved by right carotid artery, and retrograde, performed through the superior vena cava. The first showed increased tissue oxygenation while the second resulted in reduced oxygenation and increased tissue edema [28,29]. In pulmonary system we studied the technique of active perfusion, pulsatile or not, performed through cannulation of the pulmonary artery, showing a decreased expression of cytokines such as IL-1β, IL-6, TNF-α and NF-κB, as well as the caspase-3 activity [30]. In the group on which the perfusion was pulsatile, this difference was even more significant for IL-1β, IL-6 and caspase-3 activity. Finally, DeCampli et al. [31] studied the effect of regional low-flow perfusion, in which the CPB flow is directed exclusively to the brachiocephalic trunk and the left carotid artery, demonstrating increased brain PO2.

Vasoactive drugs Sildenafil, a selective inhibitor of cGMP-specific phosphodiesterase 5 was studied by Aubin et al. [42], showing reduction in pulmonary arterial pressure and arteriolar endothelium-dependent relaxation, both after application of acetylcholine as bradykinin. A drug with effects similar to sildenafil was prostacyclin, which acts as both vasodilator and inhibitor of platelet aggregation, and its only difference to sildenafil was that endothelium-dependent arteriolar relaxation on the specific action of acetylcholine was not altered [43]. Similarly, tetrahydrobiopterin, a cofactor of the synthesis of nitric oxide (NO) studied by Stevens et al. [44], appeared to increase the endothelium-dependent arteriolar relaxation only on the specific action of bradykinin, while the use of magnesium alone increased the endothelium-dependent arteriolar relaxation on the specif action of acetylcholine [45]. Lamarche et al. [46] also demonstrated that milrinone, a selective inhibitor of phosphodiesterase 3, if inhaled, in addition to reduce the heart rate and increase the mean arterial pressure has a positive effect in relaxation of pulmonary arteries in response to acetylcholine and bradykinin. El Kebir et al. [47,48] have shown, in two studies, that the inhalation of NO prior to CPB reduces neutrophils and IL-8. Aprotinin, a fibrinolysis retardant studied by Liu et al. [49] and Veres et al. [50], also reduced the levels of IL-8, in addition to increase platelet number, although has not changed the endothelium-dependent arteriolar relaxation after administration of acetylcholine or bradykinin, as the authors expected.

Other therapies Other variables were assessed by least amount of studies, but also showed relevant results to clinical practice. Gabriel et al. [32] sought to investigate the use of a coated synthetic copolymer (methacrylate), showing lower circuit platelet aggregation, but no differences in the number of leukocytes, compared with the control group. The use of mini-sternotomy was studied by Hayashi et al. [33] showing no difference with the traditional technique at the end of procedure. Maintenance of blood pH within a range of equilibrium, by adding carbon dioxide (CO2) during CPB led to increased blood flow, and consequent increase in tissue PO2 in brain [34,35] territory. Finally, Jiang et al. [36,37] studied the use of partial and full liquid ventilation after CPB, demonstrating lower neutrophil counts and lower expression of IL-6, IL-8 and myeloperoxidase, which resulted in a lower lung injury score, with more significant results with the full than the partial technique. The use of perfluoroctil bromide (PFOB), a perfluorochemical compound used as an artificial blood substitute in perfusate emulsion was studied

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Once the literature described the positive effects of NO and aprotinin on the inflammatory response and changes in microcirculation, it was suggested the concomitant use of these two compounds with prostaglandin 1 (PGE1), and this drug regimen was called blood hibernation. Zhou et al. [51] and Du et al. [52] in two studies using this technique showed, paradoxically, lower leukocyte count and increased neutrophil count, respectively, although both observe an increase in the number of platelets. Furthermore, the technique of blood hibernation decreased the plasma elastase, CD11b, myeloperoxidase and IL-8 expression, as well as the count of thrombin-antithrombin complexes and histological lesions. In turn, the use of ruthenium-based NO sequestrant (AMD6221) studied by Mayers et al. [53], demonstrated increase in the mean arterial pressure. The effect of bradykinin, a vasodilator and inflammatory mediator, was investigated by Yeh et al. [54], showing decreased levels of IL-6, IL-8, TNF-α, NF-kB, myeloperoxidase and caspase-3 activity, besides having less histological damage of brain tissue. Clark et al. [55] sought to establish the effect of xenon in a CPB scenario, but found no significant results regarding the variables considered in this review.

The use of curcumin, a natural dye with anti-inflammatory properties, studied by Liu K et al. [66] showed reduced levels of IL-8, TNF-α, NF-kB, as well as the lung injury score. The PPAR-alpha agonist effects studied by Yeh et al. [67] was similar to those of curcumin on IL-8, TNF-α and NF-κβ interleukins. The PPAR-alpha agonist also reduced the expression of IL-10, myeloperoxidase, caspase-3 activity and histological lesions in cardiac tissue, in addition to increase hemodynamic variables such as heart rate and blood pressure. Cai et al. [68] demonstrated lower histological lesion in liver tissue after using penehyclidina hydrochloride (PHC), an anticholinergic medication. Still in hepatic territory, An et al. [69] suggested that the use of growth hormone may have anti-inflammatory effect as demonstrated by lower expression of IL-1β and TNF-α, although the values of interleukins with anti-inflammatory action (IL-6 and IL-10) showed no difference when compared to the control group. Simvastatin was studied by Shao et al. [70] and Shen et al. [71] in lung and heart territories, respectively. Both studies showed reduced expression of IL-6, TNF-α, NF-κB and myeloperoxidase, which resulted in lower lung injury score in the study by Shao et al. [70]. In a study by Kellermann et al. [72], the use of moxifloxacin, an antibiotic of broad-spectrum, also led to lower expression of TNF-α and NF-κB cytokines. In pulmonary territory, sivelestat, an inhibitor of neutrophil elastase used for Wakayama et al. [73], led to reduction of IL-8, myeloperoxidase and plasma elastase, besides increasing PO2 and reducing histological lesions. De Lange et al. [74] demonstrated an increased inflammatory response to CPB with the use of perfluorocarbon, having found increased expression of IL-1β, IL-6, IL-10 and TNF-α, and higher histological lesion in brain tissue. The sulfide oxygen, in turn, was studied by Osipov et al. [75] and showed no significant effects on any of the main indicators of inflammatory response or changes in microcirculation effects.

Anti-inflammatory drugs The use of peroxynitrite was studied by Hayashi et al. [56] who demonstrated a reduction of IL-6 and IL-8 interleukins. The action of glutamine studied by the same authors showed the same results, in addition to reduced number of adherent neutrophils [57]. In another study, Hamamoto et al. [58] demonstrated that rolipram, a selective phosphodiesterase 4 inhibitor, reduces the expression of plasma elastase, TNF-α and CD11b, similarly to the use of activated protein C, which still increased PaO2 and decreased the expression of IL-1β interleukin and water content in the extracellular space [59]. Flurbiprofen, an inhibitor of prostaglandin synthetase studied by Takewa et al. [60] and Sato et al. [61], although it has not shown significant effects on the inflammatory response, improved blood flow in the mesenteric tissue. Administration of atrial natriuretic peptide (ANP) resulted in lower myeloperoxidase activity and increased tissue blood flow in renal territory in the study by Ohno et al. [62]. Also in renal territory, the use of n-acetylcysteine was studied by Zhu et al. [63], demonstrating lower expression of TNF-α and NF-κβ. Goebel et al. [64] studied the effects of inhaled carbon monoxide (CO) before and after CPB. The inhalation prior to CPB decreased the expression of IL-1β and TNF-α, in addition to increase the expression of IL-10 and attenuate the activity of caspase-3, reducing the occurrence of pulmonary apoptosis induced by CPB. The use of therapy with CO after CPB has also demonstrated anti-inflammatory effect, with reduced expression of IL-6 and TNF-α, besides reduction of caspase-3 activity [65].

CONCLUSION Studies in animal models have proved to be adequate to demonstrate the effects of CPB on inflammatory response and the microcirculation. Still, it was demonstrated the primary efficacy of various interventions, pharmacological or not, against the activation and maintenance of the inflammatory response and changes in microcirculation caused by CPB. Now, prospect studies to assess these interventions in clinical practice are needed in order to reduce the morbidity and mortality of cardiovascular surgery with CPB. ACKNOWLEDGEMENTS We would like to thank Valéria de Vilhena Lombardi

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and other employees of the Central Library of the Faculty of Medicine, University of São Paulo Medical School, for their assistance during the literature review.

after cardiopulmonary bypass in neonatal pigs. Acta Anaesthesiol Scand. 2002;46(7):853-9. 10. Fischer UM, Klass O, Stock U, Easo J, Geissler HJ, Fischer JH, et al. Cardioplegic arrest induces apoptosis signal-pathway in myocardial endothelial cells and cardiac myocytes. Eur J Cardiothorac Surg. 2003;23(6):984-90. 11. Jungwirth B, Eckel B, Blobner M, Kellermann K, Kochs EF, Mackensen GB. The impact of cardiopulmonary bypass on systemic interleukin-6 release, cerebral nuclear factor-kappa B expression, and neurocognitive outcome in rats. Anesth Analg. 2010;110(2):312-20.

Authors’ roles and responsibilities GRL AFK LFPM

Articles search and literature review Articles search and literature review Idealization and coordination

12. Homi HM, Jones WL, de Lange F, Mackensen GB, Grocott HP. Exacerbation of systemic inflammation and increased cerebral infarct volume with cardiopulmonary bypass after focal cerebral ischemia in the rat. J Thorac Cardiovasc Surg. 2010;140(3):6606, 666.e1.

13. Darling E, Searles B, Nasrallah F, Robins M, You X, Gatto L, et al. High-volume, zero balanced ultrafiltration improves pulmonary function in a model of post-pump syndrome. J Extra Corpor Technol. 2002;34(4):254-9.

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Karigyo CJT, et al.COMMUNICATION - Transfixing cardiac injury with perforations in stomach, BRIEF diaphragm and lung: unusual scenario in penetrating trauma

Transfixing cardiac injury with perforations in stomach, diaphragm and lung: unusual scenario in penetrating trauma Lesão cardíaca transfixante associada a perfurações gástrica, diafragmática e pulmonar: um cenário incomum em trauma penetrante

Carlos Junior Toshiyuki Karigyo1, MD; Otávio Goulart Fan1,2, MD; Marcelo Miyazaki Yoshida2, MD; Roberto Jonathas Menescal2, MD; Marcos José Tarasiewich2, MD

DOI: 10.5935/1678-9741.20140018

RBCCV 44205-1528

Abstract A 23-year-old man suffered a penetrating injury caused by a metallic fragment thrown from a grass-cutting tool, resulting in perforating injuries in the stomach, diaphragm, heart, and lungs.

Resumo Homem de 23 anos sofreu ferimento penetrante por estilhaço metálico desprendido de uma roçadeira, resultando em lesões perfurantes em estômago, diafragma, coração e pulmão.

Descriptors: Heart injuries. Heart ventricles. Foreign bodies.

Descritores: Traumatismos cardíacos. Ventrículos do coração. Corpos estranhos.

INTRODUCTION

paper, we present an unusual case of penetrating cardiac injury caused by a metal fragment that broke off from one of the blades of a grass-cutting tool. The fragment caused transfixing lesions in the stomach, diaphragm, and heart and lodged itself in the lungs. All lesions were repaired. The patient had an uneventful postoperative course and 2 years after surgery he is still asymptomatic.

Penetrating cardiac trauma still carries high mortality rates, even with immediate medical attention and advanced medical evacuation services. The nature of the injury itself, the involvement of an organ as vital as the heart as well as rapid clinical deterioration all cooperate to unfavorable outcomes in both prehospital and inhospital environments. In addtion, the rampant growth of urban violence and increased access of civilians to firearms have contributed to the increased incidence of penetrating cardiac injuries [1-3]. Although accidental injuries constitute a very small part of penetrating cardiac injuries, they are still serious. In this

CLINICAL CASE This work was performed after informed consent from the patient and approval of the Ethics Committee of the Santa Casa de Londrina Hospital (Londrina, PR, Brazil).

1. Universidade Estadual de Londrina, Londrina, PR, Brazil. 2. Santa Casa de Londrina Hospital, Londrina, PR, Brazil.

Hospital da Santa Casa de Londrina e Hospital Regional João de Freitas de Arapongas Rua Espírito Santo, 523 – Centro – Londrina, PR, Brazil – Zip Code: 86010510. E-mail: ctkarigyo@hotmail.com

Work carried out at Santa Casa de Londrina Hospital and João de Freitas Hospital Regional, Arapongas, Londrina, PR, Brazil. Correspondence address: Carlos Junior Toshiyuki Karigyo

Article received on July 8th, 2012 Article accepted on January 28th, 2013

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entry. Chest radiography showed a solid fragment lodged in the heart projection (Figure 1A), and computed tomography showed possible heart damage due to myocardial tapering in ventricular apex (Figure 1B) and presence of a small volume pneumoperitoneum. According to computed tomography images and reconstruction of the trajectory, the shrapnel transfixed the ventricular apex and lodged itself in the lower lobe of the left lung (Figure 1C and D). Faced with a possible cardiac injury, imminent hemodynamic collapse, and presence of intra-abdominal injuries, the patient was referred to surgical exploration. The access to the chest cavity was obtained by left anterolateral thoracotomy and soon after its opening lots of blood and food debris were observed, as well as injuries to diaphragm and lower lobe of the left lung.

Abbreviations, acronyms & symbols CT

Computed tomography

A 23-year-old male patient was referred to the emergency department of the Santa Casa de Londrina Hospital with perforating wound by a metallic artifact (shrapnel) in the thoracoabdominal face. The shrapnel, according to witnesses and the victim himself, broke off from a blade of the grass-cutting tool he was operating while working in the middle of a highway. Signs of hemodynamic instability started during transport to the hospital, with hypotension and confusion upon admission. Support measures were initiated immediately after his

Fig. 1 â&#x20AC;&#x201C; A: Fragment lodged in the heart shadow (arrow). B: Myocardial thinning in the ventricular apex (asterisk). C: Trajectory of the fragment, note the possible points of entry and exit in the ventricle. D: Three-dimensional reconstruction of the trajectory and the fragment

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The cavity was washed and the diaphragmatic hole was closed by continuous suture. After pericardial dissection we observed two sources of active bleeding (inlet and outlet) in topography ventricular apex, one anteriorly and the other posteriorly. The lesions were punctate and it was possible to fix them without the use of extracorporeal circulation by directly suturing the wounds with 2.0 polyester sutures with pledges. After removal of the fragment lodged in the lung the injury was repaired by continuous suture with polyglactin 910 3.0. The diaphragmatic injury, previously closed by continuous suture, was repaired again with interposition of a bovine pericardial patch. We also performed an exploratory laparotomy, which revealed a large amount of food debris, a transfixing injury in the stomach, and no lesions in other organs. The gastric injury was repaired by direct suture and the abdominal cavity was subjected to profuse washes before its closure, in accordance with standard technique. The patient had an uneventful postoperative course and was discharged 11 days after admission. He has been asymptomatic for 2 years since surgery, without the use of medication. At follow-up, routine exams showed no changes: echocardiography with preserved ventricular function, normal left ventricular segmental con-

tractility, heart valves with good opening and mobility, atrial and ventricular septal integrity, and an ejection fraction of 66%; ergometric test without evidence of ischemia; and chest CT angiography with only remnants of a repaired myocardial injury (Figure 2). DISCUSSION The heart, a vital organ protected by the thoracic cage, rarely suffers penetrating injuries. Penetrating cardiac injuries had been considered lethal for centuries, with sporadic clinical observations suggesting possible survival, until in 1896 Rehn demonstrated the feasibility of suturing a heart wound [4]. Nevertheless, it was Harken who during World War II, compiled an impressive number of 130 soldiers operated on due to cardiac lesions by shrapnel, with no deaths recorded [4]. In Brazil, the first successful sutures of a cardiac injury were performed by Brauner in 1927, and Zerbini in 1942, who operated on a 6-year-old boy who was hit by metallic shrapnel in the precordium and suffered an injury in the anterior descending coronary artery, marking the first steps of Brazilian heart surgery [5,6].

Fig. 2 â&#x20AC;&#x201C; A: Possible fibrous formation in the site of wound repair is seen (asterisk). B: Threedimensional view of the chest and heart. C and D: pledgets used in wound repair in the myocardial apex (arrows)

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Despite the historical importance of cardiac trauma in the development of medicine, heart penetrating wounds are rarely seen in emergency rooms, since most victims do not survive the complications of trauma prior to admission. Death usually results from cardiac tamponade or exsanguination, conditions that lead to death within minutes if not diagnosed and treated in time. Therefore, little is known about real mortality rates – prehospital mainly – of penetrating cardiac injuries [1,2]. The most frequent causes are injuries caused by knives and guns, mainly due to increasing urban violence [1-3]. Penetrating trauma caused by these weapons usually affect the right ventricle, which lies in the anterior chest wall, followed by left ventricle and right atrium, respectively [7]. Injuries caused by objects other than those mentioned above – like needles, shards, splinters, bone fragments, and surgical artifacts – are commonly associated with unintended injuries, and can result from iatrogenic complications during invasive procedures [1,8,9]. In the case patient described in this report, the small size, pointed shape, high speed and punctiform area of the the metal inflicted against the tissues of the victim induced the shrapnel to act as a projectile triggered from a reduced distance, with an upward trend, reaching and transfixing the myocardium but without the explosive capacity characteristic of a gun projectile. It is likely that the severity of the cardiac damage was mitigated by the low energy dissipated by the artifact. In addiction, the ventricular myocardium may have staunched the bleeding partially and temporarily. Penetrating heart injuries configure not only a challenge against time for emergency medical services, but also a scenario of difficult diagnosis since their clinical presentation may vary from a stable and innocent condition to extreme hemodynamic collapse and potential catastrophic outcome. As for the surgeons, they need to become familiar with the possibility of cardiac lesions in cases of penetrating injuries in the thoracic region, specifically in the area located between the clavicles, the costal margin, and the hemi-clavicular lines (“cardiac box”) [2]. However, in less conventional situations or in certain traumatisms resulted from peculiar kinematics, cardiac lesions may require more precise tests to be diagnosed. Among the less common causes of cardiac trauma, foreign bodies, such as fragments or shrapnel, represent a small portion of accident statistics for these objects. A study conducted by Vollman et al. [10] in the pediatric population in the period of 1990-2004 showed lesions in extremities were the most frequent injuries involving grass-cutting tool machinery. According to the study, they were mostly due to direct contact with the blades, with less than 10% of the lesions being associated with foreign objects thrown or given off by these machines, and there were no cases of cardiac injury. We found only two reports of two patients who suffered cardiac wounds due to similar artifacts to the one from our

patient. In both cases, the right ventricle was affected and immediate surgical correction was successful [8,9]. CONCLUSION Immediate medical care, accurate diagnosis and prompt surgical intervention are crucial to favorable outcomes in patients with heart penetrating injuries. In some peculiar cases, diagnosis can be difficult and may require more precise exams and subsequent surgical correction, as in the case presented here.

Authors’ roles & responsibilities CJTK OGF MMY RJM MJT

Drafting of work, making the images and discussion Discussion Manufacture of images. Manufacture of images. Discussion

REFERENCES

1. Kang N, Hsee L, Rizoli S, Alison P. Penetrating cardiac injury: overcoming the limits set by nature. Injury. 2009;40(9):919-27. 2. O’Connor J, Ditillo M, Scalea T. Penetrating cardiac injury. J R Army Med Corps. 2009;155(3):185-90. 3. Karigyo CJ, Fan OG, Rodrigues RJ, Tarasiewich MJ. Transfixing gunshot wound to the heart: case report. Rev Bras Cir Cardiovasc. 2011;26(2):298-300. 4. Symbas PN, Justicz AG. Quantum leap forward in the management of cardiac trauma: the pioneering work of Dwight E. Harken. Ann Thorac Surg. 1993;55(3):789-91. 5. Costa IA. História da cirurgia cardíaca brasileira. Rev Bras Cir Cardiovasc. 1998;13(1):1-7. 6. Stolf NA, Braile DM. Euryclides de Jesus Zerbini: a biography. Rev Bras Cir Cardiovasc. 2012;27(1):137-47. 7. Baum VC. The patient with cardiac trauma. J Cardiothorac Vasc Anesth. 2000;14(1):71-81. 8. Monney DP, Malcynski JT, Gupta R, Shorter NA. An unusual cause of penetrating cardiac injury in a child. J Pediatr Surg. 1996;31(5):707-8. 9. Rubio PA, Reul GJ Jr. Penetrating cardiac injury by wire thrown from a lawn mower. Int Surg. 1979;64(1):9-11. 10. Vollman D, Smith GA. Epidemiology of lawn-mower-related injuries to children in the United States, 1990-2004. Pediatrics. 2006;118(2):e273-8.

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Canale LS & Bonatti J -TO Mammary HOW DO IT artery harvesting using the Da Vinci Si robotic system

Mammary artery harvesting using the Da Vinci Si robotic system Dissecção da artéria mamaria com uso de sistema robótico Da Vinci Si

Leonardo Secchin Canale1, MD; Johannes Bonatti2, MD DOI: 10.5935/1678-9741.20140019

RBCCV 44205-1529

Abstract Internal mammary artery harvesting is an essential part of any coronary artery bypass operation. Totally endoscopic coronary artery bypass graft surgery has become reality in many centers as a safe and effective alternative to conventional surgery in selected patients. Internal mammary artery harvesting is the initial part of the procedure and should be performed equally safely if one wants to achieve excellence in patency rates for the bypass. We here describe the technique for mammary harvesting with the Da Vinci Si robotic system.

Resumo Dissecção da artéria mamária interna é parte essencial de qualquer operação de revascularização do miocárdio. Cirurgia de revascularização do miocárdio totalmente endoscópica se tornou realidade em muitos centros como uma alternativa segura e efetiva, comparável à cirurgia convencional, em pacientes selecionados. Dissecção da artéria mamária interna é a parte inicial do procedimento e deve ser realizada com igual segurança se quisermos atingir excelentes taxas de patência para a ponte. Descreveremos aqui a técnica de dissecção de artéria mamária interna com o sistema robótico Da Vinci.

Descriptors: Surgical procedures, minimally invasive. Mammary arteries. Thoracoscopy. Robotics.

Descritores: Procedimentos cirúrgicos minimamente invasivos. Artéria torácica interna. Toracoscopia. Robótica.

The internal mammary artery (IMA) has consolidated itself as the preferable graft for coronary artery bypass surgery (CABG). Classically harvested through a sternotomy it is one of the initial but essential steps in CABG surgery. Pediculated and skeletonized techniques were developed, the last one providing longer graft length and preserved blood supply for the sternum. The use of robotic assistance to perform totally endoscopic CABG has become an accepted option for surgical coronary artery revascularization. Again, the first step in this

surgery is the process of IMA take down, which we will describe here. Anesthesia uses a double lumen endotracheal tube and places R2 defibrillator patches in the right infraclavicular region and the dorsal part of the left lower chest. The patient is placed in supine position with the left chest slightly elevated. Both arms are tucked to the chest and flank. During prepping and draping care has to be taken that the drapes do not reach beyond the posterior axillary line so as to have enough space for port placement or placement of a minithoracotomy.

See the video by clicking: http://rbccv.org.br/video/2226/Mammary_artery_harvesting_using_the_Da_Vinci_Si_robotic_system 1. Cleveland Clinic Foundation, Cleveland, Ohio, USA. 2. Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.

This study was carried out at Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Correspondence address: Leonardo Secchin Canale Cleveland Clinic Foundation 9500 Euclid Avenue, J-4-133 – Cleveland, Ohio, USA – Zip code: 44195 E-mail: leonardo.canale@gmail.com

No financial support. Article received on November 17th, 2013 Article accepted on January 6th, 2014

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lizing energy. The camera provides a 10 times magnification which lead to great visualization of the procedure, but also tends to overestimate the size of branches and the amount of bleeding. We tend to cauterize the small branches (far from the mammary and close to the chest wall) and clip the large ones (Figures 2 and 3). Although there is some bleeding from the transverse thoracic muscle and very small branches with this approach, these are always self limiting. When all the extension of the artery is free from the chest wall the patient is heparinized, and 2 clips are applied to the distal end. One clip is placed slightly proximal to the distal end and the vessel is divided using robotic Pott’s scissors.

Abbreviations, acronyms & symbols CABG IMA LIMA RIMA

Coronary artery bypass surgery Internal mammary artery Left internal mammary artery Right internal mammary artery

The Da Vinci SI robotic patient cart (Intuitive Surgical, Inc.) which carries three or four robotic arms approaches the patient perpendicular from the right side. With the left lung deflated (using a dual tube endotracheal tube), a 12 mm camera port is initially inserted in the 5th intercostals space on the anterior axillary line. Carbon dioxide is insufflated to the chest (6-10 mmHg). The camera port hole can be predilated with an 8 mm instrument port. Port insertion has to be performed very gently and awareness of the presence of adhesions and the fact that the heart may be close to the chest wall is very important so as to avoid injury of intrathoracic structures. During this phase, the arterial blood pressure needs to be observed as insufflation may lead to hemodynamic compromise. In this case the insufflation pressure is lowered to a minimum. The robotic camera is used to inspect the thoracic cavity for adhesions and orient the insertion of the other 2 ports. The right arm port (8 mm) is inserted in the 3rd intercostal space 3 cm anterior to the camera port, so avoid conflict between the robotic arm and the patients left shoulder. The left arm port (8 mm) is inserted in the 7th intercostal space 3 cm anterior to the level of the camera port. By doing so, we position the three arms in a flat triangle, which is a principle for any video assisted port procedure. For a rough orientation the surgeon can place the tip of his/her right third finger on the patient’s jugulum and the tip of his/her left third finger on the xiphoid angle. Where the tips of the stretched out thumbs meet is the camera port insertion site. The instrument ports are placed four finger breaths apart from the camera port. The robotic surgeon then performs an inspection of the left pleural space. For anatomic orientation he visualizes the left subclavian artery and the distal aortic arch. The pericardium and its covering fat pad first come into view. The left internal mammary artery (LIMA) can then be visualized beneath the endothoracic fascia. Harvesting starts where the surgeon sees the artery pulsating which is usually in its cranial part. A 30 degree camera is used “facing up”. For most of the procedure the left robotic arm is equipped with EndoWrist fine tissue forceps (Intuitive Surgical, Inc.) and the right robotic arm with a EndoWrist spatula cautery (Intuitive Surgical, Inc.), connected to low power monopolar energy (15W). The parietal pleura, fascia and muscles are then opened all along the lateral aspect of the artery (close to the camera). The LIMA is then carefully detached from the chest wall from distal to proximal end in a skeletonized fashion (Figure 1). Dissection is performed using sweeping movements alongside the artery, part of the time without uti-

Fig. 1 – Harvesting of the left internal thoracic artery with fine forceps and spatula

Fig. 2 – Use of endoscopic clip to ligate branch of the mammary artery

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mammary artery. This small instrument can be introduced in the chest through one of the 8 mm ports and goes around the IMA, held by regular robotic forceps. Experiments in dogs showed a decrease in total time of harvesting. Watanabe et al. [6] developed an electrical chest wall retractor to allow robotic mammary without the use of CO2 insufflations. It is recognized that CO2 pressures above 10 mmHg can lead to hemodynamic instability. Also some patients have a very small chest cavity space to allow for easy harvesting (obese patients, cardiomegaly). The authors present a device capable of raising the sternum up to 5-10 cm which avoids completely the use of CO2. In summary, robotic totally endoscopic IMA harvesting is feasible and safe. This article also presents a video and pictures of our preferred technique. A learning curve phenomenon is clearly present. More than one technique is available. Further fine adjustments might improve time and easy of operation even further.

Fig. 3 – Use of endoscopic Potts scissors to cut branch

If bilateral IMAs are being planned, the right internal mammary artery (RIMA) should be dissected first. This is to avoid damage to an already harvested LIMA once the instruments go forward to the right side of the chest. To reach the RIMA, a dissection of the substernal plane is carried out all the way to the right pleura. The pericardium should not be opened at this time. The technique for RIMA takedown is overall similar to the LIMA. Harvesting of the very proximal part can at times be difficult. If the surgeon during harvesting feels difficulties reaching structures on the distal part of the IMA, ports should be checked for exact position from inside the chest. Ports can be pushed in for better reach and the right instrument port can be lifted into sternal direction. A full description of the rest of a totally endoscopic CABG can be found elsewhere [1]. Regarding time to perform this procedure, an important learning curve has been observed. Oehlinger et al. [2] assessed the first 100 LIMAs harvested by the senior surgeon and noticed a decline in total time. The mean time for all cases was 48 minutes. While the first 10 cases required a mean of 140 minutes each, the last 10 cases required only 34 minutesd. More recently Yang et al. [3] reported on their first 200 harvested IMAs. Mean time for IMA harvesting was 35 minutes and a significant learning curve was observed: from 41 minutes in the first 30 cases to 29 minutes in the last 30 cases. In both studies the IMA was skeletonized. A somewhat similar technique for mammary harvesting is described by Ishikawa et al termed “slide fascia technique” [4]. Instead of using a spatula for fascia opening the authors use a forceps connected to the monopolar energy. Despite these excellent experiences with IMA harvesting, some investigators are trying to push the technique even more forward. Ishikawa et al. [5] developed a tridimensional triangular hook to facilitate handling and traction of the

Authors’ roles & responsibilities LSC JB

Manuscript writting, video images editing Manuscript writting, video images editing

REFERENCES 1. Canale LS, Mick S, Mihaljevic T, Nair R, Bonatti J. Robotically assisted totally endoscopic coronary artery bypass surgery. J Thorac Dis. 2013;5(Suppl 6):S641-9. 2. Oehlinger A, Bonaros N, Schachner T, Ruetzler E, Friedrich G, Laufer G, et al. Robotic endoscopic left internal mammary artery harvesting: what have we learned after 100 cases? Ann Thorac Surg. 2007;83(3):1030-4. 3. Yang M, Gao CQ, Wu Y, Liu S. Robotic internal thoracic artery harvesting: the learning curve and graft patency. Chin Med J (Engl). 2013;126(10):1982-3. 4. Ishikawa N, Watanabe G, Tomita S, Ushijima T, Yamaguchi S, Nishida S, et al. Robotic skeletonized internal thoracic artery harvesting: the sliding fascia technique. Artif Organs. 2010;34(6):516-8. 5. Ishikawa N, Sun YS, Nifong LW, Watanabe G, Chitwood WR Jr. New instrument for robotic-enhanced skeletonized internal thoracic artery harvesting: triangular hook. Innovations. 2007;2(2):73-5. 6. Watanabe G, Matsumoto I, Kiuchi R. Novel sternum lifting technique for robotic internal thoracic artery graft harvesting. Innovations. 2013;8(1):76-9.

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Letters to the Editor/Cartas ao Editor

Letters to the Editor/Cartas ao Editor DOI: 10.5935/1678-9741.20140020

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Comments on “Innovation and Excellence: Changing to prevail the Brazilian Cardiovascular Surgery”

Such department could go a long way in helping even to restructure existing services that have had their quality, spirits, and motivation diminish over time. Congratulations to the Editor and the author on the services rendered to our cause. I wish them good health and Peace in 2014.

Dear editor, I have read the “Innovation and Excellence: Changing to prevail the Brazilian Cardiovascular Surgery” editorial written by Professor Walter J. Gomes [1], and found it to be at the same time lucid and honest, as the story is told by its protagonist. I want to congratulate the author on his tenure at the Brazilian Society of Cardiovascular Surgery (SBCCV), on his actions, and on his dedication to the causes involving cardiovascular surgeries, which are known to all, but are worth mentioning. I reflect on an important topic discussed in the editorial: ever since I had the honor of being President of the Brazilian Association of Cardiovascular Surgery Residents (ABRECCV) in 2010, I have raised what I consider a critical issue in the cardiovascular surgery chain: doctors entering this specialty. That year, at one of the meetings of the Society of Cardiovascular Surgery of the State of São Paulo (SCICVESP), I had the opportunity to present an article entitled “Shortage of cardiothoracic surgeons is likely by 2020” [2], which had been recently published in the Circulation and subsequently well-reviewed on the Heartwire Medscape Cardiology website [3]. The article predicted a lack of cardiovascular surgeons in the USA in 2020. However, we can say that this is already a reality in Brazil. One of the great difficulties on the path to creating new services in cardiovascular surgery is finding other surgeons with the profile and willingness to implement those services. It seems clear that this happens because there are few of us. Therefore, it is essential that the next management team stand firm on the demands to waive the general surgery prerequisite and to improve the quality of training in residencies, which I believe would make our specialty viable in the future. After talking with both young and older surgeons, it seems that we could consider creating a department within SBCCV that would provide guidance to surgeons (human beings raised behind closed doors, with little incentive to interact with the world around them) on how to develop and implement a viable project for service in cardiovascular surgery. The project would cover the basic needs required of the public manager, whether philanthropic or private, who wishes to invest in this idea, including: structure; human resources; protocols; trade negotiations with hospitals, health insurances, and cooperatives; guidance on legislation (decrees, laws, SUS); and assistance in adapting models to local needs.

Sergio Francisco dos Santos Junior1 1. Cardiovascular Surgeon, SBCCV-AMB Specialist / Santa Casa de Itabuna, Itabuna, BA, Brazil. REFERENCES 1. Gomes WJ. Inovação e excelência: transformando para prevalecer a cirurgia cardiovascular brasileira. Rev Bras Cir Cardiovasc. 2013;28(4):III-IV. 2. Grover A, Gorman K, Dall TM, Jonas R, Lytle B, Shemin R, et al. Shortage of cardiothoracic surgeons is likely by 2020. Circulation. 2009;120(6):488-94. 3. Busko M. Cardiothoracic surgeon shortage likely by 2020, study predicts. Heartwire; 2009. Disponível em: http://www.medscape. com/viewarticle/706571.

About Technique for Planning Interventional Treatments The article “Proposal for geometric virtual correction of the ostial projection of renal artery in the surgery study of infrarenal aneurysms: initial results of a pilot study” presents a simple technique of great importance in planning interventional treatment technique. The skill with the manipulation of digital medical image formats allows the recovery of a greater volume of data and allows the interventional procedures are performed more efficiently, with less time for adjusting the projection of images, injections of contrast and ionizing radiation exposure. In addition to the renal artery ostial projection, the technique can be applied in treatment of thoracic aorta and transcatheter aortic valve implants. It is important to note that the study was performed using a free software and personal computers, indicating that

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the knowledge of this technique is independent of major investments, which makes encouraging and demystifies the use of softwares for viewing medical images. Obviously, expertise and familiarity come with the practice of using, but it is evident that this is an important tool given the current scenario where more and more procedures are guided by images.

a very poor prognosis without treatment [2,3]. Considering that if not treated, patient’s prognosis are usually lethal; either single or two stage surgeries should be managed depending on the surgeon’s experience and patient’s condition [2-4]. In contrast to conservative management, early treatment of IAA prevents possible aortic rupture and associated cardiac dysfunction in such a critical patient.

Guilherme Agreli1 1. Bachelor’s Degree in Medical Physics, São José do Rio Preto, SP, Brazil.

Emre Yalcinkaya1, MD; Murat Celik2, MD 1. Aksaz Military Hospital, Chief of coronary care unit, Marmaris, Mugla, Turkey. 2. Gulhane Military Medical Faculty, Istanbul, Turkey.

REFERENCE

1. Molinari GJP, Dalbem AMO, Menezes FH, Guillaumon AT. Proposal of renal artery's ostial projection under virtual geometric correction in infrarenal aneurysms: initial results of a pilot study. Rev Bras Cir Cardiovasc. 2014;29(1):78-82.

REFERENCES

1. Dallan LAO, Milanez A, Lisboa LAF, Jatene FB. Cardiogenic shock due to coronary artery disease associated with interrupted aortic arch. Rev Bras Cir Cardiovasc. 2013;28(2):290-1. 2. Burton BJ, Kallis P, Bishop C, Swanton H, Pattison CW. Aortic root replacement and extraanatomic bypass for interrupted aortic arch in an adult. Ann Thorac Surg. 1995;60(5):1400-2. 3. Lafci G, Yalcinkaya A, Ecevit AN, Tasoglu I, Kadirogullari E, Turkvatan A, et al. Single-stage aortic valve-sparing root replacement and extra-anatomic bypass for aortic arch interruption in an adult. Tex Heart Inst J. 2012;39(3):398-400.

Repair of an interrupted aortic arch in concomitant diseases

4. Issa M, Avezum A, Dantas DC, Almeida AF, Souza LC, Sousa AG. Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery. Rev Bras Cir Cardiovasc. 2013;28(1):10-21.

To the Editor, We read with great interest the article by Dallan et al. [1], entitled “Cardiogenic shock due to coronary artery disease associated with interrupted aortic arch”, which is recently published in Brazilian Journal of Cardiovascular Surgery/ Revista Brasileira de Cirurgia Cardiovascular. The authors presented a case of a cardiogenic shock due to serious right and left main coronary artery disease associated with interrupted aortic arch (IAA). They just performed an off-pump left anterior descending artery bypass, and they managed the treatment of IAA conservatively. We thank authors for their excellent management of coronary artery disease and valuable article but some comments may be of beneficial. IAA is a rare congenital malformation and could be seen very rarely in late adulthood [2,3]. Complex diseases associated with IAA should be managed in either of single stage or two-stage procedures [2-4]. Although Burton et al. [2] and Lafci et al. [3] reported a successful single-stage treatment of IAA and aortic root replacement, and Yu et al. [5] and Riess et al. [6] reported a successful single stage treatment of IAA and coronary artery bypass grafting; as in this case, single stage surgeries could be challenging and are associated with high morbidity and mortality [2-4]. IAA is usually accompanied by hypertension, and confers

5. Yu L, Shi E, Gu T. Single-stage repair of interrupted aortic arch with simultaneous coronary artery bypass grafting without cardiopulmonary bypass in an adult. Ann Thorac Surg. 2011;92(3):1110-3. 6. Riess FC, Danne M, Stripling JH, Bergmann H, Bleese N. Surgical treatment of interrupted aortic arch with extraanatomical bypass simultaneous to coronary artery bypass grafting and aortic valve replacement. Heart Surg Forum. 2004;7(5):E394-7.

Answer We thank Yalcinkaya et al. [1] for their interest in our article: cardiogenic shock due to coronary artery disease associated with interrupted aortic arch [2] and for the interesting points they raised. Yalcinkaya et al. in agreement that either single or two stage surgeries should be managed for repair interrupted aortic arch (IAA), considering that if not treated it may confer a very poor prognosis. We have experience in surgical repair of

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the aortic arch coarctation in adults using the extra-anatomic aortic bypass technique using Dacron graft [3]. However, in this case we chose the simplest surgical approach (saphenous graft to left anterior descending) because we believed that such an instable and critical patient’s condition would not let allow a simultaneous correction (tube between ascending and descending aorta as well as coronary artery bypass graft). We know that IAA rarely develops to old age since it is early diagnosed. However, the beneficial effect of surgical repair or transcatheter intervention in terms of diminished mortality in very old patients is still questionable, which makes conservative management with antihypertensive drug therapy an acceptable treatment options in such patients [4]. We agree with Yalcinkaya et al., that clinical stable adult patients with complex diseases associated with IAA should be managed in either single stage or two-stage procedures.

gram showed normal sinus rhythm, inverted T waves in the anterior and inferior wall, and only mild mitral regurgitation in two-dimensional echocardiography. Myocardial perfusion imaging demonstrated an area of severe reversible uptake at great length in the septal and inferior regions of the left ventricle (LV), reduced global left ventricular systolic function, decreased ejection fraction during stress, and transient left ventricular dilation post-stress.

Luís Alberto Oliveira Dallan, Adriano Milanez, Luiz Augusto F. Lisboa, Fabio B. Jatene. São Paulo, SP. REFERENCES 1. Yalcinkaya E, Celik M. Repair of an interrupted aortic arch in concomitant diseases. Rev Bras Cir Cardiovasc. 2013;29(1)111. 2. Dallan LA, Milanez A, Lisboa LA, Jatene FB. Cardiogenic shock due to coronary artery disease associated with interrupted aortic arch. Rev Bras Cir Cardiovasc. 2013;28(2):290-1. 3. 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. 4. Cevik S, Izgi C, Cevik C. Asymptomatic severe aortic coarctation in an 80-year-old man. Tex Heart Inst J. 2004;31(4):429-31.

Early coronary artery disease as a complication of radiotherapy for Hodgkin's disease Dear Editor, We would like to share our experience with a 28-year-old patient, who had been complaining of chest pain and dyspnea after minimal efforts for 10 days. He denied having hypertension and diabetes and smoking. He had undergone supra-diaphragmatic radiotherapy associated with chemotherapy for Hodgkin’s disease 15 years ago. His physical examination was normal. The electrocardio-

Fig. 1 - Coronary CT angiography. A – patency of the left internal mammary artery - anterior descendent artery graft. B - patency of radial artery - right coronary artery graft. C - patency of saphenous bypass - diagonal artery graft

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Letters to the Editor/Cartas ao Editor

In the coronary angiography, we observed normal systolic function with mild dyskinesia in apical wall; occlusion of the right coronary artery (RCA) in the distal third, and severe lesions in the middle third of the anterior descending artery (DA) and in the origin of the circumflex artery. He underwent coronary artery bypass surgery on the fifth day with anastomosis of the left internal thoracic artery to the descending artery and right internal thoracic artery to the diagonalis artery as well as saphenous bypass of diagonal aorta and radial aorta for right coronary. He was discharged on the sixth postoperative day. CT angiography of the coronary arteries in the sixth year of follow-up showed patent grafts (Figure 1) and the patient progressed asymptomatic. We aimed to draw attention to the fact that even though coronary disease in young patients is rare, it is frequent in young patients who underwent mediastinal irradiation as treatment for Hodgkin’s disease. In addition, the most common cause of late mortality is acute myocardial infarction [1,2], with 8% risk for fatal and nonfatal infarction, up to 22 years after treatment [3]. Therefore, these patients should undergo regular cardiac evaluation for early diagnosis. Mediastinal irradiation can lead to endothelial injury, fibroblast proliferation, collagen deposition, changes to the intima of the vessels, and acceleration of coronary disease [4]. When irradiation occurs in the anterior mediastinum, it is more damaging to the trunk of the left coronary artery [5], the anterior descending, and the right coronary artery ostium, while the posterior irradiation affects mostly the circumflex artery [6]. The risk appears higher when associated with chemotherapy, especially with vinblastine [3], due to the possibility of occlusion of the right coronary artery, as well as radiotherapy with doses greater than 30 GY [4].

Concerning surgery, internal thoracic artery grafts do not seem to be influenced by prior radiotherapy, but by cardiovascular risk factors, with a survival rate of 87% in five years. Tereza Cristina Barbosa Lins1; Lúcia Maria Vieira de Oliveira Salerno1; Pedro Rafael Salerno1; Emanuel Sávio Cavalcanti Sarinho2 1. HOPE-Esperança Hospital, Recife, PE, Brazil. 2. Federal University of Pernambuco, Recife, PE, Brazil.

REFERENCES

1. Filopei J, Frishman W. Radiation-induced heart disease. Cardiol Rev. 2012;20(4):184-8. 2. Salemi VM, Dabarian AL, Nastari L, Gama M, Soares Júnior J, Mady C. Treatment of left main coronary artery lesion after late thoracic radiotherapy. Arq Bras Cardiol. 2011;97(3):e53-5. 3. Lee MS, Finch W, Mahmud E. Cardiovascular complications of radiotherapy. Am J Cardiol. 2013;112(10):1688-96. 4. Brennan S, Hann LE, Yahalom J, Oeffinger KC, Rademaker J. Imaging of late complications from mantle field radiation in lymphoma patients. Radiol Clin North Am. 2008;46(2):419-30. 5. Victor EG, Parente GBO. Radioterapia mediastínica e lesão ostial de tronco de coronária esquerda. Arq Bras Cardiol. 2004;82(3):295-7. 6. Mulrooney DA, Ness KK, Solovey A, Hebbel RP, Neaton JD, Peterson BA, et al. Pilot study of vascular health in survivors of Hodgkin lymphoma. Pediatr Blood Cancer. 2012;59(2):285-9.

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REVIEWERS

Reviewers BJCVS 29.1 Revisores RBCCV 29.1

Below is a list of reviewers who evaluated the articles published in this issue of the Brazilian Journal of Cardiovascular Surgery / Revista Brasileira de Cirurgia Cardiovascular (BJCVS / RBCCV). To them, my thanks for their crucial work for our journal enhance its scientific level.

Domingo Braile Editor-in-Chief RBCCV

Alfredo Fiorelli

Marcos Aurélio B. Oliveira Mauricio de Nassau Machado Mauro Paes Leme de Sá Melchior Luiz Lima

Carlos Manuel de A. Brandão Dorotéia Souza

Omar Mejia Otoni Moreira Gomes

Fábio Gaiotto Fernando R. Moraes Neto

Paulo Evora Paulo Roberto Brofman

Guilherme Agreli João Roberto Breda José Ernesto Succi José Glauco Lobo Filho

Raquel Ferrari Piotto Reinaldo Bestetti Reinaldo W. Vieira Renato T. Arnoni Roberto Costa Rodrigo Milani

Karlos A de Souza Vilarinho Leonardo A. Mulinari Lindemberg M. Silveira Filho Luciano C. Albuquerque Luiz Cesar Guarita Souza Luiz Felipe P. Moreira

Stevan Krieger Martins

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RBCCV em números 28 anos de circulação ininterrupta Fator de Impacto 0,809

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