Brazilian Journal of Cardiovascular Surgery 30.2

30.2 MARCH/APRIL 2015

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY | REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

VOL. 30 Nยบ 2 MARCH/APRIL 2015

速

BJCVS

EDITOR-IN-CHIEF Prof. Dr. Domingo M. Braile - PhD

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

São José do Rio Preto - SP - Brasil domingo@braile.com.br

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

FORMER EDITORS • Prof. Dr. Adib D. Jatene • Prof. Dr. Fábio B. Jatene

EXECUTIVE EDITOR Ricardo Brandau Postgraduate in Science Journalism - S. José do Rio Preto (BRA) brandau@sbccv.org.br

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

PhD - São Paulo (BRA) [1986-1996] PhD - São Paulo (BRA) [1996-2002]

Camila Safadi S. José do Rio Preto (BRA) camila@sbccv.org.br

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 O. Vrandecic Peredo • 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)

STATISTICS EDITOR • Orlando Petrucci Jr.

Campinas (BRA)

EDITORIAL BOARD • 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) 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)

ENGLISH VERSION • Fernando Pires Buosi • Marcelo Almeida

• Maria Carolina Zuppardo

GRAPHIC DESIGN AND LAYOUT • Heber Janes Ferreira

• 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 Alves 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)

OFFICIAL ORGAN OF THE BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY SINCE 1986

ADDRESS/ENDEREÇO

Sociedade Brasileira de Cirurgia Cardiovascular

Rua Afonso Celso, 1178 • Vila Mariana • Phone: 55 11 3849-0341. Fax: 55 11 5096-0079.

Zip code: 04119-061 • São Paulo, SP, Brazil E-mail BJCVS/RBCCV: revista@sbccv.org.br • E-mail SBCCV: sbccv@sbccv.org.br • Site SBCCV: www.sbccv.org.br • Sites BJCVS/RBCCV: www.scielo.br/rbccv/www.rbccv.org.br/www.bjcvs.org (also for article submission)

Bimonthly publication/Publicação bimestral Print edition - Print run: 250 copies (*)

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: 1,2,3,4 2014, 29: 1 [supl] 2015, 30: 1,2 2015, 30: 2 [supl]

ISSN 1678-9741 - On-line version. ISSN 0102-7638 - Print version 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

INDEXED IN • Thomson Scientific (ISI) http://science.thomsonreuters.com • PubMed Central www.ncbi.nlm.nih.gov/pmc/

• LATINDEX - Sistema Regional de Información en Línea para Revistas Cientificas de America Latina, el Caribe, España y Portugal www.latindex.unam.mx

• PubMed/Medline www.ncbi.nlm.nih.gov/sites/entrez

• Index Copernicus www.indexcopernicus.com

• SciELO - Scientific Library Online www.scielo.br

• Google scholar http://scholar.google.com.br/scholar

• Scopus www.info.scopus.com

• EBSCO www2.ebsco.com/pt-br

• LILACS - Literatura Latino-Americana e do Caribe em Ciências da Saúde. www.bireme.org

BRAZILIAN SOCIETY OF CARDIOVASCULAR SURGERY

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

“Enhancing the professional on behalf of the patient” BOARD OF DIRECTORS 2014 - 2015 President: Vice-President: Secretary General: Treasurer: Scientific Director:

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

Advisory Board:

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

Journal Editor: Site Editor: Newsletter Editors:

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 Ribeiro Moraes Neto (PE)

Presidents of Regional Afilliates 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

Departments DCCVPED: DECAM: DECA: DECEM: 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) Leila Nogueira Barros (SP) Paulo Marcelo Barbosa Mesquita (SP)

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

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

ISSN 1678-9741 - On-line ISSN 0102-7638 - Print RBCCV 44205

Impact Factor: 0.632

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR Braz J Cardiovasc Surg/Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brazil) Mar/Apr - 2015;30(2):139-294

CONTENTS EDITORIALS BJCVS/RBCCV is indexed on Pubmed Central BJCVS/RBCCV está indexada no PubMed Central Domingo M. Braile.................................................................................................................................................................................. I Clinical value of BNP as an independent predictor of mortality following heart surgery Valor clínico do BNP como um preditor independente de mortalidade após cirurgia cardíaca Edmo Atique Gabriel..............................................................................................................................................................................III ORIGINAL ARTICLES 1625 Simplified method for esophagus protection during atrial fibrillation radiofrequency catheter ablation - prospective study of 704 cases Método simplificado para proteção do esôfago durante a ablação da fibrilação atrial com cateter por radiofrequência - estudo prospectivo de 704 casos José Carlos Pachón Mateos, Enrique I Pachón Mateos, Tomas G Santillana Peña, Tasso Julio Lobo, Juán Carlos Pachón Mateos, Remy Nelson A Vargas, Carlos Thiene C Pachón, Juán Carlos Zerpa Acosta...............................................................................................139 1626 Stratification of complexity in congenital heart surgery: comparative study of the Risk Adjustment for Congenital Heart Surgery (RACHS-1) method, Aristotle basic score and Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STS-EACTS) mortality score Estratificação da complexidade em cirurgias de cardiopatias congênitas: comparação dos modelos Risk Adjustment for Congenital Heart Surgery (RACHS-1), escore básico de Aristóteles e escore de mortalidade da Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STS-EACTS) Paulo Ernando Ferraz Cavalcanti, Michel Pompeu Barros de Oliveira Sá, Cecília Andrade dos Santos, Isaac Melo Esmeraldo, Mariana Leal Chaves, Ricardo Felipe de Albuquerque Lins, Ricardo de Carvalho Lima.................................................................................148 1627 Study of novel coating strategy for coronary stents: simutaneous coating of VEGF and anti-CD34 antibody Estudo da nova estratégia de revestimento para stents coronários: revestimento simultâneo de VEGF e anticorpo anti-CD34 Chun-Li Song, Qian Li, Yun-Peng Yu, Guan Wang, Jin-Peng Wang, Yang Lu, Ji-Chang Zhang, Hong-Ying Diao, Jian-Gen Liu, YiHang Liu, Jia Liu, Ying Li, Dan Cai, Bin Liu......................................................................................................................................159 1628 Atrioventricular block in coronary artery bypass surgery: perioperative predictors and impact on mortality Bloqueio atrioventricular pós-cirurgia de revascularização do miocárdio: fatores preditores perioperatórios e impacto na mortalidade Ricardo Medeiros Piantá, Andres Di Leoni Ferrari, Aline Almeida Heck, Débora Klein Ferreira, Jacqueline da Costa Escobar Piccoli, Luciano Cabral Albuquerque, João Carlos Vieira da Costa Guaragna, João Batista Petracco............................................................164 1629 Effect of N-acetylcysteine in hearts of rats submitted to controlled hemorrhagic shock Efeito da N-acetilcisteína em corações de ratos submetidos ao choque hemorrágico controlado Luiz Dantas de Oliveira Filho, Karen Ruggeri Saad, Paulo Fernandes Saad, Marcia Kiyomi Koike, Sônia Maria da Silva, Edna Frasson de Souza Montero.................................................................................................................................................................................173 1630 Predictors of mortality in cardiac surgery: brain natriuretic peptide type B Preditores de mortalidade em cirurgia cardíaca: peptídeo natriurético cerebral tipo B Jamil Alli Murad Junior, Marcelo Arruda Nakazone, Mauricio de Nassau Machado, Moacir Fernandes de Godoy..........................182 1631 A propose of pulmonary dysfunction stratification after valve surgery by physiotherapeutic assistance level Proposta de estratificação da disfunção pulmonar após cirurgia valvar segundo níveis de assistência fisioterapêutica Satiko Shimada Franco, Luiz Marcelo Sá Malbouisson, Max Grinberg, Maria Ignêz Zanetti Feltrim...............................................188 1632 Factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of repair of incomplete atrioventricular septal defect Fatores associados à insuficiência moderada ou grave da valva atrioventricular esquerda nos primeiros 30 dias de correção de defeito de septo atrioventricular incompleto Marcelo Felipe Kozak, Ana Carolina Leiroz Ferreira Botelho Maisano Kozak, Carlos Henrique De Marchi, Moacyr Fernandes de Godoy, Ulisses Alexandre Croti, Airton Camacho Moscardini............................................................................................................198

1633 Surgical treatment of complex aneurysms and thoracic aortic dissections with the Frozen Elephant Trunk technique Tratamento cirúrgico dos aneurismas complexos e dissecções da aorta torácica utilizando a técnica "Frozen Elephant Trunk" Ricardo Ribeiro Dias, José Augusto Duncan, Diego Sarty Vianna, Leandro Batisti de Faria, Fábio Fernandes, Félix José Álvares Ramirez, Charles Mady, Fábio Biscegli Jatene....................................................................................................................................205 1634 Analysis of immunostaining and western blotting of endothelin 1 and its receptors in mitral stenosis Análise da expressão imunohistoquímica e de western blotting da endotelina 1 e seus receptores na estenose mitral Sydney Correia Leão, Michael R. Dashwood, Mateus Santana de Andrade, Nicolas Nascimento Santos, Olivia Regina Lins Leal Teles, Williasmin Batista de Souza, Tania Maria de Andrade Rodrigues.......................................................................................................211 1635 Epidemiology of congenital heart disease in Brazil Epidemiologia da cardiopatia congênita no Brasil Valdester Cavalcante Pinto Júnior, Klébia Magalhães P. Castello Branco, Rodrigo Cardoso Cavalcante, Waldemiro Carvalho Junior, José Rubens Costa Lima, Sílvia Maria de Freitas, Maria Nazaré de Oliveira Fraga, Nayana Maria Gomes de Souza......................219 REVIEW ARTICLES 1636 Stroke of a cardiac myxoma origin Acidente vascular cerebral com origem em mixoma cardíaco Shi-Min Yuan, Gulimila Humuruola....................................................................................................................................................225 1637 Cardiopulmonary bypass: development of John Gibbon's heart-lung machine Circulação extracorpórea: desenvolvimento da máquina de coração-pulmão de John Gibbon Andréia Cristina Passaroni, Marcos Augusto de Moraes Silva, Winston Bonetti Yoshida..................................................................235 SPECIAL ARTICLES 1638 Endnote Web tutorial for BJCVS/RBCCV Tutorial do Endnote Web para o BJCVS/RBCCV Marcos Aurélio Barboza de Oliveira, Carlos Alberto dos Santos, Antônio Carlos Brandi, Paulo Henrique Husseini Botelho, Adília Maria Pires Sciarra, Domingo Marcolino Braile.................................................................................................................................246 1639 Bibliometric indexes, databases and impact factors in cardiology Índices bibliométricos, bases de dados e fatores de impacto em cardiologia Igor R C Bienert, Rogério Carvalho de Oliveira, Pedro Beraldo de Andrade, Carlos Antonio Caramori...........................................254 SPECIAL ARTICLE - HISTORICAL RECOVERY 1640 Andreas Vesalius 500 years - A Renaissance that revolutionized cardiovascular knowledge Andreas Vesalius 500 anos - Um renascentista que revolucionou o conhecimento cardiovascular Evandro Tinoco Mesquita, Celso Vale de Souza Júnior, Thiago Reigado Ferreira..............................................................................260 EXPERIMENTAL STUDY 1641 Effects of ischemia and omeprazole preconditioning on functional recovery of isolated rat heart Efeitos da isquemia e pré-condicionamento com omeprazol na recuperação funcional do coração isolado de rato Nevena Jeremic, Anica Petkovic, Ivan Srejovic, Vladimir Zivkovic, Dragan Djuric, Vladimir Jakovljevic......................................266 BRIEF COMMUNICATION 1642 Prognostic prediction of troponins in cardiac myxoma: case study with literature review Previsão de prognóstico de troponinas em mixoma cardíaco: estudo de caso e revisão da literatura Shi-Min Yuan.......................................................................................................................................................................................276 MEMORY 1643 Geraldo Verginelli, the search for elegance and perfectionism in cardiovascular surgery Geraldo Verginelli, a busca da elegância e do perfeccionismo em cirurgia cardiovascular Noedir A. G. Stolf, Domingo M. Braile...............................................................................................................................................283 Reviewers BJCVS 30.2........................................................................................................................................................................286 Erratum.................................................................................................................................................................................................287 Information for authors........................................................................................................................................................................288 Meetings Calendar................................................................................................................................................................................293 Printed in Brazil

Editorial

BJCVS is indexed in PubMed Central BJCVS está indexada no PubMed Central

Domingo M. Braile1

DOI: 10.5935/1678-9741.20150031

T

he Brazilian Journal of Cardiovascular Surgery (BJCVS) has one more reason to celebrate: finally we have been indexed in PubMed Central – PMC (www.ncbi.nlm.nih.gov/pmc/), on-line repository, free access of publications on health area, basis of 3.3 million of full content articles provided by 4.916 journals[1] which BJCVS is part of them now.

It is one more platform we are present and I am confident that with the adoption of English language as the official language and the changing from quarterly to bimonthly, it will allow the Journal to be more recognized, accessed, attracting new readers and consequently more people will be interested in publishing their articles making our Impact Factor (IF) could grow again.

The presence on PMC is one more award of the work performed since the beginning of my supervision as a Chief-Editor of BJCVS in 2002, in order to provide the journal a wider recognition in the international scenario.

Since 2005, the submission and review of the manuscripts have been performed by our website (www.bjcvs.org), we have achieved the indexation in important databases such as PubMed/Medline, ISI-Thomson-Reuters, Scopus, and now PMC. It has been a tough task but pleasant and I feel glad for reaching this current level.

It was only possible thanks to the support of the Editorial Staff and also the Brazilian Society of Cardiovascular Surgery (SBCCV), through the several Board of Directors ahead our Society during this time where they have never denied any support or motivation.

I also cannot forget to praise my predecessors such as the late Prof. Dr. Adib Jatene, founder of BJCVS and Prof.

Dr. Fábio Jatene, who, with a lot of effort have overcame several obstacles to keep a national journal dedicated to heart surgery.

I cannot forget to mention GN1, our partner for 10 years, whose support and expertise in Information Technology were essential for our approval at PMC. GN1 is also responsible for creating the files of BJCVS in XML extension, a type of language that allows the sharing through the Internet of information

and also connects with other languages used by some databases such as Scielo and PubMed Central.

30 years In 2016 we will reach 30 years of uninterrupted circulation, something not easy in a country with little tradition in supporting scientific activities, like Brazil. In order to celebrate this data as it deserves to be, we have been planning together with SBCCV many actions that will be released soon.

42nd Congress of SBCCV From 26th to 28th of March in Curitiba, PR, it was held the nd 42 Congress of SBCCV. As usual, the event presented a high scientific level with classes and lectures which discussed the news on cardiovascular surgery, similar areas and activities as the traditional and praised “Hands on”.

The following Free Subjects of the Medical Congress were awarded: 1st place – “Developing and experimental study of aortic bioprosthesis of rapid release (no suture)” by Dr. Walter Gomes (SP) and colleagues; 2nd place – “Calcification and deformity of the aortic valve annulus associated to the severity of aortic stenosis and the greater transvalvar gradient after TAVI”, by Dr. Alvaro Machado Rosler (RS) and colleagues, 3rd place – “Valve-in-valve Mitral: A new frontier in reoperations?

Increasing the limits of indication through hydrodynamic tests in vitro”, by Dr. Thiago Vila Nova (SP) and colleagues.

The award “Professional of the year” was delivered, deservedly to Dr. Paulo Roberto Slud Brofman, an icon of cardiovascular surgery, not only in the state of Paraná but also in the whole country. The Editorial Board of BJCVS met to evaluate the changes of the journal and its impact on the authors and reviewers. It was also discussed the new system to streamline the process of evaluation and approving of works, which the associate editors will have a fundamental role, as previously detailed on last edition[2].

I would like to highlight in this edition, apart from the articles of a wide range of cardiac surgery areas, the work of Igor Bie Biernet, Rogério Carvalho de Oliveira, Pedro Beraldo de Andrade and Carlos Antonio Caramori (page 254), covering

I

Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

with a great propriety the bibliometrics index issues, as the Impact Factor, which has been the object of several discussions among the academic environment. Evandro Mesquita Tinoco, Celso Vale de Souza Júnior and Thiago Reigado Ferreira from page 260 tell the story of Andreas Vesalius, a Renaissance that revolutionized the anatomy and cardiovascular knowledge.

The EMC is an useful tool for testing and updating the knowledge and it is worth 0.5 score towards SBCCV exam of Title and 1.0 at revalidation of specialist title exam. I draw attention to this laborious tool, counting on commited reviewers who has been helping us to elaborate questions and answers.

We will contact the authors of the chosen articles counting on their cooperation in order to express the best evidence shown on the publication. There are five questions with five alternatives in each of the chosen articles per Edition. It is essential that the Author send us together with question the accurate highlighted part where the question was generated.

Counting on the goodwill of the noble Authors who honor us with their preferences for BJCVS.

Geraldo Verginelli A little of the rich life of professor Geraldo Verginelli, who left us in 2014, is told from page 283 in an article by Prof. Dr. Noedir Stolf and I as a second author. Dr. Verginelli accomplished like a few people did, the triple mission of assisting patients, teaching and researching. Regarding assisting patients, he had a key role in developing cardiovascular surgery at Clinics Hospital at Medical School of the University of São Paulo, acting in all areas and specialties. As for teaching, many cardiovascular surgeons in Brazil own a lot of their graduation to him.

May all receive my warmest regards, Domingo M. Braile 1 Editor-in-Chief BJVCS

EMC The following articles are available for testing of Continuously Medical Education (EMC) in this edition: I-“Stratification of complexity in congenital heart surgery: comparative study of the Risk Adjustment for Congenital Heart Surgery (RACHS-1) method, Aristotle basic score and Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STS-EACTS) mortality score” (page 148), II-“Atrioventricular block in coronary artery bypass surgery: perioperative predictors and impact on mortality” (page 164), III-“Effect of N-acetylcysteine in hearts of rats submitted to controlled hemorrhagic shock” (page 173), IV-“Analysis of immunostaining and western blotting of endothelin 1 and its receptors in mitral stenosis” (page 211) and V-“Andreas Vesalius 500 years - A Renaissance that revolutionized cardiovascular knowledge” (page 260).

REFERENCES 1. PubMed Central [cited Apr 30, 2015]. Available from: http://www. ncbi.nlm.nih.gov/pmc/ 2. Braile DM. English: the new official language of BJCVS. Rev Bras Cir Cardiovasc. 2015;30(1):I-III.

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Editorial

Clinical value of BNP as an independent predictor of mortality following heart surgery Valor clínico do BNP como um preditor independente de mortalidade após cirurgia cardíaca

Edmo Atique Gabriel1, MD, PhD DOI 10.5935/1678-9741.20150025

Detection and characterization of mortality predictors is becoming an interesting approach in the field of cardiovascular surgery, particularly in valve and CABG procedures. Yet there is a paucity of trials in order to obtain precise data on this topic using statistic criteria. In the last decades, many cardiologists have turned attention to underlying role of inflammation in heart diseases and different types of heart operation. The key point raised by these experts is that main expression from inflammatory cardiovascular process can be translated into serologic appearance of some markers[1-3].

From the publication “Predictors of mortality in cardiac surgery: B-type natriuretic peptide’’ by Murad Junior et al.[4], the first observation can be drawn is epidemiologic quality of retrospective study of valve and CABG patients. Undoubtedly main step for identifying a mortality predictor using statistical analysis is to know how patients were selected and included in the study.

REFERENCES 1. Sudoh T, Kangawa K, Minamino N, Matsuo H. A new natriuretic peptide in porcine brain. Nature. 1988;332(6159):78-81.

2. Augusto CA, Vicente WVA, Evora PRB, Rodrigues AJ, Klamt JG, Carlotti APCP et al. High-dose aprotinin does not affect troponin I, N-terminal pro-B-type natriuretic peptide and renalfunction in children submitted to surgical correction with extracorporeal circulation. Rev Bras Cir Cardiovasc 2009;24(4):519-32.

3. Gabriel EA, Locali RF, Matsuoka PK, Almeida LS, Silva PSV, Ishigai MMS, Salerno T, Buffolo E. Pulmonary artery perfusion does not improve brain natriuretic peptide (BNP) levels in suine experimental research. Rev Bras Cir Cardiovasc 2010;25(4):516-26.

4.Murad Junior JA, Nakazone MA, Machado MN, Godoy MF. Predictors of mortality in cardiac surgery: B-type natriuretic peptide. Rev Bras Cir Cardiovasc. 2015;30(2):182-7.

READ ARTICLE ON PAGE 182

5. Suzuki S, Yoshimura M, Nakayama M, Harada E, Ito T, Nakamura S, et al. Plasma level of B-type natriuretic peptide a prognostic marker after acute myocardial infarction a long-term follow-up analysis. Circulation. 2004;110(11):1387-91.

The second and most remarkable observation can be drawn from publication by Murad Junior et al.[4] is the meticulous view regarding preoperative role of BNP as a mortality predictor in the setting of valve and CABG operations. Many authors have advocated that cardiac diseases have some inflammatory burden preoperatively and, on account of it, postoperative time becomes a particular moment for so many complications and deleterious events[5-7].

This study provides a very elegant representation of preoperative BNP values and its relationship with 30-day mortality. Thus, publication by Murad et al.[4] is a cornerstone reference for brazilian cardiologic community in an attempt to preoperatively include BNP as prognostic marker in valve and CABG operations.

6. Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P, Rouleau HA. Prognostic impact of plasma n-terminal probrain natriuretic peptide in severe chroniccongestive heart failure: a sustudy of the carvedilol prospective randomizaed cumulative survival (COPERNICUS) trial. Circulation.

2004;110(13):1780-6.

7. Fellahi JL, Dacache G, Rubes D, Masseti M, Gérard JL, Hanouz JL. Does preoperative B-type natriuretic peptide better predict adverse outcome and prolonged length of stay than the standard European system for cardiac operative risk evaluation after cardiac surgery? J Cardiothorac Vasc Anesth. 2010 july 29; [Epub ahead of print].

Centro Universitario Lusíada (UNILUS), Santos, SP, Brazil.

E-mail: edag@uol.com.br 1

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

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Braz J Cardiovasc Surg | Rev Bras Cir Cardiovasc

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Pachón M JC,ORIGINAL et al. - Simplified method for esophagus protection during ARTICLE radiofrequency catheter ablation of atrial fibrillation - prospective study of 704 cases

Simplified method for esophagus protection during radiofrequency catheter ablation of atrial fibrillation - prospective study of 704 cases Método simplificado para proteção do esôfago durante a ablação por radiofrequência da fibrilação atrial - estudo prospectivo de 704 casos

José Carlos Pachón Mateos1, PhD; Enrique I Pachón Mateos2, MD; Tomas G Santillana Peña3, MD; Tasso Julio Lobo3, MD; Juán Carlos Pachón Mateos4, PhD; Remy Nelson A Vargas5, MD; Carlos Thiene C Pachón3, MD; Juán Carlos Zerpa Acosta3; MD

DOI 10.5935/1678-9741.20150009

RBCCV 44205-1625

Abstract Introduction: Although rare, the atrioesophageal fistula is one of the most feared complications in radiofrequency catheter ablation of atrial fibrillation due to the high risk of mortality.

Objective: This is a prospective controlled study, performed during regular radiofrequency catheter ablation of atrial fibrillation, to test whether esophageal displacement by handling the transesophageal echocardiography transducer could be used for esophageal protection.

Methods: Seven hundred and four patients (158 F/546M [22.4%/77.6%]; 52.8±14 [17-84] years old), with mean EF of 0.66±0.8 and drug-refractory atrial fibrillation were submitted to hybrid radiofrequency catheter ablation (conventional pulmonary vein isolation plus AF-Nests and background tachycardia ablation) with displacement of the esophagus as far as possible from the radiofrequency target by transesophageal echocardiography transducer handling. The esophageal luminal temperature was monitored without and with displacement in 25 patients.

Results: The mean esophageal displacement was 4 to 9.1cm (5.9±0.8 cm). In 680 of the 704 patients (96.6%), it was enough to

allow complete and safe radiofrequency delivery (30W/40oC/irrigated catheter or 50W/60oC/8 mm catheter) without esophagus overlapping. The mean esophageal luminal temperature changes with versus without esophageal displacement were 0.11±0.13oC versus 1.1±0.4oC respectively, P<0.01. The radiofrequency had to be halted in 68% of the patients without esophageal displacement because of esophageal luminal temperature increase. There was no incidence of atrioesophageal fistula suspected or confirmed.

Only two superficial bleeding caused by transesophageal echocardiography transducer insertion were observed.

Conclusion: Mechanical esophageal displacement by transesophageal echocardiography transducer during radiofrequency catheter ablation was able to prevent a rise in esophageal luminal temperature, helping to avoid esophageal thermal lesion. In most cases, the esophageal displacement was sufficient to allow safe radiofrequency application without esophagus overlapping, being a convenient alternative in reducing the risk of atrioesophageal fistula.

São Paulo Cardiology Institute of the University of São Paulo (USP), São Paulo Heart Hospital (Director of Pacemaker Service at IDPC), São Paulo, SP, Brazil.

2 Cardiology Institute of São Paulo Heart Hospital Dante Pazzanese, São Paulo, SP, Brazil.

3 São Paulo Heart Hospital, São Paulo, SP, Brazil.

4 São Paulo Cardiology Institute of the University of São Paulo (USP), São Paulo Heart Hospital, São Paulo, SP, Brazil.

5 São Paulo Cardiology Institute São Paulo Heart Hospital, São Paulo, SP, Brazil.

No financial support.

Descriptors: Catheter Ablation. Esophagus. Esophageal Fistula. Atrial Fibrillation.

1

Correspondence address: José Carlos Pachón Mateos Desembargador Eliseu Guilherme St, 123 – Paraíso - São Paulo, SP, Brazil Zip code: 04004-030 E-mail: jcpachon@hotmail.com

This study was carried out at Instituto Dante Pazzanese (IDPC), Hospital do Coração Hcor, University of São Paulo Medical School, São Paulo, SP, Brazil.

Article received on January 26th, 2015 Article accepted on February 2nd, 2015

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nares e ninhos de fibrilação atrial e ablação de taquicardia de background) com deslocamento do esôfago o mais longe possível do alvo da radiofrequência por manuseio do transdutor de ecocardiografia transesofágica. A temperatura luminal esofágica foi monitorada com e sem deslocamento em 25 pacientes.

Resultados: O deslocamento esofágico significativo foi de 4 a 9,1 centímetros (5,9±0,8 cm). Em 680 dos 704 pacientes (96,6%), isso foi o suficiente para permitir a entrega completa e segura de radiofrequência (30W/40°C/cateter irrigado ou 50W/60°C/cateter de 8 milímetros) sem sobreposição do esôfago. As alterações médias de temperatura luminal esofágica com e sem deslocamento de esôfago foram de 0,11±0,13oC versus 1,1±0,4oC, respectivamente, P<0,01. A radiofrequência teve que ser interrompida em 68% dos pacientes sem deslocamento de esôfago devido ao aumento da temperatura luminal esofágica. Não houve nenhum caso, suspeito ou confirmado, de fístula átrio-esofágica. Foram observados apenas dois sangramentos superficiais causados por inserção do transdutor de ecocardiografia transesofágica.

Conclusão: O deslocamento mecânico do esôfago pelo transdutor de ecocardiografia transesofágico durante a ablação com radiofrequência foi capaz de impedir o aumento da temperatura luminal esofágica, ajudando a evitar lesão térmica. Na maioria dos casos, o deslocamento esofágico foi suficiente para permitir a aplicação segura de radiofrequência sem sobreposição do esôfago, sendo uma alternativa conveniente para reduzir o risco de fístula átrio-esofágica.

Abbreviations, acronyms & symbols AF AEF ED EF ELT LA LAO PA PV RAO RF RFA TET

Atrial fibrillation Atrioesophageal fistula Esophageal displacement Ejection fraction Esophageal luminal temperature Left atrium Left anterior oblique Postero-anterior Pulmonary vein Right anterior oblique Radiofrequency Radiofrequency catheter ablation Transesophageal echocardiography transducer

Resumo Introdução: Apesar de rara, a fístula átrio-esofágica é uma das complicações mais temidas na ablação por radiofrequência da fibrilação atrial pelo alto risco de mortalidade.

Objetivo: Este é um estudo prospectivo controlado, realizado durante a ablação por radiofrequência da fibrilação atrial regular, para testar se o deslocamento do esôfago ao manipular o transdutor de ecocardiografia transesofágica poderia ser usado para a proteção de esôfago.

Métodos: Setecentos e quatro pacientes (158 mulheres e 546 homens [22,4%/77,6%]; 52,8±14 [17-84] anos), com EF média igual a 0,66±0,8 e com fibrilação atrial refratária ao tratamento medicamentoso, foram submetidos à terapia híbrida com ablação por radiofrequência (isolamento convencional das veias pulmo-

Descritores: Ablação por Cateter. Esôfago. Fístula Esofágica.

Fibrilação Atrial.

INTRODUCTION

left atrium regions that have great contact with the esophagus (pulmonary veins antrum and LA posterior wall). In addition, the use of long and even confluent LA block lines has been a common practice[8]. These aspects make the risk of esophageal injury highly prevalent. The main problem is that atrioesophageal fistula, in spite of being rare, is extremely serious with a high risk of mortality from stroke, mediastinitis, sepsis, and endocarditis. It is caused by conductive heat transfer to the esophagus with trans-mural necrosis[9,10] and possible participation of ischemia because of circulation and damage to esophageal innervation.

These considerations justify extreme caution during catheter ablation of AF in order to avoid esophageal lesion. Cooling esophageal protection systems are being developed to prevent thermal damage during ablation[11]. Several thermal monitoring[12] and esophagus location systems have been described to avoid RF release in risk areas, reducing the power applied in these places. However, energy restriction can lead to incomplete ablation, increasing its risk of failure. On the

Radiofrequency (RF) catheter ablation of atrial fibrillation (AF) has been the most widely used method to retrieve sinus rhythm when AF is refractory to drug therapy. During ablation there is a risk of thermal damage of the esophagus due to its proximity and contact with the left atrium[1] (Figure 1).

The most feared complication is atrioesophageal fistula[2-4], whose low but worrisome occurrence has been estimated to be <1%[5,6]. However, its true incidence is certainly unknown since there is no systematic report of this complication. A recent study of esophagogastroscopy performed in 28 patients 24 hours after catheter ablation without control of the esophagus position showed that 47% and 18% of the patients had esophageal lesions compatible with superficial thermal injury and necrosis or ulcer, respectively[7].

Technical developments in catheter ablation of AF have seen increasing use of high power large surface catheters (8 mm) and high power transfer systems (irrigated catheters) in

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Fig. 1 - Cardiac computed tomography with esophagus visualization in RAO, PA and LAO, respectively, from left to right. There is a large contact area between the esophagus and the left atrium. This anatomical relationship can easily explain the risk of thermal injury of the esophagus during endocardial left atrial ablations. RAO=right anterior oblique; PA=postero-anterior; LAO=left anterior oblique

details and limitations of this technique after 6 years of systematic employment and follow-up.

METHODS Seven hundred and four patients (158 female and 546 male [22.4%/77.6%]; mean±SD age, 52.8±14 [17 to 84] years) with drug-refractory AF (314 paroxysmal [44.6%], 332 persistent [47.2%], and 58 permanent [8.2%]) and treated by catheter RF endocardial ablation were included. Most patients (425, 60.4%) had no significant heart disease, with mean EF of 0.66±0.8 (0.3 to 0.8). In most cases, the LA diameter was either normal or slightly increased (39.9±6.8 mm) (Table 1).

Fig. 2 - Lateral displacement of the esophagus usually obtained during transesophageal echocardiography. In this case the total displacement was 6.5 cm, allowing isolation of the the pulmonary vein (white circles) on each side with a good distance from the esophagus.

Table 1. Main features of 704 patients included in this study.

N 704 Range or % Age (years) 52.8±13.8 17 to 84 Female/Male 158/546 22.4% /77.6% Weight (Kg) 82.5±15.8 42 to 145 Atrial Fibrillation Paroxysmal 314 44.6% Persistent 332 47.2% Permanent 58 8.2% With/Without Cardiopathy 279/425 39.6% / 60.4% Left Atrium diameter (mm) 39.9±6.8 25 to 60 Ejection fraction 0.66±0.8 0.3 to 0.8 RF shots 70.5±18.9 40 to 120 X-ray duration (min) 60.6±21.1 10 to 99 Number of sessions 1.16 ±0.4 1 to 4 Max Esophageal displacement (cm) 5.9±0.8 4 to 9.1

other hand, as the esophagus has great spontaneous motility, its pre-procedure location has little value and continuous monitoring is required[13,14].

As we regularly use transesophageal echocardiography (TEE) throughout catheter ablation of AF, we proposed that the TEE transducer could be regularly employed to divert the esophagus out of the ablation area and, in January 2005, we started this prospective study to test its possible benefits (Figure 2).

Objective The objective of this study was to test the hypothesis that controlled deflection of the TEE transducer could meet two major aims: 1. Divert the esophagus out of the area to be ablated in order to avoid heating; and 2. Keep the esophagus stable in a well-known fixed position, avoiding an undesirable and unexpected interposition in the ablation area due to its natural motility.

This is a prospective study of regular clinical application.

The purpose of this article is to show the results and discuss

Methodology In every cases, catheter RF ablation of AF was performed in both atria, the LA being reached by trans-septal access. A hybrid technique was used with pulmonary veins isolation[8,15,16], AF-Nests ablation[17-19] mapping, and ablation of the background tachycardia[20]. The St Jude Navx System was employed for electroanatomic 3D mapping.

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Patients using oral anticoagulants had the prothrombin time adjusted before the procedure (target INR ≤ 1.6). Conventional surface ECG monitoring, adhesive defibrillation patches, mechanical ventilation with intravenous or inhalation general anesthesia in addition to the placement of TEE transducer were used. After having confirmed absence of intracardiac thrombus, four right femoral vein punctures were performed and a duodecapolar catheter was placed into coronary sinus. Trans-septal puncture was used in order to introduce both an ablation and a circular catheter in the left atrium. The following additional equipment was used: Cicero anaesthesia system (Dräger); multiparameter HP/Philips M1026A monitor; HP/Philips Sonos-2500 echocardiograph; 32 channels TEB polygraph with software for spectral analysis (Pachón-TEB); computerized spectrometer (Pachón®) for real-time spectral analysis, Siemens digital radioscopy; Medtronic, Biotronik and Irvine RF generator; Philips Heartstart biphasic XL defibrillator with trans-cutaneous pacemaker and cerebral activity spectrometer (BIS). The ablations were carried out by using 8 mm catheter Blazer EPT, Medtronic Conductor and Johnson Irrigated. Activated clotting time was attained between 300 and 400 s by IV Heparin infusion. All the patients included in the study accepted the procedure being made aware of the methodology and potential complications, having signed the written informed consent.

Fig. 3 - Barium esophagography showing esophageal displacement during RF catheter ablation of AF. In A, the thermometer position is satisfactory; however, in B, the thermometer is misplaced and should not be considered for temperature control of the ablation. The yellow dotted lines show the esophageal lumen contour. Enough bilateral esophageal displacement can also be observed, allowing safe ablation.

AF=atrial fibrilation; RF=radiofrequency

Esophageal Endoscopy after Ablation After ablation the patients were kept in the hospital under strict clinical monitoring for two days. Esophageal endoscopy was indicated whenever there was any symptom or sign of esophageal discomfort or lesion.

Medication after Ablation Proton pump blockers were not used unless the patient was taking it prior to the ablation. During the first 3 months, in all cases, antiarrhythmic medication (amiodarone, propafenone or beta blockers) was used depending on the patient’s tolerance. Anticoagulation was strictly established for at least 2-3 months using warfarin (INR = 2 to 3) or dabigatran.

Esophageal Displacement and Ablation After obtaining a three-dimensional LA model with Navx system by handling the TEE, the esophagus was shifted and kept into the rightmost position before the ablation of the left half of LA (left pulmonary veins isolation and AF-Nests ablation). Afterwards, the TEE transducer was handled again in order to shift the esophagus to the leftmost location. Ablation of the half right of the LA was then performed. All positions were photographed in order to get accurate esophageal displacement measurements. In the final ablation phase, in cases with LA background tachycardia, the esophagus was again shifted far from the ablation sites. At any time, at operator discretion before turning the RF on, the esophagus was manipulated by the TEE transducer in order to keep it as far as possible from the RF delivery point.

RESULTS The anatomical course of the esophagus was quite variable. In 22.2% of the patients, it was centralized; however, in 57.5% and 20.3% of the patients, it was diverted near or superimposed onto the left or right pulmonary veins (Figures 4 and 5), respectively. In all cases, it was possible to achieve mechanical esophageal displacement. For safety reasons, the displacement was applied even in cases with centered esophagus.

Displacement ranged from 4 to 9.1 cm (5.9±0.8 cm). In 680 of the 704 patients (96.6%), the displacement was large enough to allow RF delivery with reasonable safety, even in the LA posterior wall (30W/40oC/irrigated catheter or 50W/60oC/8 mm catheter). For ablation of the LA posterior wall, the TEE transducer depth was modified as needed for each case. In 24 cases (3.4%), the esophagus had reduced and difficult mobility or allowed only one-way displacement, as seen in Figures 4 and 5. However, with stepwise handling, it was possible to obtain reasonable segmental displacement to get safe RF delivery in most areas of the pulmonary veins, although not completely sufficient for extensive treatment of the posterior LA wall.

Esophageal Temperature Monitoring versus Displacement A group of 25 patients were also studied to see the effects of displacement in the esophageal luminal temperature (ELT).

They had an esophageal probe and thermometer additionally inserted. In these cases the esophagus was contrasted with barium and ELT was monitored during the ablations, before and after displacements. With the esophagus in the natural position, since the esophageal thermometer was in a good site (Figure 3) and whenever a ≥ 1oC ELT was observed, the ablation was immediately halted and the esophagus was quickly shifted.

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In the whole group there was neither a case nor a suspicion of atrioesophageal fistula (mean follow-up of 37.9±81.9 months). Eight patients underwent esophageal endoscopy due to symptoms, with two of them showing slight bleeding. The investigation revealed normal esophagus in six of the eigh patients. The two cases with bleeding had superficial linear lesions in the high esophagus portion (above the atrial level), without signs of burning or necrosis. They were related to mechanical injury caused by introduction of the TEE transducer. Although small and superficial, the bleeding was certainly increased by anticoagulation. In both cases, the bleeding was promptly stopped with topic 1:1000 adrenaline solution. No cases presented symptoms compatible with injury to the periesophageal nerve plexus. There was no occurrence of ileus palsy or pylori spasm.

Fig. 4 - Esophagus positioned on the left at rest showing some restriction to be moved. Nevertheless, there was enough displacement for treating left pulmonary vein. In such cases, the barium esophagography is helpful to define the real esophagus boundaries and to show the extension of the displaced segment.

Study of Esophageal temperature versus Displacement The results of 25 patients having ELT monitored without and with mechanical esophageal displacement are displayed in Table 2.

DISCUSSION Several techniques have been proposed for esophageal protection during catheter ablation of AF. Any alternative limiting the amount or the sites of RF delivery increases the rate of ablation failure. Techniques have been used for: Fig. 5 - This patient had an old phrenic palsy and the esophagus was adhered to the same side showing restriction to be displaced to the left. However, enough displacement was achieved for right pulmonary vein ablation. Again, barium esophagography was helpful to define the real esophagus borders and to show the extension of the displaced segment.

1. Locating the esophagus before and/or during ablation; 2. Monitoring esophageal temperature; 3. Limitating RF energy or sites; 4. Esophageal cooling; and 5. Esophageal displacement.

Table 2. ELT changes with and without esophageal displacement. In 19/25 (76%) patients the RF was interrupted due to ELT increase > 1oC during one RF delivery at least.

N Age (years) Female/Male Weight (Kg) Atrial Fibrillation

25 58.5±10.5 8/17 78.3±14.3 Paroxysmal 6 Persistent 17 Permanent 2 9/16 40.9±8.3 0.66±0.9 70.1±13.8 65.1±16.5 1.2±0.5 6.1±1.3 0.11±0.13 1.3±0.5 19/25 0

With/Without Cardiopathy Left atrium diameter (mm) Ejection fraction RF shots X-ray duration (min) Number of sessions max Esophageal displacement (cm) max ∆ T with displacement (theC) max ∆ T without displacement (theC) ∆T > 1oC without displacement ∆T > 1oC with displacement

ELT=esophageal luminal temperature; RF=radiofrequency

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Range/% 33 to 73 32%/68% 52 to 101 24% 68% 8% 36%/64% 29 to 59 0.37 to 0.79 44 to 99 28 to 99 1 to 3 4.5 to 9.2 0 to 0.5 0 to 2 76% 0%

P

P<0.01 P<0.01

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The esophagus location before ablation has been held with barium contrast radiography, computed tomography (Figure 1), MRI or electroanatomical 3D mapping[21]. These techniques allow a fairly accurate location, but with more or less information on the extent of the contact between the LA and the esophagus. The main disadvantages are spontaneous change of esophagus position and the need of reducing the RF energy in overlapping regions that can lead to incomplete ablation.

The esophagus location during ablation has been determinated through contrast with barium, intracardiac echocardiography[22], and electroanatomical 3D mapping[23]. These methods have the great advantage of showing the actual position of the esophagus during ablation, but also limit RF delivery in overlapping areas. Therefore, if a AF relapse occurs due to restriction of RF energy release, the problem will persist in the same area in case of reablation[24].

Esophageal temperature monitoring during ablation[12] is another option, but it does not completely prevent complications because the thermometer can be located outside the point of greatest heat and, in addition, there is the problem of thermal latency of the esophagus[25]. Studies have shown low correlation between the total energy delivered in LA and LET increase[25,26]. Furthermore, heating of the esophagus restricts RF, delivery bringing out the problem of incomplete ablation.

A quite creative technique is placing a cooled balloon irrigated with saline solution inside the esophagus[27,28].

However, more detailed studies need to be conducted to verify whether anterior displacement caused by esophageal balloon insufflation could be an additional problem, thereby reducing its potential benefits.

Several techniques have advocated esophagus protection by reducing the RF power in overlapping areas. So far, there is no evidence based on guidelines defining the limits of RF energy. Speculative recommendations suggest that RF energy in overlapping areas of the esophagus should be <20W for less than 20 seconds and there should be at least 180 sec between two successive RF applications. However, the disadvantage is that even when well-implemented, incomplete and insufficient ablation may predispose to relapse.

In this study, it was possible to demonstrate that the esophagus has a large motility. If on the one hand this feature is a disadvantage due to the risk of unexpected esophageal interposition in the RF focus, on the other hand, it allows it to be mechanically displaced away from the point of RF application reducing the risk of thermal injury and atrioesophageal fistula (Figure 2). Additionally, mechanical esophageal displacement by using the TEE transducer, allows it to keep it stable and far from the RF application site. Since January 2005, we have regularly used this feature in any LA ablation as an indispensable requirement for ablation (Figure 6). Similar experience has been published supporting our observations and strengthening the idea that controlled esophageal displacement could be employed as a protection against thermal lesions[29,30].

Fig. 6 - Good esophageal displacement allowing large bilateral antrum ablation.

The extent of displacement depends on several factors such as constitutional characteristics, thorax size, patient age, presence of adhesions and/or esophageal pathologies, operator experience, transducer mobility, etc. In this study, the displacement of the esophagus ranged from 4 to 9.1 cm (5.9±0.8 cm). This allowed for secured visualized RF application (keeping a safe distance from the RF application site) in 690 patients (98.1%). Only 14 cases (1.9%) had very low esophageal mobility and a careful displacement for each pulmonary vein ablation was needed. In these cases, despite having enough displacement to ablate the pulmonary veins antrum, it was not possible to safely apply RF to the posterior LA wall.

Besides visual control of the esophageal displacement, 25 patients underwent concomitant monitoring of ELT (Figure 3). The RF was then applied with and without esophageal displacement. With displacement, it was not necessary to halt the RF energy whereas without displacement, the RF energy had to be stopped in 17 patients (68%) due to ELT increase of ≥1oC. In addition, it was found that the esophageal displacement was able to reduce 10.9 times the ELT range (∆ELT = 0.11±0.13oC with versus 1.2±0.5oC without displacement, P<0.01) (Table 2). We decided to stop the RF early in case of a slight ELT (<1oC) increase because of the thermal esophageal that could raise the temperature even after RF interruption[31]. This behavior decreases the ELT control effectiveness in preventing the esophageal thermal lesion. ELT sensitivity to safely detect esophageal warming is questionable because there is low correlation between the total amount of energy released in the left atrium and the final increase of ELT[25,26]. Moreover, the slow cooling of the esophagus is another particularity that cannot be neglected.

This feature increases the risk of thermal damage due to the cumulative effect in temperature caused by RF applications in areas relatively near as described by Pappone et al.[4].

These authors identified that ablation confluent line blocks are high-risk critical areas for the formation of atrioesophageal fistulas.

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One problem observed in this study was the potential risk of mechanical trauma of the oropharynx and upper esophagus during the introduction of the TEE transducer, causing bleeding that was intensified by anticoagulation. These observed cases were easily treated with topic application of adrenaline solution during diagnostic endoscopy. This complication occurred at the beginning of the learning curve. Based on this experience, the TEE transducer insertion procedure was changed, with more appropriate lubrication and careful handling being applied. As a result, this complication was no longer observed.

The TEE transducer should never be advanced inside the esophagus with pronounced angulation. It is important to move it with extreme care. Its position must be changed often to avoid forcing it in a single point for a long time. It could cause an ischemic injury to the esophageal mucosa.

Sometimes, malposition and low mobility of the esophagus may limit the application of this technique; however, the experience of this study shows that these cases are rare.The presence of the TEE transducer and, especially, the barium in the esophagus may reduce the radiological visibility in some degree. Currently, we have used barium only in cases with difficult esophagus displacement.

CONCLUSION Mechanical esophageal displacement using the TEE transducer during catheter RF ablation of AF was able to prevent a rise in esophageal intraluminal temperature, helping to avoid esophageal thermal lesion. In the absolute majority of cases the displacement of the esophagus was sufficient to allow the RF application in a visually safe condition. The absence of symptoms of esophageal lesions, the absence of injury to the peri-esophageal nerve plexus in a large number of patients, and the simplicity and low cost of the procedure suggest that this technique is a valuable alternative in reducing the risk of atrioesophageal fistula.

Study and Method Limitations Active and controlled esophagus displacement during catheter RF of AF ablation seems to be able to prevent esophageal temperature increase as well as esophageal thermal lesions. However, it depends on the use of the TEE transducer throughout the procedure. This may be considered a limitation for some services, but in our methodology, it becomes an advantage as we regularly use the TEE to replace the useful but more expensive intracardiac echocardiogram.

The insertion of TEE transducer depends on good sedation or general anesthesia, thus many services that perform AF ablation with a conscious patient or with superficial sedation may have difficulty employing this technique. The insertion process must be performed with additional care because since the patient will be anti-coagulated any mucosal trauma may cause significant bleeding.

Due to its significant diameter (11 mm), the TEE transducer may be considered a disadvantage as it forces the esophageal wall to the atrium, reducing the postero-anterior dimension of the LA. This could reduce the space for ablation, favoring esophageal heating. However, the proposal is to bend the transducer in order to maintain the esophagus as far as possible from the ablation site with minimal overlapping of the transducer and the LA. One limitation of this study is that endoscopy was performed only in a few symptomatic cases. Since this is a prospective study of regular clinical application, though, it would be inconvenient and ethically questionable to perform an additional semi-invasive procedure in asymptomatic patients. This must be achieved through a randomized study. Nevertheless, the high number of cases treated without any occurrence of clinical esophageal lesion is a highly positive finding. Furthermore, the study of 25 patients undergoing ablation with ELT monitoring showed the high efficacy of this method for preventing esophageal temperature increase.

Authorsâ&#x20AC;&#x2122; roles & responsibilities JCPM

EIPM

TGSP TJL JCPM RNAV CTCP JCZA

Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; design and study design; conduct of the operations and/or experiments; writing of the manuscript or critical review of its content analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; design and study design; conduct of the operations and/or experiments; writing of the manuscript or critical review of its content Conduct of operations and/or experiments Conduct of operations and/or experiments Conduct of operations and/or experiments Conduct of operations and/or experiments Analysis and/or interpretation of data; conduct of the operations and/or experiments Conduct of operations and/or experiments

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20. Mateos JC, Mateos EI, Lobo TJ, Pachón MZ, Mateos JC, Pachón DQ, et al. Radiofrequency catheter ablation of atrial fibrillation guided by spectral mapping of atrial fibrillation nests in sinus rhythm. Arq Bras Cardiol. 2007;89(3):124-34, 140-50.

8. Pappone C, Rosanio S, Oreto G, Tocchi M, Gugliotta F, Vicedomini G, et al. Circunferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation.

Circulation. 2000;102(21):2619-28.

21. Good E, Oral H, Lemola K, Han J, Tamirisa K, Igic P, et al. Movement of the esophagus during left atrial catheter ablation for atrial fibrillation. J Am Coll Cardiol.

2005;46(11):2107-10.

9. Teplitsky L, Hegland DD, Bahnson TD. Catheter based cryoablation and radiofrequency ablation for atrial fibrillation results in conductive heat transfer from and to the esophagus.

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22. Kenigsberg DN, Lee BP, Grizzard JD, Ellenbogen KA, Wood MA. Accuracy of intracardiac echocardiography for assessing the esophageal course along the posterior left atrium: a comparison to magnetic resonance imaging. J Cardiovasc Electrophysiol.

2007;18(2):169-73.

10. Ripley KL, Gage AA, Olsen DB, Van Vleet JF, Lau CP, Tse HF. Time course of esophageal lesions after catheter ablation with cryothermal and radiofrequency ablation: implication for atrioesophageal fistula formation after catheter ablation for atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(6):642-6.

23. Sherzer AI, Feigenblum DI, Kulkarni S, Pina JW, Casey JL, Salka KA, et al. Continuous nonfluoroscopic localization of the esophagus during radiofrequency catheter ablation of atrial fibrillation. J Cardiovasc Electrophysiol. 2007;18(2):157-60.

11. Arruda MS. Pre clinical “in vivo” evaluation of an esophageal protective system: Implications on esophageal thermal injury during AF ablation. Heart Rhythm. 2008;5:S16.

24. Kennedy R, Good E, Oral H, Huether E, Bogun F, Pelosi F, et al. Temporal stability of the location of the esophagus in patients undergoing the repeat left atrial ablation procedure for atrial fibrillation or flutter. J Cardiovasc Electrophysiol.

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12. Redfearn DP, Trim GM, Skanes AC, Petrellis B, Krahn AD, Yee R, et al. Esophageal temperature monitoring during radio frequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol.

2005;16(6):589-93.

25. Teplitsky L, Perzanowski C, Durrani S, Berman AE, Hranitzky P, Bahnson TD. Radio frequency catheter ablation for atrial fibrillation produces delayed and long lasting elevation of luminal esophageal temperature independent of lesion duration and power.

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14. Helms A, West JJ, Patel A, Mounsey JP, DiMarco JP, Mangrum JM, et al. Real-time rotational ICE imaging of the relationship of the ablation catheter tip and the esophagus during atrial fibrillation ablation. J Cardiovasc Electrophysiol. 2009;20(2):130-7.

26. Cummings JE, Schweikert RA, Saliba WI, Burkhardt JD, Brachmann J, Gunther J, et al. Assessment of temperature, proximity, and course of the esophagus during radiofrequency ablation within the left atrium. Circulation. 2005;112(4):459-64.

15. Haıssaguerre M, Jaıs P, Shah DC, Garrigue S, Takahashi A, Lavergne T, et al. Electrophysiological end point for catheter

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2005;50(20):N269-79.

fibrillation. Pacing Clin Electrophysiol. 2006;29(9):957-61.

30. Chugh A, Rubenstein J, Good E, Ebinger M, Jongnarangsin K, Fortino J, et al. Mechanical displacement of the esophagus in patients undergoing left atrial ablation of atrial fibrillation. Heart Rhythm. 2009;6(3):319-22.

28. Tsuchiya T, Ashikaga K, Nakagawa S, Hayashida K, Kugimiya H. Atrial fibrillation ablation with esophageal cooling with the cooled water-irrigated intraesophageal balloon: a pilot study. J Cardiovasc Electrophysiol. 2007;18(2):145-50.

31. Singh SM, D’ávila A, Doshi SK, Brugge WR, Bedford RA, Mela T, et al. Esophageal injury and temperature monitoring during atrial fibrillation ablation. Circ Arrhythm Electrophysiol.

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Cavalcanti PEF, et al. - Stratification of complexity in congenital heart surgery: ORIGINAL ARTICLE comparative study of the RACHS-1 method, Aristotle basic score and STSEACTS mortality score

Stratification of complexity in congenital heart surgery: comparative study of the Risk Adjustment for Congenital Heart Surgery (RACHS-1) method, Aristotle basic score and Society of Thoracic Surgeons-European Association for CardioThoracic Surgery (STS-EACTS) mortality score Estratificação da complexidade em cirurgias de cardiopatias congênitas: comparação dos modelos Risk Adjustment for Congenital Heart Surgery (RACHS-1), escore básico de Aristóteles e escore de mortalidade da Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STS-EACTS)

Paulo Ernando Ferraz Cavalcanti1, MD, MSc; Michel Pompeu Barros de Oliveira Sá1, MD, MSc; Cecília Andrade dos Santos1, MD; Isaac Melo Esmeraldo1, MD; Mariana Leal Chaves1, MD; Ricardo Felipe de Albuquerque Lins1, MD, MSc; Ricardo de Carvalho Lima2; MD, MSc, PhD

DOI 10.5935/1678-9741.20150001

RBCCV 44205-1626

Abstract Objective: To determine whether stratification of complexity models in congenital heart surgery (RACHS-1, Aristotle basic score and STS-EACTS mortality score) fit to our center and determine the best method of discriminating hospital mortality.

Methods: Surgical procedures in congenital heart diseases in patients under 18 years of age were allocated to the categories proposed by the stratification of complexity methods currently available. The outcome hospital mortality was calculated for each category from the three models. Statistical analysis was

performed to verify whether the categories presented different mortalities. The discriminatory ability of the models was determined by calculating the area under the ROC curve and a comparison between the curves of the three models was performed.

Results: 360 patients were allocated according to the three methods. There was a statistically significant difference between the mortality categories: RACHS-1 (1) - 1.3%, (2) - 11.4%, (3)27.3%, (4) - 50 %, (P<0.001); Aristotle basic score (1) - 1.1%, (2) - 12.2%, (3) - 34%, (4) - 64.7%, (P<0.001); and STS-EACTS mortality score (1) - 5.5 %, (2) - 13.6%, (3) - 18.7%, (4) - 35.8%,

Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco (PROCAPE) and Universidade de Pernambuco (UPE), Recife, PE, Brazil.

2 Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco (PROCAPE), Universidade de Pernambuco (UPE), Recife, PE, Brazil and Escola Paulista de Medicina da Universidade Federal de São Paulo (EPM/Unifesp), São Paulo, SP, Brazil.

No financial support.

1

Correspondence address: Paulo Ernando Ferraz Cavalcanti Pronto Socorro Cardiológico de Pernambuco - PROCAPE Rua dos Palmares, S/N – Santo Amaro, Recife, PE Brazil - Zip code: 50100-060 E-mail: pauloernando@sbccv.org.br

This study was carried out at Division of Cardiovascular Surgery of Pronto Socorro Cardiológico de Pernambuco - PROCAPE. University of Pernambuco (UPE), Recife, PE, Brazil.

Article received on June 4th, 2014 Article accepted on January 13th, 2015

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Métodos: Procedimentos em pacientes menores de 18 anos foram alocados nas categorias propostas pelos modelos de estratificação da complexidade. O desfecho de mortalidade hospitalar foi calculado para cada categoria dos três modelos. Análise estatística foi realizada para verificar se as categorias apresentavam distintas mortalidades dentro de cada modelo. A capacidade discriminatória dos modelos foi determinada pelo cálculo de área sob a curva ROC e uma comparação entre as curvas dos três modelos foi realizada.

Resultados: 360 pacientes foram alocados pelos três modelos.

Houve diferença estatisticamente significante entre as mortalidades das categorias propostas pelos modelos de RACHS-1 (1) - 1,3%, (2) - 11,4%, (3) - 27,3%, (4) - 50%, (P<0,001); escore básico de Aristóteles (1) - 1,1%, (2) - 12,2%, (3) - 34%, (4) - 64,7%, (P<0,001); e escore de mortalidade do STS-EACTS (1) - 5,5%, (2) - 13,6%, (3) - 18,7%, (4) - 35,8%, (P<0,001). Os três modelos tiveram semelhante capacidade discriminatória para o desfecho de mortalidade hospitalar pelo cálculo da área sob a curva ROC: RACHS-1- 0,738; STS-EACTS- 0,739; Aristóteles- 0,766.

Conclusão: Os três modelos de estratificação da complexidade atualmente disponíveis na literatura tiveram utilidade com distintas mortalidades entre as categorias propostas, com semelhante capacidade discriminatória para o desfecho de mortalidade hospitalar.

Abbreviations, acronyms & symbols CI EACTS RACHS-1 STAT STS

Confidence Interval European Association for Cardio-Thoracic Surgery Risk Adjustment for Congenital Heart Surgery-1 Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Society of Thoracic Surgeons

(P<0.001). The three models had similar accuracy by calculating the area under the ROC curve: RACHS-1- 0.738; STS-EACTS0.739; Aristotle- 0.766.

Conclusion: The three models of stratification of complexity currently available in the literature are useful with different mortalities between the proposed categories with similar discriminatory capacity for hospital mortality.

Descriptors: Hospital Mortality. Heart Defects, Congenital.

ROC Curve. Cardiac Surgical Procedures.

Resumo Objetivo: Verificar se os modelos de estratificação da complexidade em cirurgias de cardiopatias congênitas atualmente disponíveis (RACHS-1, escore básico de Aristóteles e escore de mortalidade do STS-EACTS) se adequam ao nosso serviço, determinando o de melhor acurácia em discriminar a mortalidade hospitalar.

Descritores: Mortalidade Hospitalar. Cardiopatias Congênitas.

Curva ROC. Procedimentos Cirúrgicos Operatórios.

INTRODUCTION

strata, so that the comparisons between the outcomes were performed within each category. In pediatric cardiac surgery, mortality analysis without stratification of complexity is considered failure[7] and this risk stratification has been identified as essential in the organization of multicenter database STS-EACTS and appears as one of the key points in a recent article that aimed at assessing and improving the quality[8,9].

After half a century of developments in the diagnosis and surgical treatment of congenital heart disease, significant progress has been made and, nowadays, we may state that the natural history of these patients has been modified[1].

In parallel evolution, we had the development of universally accepted tools that allowed the establishment of benchmark outcomes, crucial for comparisons between different periods and institutions. In this scenario, aiming to improve the quality of patient care for surgical congenital heart diseases, scientific societies joined forces (STS- Society of Thoracic Surgeons, EACTS- European Association for Cardio-Thoracic Surgery and the Association for European Paediatric Cardiology) seeking a common classification for use in a multicenter database[2,3].

Among the essential elements for the establishment of a database universally accepted, stands out beyond the need for a standard nomenclature of congenital defects and surgical procedures, the creation of stratification of complexity methods[4-6].

Given the large number of different surgical procedures (more than 150) in congenital heart disease, it became necessary the grouping into categories or relatively homogeneous

The stratification of complexity methods RACHS-1 method The RACHS-1 method was developed by the Children’s Hospital Boston team through a panel of 11 nationally representative members of pediatric cardiologists and cardiac surgeons. Initially using clinical judgment, with further refinement based on 2 national databases data, it allocated 207 surgical procedures in 6 different categories with similar risk for hospital mortality. Three additional clinical factors (age, prematurity and noncardiac congenital structural abnormalities) complement the model and, when used, increase the discriminatory power of the model.

Aristotle score In 1999, Lacour Gayet and a committee of experts created

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a tool for stratification of complexity and called it a score of Aristotle, in reference to the philosophy of Aristotle (Rhetoric, Book I, 350 BC): “Where there is no available scientific answer, the opinion perceived and accepted by the majority has the truth value”.

A group of 50 surgeons from 23 countries, representatives of the four largest international societies of pediatric cardiac surgery (STS, EACTS, Congenital Heart Surgeons Society - CHSS and ECHSA), postulated that the complexity of a procedure would be the sum of 3 factors: 1- Potential for operative mortality; 2- Potential for operative morbidity and 3- Technical difficulty of the surgery.

Each surgical procedure received a score for each of the three factors ranging from 0.5 to 5, forming a score which ranged from 1.5 (0.5 + 0.5 + 0.5) to 15 (5 + 5 + 5 ). The procedures were divided into categories (similar to RACHS-1) according to the score: Level 1 (1.5 to 5.9); Level 2 (6.0 to 7.9); Level 3 (8.0 to 9.9) and Level 4 (10.0 to 15.0). According to the required analysis, both score and level (categories) may be used.

In a second step, the Aristotle score received some refinements according to the patient characteristics, until then, stratified only taking into account the type of procedure performed. The so-called “Comprehensive Aristotle Score” adds some patient factors dependent or not of the procedure. Because it is not part of the aim of our study, we will not go into details of this method.

showing different mortality rates between the proposed categories, and to determine which method is best suited to our institution.

STS-EACTS mortality score The newest of the three tools for stratification of complexity is the STS-EACTS mortality score, published in 2008. It was developed primarily using objective data, with minimal use of subjective probability. The mortality risk was estimated for 148 procedure types, using real data from 77,294 patients (33,360 patients from the EACTS and 43,934 patients from the STS) between 2002 and 2007. Using Bayesian statistics that fits the data for small denominators, mortality rates were calculated for each procedure.

Each procedure received a score which ranged from 0.1 to 5.0, based on the estimated mortality. The procedures were then distributed by the growing risk and grouped into 5 categories. This model had its performance subsequently evaluated in an independent sample of 27,700 patients and compared with previous methods (RACHS-1 and Aristotle).

The STS-EACTS mortality score represents an evolution of the previous stratification models which were highly subjective.

The new score stratifies the mortality according to real data for each surgical procedure from the STS-EACTS multicenter database.

The main objective of this study is to verify whether the stratification of the complexity methods for congenital heart surgery currently available (RACHS-1, Aristotle basic score and STS-EACTS mortality score) is useful,

The variables used to characterize the patients were: gender, age, weight and height.

The exclusion criteria were: reoperation for hemostasis, permanent pacemaker implantation and those cases in which the proposed surgery could not be performed after the surgical access. When a patient had undergone more than one surgical procedure in the same hospital admission, the most complex procedure was computed.

Pictures of the surgical reports were taken and the image files were assessed by two surgeons independently. Then, each surgical procedure was allocated in a category using the three methods of stratification. In case of disagreement between the two surgeons, the case was discussed and direct consultation with the surgeon who performed the surgical procedure was made when necessary. We consider this method the most appropriate for allocation of each surgical procedure in a certain category, given the complexity of the subject.

METHODS Patients We retrospectively reviewed 360 consecutive patients who underwent surgical treatment for congenital heart disease from June 2007 to December 2012, at the Pronto Socorro Cardiológico de Pernambuco (PROCAPE), University of Pernambuco. The Research Ethics Committee has been approved the study (CAAE 06036313.5.0000.5192 number).

Patients aged under 18 years, who underwent palliative surgery or definitive correction were eligible, including those who presented with any dysfunction or organ failure at the time of correction (hemodynamic, respiratory, renal, hepatic, neurological and hematological). The patients who underwent surgery had their outcomes established (hospital mortality or discharge).

Data collection was performed through multiple sources of information available, and at each step the data consistency was verified. Surgical reports, extracorporeal perfusion report, administrative data from the hospital system and patient files were checked in search for the information. Data were collected and stored in the Excel software, with double data entry.

Independent variables: the categories from the stratification of complexity methods The independent variables of interest for our study were the categories proposed by the stratification of complexity methods currently available and briefly explained below (Chart 1).

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Chart 1. The risk categories from the stratification of complexity methods with some procedures.

RACHS-1

STS-EACTS (STAT) mortality score

Aristotle basic score

Category 1 PDA>30d, OS ASD, sinus venosus septal defect, aortic coarctation>30d, PAPVC

Category 1 ASD, VSD, Fontan (lateral tunnel, fenestrated), aortic coarctation repair (end to end), TOF repair (no TAP)

Category 1 ASD repair, AVSD repair (intermediate and partial), PDA, PAPVC repair

Category 2 VSD, TOF, Glenn, OP ASD, aortic coarctation at age≤30d, ASD and VSD, repair of total anomalous pulmonary veins at age >30d

Category 2 PDA, mitral plasty, Glenn, TOF (TAP), Fontan (external conduit, fenestrated)

Category2 VSD, Glenn, Systemic to pulmonary shunt (MTBS and central), TOF (ventriculotomy, non-TAP)

Category 3 Fontan procedure, Systemic to pulmonary artery shunt, mitral valvotomy or valvuloplasty, MVR, PA banding

Category 3 Arterial switch operation, coarctation repair (patch aortoplasty), AVSD repair (complete), coarctation repair + VSD repair, Rastelli.

Category 3 TOF (TAP), Fontan, TAPVC repair, mitral valvuloplasty, MVR

Category 4 Arterial switch operation with VSD closure, atrial septectomy, repair of total anomalous pulmonary veins at age ≤30d

Category 4 Arterial switch operation and VSD repair, Arterial switch procedure + aortic arch repair, PA banding, systemic-pulmonary shunt (MBTS or central), MVR, TOF-AVSD repair

Category 4 Senning, ASO, ASO and VSD, DORV (intraventricular tunnel repair), Rastelli, Norwood

Category 5 Repair of truncus arteriosus and interrupted arch, tricuspid valve repositioning for neonatal Ebstein anomaly at age ≤30d

Category 5 Norwood procedure, Damus-Kaye-Stansel procedure

Category 6 Norwood operation, Damus-Kaye-Stansel procedure PDA=patent ductus arteriosus; OS ASD=ostium secundum atrial septal defect; PAPVC=partial anomalous pulmonary venous connection; VSD=ventricular septal defect, TOF=tetralogy of Fallot; OP ASD=ostium primum atrial septal defect; MVR=mitral valve replacement, PA=pulmonary artery; TAP=transannular patch; AVSD=atrioventricular septal defect; MBTS=modified Blalock-Taussig shunt; TAPVC=total anomalous pulmonary venous connection; ASO=arterial switch operation; DORV=double-outlet right ventricle

Dependent variable: hospital mortality (in-hospital mortality) Concepts in relation to diagnostic and surgical procedures employed, as well as precise definitions of outcomes to be measured are of paramount importance in order to seek a standardization of what is being studied and analyzed.

The definition of operative mortality reported traditionally refers to any mortality after surgery, regardless of cause, in the first 30 days of surgery (whether the inpatient or home), or even after the 30 days during the same hospitalization[10].

In face the of data unavailability to check whether patients who were discharged alive are in good cindition or not on the thirtieth day of surgery, our reported outcome was hospital or in-hospital mortality (i.e. any mortality after the procedure performed, regardless of length of hospital stay). It is important to underline that there is no hospital for referral of chronic patients.

Statistical analysis Statistical analysis was performed using the SPSS (Statistical Package for Social Sciences) for Windows, version 17 and Medcalc for Windows, version 12.5 (MedCalc Software, Ostend, Belgium). Categorical variables were represented as frequencies; the numeric variables as mean or median with the respective measures of dispersion.

Comparisons between groups were performed using Pearson’s chi-square test. Analysis of the discriminatory ability of the surgical risk stratification methods were performed using the C statistic comparison with ROC curves of the three methods according to DeLong et al.[11].

RESULTS Profile of operated patients and hospital mortality The data in Table 1 and 2 below summarizes the used

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variables to characterize the study sample. One hundred and ninety-eight patients were male (55%) with a median age of 2.1 years (0.1 to 17.9 years). The median weight was 10.2 Kg (1.5-61 Kg) and 122 patients (34.1%) had less than 8 Kg. The distribution of patients according to the categories proposed by 3 different risk stratification methods are described in Figure 1.

To demonstrate the variability of surgical cases, we used the nomenclature of the Aristotle score (Figure 2).

Given the large number of performed procedures and in order to facilitate the description of the center profile and the operated cases, we allocated the cases in diagnostic groups and then divided the total sample into two large groups, as follows (Table 3): GROUP 1 - Procedures that had more than 10 cases during the study period (5.5 years) - 280 patients or 77.7% of the sample: TOF, VSD, VSD and ASD, systemic-pulmonary shunt, ASD (including OP ASD), PDA (> 30 days), complete or transitional AVSD and aortic coarctation; and GROUP 2 - Procedures that had fewer than 10 cases during the study period - 80 patients or 22.3% of the sample.

Hospital mortality of the total sample was 14.7%.

found distinct rates in each of their categories with statistically significant differences, as shown in Table 4.

To determine the stratification method with the best discriminatory ability for the hospital mortality outcome, i.e. with the best accuracy, we performed the analysis of the area under the ROC curve or statistical C. In other words, this method represents the probability that a randomly selected patient, who has an outcome of interest (such as mortality), has a higher predicted risk for the outcome when compared with a randomly selected patient who does not have this outcome. An unable method to discriminate between patients evolving to death or discharge has an area under the ROC curve of 0.5. A method that can perfectly discriminate between death or discharge has an area of 1.0.

The results of the areas under the ROC curve of our study are shown in Figure 3. The RACHS-1 categories, Aristotle and STAT (STS-EACTS) had a satisfactory performance (above 0.7). There was no statistical difference between the three forms of categorization and the areas under the ROC curve of the 3 methods for the discriminatory capacity for hospital mortality outcome were similar (Table 5).

Hospital mortality stratified by categories When we look at the mortality rates according to the proposed categories by the three risk stratification methods, we Table 1. Characteristics of patients.

Variables Gender Male Female Age < 3 months 3-6 months 6-12 months 1-12 years 12-18 years Weight(1) <8 Kg 8-16 Kg >16 Kg Cardiopulmonary bypass Yes No Total

N

%

198 162

55.0 45.0

27 36 52 208 37

7.5 10.0 14.4 57.8 10.3

122 129 107

34.1 36.0 29.9

268 92 360

74.4 25.6 100.0

Fig. 1 - Distribution of procedures in the categories of the three methods of stratification of complexity: RACHS-1, STS-EACTS (STAT) and Aristotle Basic (ABC). RACHS-1 (Categories 1,2,3,4,5 and 6); STS-EACTS (STAT) (1,2,3,4 and 5 categories); Aristotle basic (ABC) (categories 1,2,3 and 4). We did not have procedures in categories 5 and 6 according to RACHS-1, as well as the category 5 STAT.

(1)=information unavailable for two patients Table 2. Characteristics of patients.

Mean±SD Min Variables Q1 4.1±4.4 0.05 Age (Years) 0.8 1.5 14.3±11.8 6.3 Weight (Kg) 91.7±31.8 30.0 Height (Cm) 68.0 SD=standard deviation; Q1=first quartile; Q3=third quartile

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Q3 5.9 18.0 112.0

Max 17.9 61.0 172.0

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Fig. 2 - Distribution according to the nomenclature of the procedures proposed by Aristotle score. Graph showing the variability of the treated patients between surgical cases. To facilitate the graphical representation of the total sample, 15 different procedures grouped under 2 cases in the entire period under â&#x20AC;&#x153;Other procedures" (<2 cases).

Table 3. In-hospital mortality according to the 2 groups.

Group 1

Percentage of the total sample 77.7%

Group 2

22.3%

Group

Description of the Group Procedures that had 10 or more cases in the studied period Procedures that had fewer than 10 cases in the studied period

*Except the systemic to pulmonary shunts whose mortality was 26.82%.

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In-hospital mortality 6.69%* 32.5%

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Table 4. In-hospital mortality according to the categories of the three models of risk stratification.

Categories RACHS-1 1 2 3 4 STS-EACTS (STAT) 1 2 3 4 Aristotle 1 2 3 4

N

Death

Outcome Discharge % N %

P-value

Case N

%

1 20 24 8

1.3 11.4 27.3 50.0

79 156 64 8

98.8 88.6 72.7 50.0

80 176 88 16

100.0 100.0 100.0 100.0

P(1) <0.001*

10 11 3 29

5.5 13.6 18.7 35.8

172 70 13 52

94.5 86.4 81.3 64.2

182 81 16 81

100.0 100.0 100.0 100.0

P(1) <0.001*

1 25 16 11

1.1 12.2 34.0 64.7

90 180 31 6

98.9 87.8 66.0 35.3

91 205 47 17

100.0 100.0 100.0 100.0

P(1) <0.001*

(1)Chi2 test

Fig. 3 - Area under the ROC curve of the categories proposed by laminating three models hospital mortality as the endpoint. Graph of the ROC curves (Receiver Operating Characteristic) for the three models plotted with different colors. Observe the superposition of three curves.

Table 5. Results regarding area under the ROC curve and comparative results between the methods concerning the mortality outcome.

Model/Method RACHS-1 STS-EACTS (STAT) Aristotle (ABC)

Area uinder ROC curve 0.738 0.739 0.766

CI 95% 0.690-0.783 0.691-0.784 0.718-0.808

P-value P1=0.9651 P2=0.9651 P3=0.5054

P1=DeLong at al.[11] test - RACHS-1 x STAT; P2=DeLong at al.[11] test - RACHS-1 x ABC; P3=DeLong at al.[11] test - STAT x ABC; CI=confidence interval

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DISCUSSION

The latest publication includes results of patients operated over 4 years ago and reports 10 years of surgical treatment of congenital heart disease (including adults) in the state of Sergipe, examining differences in outcomes after the surgery centralization from three hospitals[21].

Having operated an average of 93 patients/year, the overall hospital mortality (including congenital adult patients) was 8.3%, whereas in the group under 12 years was 10.32% (77 deaths in 746 patients). There was statistical difference between the mortality of the two analyzed periods with a drop in the overall mortality from 9.8% (58/586) to 5.4% (19/346) (P=0.02). When assessing the predictive ability of RACHS-1 categories for the hospital mortality outcome, the result was an area under the ROC curve of 0.860 (95% CI, 0.818-0.902).

In relation to the stratified mortality by RACHS-1, the group found the following mortality rates at the total period: Category 1=0.26% (1/386); Category 2=6.60% (27/409); Category 3=11.11% (7/63); Category 4=62.07% (36/58) and Category 6=100% (3/3). Considering that the mortality in children was grouped with the adults for statistical reasons, as mentioned in the study, we did not carry out comparative analysis between our results and those found by the authors, because our study did not involve adult population.

In our state (Pernambuco), Mattos et al.[20] studied 818 patients who had undergone surgery between 2000 and 2004 by 4 different surgical teams. Analyzing five main variables (age, nutritional status, presence of clinical risk factors, surgical complexity stratified by RACHS-1 and Aristotle and time of cardiopulmonary bypass), a risk score was developed and showed to be useful in predicting the mortality outcome when performed at the bedside during ICU admission.

With the overall mortality similar to ours, 14.7% (120/818), this study stands out for its excellent methodology and details of the information reported. Using the RACHS-1 categories to stratify the complexity of the cases, the authors reported mortality of 8.76% (48/548) for categories 1 and 2 pooled and 26.12% (70/268) to the categories 3 and 4. In the presence of clinical factors associated (Chart 2), the mortality reported in the study was 23.04% (OR, 4.73 [95% CI, 2.84-7.90]; P<0.0001) when only one factor was present, and 53.95% when 2 or more factors were present (OR, 18.52 [95% CI, 10.03-34.36]; P<0.0001).

What is the best method for stratification of complexity?

There are several published studies that compared different methods of stratification of complexity, using both the score from the models (Aristotle and STS-EACTS) as well as the predictive capacity of the proposed categories[8,12-17]. In our country, we did not find published studies that made comparisons between the methods of stratification of complexity. Al-Radi et al.[14], in order to compare the predictive value of the RACHS-1 and Aristotle basic score for the hospital mortality outcome, allocated 11,438 patients in the mortality categories. With a higher area under the ROC curve in both the unadjusted and adjusted models to the year of surgery, the RACHS-1 method was the best one (0.733 x 0.698, P=0.018 and 0.763 x 0.737, P=0.03, respectively).

In a study performed by Bojan et al.[13] that enrolled 1384 patients, the RACHS-1 method was compared to the comprehensive Aristotle score (not used in our study) regarding the discriminatory capacity for operative mortality outcome.

There were statistical differences in favor of the Aristotle comprehensive model showing higher area under the ROC curve (difference of 0.044 to 0.196; P=0.003). However, after use of the full model proposed by RACHS-1, i.e., the model adjusted for age, prematurity and extra-cardiac abnormalities, the difference between the two methods (RACHS-1 and comprehensive Aristotle) became statistically non-significant (0.05 [-0.023-0.131]; P=0.19).

In the study that resulted in the STS-EACTS model, Oâ&#x20AC;&#x2122;Brien et al.[6] made comparisons of the new model with its predecessors. In a subgroup of patients whose procedures could also be grouped into RACHS-1 categories and received the Basic Aristotle score, the discriminatory capacity of STS-EACTS categories by area under the ROC curve (0.778) was higher than the RACHS-1 (0.745) and Aristotle basic score (0.687).

Following an evolutionary process starting from highly subjective methods (RACHS-1 and Aristotle), the method proposed by the STS-EACTS was superior in discriminatory capacity and has been recommended to the data gathering in the STS-EACTS multicenter database[18].

Notwithstanding its advantage over other methods due to the differences in the design methodology, the STS-EACTS (STAT) was not better than other methods when used in our study. Probably owing to the size of our sample, we did not find any statistical differences between the areas under the curves of the three models.

Considerations about our hospital mortality Before designed studies with the appropriate methodology for the study of risk factors (before, during and after surgery) associated with mortality are performed in our service, we highlight four important points whose influence on our hospital mortality is not negligible.

Stratified hospital mortality in Brazil In a literature review, we identified a lack of studies reporting data related to hospital or operative mortality in congenital heart disease in our country over the last 10 years[19-21].

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Chart 2. Clinical risk factors and definitions considerated in Mattos' study.

Risk factor Pulmonary hypertension Refractary cardiac failure Severe cyanosis Acidosis Presence of infection Genetic syndrome Mechanical ventilation Prolonged hospital stay

Definition Pulmonary arterial systolic pressure over two-thirds of the systemic pressure (Doppler echo) When it was not well controlled despite adequate doses of diuretics and vasodilators Peripheral arterial saturation <75% at rest pH <7.25 clinical + radiological or laboratorial documentation clinical grounds When it was commenced because of a deterioration in the clinical condition Preoperative period of hospitalization of over one week

First point - Center in establishment phase: Considering the initial establishment of a center (first five years), even with experience in the surgical treatment of congenital heart disease (team with more than 30 years working together), the patient outcomes are extremely dependent of the infrastructure at pre, trans- and postoperative times, with special emphasis on the many difficulties faced in the establishment process of a surgical center of high complexity in our country.

In a study published by Nina et al.[19] reflecting the first two years of establishment of a universitary center of cardiac surgery in the Northeast, we found that mortality rates also reflect the many difficulties encountered, even in cases of low complexity (3.8% for category 1 and 26% for category 2, using the RACHS-1 method).

Second point - low total volume: Despite having a cardiovascular surgery center and a medical residency program with an annual volume of cardiac surgeries in 2011 and 2012 exceeding 600 surgeries/year, the annual average of surgery in congenital heart disease in patients under 18 years is fewer than 80 surgeries/year.

The surgical volume is a factor whose association with hospital mortality is well established in the literature[22-24]. We bring to attention the recent retrospective study of Vinocur et al.[25] enrolling 49 American centers, which was included in the Pediatric Cardiac Care Consortium database. After analysis of 85,023 surgeries (45.5% of which were Category 1 and 2 by RACHS-1 method), the mortality rate was 6.2%.

Multivariate analysis including the volume of the centers as a continuous variable showed a significant inverse correlation between the surgical volume and the mortality (OR 0.84 per additional 100 operations/year; 95% CI, 0.78–0.90; P<0.0001).

It is important to underline the findings of the study of Welke et al.[24] and the fact that the inverse correlation between volume and mortality has been demonstrated for the group with more complex procedures (Aristotle score> 3).

Centers with a volume <150 surgeries / year had higher mortality rates in comparison with centers with volume ≥350 surgeries (OR, 2.41 [95% CI, 1.89-3.06]; P<0.0001).

Our view agrees with what was described in the study

by Welke et al.[24], in which there might be intrinsic factors

associated with the centers, other than surgical volume itself, influencing the outcomes. It is necessary to identify these factors with appropriate studies in parallel to the employment of measures aiming to augment the surgical volume. It is precisely this increase of the volume that theoretically reduces the influence of these factors, promoting the interaction of staff and the establishment of a necessary routine in all steps involved (pre-, trans- and postoperative).

Third point - Impaired “analysis per procedure”: The PROCAPE presents a clinical profile of heterogeneous congenital patients regarding the procedures performed, obviously decreasing the N of each specific procedure, which impairs the analysis of individual mortality. To analyze the specific mortality for some procedures as total anomalous pulmonary venous correction, Glenn or Fontan or arterial switch operation lacks scientific value, in that our volume for such procedures is not significant (less than 10 cases in a 5.5-year period). Alternatively, we gathered a group of such diseases based on surgical volume: GROUP 1 (> 10 cases/ total period) and GROUP 2 (≤ 10 cases / total period) above mentioned, leaving aside the systemic-pulmonary shunts for further analysis (although it belongs in the GROUP 1).

This group, created by convenience, achieved a mortality for the GROUP 1 of 6.69% (except for the shunts), GROUP 2 of 32.5% and systemic-pulmonary shunts of 26.82%. We observe that even without proper statistical analysis correlating the volume with mortality, in spite of the different sample sizes between groups, we obtained very different mortality rates for heart diseases in which fewer than 10 cases in the total period were operated. In addition, we underline the higher mortality of systemic-pulmonary shunts in the procedures of GROUP 1. When the analysis of cases through the STS-EACTS stratification method was performed, the hospital mortality was 33% for more complex procedures (STS-EACTS categories 3 and 4) against 7.98% for the less complex (STS-EACTS categories 1 and 2).

Fourth point - urgent/emergency surgery - Given our wide area coverage, taking patients from outpatient clinics and referrals of 3 large hospitals in the region, as well as coverage of patients regulated by CNRAC (National Center of High Complexity Setup) coming from the North and the Northeast, our institution becomes a reference for the more complex

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cases and emergencies. Such critical situations are characterized by a need of surgical approach normally without time to appropriate preoperative imaging diagnosis and exams. In the presence of clinical dysfunctions already installed, patients undergo the surgical procedure with increased risk of mortality, as previously mentioned in the study by Mattos et al.[20]. This study demonstrated that the presence of 2 or more clinical factors associated (commonly found in patients with indication for emergency surgery) resulted in a mortality rate of approximately 55%.

This is demonstrated by our prevalence of systemic-pulmonary shunts surgeries, corresponding to 11.38% of all surgeries performed. Taking into consideration that the STSEACTS mortality score[6] groups both the central shunt as the Blalock-Taussig shunt in risk category 4 (range up to 5), whose mortality rates were respectively 12.3% (95% CI, 9.9%-15%) and 8.9% (95% CI, 7.9%-10.1%), we have a scenario formed by a high prevalence of surgical procedures associated with high mortality. Although a study of the profile of patients undergoing systemic-pulmonary shunts in our service is needed to better characterize the sample, we state that the vast majority of this patients were not eligible for a biventricular repair or staging Fontan.

Given the nature of the current study, retrospective and without the purpose of measuring the risk of preoperative clinical disorders (or only clinical factors associated) for mortality outcome, we have no objective data to discussion of our series. We infer only that the presence of such clinical factors and even organ dysfunction in our sample is not negligible, imposing a negative influence on our results.

hospitals with low mortality rates don’t have fewer complications but a lower mortality on those that face complications [27].

CONCLUSION In order to improve the quality of our care for congenital heart disease, knowing that we still face high hospital mortality rates especially for more complex groups (categories 3 and 4), the stratification methods appear as useful tools, so that we could direct the necessary attention towards the high-risk groups.

The three models of stratification of complexity currently available in the literature are useful even with different mortality rates between the categories proposed. With similar discriminatory capacity for hospital mortality outcome, it was not possible to determine the superiority of one method over another in the sample.

Authors’ roles & responsibilities PEFC

MPBOS CAS IME MLC RFAL

Limitations of the stratification of complexity and hospital mortality as a quality indicator Unlike the adult population in that the regression analysis is often used in the analysis of outcomes in cardiac surgery in the postoperative period, in children involving congenital heart disease we used the statistical tool called stratification of complexity. Whereas the regression analysis is a mathematical equation developed to predict an individual’s risk of a patient developing a specific outcome, based on predetermined relevant clinical variables, the stratification of complexity controls only the variables used to create the strata and other variables may influence the outcomes.

Recent studies have questioned the use of hospital mortality as an indicator of quality of a center[26,27]. In an article published by Pasquali et al. whose title refers to a new indicator called “failure to rescue”, 40,930 patients (STS bank between 2006 and 2009) of 72 different centers had their results analyzed taking into consideration the prevalence of postoperative complications and hospital mortality. With an overall complication rate of 39.3%, the hospitals with lower mortality rate had significantly lower rates of “failure to rescue” (6.6% vs. 12.4%; P<0.0001). In other words, this study suggests that

RCL

Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; operations and/ or experiments conduct; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; writing of the manuscript or critical review of its content Conception and design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Conception and design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Conception and design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript; study design; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; writing of the manuscript or critical review of its content

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16. Heinrichs J, Sinzobahamvya N, Arenz C, Kallikourdis A, Photiadis J, Schindler E, et al. Surgical management of congenital heart disease: evaluation according to the Aristotle score. Eur J Cardiothorac Surg. 2010;37(1):210-7.

6. O’Brien SM, Clarke DR, Jacobs JP, Jacobs ML, Lacour-Gayet FG, Pizarro C, et al. An empirically based tool for analyzing mortality associated with congenital heart surgery. J Thorac Cardiovasc Surg; 2009;138(5):1139-53.

17. Vijarnsorn C, Laohaprasitiporn D, Durongpisitkul K, Chantong P, Soongswang J, Cheungsomprasong P, et al. Surveillance of pediatric cardiac surgical outcome using risk stratifications at a tertiary care center in Thailand. Cardiol Res Pract. 2011;2011.

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7. Jacobs JP, Edwards FH. Quality improvement and risk stratification for congenital cardiac surgery. In: Sellke FW, Del Nido PJ, Swanson SJ, eds. Sabiston and Spencer Surgery of the chest. 8th ed. Philadelphia: Elsevier Publishing; 2010. p. 2105-123.

18. Jacobs JP, Jacobs ML, Austin EH 3rd, Mavroudis C, Pasquali SK, Lacour-Gayet FG, et al. Quality measures for congenital and pediatric cardiac surgery. World J Pediatr Congenit Heart Surg. 2012;3(1):32-47.

8. Jacobs JP, Jacobs ML, Lacour-Gayet FG, Jenkins KJ, Gauvreau K, Bacha E, et al. Stratification of complexity improves the utility and accuracy of outcomes analysis in a Multi-Institutional Congenital Heart Surgery Database: Application of the Risk Adjustment in Congenital Heart Surgery (RACHS-1) and Aristotle Systems in the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database. Pediatr Cardiol. 2009;30(8):1117-30.

19. Nina RVAH, Gama MEA, Santos AM, Nina VJS, Figueiredo Neto JA, Mendes VGG, et al. O escore de risco ajustado para cirurgia em cardiopatias congênitas (RACHS-1) pode ser aplicado em nosso meio? Rev Bras Cir Cardiovasc. 2007;22(4):425-31.

20. Mattos SS, Neves JR, Costa MC, Hatem TP, Luna CF. An index for evaluating results in paediatric cardiac intensive care. Cardiol Young. 2006;16(4):369-77.

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2012;3(1):32-47.

21. Leite DC, Mendonça JT, Cipolotti R, Melo EV De. Heart defects treatment in Sergipe: propose of resources’ rationalization to improve care. Rev Bras Cir Cardiovasc. 2012;27(2):224-30.

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23. Pasquali SK, Li JS, Burstein DS, Sheng S, O’Brien SM, Jacobs ML, et al. Association of center volume with mortality and complications in pediatric heart surgery. Pediatrics.

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24. Welke KF, O’Brien SM, Peterson ED, Ungerleider RM, Jacobs ML, Jacobs JP. The complex relationship between pediatric cardiac surgical case volumes and mortality rates in a national clinical database. J Thorac Cardiovasc Surg. 2009;137(5):1133-40.

13. Bojan M, Gerelli S, Gioanni S, Pouard P, Vouhé P. Comparative study of the Aristotle Comprehensive Complexity and the Risk Adjustment in Congenital Heart Surgery scores. Ann Thorac Surg. 2011;92(3):949-56.

25. Moller JH, Hills CB, Pyles LA. A multicenter cardiac registry: a method to assess outcome of catheterization intervention or surgery. Prog Pediatr Cardiol. 2005;20:7-12

14. Al-Radi OO, Harrell FE Jr, Caldarone CA, McCrindle BW, Jacobs JP, Williams MG, et al. Case complexity scores in congenital heart surgery: a comparative study of the Aristotle Basic Complexity score and the Risk Adjustment in Congenital Heart Surgery (RACHS-1) system. J Thorac Cardiovasc Surg. 2007;133(4):865-75.

26. Welke KF, Karamlou T, Ungerleider RM, Diggs BS. Mortality rate is not a valid indicator of quality differences between pediatric cardiac surgical programs. Ann Thorac Surg. 2010;89(1):139-44.

27. Pasquali SK, He X, Jacobs JP, Jacobs ML, O’Brien SM, Gaynor JW. Evaluation of failure to rescue as a quality metric in pediatric heart surgery: an analysis of the STS Congenital Heart Surgery Database. Ann Thorac Surg. 2012;94(2):573-9.

15. Dilber D, Malcic I. Evaluation of paediatric cardiosurgical model in Croatia by using the Aristotle basic complexity score and the

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Song CL, et ORIGINAL al. - Study of novel coating strategy for coronary stents: ARTICLE simutaneous coating of VEGF and anti-CD34 antibody

Study of novel coating strategy for coronary stents: simutaneous coating of VEGF and antiCD34 antibody Estudo da nova estratégia de revestimento para stents coronários: revestimento simultâneo de VEGF e anticorpo anti-CD34

Chun-Li Song1, MD; Qian Li1, MD; Yun-Peng Yu1, PhD; Guan Wang1, PhD; Jin-Peng Wang1, MD; Yang Lu1, PhD; Ji-Chang Zhang1, PhD; Hong-Ying Diao1, MD; Jian-Gen Liu1, MD; Yi-Hang Liu1, MD; Jia Liu1, MD; Ying Li1, MD; Dan Cai1, MD; Bin Liu1, PhD

DOI 10.5935/1678-9741.20150016

RBCCV 44205-1627

Abstract Introduction: Intravascular coronary stenting has been used in the treatment of coronary artery disease (CAD), with a major limitation of in-stent restenosis (ISR). The 316 stainless steel has been widely used for coronary stents. In this study, we developed a novel coating method to reduce ISR by simultaneously coating vascular endothelial growth factor (VEGF) and anti-CD34 antibody on 316L stainless steel.

Methods: Round 316L stainless steel sheets in the D-H group were polymerized with compounds generated from condensation reaction of dopamine and heparin using N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS). Sixteen sheets from the D-H group were further immersed into 1ug/ml VEGF165 and 3mg/ml heparin sodium one after another for 10 times, and named as the D-(H-V)10 group.

Eight sheets from the D-(H-V)10 group were coated with anti-CD34 antibody and termed as the D-(H-V)10-A group. Immunofluorescence assay and ELISA were used to evaluate whether the 316L stainless steel disks were successfully coated with VEGF and anti-CD34 antibody.

Results: The results of immunofluorescence assay and ELI-

SA showed that VEGF could be detected in the D-(H-V)10 and D-(H-V)10-A group, suggesting the steel sheets were successfully covered with VEGF. Anti-CD34 antibody could only be observed in the D-(H-V)10-A group, which was the only group coated with CD34 antibody. Both results suggested that the 316L stainless steel sheets were successfully coated with VEGF and anti-CD34 antibody.

Conclusion: Our study developed a method to simultaneously coat VEGF and anti-CD34 antibody to stainless metal steel.

This research serves as a fundamental role for a novel coating strategy.

The Second Hospital of Jilin University, Changchun, Jilin, China.

Correspondence address: Bin Liu The Second Hospital of Jilin University Department of Cardiology - The Second Hospital of Jilin University, 218 Ziqiang Street - Changchun, Jilin, China - Zip Code 130041 E-mail: liubin_china999@163.com

1

Descriptors: Coronary Artery Disease. Drug-Eluting Stents.

Coronary Restenosis. Vascular Endothelial Growth Factor. Antigens, CD34.

Resumo Introdução: O stent coronário intravascular tem sido utilizado no tratamento de doença arterial coronária, com uma maior limitação de restenose intra-stent (RIS). O aço inoxidável

This study was carried out at the Department of Cardiology, at the Second Hospital of Jilin University Changchun, Jilin, China.

Financial support: see in "Acknowledgements".

No conflict of interest.

Article received on August 18th, 2014 Article accepted on February 22nd, 2015

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minado como o grupo D-(HV)10. Oito folhas de D-(HV)10 foram revestidas com anticorpo anti-CD34 e denominado como grupo D-(HV)10-A. Testes de imunofluorescência e ELISA foram usados para avaliar se os discos de aço inoxidável 316L foram revestidos com sucesso com VEGF e anticorpo anti-CD34.

Resultados: Os resultados dos testes de imunofluorescência e ELISA mostraram que o VEGF pôde ser detectado nos grupos D-(HV)10 e D-(HV)10-A, evidenciando que as chapas de aço foram cobertas com VEGF com sucesso. O anticorpo anti-CD34 podia apenas ser observado no grupo D-(HV)10-A, o único grupo revestido com anticorpo CD34. Ambos os resultados sugerem que as chapas de aço inoxidável 316L foram revestidas com sucesso com VEGF e anticorpo anti-CD34.

Conclusão: Nosso estudo desenvolveu um método para revestir simultaneamente VEGF e anti-CD34 de aço inoxidável.

Esta pesquisa tem um papel fundamental para a nova estratégia de revestimento.

Abbreviations, acronyms & symbols BSA Bovine serum albumin CAD Coronary artery disease DESs Drug eluting stents EDC N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide ISR In-stent restenosis NHS N-hydroxysuccinimide VEGF Vascular endothelial growth factor

316 tem sido amplamente utilizado para stents. Neste estudo, foi desenvolvido um novo método de revestimento para reduzir a RIS para revestir simultaneamente o fator de crescimento endotelial vascular (VEGF) e anti-CD34 em aço inoxidável 316L. Métodos: Placas de aço inoxidável 316L redondas no grupo DH foram polimerizadas com compostos gerados a partir da reacção de condensação de dopamina e heparina utilizando N- (3-dimetilaminopropil) -N’-etilcarbodiimida (EDC) e N-hidroxissuccinimida (NHS). Dezesseis folhas a partir do grupo DH foram ainda imersas em 1 ug/ml de VEGF 165 e 3 mg/ml de heparina sódica, um após outro por 10 vezes, sendo deno-

Descritores: Doença Arterial Coronariana. Stents Farmacológicos. Reestenose Coronária. Fator de Crescimento Endotelial Vascular. Antígenos CD 34.

INTRODUCTION

factor for re-endothelialization[11]. The EPC capture stents have been developed using immobilized antibodies targeted at EPC surface antigens, such as CD34[12].

In this report, to further accelerate re-endothelialization, we aimed to develop method to simultaneously coat VEGF and anti-CD34 antibody. Our results showed that VEGF and anti-CD34 antibody were successfully coated onto the 316 stainless steel.

In-stent restenosis (ISR) was mainly caused by complications of intracoronary stent placement, including thromboembolic events and neointimal hyperplasia due to smooth muscle cell hyperproliferation. Drug eluting stents (DESs) have been designed mainly to reduce cellular proliferation and thus reduce ISR. Drug-eluting stents currently on the market release cytotoxic drugs such as paclitaxel and rapamycin to inhibit neointimal hyperplasia at the expense of delaying endothelialization[1,2].However, the incomplete endothelialization of the stent surface has been suggested that may lead to the increased long-term incidence of thrombosis and ISR[3].The critical role of the vascular endothelium in preventing thrombosis and regulating neointimal hyperplasia has resulted in restenosis prevention strategies that focus on enhancing endothelialiazation[4-6].

Vascular epithelial growth factor (VEGF), a cytokine originally described in 1983[7], is involved in processes essential to the growth, maintenance and repair of vascular structures. Exogenous VEGF has been reported to show accelerated re-endothelialization of damaged arteries in the rat carotid artery and attenuated intimal hyperplasia[8]. The delivery of VEGF using VEGF-eluting stents showed that it has been used to promote revascularization and re-endothelialization by stimulating endothelial progenitor cell migration and maturation [9,10]. Circulating endothelial progenitor cells (EPCs), a subset of bone marrow-derived stem cells, possess the ability to differentiate into functional and mature endothelial cells and recently have been identified as a key

Experimental procedures Preparation of the coated steel sheet Round 316L stainless steel sheets (diameter 6 mm, thickness 1 mm) were used to facilitate the measurement and evaluation of the properties of the coating, instead of bare metal stents with limited testable aspects and relatively high costs.

The metal surface was polished, washed and dried at 60oC for 24 hours, then sterilized by ultraviolet radiation. Heparin was conjugated to dopamine using N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide (EDC) and N-hydroxysuccinimide (NHS)[13].The sterilized sheet was polymerized with compounds generated from condensation reaction of dopamine (Aladdin, Shanghai, China) and heparin (Aladdin) as described[13], and termed as the D-H group.

Then, sixteen sheets from the D-H group were immersed into 1ug/ml VEGF165 (Life technologies) dissolved in phosphate-buffered saline (PBS, PH 7.4) for 30 min at room temperature (RT). Washed with Milli-Q water for 3 times (5 min per time) and dried under nitrogen. Then, a Milli-Q water solution of heparin sodium (3mg/ml) was subsequently dip-coated for 30 min at RT. Washed with Milli-Q water for 3

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times (5 min per time) and dried under nitrogen. These coating procedure were repeated 10 times, and these sixteen steel disks were set as the D-(H-V)10 group.

The D-(H-V)10-A group was obtained by the following procedures. Eight steel disks from the D-(H-V)10 group were immersed into 0.1mg/ml protein A (Aladdin) dissolved in PBS for 30 min at RT, blocked in 10 mg/ml bovine serum albumin (BSA; BD Biosciences) for 24 hours at 4 oC and immersed with 2 μg/ml rabbit anti-human CD34 antibody (Abcam, Cambridge, UK) for 24 hours at 4 oC. After the whole procedure, three groups of sheets were obtained (8 sheets/ each group) for further evaluations.

could be detected in the D-(H-V)10 and D-(H-V)10-A group, suggesting the steel sheets were successfully covered with VEGF. Anti-CD34 antibody could only be observed in the D-(H-V)10-A group, which was the only group that coated with CD34 antibody (Figure 1). Our findings suggested that the 316L stainless steel sheets were successfully coated with VEGF and anti-CD34 antibody.

ELISA detection of coated VEGF and anti-CD34 antibody To further evaluate the coverage of VEGF and anti-CD34 antibody, ELISA was performed in the D-H group, D-(H-V)10 group and D-(H-V)10-A group. Similar to the results of immunofluorescence assay, VEGF could be detected in the D-(H-V)10 and D-(H-V)10-A group, and anti-CD34 antibody could only be observed in the D-(H-V)10-A group (Figure 2). The results of ELISA further confirmed that we successfully coated VEGF and anti-CD34 antibody onto the 316 stainless steel.

Immunofluorescence detection of the coated VEGF and anti-CD34 antibody The levels of coated VEGF and anti-CD34 antibody of the stainless steel sheets were detected using immunofluorescence microscopy in the D-H group, D-(H-V)10 group and D-(HV)10-A group. The sheets were soaked for 1 hour in blocking solution (PBS containing 3% BSA). For the detection of VEGF, all the three groups were incubated with rabbit anti-human VEGF primary antibodies (1:100; Abcam) overnight at 4 oC, washed three times with PBS, and then incubated with Alexa Fluor® 488 Goat Anti-Rabbit IgG (Life technologies) at room temperature for 1 hour. For the detection of rabbit anti-human CD34 antibody, secondary antibodies- Alexa Fluor® 488 Goat Anti-Rabbit IgG were directly incubated. Wash three times to remove non-specific binding of the secondary antibodies and observe using a Laser scanning confocal microscope (Leica TCS SP5; Leica Microsystems, Germany).

Fig. 1 - Immunofluorescence detection of the coated VEGF and antiCD34 antibody. The levels of coated VEGF and anti-CD34 antibody of the 316L stainless steel were detected using immunofluorescence microscopy in the D-H group, D-(H-V)10 group and D-(H-V)10-A group.

The detection of coated VEGF and anti-CD34 antibody

by ELISA Coated steel sheets from the D-H group, D-(H-V)10 group and D-(H-V)10-A group were immersed into RIPA lysis buffer for 24 hours at 4 oC to dissolve VEGF and anti-CD34 antibody.

The levels of VEGF and anti-CD34 antibody were detected using VEGF165 ELISA Kit (Life technologies) and Rabbit IgG ELISA Kit (Novus Biologicals, USA), respectively.

Statistical analysis Statistical significance was evaluated by comparing mean values (±standard deviation) using the two-tailed Student’s t-test for independent groups. The probability value P<0.05 was considered to be statistically significant.

RESULTS Immunofluorescence staining To evaluate whether the 316L stainless steel sheets were successfully coated with VEGF and anti-CD34 antibody, immunofluorescence assay was performed. The results of immunofluorescence assay showed that VEGF

Fig. 2 - Detection of the coated VEGF and anti-CD34 antibody by ELISA. The results of detection of coated VEGF (left) and anti-CD34 antibody (right) by ELISA. Data are reported as mean ± SD for three independent experiments. Statistically significant differences are indicated as **P<0.01, student’s t-test.

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Song CL, et al. - Study of novel coating strategy for coronary stents: simutaneous coating of VEGF and anti-CD34 antibody

DISCUSSION

ACKNOWLEDGEMENTS

Intravascular coronary stenting has been widely used for many years, and it has increased the quality of life and life expectancy of patients with coronary disease. The 316 stainless steel is one of the most widely used materials for coronary stents with a board range of mechanical properties. However, the exposure of flowing blood to the bare metal stent may lead to thrombus formation and smooth muscle cell proliferation, and finally cause in-stent restenosis (ISR).Therefore, huge amount of recent work has attempted to develop non-thrombogenic coating for these metallic stents[14-16].

Early drug-eluting stents coating with various kind of drugs have been designed to reduce the restenosis through minimize vascular inflammation and cellular proliferation[17], which including a polymer-based drug delivery platform and a pharmacologic agent (usually an immunosuppressant and/ or antiproliferative compound).Though early trials seem to be exciting with markedly reduction rates of ISR (5%-8%) [18,19] , long-term follow-up studies showed that DESs implantation increased the long-term risk of thrombosis by 15% -35% compared with bare-metal stents implantation[20].

Based on our expanding understanding of pathophysiology of restenosis, novel stent coating strategies have been developed, such as delivery of VEGF (e.g., VEGF-eluting stents[9]) and the use of antibodies that recognize epitopes specific to endothelial progenitor cells (e.g., anti-CD34-coated stents[12]). Both coating strategies have been designed to inhibit thrombosis mainly through promoting re-endothelialization of cardiovascular stents. Many clinical studies suggest that the Genous EPC-capture stent is a safe choice for patients with coronary disease[21-24]. However, Adrian et al.[25] reported that a similar late luminal loss of Genous EPC-capture stent to that of a bare-metal stent, despite initial optimism of rapid endothelialization.

In this study, our approach of surface modification has included the combination of VEGF and anti-CD34 antibody.

The goal of this combination is to further accelerate endothelial repair, and thus further reduce the exposure time of stents in blood, decrease the rate of long-term thrombosis and shorten the time of antiplatelet therapy for patients. We firstly used dopamine-mediated heparin coating[13] and then a layer-by-layer method was employed to build multilayer films composed of heparin and VEGF on metal substrates. Based on the specific affinity of protein A and IgG antibodies, the protein A allows the subsequent immobilization of the anti-CD34 antibody. Our primary results of immunofluorescence and ELISA showed that the stainless metal steel was successfully coated with VEGF and anti-CD34 antibody (Figures 1 and 2).

This research serves as a fundamental role for the novel coating strategy of simultaneous coating of VEGF and anti-CD34 antibody and further studies on the toxicity and effect of the combined coating are currently ongoing.

The study was supported by the following funds: National Natural Science Foundation of China through the National Outstanding Youth Science Fund (Grant number: 51103059); National Natural Science Foundation of Jilin Province (Grant numbers: 201115071, 20140101054JC); Jilin Industrial Technology Research and Development Project (Grant number: 2013C023-3); Science and Technology Development Planning Project of Jilin Province (Grant number: 20150519025JH); Scientific Research Planning Project of the Education Department of Jilin Province (Grant number: 2015).

Authorsâ&#x20AC;&#x2122; roles & responsibilities CLS QL YPY GW JPW YL JCZ HYD JGL YHL JL YL DC BL

Analysis and interpretation of data; statistical analysis; design and study design; carried out operations and experiments Analysis and interpretation of data; statistical analysis; carried out operations and experiments Analysis and interpretation of data; statistical analysis; carried out operations and experiments Analysis and interpretation of data; statistical analysis; carried out operations and experiments Analysis and interpretation of data; statistical analysis; carried out operations and experiments Analysis and interpretation of data; statistical analysis; carried out operations and experiments Analysis and interpretation of data; statistical analysis; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments Analysis and interpretation of data; carried out operations and experiments

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2. Nakazawa G, Otsuka F, Nakano M, Vorpahl M, Yazdani SK, Ladich E, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol.

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7. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983;219(4587):983-5.

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10. Lahtinen M, Blomberg P, Baliulis G, Carlsson F, Khamis H, Zemgulis V. In vivo h-VEGF165 gene transfer improves early endothelialisation and patency in synthetic vascular grafts. Eur J Cardiothorac Surg. 2007;31(3):383-90.

23. Aoki J, Serruys PW, van Beusekom H, Ong AT, McFadden EP, Sianos G, et al. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALINGFIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. J Am Coll Cardiol.

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Piantá RM, etORIGINAL al. - Atrioventricular block in coronary artery bypass surgery: ARTICLE perioperative predictors and impact on mortality

Atrioventricular block in coronary artery bypass surgery: perioperative predictors and impact on mortality Bloqueio atrioventricular pós-cirurgia de revascularização do miocárdio: fatores preditores perioperatórios e impacto na mortalidade

Ricardo Medeiros Piantá1, MD; Andres Di Leoni Ferrari2, MD; Aline Almeida Heck3, MD; Débora Klein Ferreira3, MD; Jacqueline da Costa Escobar Piccoli4, PhD; Luciano Cabral Albuquerque5, PhD; João Carlos Vieira da Costa Guaragna6, PhD; João Batista Petracco7, MD, MSc DOI 10.5935/1678-9741.20140086

RBCCV 44205-1628

Abstract Introduction: Disturbances of the cardiac conduction system are frequent in the postoperative period of coronary artery bypass surgery. They are mostly reversible and associated with some injury of the conduction tissue, caused by the ischemic heart disease itself or by perioperative factors.

Objective: Primary: investigate the association between perioperative factors and the emergence of atrioventricular block in the postoperative period of coronary artery bypass surgery. Secondary: determine the need for temporary pacing and of a permanent pacemaker in the postoperative period of coronary artery bypass surgery and the impact on hospital stay and hospital mortality.

Methods: Analysis of a retrospective cohort of patients submitted to coronary artery bypass surgery from the database of the Postoperative Heart Surgery Unit of the Sao Lucas Hospital

of the Pontifical Catholic University of Rio Grande do Sul, using the logistic regression method.

Results: In the period from January 1996 to December 2012, 3532 coronary artery bypass surgery were carried out. Two hundred and eighty-eight (8.15% of the total sample) patients had atrioventricular block during the postoperative period of coronary artery bypass surgery, requiring temporary pacing.

Eight of those who had atrioventricular block progressed to implantation of a permanent pacemaker (0.23% of the total sample). Multivariate analysis revealed a significant association of atrioventricular block with age above 60 years (OR=2.34; CI 95% 1.75-3.12; P<0.0001), female gender (OR=1.37; CI 95% 1.06-1.77; P=0.015), chronic kidney disease (OR=2.05; CI 95% 1.49-2.81; P<0.0001), atrial fibrillation (OR=2.06; CI 95% 1.16-3.66; P=0.014), functional class III and IV of the New York Heart Association (OR=1.43; CI 95% 1.03-1.98; P=0.031),

Specialist in Cardiovascular Surgery by the Brazilian Society of Cardiovascular Surgery, Cardiovascular Surgeon at the Sao Lucas Hospital of the Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.

2 Specialist in Internal Medicine by the Brazilian Medical Association and in Cardiology through the Brazilian Society of Cardiology, Assistant Cardiologist of the Cardiac Pacing Unit at the Sao Lucas Hospital - PUCRS, Porto Alegre, RS, Brazil.

3 Resident Physician for Cardiovascular Surgery of the Medical Residency Program for Cardiovascular Surgery of Sao Lucas Hospital - PUCRS, Porto Alegre, RS, Brazil.

4 Adjunct Professor at the Federal University of Pampa - Uruguaiana Campus, RS, Brazil.

5 PhD in Health Sciences with Area of Concentration in Cardiology at the Federal University of Rio Grande do Sul, Cardiovascular Surgeon at the Sao Lucas Hospital - PUCRS, Porto Alegre, RS, Brazil.

6 Chief of Cardiology at the Sao Lucas Hospital - PUCRS, Head of the Postoperative Cardiac Surgery at the Sao Lucas Hospital - PUCRS, Porto Alegre, RS, Brazil.

7

Master of Internal Medicine - Cardiology at the Federal University of Rio Grande do Sul, Chief of the Department of Cardiovascular Surgery at the São Lucas Hospital - PUCRS, Porto Alegre, RS, Brazil.

1

This study was carried out at the Department of Cardiology, Electrophysiology Laboratory, Department of Cardiovascular Surgery, SSao Lucas Hospital of the Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.

No financial support.

Correspondence address: Ricardo Medeiros Piantá Av. Ipiranga, 6690 – Conj. 615 – Jardim Botânico – Porto Alegre, RS, Brazil Zip Code: 90610-000 E-mail: r18pianta@gmail.com Article received on December 16th, 2013 Article accepted on Juny 29th, 2014

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artificial temporária e de marca-passo definitivo no pós-operatório de cirurgia de revascularização do miocárdio e seu impacto na permanência e na mortalidade hospitalar.

Métodos: Análise de Coorte retrospectiva de pacientes submetidos à cirurgia de revascularização do miocárdio, do banco de dados da unidade de Pós-Operatório de Cirurgia Cardíaca do Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, pelo método de regressão logística.

Resultados: No período de janeiro de 1996 a dezembro de 2012, foram realizadas 3532 cirurgias de revascularização do miocárdio. Duzentos e oitenta e oito (8,15%) pacientes apresentaram bloqueio atrioventricular durante o pós-operatório de cirurgia de revascularização do miocárdio, necessitando de estimulação cardíaca artificial temporária. Oito dos que apresentaram bloqueio atrioventricular evoluíram para implante de marcapasso definitivo (0,23% do total da amostra). A análise multivariada evidenciou associação significativa de bloqueio atrioventricular com idade acima de 60 anos (OR=2,34; IC 95% 1,75-3,12; P<0,0001), sexo feminino (OR=1,37; IC 95% 1,06-1,77; P=0,015), doença renal crônica (OR=2,05; IC 95% 1,49-2,81; P<0,0001), fibrilação atrial (OR=2,06; IC 95% 1,16-3,66; P=0,014), classe funcional III e IV da New York Heart Association (OR=1,43; IC 95% 1,03-1,98; P=0,031), infarto agudo do miocárdio perioperatório (OR=1,70; IC 95% 1,26-2,29; P<0,0001) e com o uso do balão intra-aórtico no pós-operatório de cirurgia de revascularização do miocárdio (OR=1,92; IC 95% 1,21-3,05; P=0,006). A presença de bloqueio atrioventricular acarretou um aumento significativo da mortalidade (17,9% vs. 7,3% nos que não desenvolveram bloqueio atrioventricular) (OR=2,09; IC 95% 1,46-2,99; P<0,0001) e um tempo mais prolongado de permanência hospitalar (12,75 dias vs. 10,53 dias nos que não desenvolveram bloqueio atrioventricular) (OR=1,01; IC 95% 1,00-1,02; P=0,01).

Conclusão: O bloqueio atrioventricular, no pós-operatório de cirurgia de revascularização do miocárdio, é, na maioria dos casos, transitório, sendo associado a diversos fatores perioperatórios: idade acima de 60 anos, sexo feminino, doença renal crônica, fibrilação atrial, classe funcional III e IV da New York Heart Association, infarto agudo do miocárdio perioperatório e uso do balão intra-aórtico. Sua ocorrência prolonga a internação hospitalar e, sobretudo, duplica o risco de mortalidade.

Abbreviations, acronyms & symbols AVB CABG NYHA PO POHS PPM PUCRS TP

Atrioventricular block Coronary artery bypass surgery New York Heart Association Postoperative period Postoperative Heart Surgery Unit Permanent pacemaker Pontifical Catholic University of Rio Grande do Sul Temporary pacing

perioperative acute myocardial infarction (OR=1.70; CI 95% 1.26-2.29; P<0.0001) and with the use of the intra-aortic balloon in the postoperative period of coronary artery bypass surgery (OR=1.92; CI 95% 1.21-3.05; P=0.006). The presence of atrioventricular block resulted in a significant increase in mortality (17.9% vs. 7.3% in those who did not develop atrioventricular block) (OR=2.09; CI 95% 1.46-2.99; P<0.0001) and a longer hospital stay (12.75 days x 10.53 days for those who didn’t develop atrioventricular block) (OR=1.01; CI 95% 1.00-1.02; P=0.01).

Conclusions: In most cases, atrioventricular block in the postoperative period of coronary artery bypass surgery is transient and associated with several perioperative factors: age above 60 years, female sex, chronic kidney disease, atrial fibrillation, New York Heart Association functional class III or IV, perioperative acute myocardial infarction and use of an intra-aortic balloon. Its occurrence prolongs hospitalization and, above all, doubles the risk of mortality.

Descriptors: Atrioventricular block. Artificial Pacemaker.

Coronary Artery Bypass. Postoperative Complications.

Resumo Introdução: Os distúrbios do sistema de condução cardíaca são frequentes no pós-operatório de cirurgia de revascularização do miocárdio. Majoritariamente reversíveis, estão associados com alguma injúria do tecido de condução, causada pela própria cardiopatia isquêmica ou por fatores perioperatórios.

Objetivo: Primário: investigar a associação entre fatores perioperatórios com o surgimento de bloqueio atrioventricular no pós-operatório de cirurgia de revascularização do miocárdio.

Secundários: determinar a necessidade de estimulação cardíaca

Descritores: Bloqueio Atrioventricular. Marcapasso Artificial.

Revascularização do Miocárdio. Complicações Pós-Operatórias.

INTRODUCTION

tion disorders that require temporary pacing (TP). 0.4 to 1.1% of patients, however, when faced with the irreversibility of the condition, will have to undergo a permanent pacemaker (PPM) implant during their hospital stay[10]. This study, which is unprecedented in the national literature, tries to identify the relationship between pre-, intra and postoperative (perioperative) factors associated with the emergence of AVB, the need for TP and, if the case, the implantation of a PPM in the PO of CABG.

Disturbances of the cardiac conduction system are relatively frequent in the postoperative period (PO) of coronary artery bypass grafting (CABG), with an incidence ranging from 18 to 55% of cases[1-6]. Atrioventricular block (AVB) is one of these conduction disturbances and its incidence ranges from 0.5 to 16%[3,5-9]. Most patients have transitory and reversible conduc-

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METHODS

were transferred to the ICU of the POHS with mechanical ventilation.

Population and sample Between January 1996 and December 2012, 3532 CABGs with cardiopulmonary bypass (CPB) were performed at the Sao Lucas Hospital of the Pontifical Catholic University of Rio Grande do Sul (PUCRS).

Statistical Analysis The data was plotted in a digital Microsoft Access® spreadsheet and analyzed using version 17.0 of the statistical software SPSS. The descriptive analysis was performed through frequency and mean ± standard deviation analysis, according to the case. For the univariate analysis the following tests were performed: chi-square and/or Fisher’s Exact Test for ordinal variables and the Student’s T-test for quantitative data. The multivariate analysis was performed using logistic regression (backward conditional method). The difference was considered as statistically significant for the value of P<0.05.

Study Design Historical cohort observation study. Data were collected prospectively and entered into the database of the Postoperative Heart Surgery Unit (POHS) of the São Lucas Hospital of PUCRS. Inclusion Criteria Patients with age equal to or greater than 18 years who were submitted to isolated CABG.

Ethical Considerations The design of this study was submitted to the Research Ethics Committee of the Faculty of Medicine of the PUCRS, under registration number 060/3478.

Exclusion Criteria Patients who had been undergo valvular surgery, for left ventricular aneurysmectomy or correction of the interventricular communication associated with CABG.

RESULTS

Study Variables Age - the mean age was calculated and also divided into groups for analysis: less than 60 years and greater than or equal to 60 years, according to the reference in the literature[11,12]; gender (male and female); left ventricular ejection fraction (EF) - evaluated by echocardiography or radiocardiography, with the values being subdivided for analysis into ≤ 40% and > 40 %; chronic kidney disease (CKD) - diagnosed through serum creatinine level > 1.5 mg/dl, according to the reference in the literature[11,12]; Diabetes Mellitus (DM); atrial fibrillation (AF); previous use of beta-blockers; previous use of statins; previous use of other antiarrhythmics (propafenone and/or amiodarone); acute myocardial infarction (AMI) prior to CABG; New York Heart Association functional (NYHA) class; presence of calcification of the aorta; time of cardiopulmonary bypass (CPB); aortic clamping time; need for the use of intra-aortic balloon (IAB) in the PO of CABG; perioperative AMI; length of hospital stay and hospital death.

Of the 3532 patients undergoing CABG in the period under analysis, 288 (8.15%) presented the clinical and electrocardiographic signs of AVB during the postoperative period, with an indication for temporary pacing (TP).

Table 1 shows the demographic profile of the patients studied. The univariate analysis of the preoperative data revealed a greater need for TP in the PO of CABG in patients above 60 years of age (OR=2.48; CI 95% 1.90-3.24; P<0.0001), of the female gender (OR=1.03; CI 95% 1.001.05; P=0.012), with CKD (OR=2.03; CI 95% 1.55-2.65; P<0.0001), the presence of AF (OR=2.38; CI 95% 1.49-3.72; P<0.0001) and in patients with NYHA functional class III or IV (OR=1.60; CI 95% 1.21-2.12; P=0.001).

Table 2 presents the trans and postoperative data, together with their univariate analysis. Here we can observe the association of AVB with the need of TP in patients who presented calcification of the aorta, perioperative AMI and the need for the use of an IAB. Of statistically significant relevance, the univariate analysis also revealed the association of TP caused by AVB with increased mortality (17.9% vs. 7.3%) and with a longer hospital stay (mean hospitalization time of 12.75 days compared to 10.53 days for those who did not require TP).

These data were submitted to multivariate analysis (Table 3), which revealed a higher risk of AVB in the PO of CABG in patients with: age > 60 years, female sex, CKD, AF, NYHA functional class III or IV, perioperative AMI and with the use of an IAB. Patients with EF≤40 %, DM, the use of beta-blockers, statins and other antiarrhythmic drugs, prior AMI and CPB and aortic clamping

Outcome Development of AVB in the PO of CABG and the need for TP and implantation of a PPM. Procedures The CABGs were performed under general anesthesia. In all cases, a hyperkalemic cardiac arrest was induced using a cold cardioplegic blood solution in the anterograde flow, with the infusion being repeated every 20 minutes. A mild systemic hypothermia (32ºC) was used. After surgery, all patients

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times didn’t prove to be independent risk variables for the development of AVB in the PO of CABG. In the multivariate analysis, the presence of AVB resulted in a longer hospital stay (12.75 days vs. 10.53 days for those who didn’t develop AVB) (OR=1.01; CI 95% 1.00-1.02; P=0.01) and in a significant increase in the risk of mortali-

ty (17.9% vs. 7.3% for patients without AVB) (OR=2.09; CI 95% 1.46-2.99; P<0.0001).

In the subgroup of 288 patients who had AVB and who had undergone TP, 08 (2.78 %) required a PPM implant, corresponding to 0.23% of the total cohort analyzed. The average time elapsed since the surgery until the PPM implant was 12.25 days.

Table 1. Preoperative characteristics of the groups and univariate analysis.

Variable Age ≥ 60 <60 Gender Male Female EF ≤ 40 > 40 CKD (Creat>1.5) Yes No DM Yes No AF Yes No Antiarrhythmic Agents Yes No BB Yes No Digoxin Yes No Previous AMI Yes No NYHA FC III and IV I and II

Total 3532 (100%)

TP 288 (8.15%)

NTP 3244 (91.85%)

OR

CI 95%

P

2030 (57.5%) 1502 (42.5%)

222 (10.9%) 66 (4.4%)

1808 (89.1%) 1436 (95.6%)

2.48

1.90 – 3.24

<0.0001

2393 (67.8%) 1139 (32.2%)

176 (7.4%) 112 (9.8%)

2217 (92.6%) 1027 (90.2%)

0.75 1.03

0.57 – 0.94 1.00 – 1.05

0.012

730 (20.7%) 2802 (79.3%)

64 (8.8%) 224 (8.0%)

666 (91.2%) 2578 (92.0%)

1.11

0.85 – 1.45

0.44

398 (11.3%) 3134 (88.7%)

59 (14.8%) 229 (7.3%)

339 (85.2%) 2905 (92.7%)

2.03

1.55 – 2.65

<0.0001

1129 (32.0%) 2403 (68.0%)

98 (8.7%) 190 (7.9%)

1031 (91.3%) 2213 (92.1%)

1.09

0.87 – 1.39

0.433

86 (2.4%) 3446 (97.6%)

16 (18.6%) 272 (7.9%)

70 (81.4%) 3174 (92.1%)

2.38

1.49 – 3.72

<0.0001

90 (2.5%) 3442 (97.5%)

12 (13.3%) 276 (8.0%)

78 (86.7%) 3166 (92.2%)

1.66

0.97 – 2.85

0.069

2500 (70.8%) 1032 (29.2%)

208 (8.3%) 80 (7.8%)

2292 (91.7%) 952 (92.2%)

1.07

0.84 – 1.37

0.575

204 (5.8%) 3328 (94.2%)

23 (11.3%) 265 (8.0%)

181 (88.7%) 3063 (92.0%)

1.42

0.95 – 2.12

0.093

1600 (45.3%) 1932 (54.7%)

117 (7.3%) 171 (8.9%)

1483 (92.7%) 1761 (91.1%)

0.826

0.66 – 1.03

0.096

453 (12.8%) 3079 (87.2%)

55 (12.1%) 233 (7.6%)

398 (87.9%) 2846 (92.4%)

1.604

1.21 – 2.12

0.001

AF=atrial fibrillation; AMI=acute myocardial infarction; BB=beta-blockers; CI=confidence interval; CKD=chronic kidney disease; DM=diabetes mellitus; EF=left ventricular ejection fraction; FC=functional class; NYHA=New York Heart Association; NTP=no use of temporary pacing; OR=odds ratio; P=statistical significance; TP=temporary pacing

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Table 2. Trans and postoperative data of groups and univariate analysis.

Variable CPBT ≥ 90 min < 90 min Tclamping ≥ 40 min < 40 min Calcification Ao Yes No Peri AMI Yes No IAB Yes No Death Yes No

Total 3532 (100%)

TAHP 288 (8.15%)

N TAHP 3244 (91.85%)

OR

CI 95%

P

1567 (44.4%) 1965 (55.6%)

136 (8.7%) 157 (8.0%)

1430 (91.3%) 1807 (92%)

1.08

0.86 – 1.35

0.494

2512 (71.1%) 1020 (28.9%)

208 (8.3%) 87 (8.5%)

2304 (91.7%) 933 (91.5%)

0.978

0.77 – 1.25

0.86

350 (9.9%) 3182 (90.1%)

44 (12.6%) 244 (7.7%)

306 (87.4%) 2938 (92.3%)

1.639

1.21 – 2.22

0.001

555 (15.7%) 2977 (84.3%)

78 (14.1%) 210 (7.1%)

477 (85.9%) 2767 (92.9%)

2.155

1.63 – 2.84

<0.0001

141 (4.0%) 3391 (96.0%)

29 (20.6%) 259 (7.6%)

112 (79.4%) 3132 (92.4%)

2.69

1.90 – 3.80

<0.0001

285 (8.1%) 3247 (91.9%)

51 (17.9%) 237 (7.3%)

234 (82.1%) 3010 (92.7%)

2.452

1.86 – 3.23

<0.0001

Calcification Ao=calcification of the aorta; CPBT=cardiopulmonary bypass time; IAB=intra-aortic balloon; Peri AMI=perioperative acute myocardial infarction; Tclamping=aortic clamping time; Others: see Table 1

these conduction disturbances and its incidence ranges from 0.5 to 16%[3,5-9]. Our incidence of AVB is in line with this data, since 8.15% of our patients developed AVB in the PO of CABG. The etiology of AVB seems to be multifactorial. The patient’s age (>60 years), hypertension, number of revascularized vessels, aortic clamping time, total time of CPB, use of digitalis and beta-blockers, type of cardioplegia and previously existing left bundle branch block may be related to its appearance[1-4,8,9,13,14].

Myocardial ischemia seems to be the factor that is most implicated in the emergence of AVB, since there is a correlation with coronary artery disease (CAD) and preoperative AMI[4]. Studies[3,10] have demonstrated that perioperative AMI also increases the incidence of AVB in the PO of CABG. Caspi et al.[7] reported a higher occurrence of AVB in patients with AMI in the PO of CABG (12% vs. 2 %, P<0.05).

However, AMI before CABG was not a significant factor for the appearance of AVB in our study, which is consistent with the world literature[3,7,8,15,16]. This shows there is no difference in the incidence of AVB between patients who had preoperative AMI and those who didn’t, regardless of its electrocardiographic location.

Caspi et al.[7] have shown that the combination of left main disease and proximal obstruction of a dominant right coronary artery was more frequent in patients who exhibited AVB (32%) than in those who without it (12%, P<0.05). The explanation for this effect is the fact that the cardioplegic solution is not properly distributed to the coronary beds because of

Table 3. Multivariate analysis of the risk factors and outcomes of AVB in the PO of CABG. Variable Age > 60 years Female Gender Atrial Fibrillation Previous CKD FC III and IV Perioperative AMI IAB Hospitalization Time Death

OR 2.34 1.37 2.06 2.05 1.43 1.70 1.92 1.01 2.09

CI 95% 1.75 – 3.12 1.06 – 1.77 1.16 – 3.66 1.49 – 2.81 1.03 – 1.98 1.26 – 2.29 1.21 – 3.05 1.00 – 1.02 1.46 – 2.99

P < 0.0001 0.015 0.014 < 0.0001 0.031 < 0.0001 0.006 0.01 < 0.0001

AMI=acute myocardial infarction; AVB=atrioventricular block; CABG=coronary artery bypass grafting; CKD=chronic kidney disease; FC=functional class; IAB=intra-aortic balloon; PO=postoperative

DISCUSSION CABG is a proven therapeutic strategy for the treatment of Coronary Artery Disease (CAD). Although it is well tolerated by most patients, perioperative complications can occur, among which we find disturbances in the cardiac conduction system in varying degrees, including AVB. Previous studies have reported an incidence of conduction disturbances (CD) after CABG that varies from 18 to 55% of cases[1-6], with the right bundle branch block being the most common[4]. Atrioventricular block (AVB) is one of

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their high degree of obstruction, which compromises myocardial protection and, in some cases, because of the impossibility of bypassing the right coronary artery.

The impairment of myocardial irrigation gets worse with age, just as the frequency of degenerative diseases of the conduction system, increasing the probability of AVB[9,11,15,17-19].

In this scenario, our patients above 60 years of age presented a significant risk (OR=2.34; CI 95% 1.75-3.12; P<0.0001) for the development of AVB in the PO of CABG, corroborating the findings of other studies[7,8,13,14].

The electrical cardiac conduction tissue differs from cardiac myocytes by being less tolerant to the effects of ischemia, hyperkalemia and hypothermia (whether these are systemic or, mostly, induced by a cardioplegic solution that is cold and rich in potassium). This may cause a transient block of the conduction system[11]. The advent of cold cardioplegia as a method of myocardial protection has increased the incidence of CD from 20 to 58%[13]. The more significant incidence of conduction disturbances occurred in patients who received cold cardioplegia, as opposed to warm (19.6% vs.

1.7 %, respectively)[13], a finding that has also been described

by Sirlak et al.[20]. Specifically with respect to AVB, the incidence was of 3.8% in the hypothermia group and zero in the normothermal group[13]. All patients in our study underwent surgery with the myocardial protection performed by infusion of a cold cardioplegic blood solution at the root of the aorta every 20 minutes, which contributed to the genesis of AVB cases.

As such, the perfusion injury determined by the myocardial ischemia and the hypothermic injury caused by the cardioplegic solution are the mechanisms that are most involved in the genesis of AVB, acting on the proximal portions of the bundle of His, which are more sensitive to this type of aggression than the more distal conduction tissue, determining the emergence of bundle branch blocks and increasing the risk of AVB[4].

In this scenario, the extent of the CAD, the duration of CPB and the aortic clamping time could compromise myocardial protection during surgery, increasing the risk of an ischemic injury and of metabolic damage to the conduction tissue[11]. However, our CPB time of ≥ 90 min and aortic clamping time of ≥ 40 min showed no influence on the development of AVB, which is supported by the literature[5-7,16,19].

Baerman et al.[1], however, demonstrated that patients with lower CPB (101±32min x 121±34min; P<0,01) and aortic clamping (44±19min x 53±17min; P<0.05) times didn’t show evidence of AVB in the PO of CABG. Our study has shown that the female gender is a risk factor for the occurrence of AVB (OR=1.37, CI 95% 1.06-1.77; P=0.015), which contrasts with the results of Gordon et al.[19] who observed a higher need for PPM implants in men (P=0.041). Other studies[3,8,15,20], however, didn’t point to any of the genders as risk factor. Cadore et al.[12] had already pointed to the female gender as a risk predictor for mortality

in CABG, which can be an expression of the greater severity of the ischemic impairment in this gender and explain their greater tendency for developing the block, as seen in our study.

The presence of CKD was also verified to be a risk factor for the development of AVB (OR = 2.05; CI 95% 1.49-2.81; P<0.0001). A previous study[19] indicated the presence of CKD as more significant among those patients who required PPM implantation in the PO of CABG. Like the female gender variable, CKD was also found to be a predictor of mortality in patients underwent CABG according to the score by Cadore et al.[12], expressing its potential for increasing the risk of complications in the PO of CABG. Another risk predictor for the occurrence of AVB was the more advanced functional class of the NYHA (III and IV) (OR = 1.43; CI 95% 1.03-1.98; P=0.031). Studies[18,19] have corroborated this finding, indicating that patients who underwent heart surgery and needing a PPM implant were in the more severe functional class of the NYHA (III and IV) when compared to patients who did not require such an implant (57% vs. 35%, respectively, P<0.0001)[18]. Bateman et al.[6] showed that of those patients who passed away within the first 30 days of the PO of CABG and who had developed some degree of blockage, 90% were into class IV of the NYHA in the preoperative period.

The patients in this study who had EF≤40% did not present a significant risk for the appearance of AVB in the PO of CABG (OR=1.11; CI 95% 0.85-1.45; P=0.44), a finding supported by Gordon et al.[19] who didn’t observe any significant impact of EF on the need for PPM implantation in the PO of isolated CABG. Caspi et al.[7], however, found a greater susceptibility to the development of atrioventricular block in patients submitted to CABG with a lower EF. Although Merin et al.[18] mention that the use of antiarrhythmic agents is more frequent in the group of patients that develops blockage after heart surgery (CABG, valve or combined), our data does not reflect this influence. Regarding the use of beta-blockers, we also didn’t find any association with the development of AVB, which has already been described by other authors[2,3,16].

The need for the use of an IAB in the PO of CABG occurred in 141 patients (4%) of the total sample of 3532 patients, of which 20.6% developed AVB, leading to the need for TP (OR=1.92; CI 95% 1.21-3.05; P=0.006). The need for the use of the IAB has been associated with a greater probability of developing blocking and has been indicated as a predictor of its occurrence and of the need for a PPM implant[6,17,19]. Probably because its use is an expression of a more significant ischemic cardiopathy, i.e., of patients with more severe compromising. This finding is important because the patients did not have AVB in the preoperative period, presumably reflecting a greater perioperative myocardial injury[6].

Perioperative AMI was a risk factor for the emergence of AVB (OR=1.70; CI 95% 1.26-2.29; P<0.0001), and this was

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corroborated by the study of Caspi et al.[7] who identified the occurrence of low cardiac output (34% vs. 3%) and perioperative AMI (12% x 2%) as risk factors for AVB in the PO of CABG. Perioperative AMI also increases the need for a PPM implant[10], reflecting acute ischemic damage of the conduction tissue.

The need for TP showed a significant association with mortality (OR=2.09; CI 95% 1.46-2.99; P<0.0001), which was 17.7% for patients with AVB and 7.2% for those who didn’t develop it. Zeldis et al.[3] had already reported a mortality of 19.2% in the group of patients who developed block of the left conduction system (left bundle branch block or left anterior hemiblock or both), compared with a 7% mortality rate in the group of patients without such block. Specifically with respect to AVB, Caspi et al.[7] observed a significantly higher mortality in the group of patients who developed AVB (7% vs. 0.6%). On the other hand, patients who develop right bundle branch block or fascicular block have a more favorable prognosis, because these are more transient disorders and because they do not increase mortality[6,21].

The patients who developed AVB had a significantly longer hospital stay (mean hospitalization time of 12.75 days compared to 10.53 days for those who did not need TP for AVB (OR=1.01 CI 95% 1.00-1.02; P=0.01). Gordon et al.[19] have shown that the need for a PPM implant significantly increased hospital stay (23.3±18.7 days vs. 9.6±9.0 days for patients without need of implant, P=0.0001) and ICU stay (5.6±10.5 days vs. 2.2±3.3 days, P=0.0258). Other studies[11,18] also corroborate this finding of a longer hospital stay in the presence of AVB and the need of TP. In our study, the need for a PPM implant occurred in 08 of the 3532 patients studied (0.23%), which is lower than the rate found in the literature, which points to the need for PPM implants in 0.49% of AVB cases[8]. Gordon et al.[19] implanted PPMs in 50 of their 6859 patients submitted to CABG (0.73%). When other types of post-CABG conduction blocks are considered, the incidence of implants rises and ranges from 0.4 to 1.1%[10]. The calculated risk for need of a PPM implant in the PO of non-complicated CABG is 0.9%[19].

Nascimento et al.[22] couldn’t identify any prognosis criterion for the reversibility of AVB in the PO of heart surgery.

The ideal moment for the implantation of a PPM in the PO of CABG hasn’t yet been properly established. According to the Brazilian Guidelines for Implantable Electronic Heart Devices[23], patients with asymptomatic AVB with wide QRS after cardiac surgery that persists after 15 days, are indicated for a PPM implantation (Class I, level of evidence C). In the cases of asymptomatic AVB persisting after 15 days, resulting from cardiac surgery, with narrow QRS or nodal escape rhythm and good chronotropic response, and in those cases without the prospect of reversal (< 15 days) PPM implantation is also indicated (Class IIa, level C).

According to the criteria of the American College of Cardiology and the American Heart Association, a PPM implant

is indicated in 3rd and advanced 2nd degree AVB in the postoperative period of heart surgery, in addition to cases without expectation of resolution. The decision regarding the time of the implant should be taken by the physician[24].

The European Society of Cardiology recommends a waiting period of 5 to 7 days for the resolution of transient bradyarrhythmias after cardiac surgery, before the decision for the implant is made[25].

According to Pires et al.[13] and Merin et al.[18], the decision to perform the implant should be taken between the 4th and 5th day of the PO, because if the AVB or dysfunction of the sinus node are still present up to this moment, then they tend to be permanent. This would facilitate the early mobilization of patients and shorten their hospitalization time.

Of the 288 patients in our study who had AVB, 08 received a PPM implant after an average of 12.25 days into the PO, which is in line with the Brazilian (Class IIa, level of evidence C), American and European (Class I, level C) guidelines. Emlein et al.[8] described a series of 8 patients who underwent a PPM implant after developing AVB with an average of 10.5±6.5 days into the PO. Limitations of the Study The limitations of this study are those inherent to a retrospective database analysis, but they reflect the significant years of experience of an academic institution. Within these limitations we can cite the relative difficulty of accessing the full data, which causes a potential risk of not measuring some random variables. The fact that the results come from the sample of a single center can also represent some degree of bias in the treatment. Another limitation of this study is the absence of more precise information regarding the height of the atrioventricular conduction disorder and the existence or not of any escape rhythm.

Regarding the PPM implants performed in our study, they followed the recommendations of Brazilian, American and European guidelines almost strictly. In this small group of patients a more thorough analysis was compromised, but this could be the target of a more detailed study to be developed in the future.

CONCLUSION This work sheds light on the risk factors associated with the development of AVB in the PO of CABG and the consequent need for TP and a definitive pacemaker. Based on this we could establish that female patients, 60 years of age or more, with the diagnosis of AF and CKD, in stages III and IV of the functional class, who had perioperative AMI and required the use of an IAB, have a higher risk of developing AVB in the PO of CABG. AVB determines a more prolonged hospitalization and, what is more important, doubles the risk of mortality.

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Authors’ roles & responsibilities RMP

ADLF AAH DKF JCEP LCA JCVCG JBP

8. Emlein G, Huang SK, Pires LA, Rofino K, Okike ON, Vander Salm TJ. Prolonged bradyarrhythmias after isolated coronary artery bypass graft surgery. Am Heart J. 1993;126(5):1084-90.

Analysis and/or interpretation of data; final approval of the manuscript; study design; conduct of operations and/or experiments; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; study design; conduct of operations and/or experiments; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; actual operations and/ or experiments; writing of the manuscript or critical review of its content Analysis and/or interpretation of the data Analysis and/or interpretation of the data; statistical analysis Final approval of the manuscript; conduct of operations and/ or experiments; writing of the manuscript or critical review of its content Final approval of the manuscript; writing of the manuscript or critical review of its content Conduct of operations and/or experiments; writing of the manuscript or critical review of its content

9. Rocha AS, Pitella FJ, Lorenzo AR, Barzan V, Colafranceschi AS, Brito JO, et al. Age influences outcomes in 70-year or older patients undergoing isolated coronary artery bypass graft surgery.

Rev Bras Cir Cardiovasc. 2012;27(1):45-51.

10. Emkanjoo Z, Mirza-Ali M, Alizadeh A, Hosseini S, Jorat MV, Nikoo MH, et al. Predictors and frequency of conduction disturbances after open-heart surgery. Indian Pacing Electrophysiol J. 2008;8(1):14-21.

11. Ferrari AD, Süssenbach CP, Guaragna JC, Piccoli JC, Gazzoni GF, Ferreira DK, et al. Atrioventricular block in the postoperative period of heart valve surgery: incidence, risk factors and hospital evolution. Rev Bras Cir Cardiovasc. 2011;26(3):364-72.

12. Cadore MP, Guaragna JC, Anacker JF, Albuquerque LC, Bodanese LC, Piccoli Jda C, et al. A score proposal to evaluate surgical risk in patients submitted to myocardial revascularization surgery.

Rev Bras Cir Cardiovasc. 2010;25(4):447-56.

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Oliveira FilhoORIGINAL LD, et al. - Effect of N-acetylcysteine in hearts of rats submitted ARTICLE to controlled hemorrhagic shock

Effect of N-acetylcysteine in hearts of rats submitted to controlled hemorrhagic shock Efeito da N-acetilcisteína em corações de ratos submetidos ao choque hemorrágico controlado

Luiz Dantas de Oliveira Filho1, MD; Karen Ruggeri Saad2, MSc, PhD; Paulo Fernandes Saad2, MD, MSc, PhD; Marcia Kiyomi Koike3, PhD; Sônia Maria da Silva1, PhD; Edna Frasson de Souza Montero1,3, MD, PhD

DOI 10.5935/1678-9741.20140097

RBCCV 44205-1629

Abstract Introduction: Pharmacological therapy is a strategy for the prevention of complications associated with ischemia and reperfusion injury that occurs after volume replacement in the treatment of hemorrhagic shock.

Objective: The aim of this study was to evaluate the effect of N-acetylcysteine associated with fluid resuscitation in cardiac injury in a rat hemorrhagic shock model.

Methods: Mice Wister male rats were randomly and subjected to controlled hemorrhagic shock for 60 min. and then, subjected to resuscitation with Ringer lactate. In a group of six animals, 150mg/kg of N-acetylcysteine were added to fluid volume replacement. The animals were observed for 120 min and after this period, were euthanized and cardiac tissue was collected for histopathological analysis and measurement of thiobarbituric acid reactive substances and pro-and anti-inflammatory interleukin.

Results: Cardiac tissue of the group treated with N-acetylcysteine showed lower concentrations of thiobarbituric acid reactive substances (0.20±0.05 vs. 0.27±0.05, P=0.014) and re-

duced histopathological damage and edema when compared to the group whose volume replacement occurred only with Ringer lactate. There was no difference in the expression of cytokines interleukin 6 (2,138.29±316.89 vs. 1,870.16±303.68, P=0.091) and interleukin 10 (1.019,83±262,50 vs. 848.60±106.5, P=0.169) between the treated groups.

Conclusion: The association of N-acetylcysteine on volume replacement attenuates oxidative stress in the heart, as well myocardial damage and edema, but does not modify the expression of inflammatory cytokines.

Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.

Universidade Federal do Vale do São Francisco (UNIVASF), Petrolina, PE, Brazil.

3 Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.

Correspondence address: Edna Frasson de Souza Montero Laboratório de Fisiopatologia Cirúrgica - LIM-62 Faculdade de Medicina - USP Av. Dr. Arnaldo, 455 - 2 andar Cerqueira César, São Paulo, SP, Brazil - Zip Code: 01246-903 E-mail: edna.montero@gmail.com

Descriptors: Shock, Hemorrhagic. Heart. Acetylcysteine.

Oxidative Stress. Inflammation.

Resumo Introdução: A terapia farmacológica é uma estratégia de prevenção das complicações associadas à lesão de isquemia e reperfusão tecidual que ocorre após a reposição volêmica no tratamento do choque hemorrágico.

1 2

This study was carried out at Laboratório de Cirurgia e Experimentação da Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil.

Article received on February 17th, 2014 Article accepted on July 24th, 2014

No financial support.

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submetidos à eutanásia e coleta do tecido cardíaco para análise histopatológica e dosagem de substâncias reativas ao ácido tiobarbitúrico e interleucinas pró e anti-inflamatórias.

Resultados: Foi observada menor concentração de substâncias reativas ao ácido tiobarbitúrico (0,20±0,05 vs. 0,27±0,05, P=0,014) e menor dano histopatológico e edema no tecido cardíaco do grupo tratado com N-acetilcisteína em relação ao grupo cuja reposição volêmica ocorreu somente com Ringer Lactato. Não foi observada diferença da expressão das citocinas interleucina 6 (2.138,29±316,89 vs. 1.870,16±303,68, P=0,091) e interleucina 10 (1.019,83±262,50 vs.

848,60±106,5, P=0,169) entre os grupos tratados.

Conclusão: A associação da N-acetilcisteína na reposição volêmica atenua o estresse oxidativo no coração, assim como dano e edema miocárdicos, porém, não modifica a expressão de citocinas inflamatórias.

Abbreviations, acronyms & symbols CONCEA Council for the Control of Animal Experimentation IR Reperfusion injury MAP Mean arterial pressure NAC N-acetylcysteine ROS Reactive oxygen species TBARS Thiobarbituric acid reactive substances TNF-α Tumor necrosis factor alpha

Objetivo: O objetivo deste estudo foi avaliar a repercussão da N-acetilcisteína associada à reposição volêmica na lesão cardíaca em modelo de choque hemorrágico em ratos.

Métodos: Ratos Wistar, machos, foram randomizados e submetidos ao choque hemorrágico controlado por 60 minutos e, depois, submetidos à reposição volêmica com Ringer Lactato.

Em um grupo de seis animais, foram adicionados 150 mg/Kg de N-acetilcisteína ao fluido de reposição volêmica. Os animais foram observados por 120 minutos e após este período foram

Descritores: Choque Hemorrágico. Coração. Acetilcisteína.

Estresse Oxidativo. Inflamação.

INTRODUCTION

end products of lipid peroxidation, among which the thiobarbituric acid reactive substances (TBARS)[4]; the other, by the interaction of polymorphonuclear and capillary endothelial cells, mediated by inflammatory cytokines and cell adhesion molecules[5].

In an attempt to minimize the damages caused by ROS, cardiac myocytes use antioxidant systems – substances that slow down or inhibit oxidative aggression. The most important endogenous antioxidants are the superoxide dismutase, catalase, glutathione peroxidase, and vitamin E. These systems are overloaded after ischemia and reperfusion[6].The damage to cardiac myocytes can happen, then, by cell-to-cell contact (neutrophils – myocyte) with the release of oxidative cytokines and proteolytic enzymes. This accumulation and infiltration of neutrophils in the organ’s parenchyma is a fundamental step for development of the trauma’s secondary injury[7]. The cardiac dysfunction established contributes to aggravate the hypoperfusion injury in other organs during the shock and may result in death.

Associated with fluid replacement therapy, the pharmacological therapy has gained prominence in the reduction of deleterious effects of immune-inflammatory phenomena of bleeding and the volume replacement therapy[8]. Among the antioxidant drugs, the N-acetylcysteine (NAC) – a low-

Trauma is the third death cause in the world, compromising mainly young and adult people.Bleeding is the major cause of the early death related to trauma.Additionally, deaths will occur due to severe injury to internal organs in the next hours, or due to multi-organ failure and sepsis, lately[1].

Hypoperfusion, following hemorrhagic shock, generates a global hypoxia that promotes the release of inflammatory cytokines and neutrophils activated from the splanchnic territory, notably from the liver and intestine, which via the bloodstream or lymphatic circulation promotes injuries to distant organs. This acute phase response of the trauma is characterized by the production and release of cytokines such as the alpha tumor necrosis factor alpha (TNF-α), interleukins 1β, 6 and 8[2].Although oxygen is essential for the survival of the tissues, during the restoration of perfusion, the cells suffer a harmful effect, characterizing the reperfusion injury[3].

Alterations induced by ischemia and reperfusion injury (IR) can be related to two different mechanisms. One of them, characterized by excessive production and subsequent release of reactive oxygen species (ROS), highly cytotoxic during the reperfusion phase, whose oxidative state biochemical markers are the

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cost, highly available, low-adverse effects substance – must be highlighted. Widely used in a number of medical science fields, it was initially used as a mucolytic agent. Its use was then extended to antidote for acetaminophen poisoning and prevention of contrast-induced nephropathy[9].

The in vivo NAC is metabolized in cysteine, which is a precursor of glutathione.In its reduced and oxidized forms, the glutathione participates – together with the glutathione peroxidase – in the ROS degradation cascade, removing free radicals. Thus, NAC can help restoring depleted glutathione reserves, replenishing cellular thiols during the IR process[10].

On IR injury, the NAC mechanism of action occurs by direct reaction with nitric oxide. This effect seems to occur after ROS release, protecting endothelial cells and subsequent activation of Kupffer cells. Its action through the sulfhydryl groups prevents the reaction of nitric oxide with the superoxide radical, hydrogen peroxide, and hydroxyl radical, preventing the formation of peroxynitrite and its consequences, such as lipid peroxidation, protein denaturation and DNA damage[11].

Despite of being widely used in medical practice and experimental models of IR injury, the literature about the use of NAC in the treatment of hemorrhagic shock and its possible protective effect in cardiomyocytes is scarce. As satisfactory results were observed with the use of NAC as protective drug of lung and liver tissue in experimental studies with controlled hemorrhagic shock models[12,13], as well as in other studies that used tissue IR injury models[14-16], the aim of this study was to assess the possible cardioprotective effect of adding NAC to volume replacement solution after induction and maintenance of controlled hemorrhagic shock.

with loss of righting reflexes and member withdrawal after painful stimulus caused by gripping and palpebral reflex.

Additional doses of the anesthetic cocktail (half the initial dose) were provided to animals as necessary during the procedure, which were also kept spontaneously ventilating in ambient air.

The right common carotid artery, right external jugular vein, and the right femoral artery were cannulated with Intracath® 22G (Bencton-Dicknson, Sandy, EUA).Heparin and resuscitation fluids were injected with venous catheter, according to the experimental groups; arterial catheters were used to the bleeding that caused the shock and monitoring of the mean arterial pressure (MAP), whose values allowed establishing the effectiveness of the procedures employed.

Experimental groups and induced controlled hemorrhagic shock After the surgical procedure, the animals were divided into the following study groups: Control group (GC, n=6): without induction of hemorrhagic shock, suffering euthanasia shortly after the post-operative stabilization period [15 minutes (min)]; Ringer’s lactate group (RL, n=6): induced hemorrhagic shock. 33 mL/kg of Ringer’s lactate solution (RL) plus 50% of the blood withdrawn were used for volume replacement for 20 min.

Ringer’s lactate group combined with NAC (RLNAC, n=6): induced hemorrhagic shock. 150 mg/kg of NAC[17] dissolved in 33 mL/kg of RL solution plus 50% of the blood withdrawn were used for volume replacement for 20 min.

Non-fractional sodium heparin was infused before induction of hemorrhagic shock (100 UI/rat). Next, blood was removed through the arterial catheter for an interval of 10 min, using a 10 mL previously heparinized syringe, until reaching MAP of 35 mmHg. This pressure was maintained for 60 min, removing or reinserting heparinized whole blood, in the case of ±5 mmHg change in MAP. To control the MAP, the arterial catheter was connected to a pressure transducer, connected to a calibrated preamp and a data acquisition computerized system (Dixtal DX 2020), in which the hemodynamic data (MAP and heart rate) were stored.

After 60 min of the beginning of hemorrhagic shock, the animals were submitted to volume replacement with the treatments specified above. The volume resuscitation was considered successful when the MAP remained above 80 mmHg for at least 5 min. After the shock and resuscitation stages, the animals were monitored for another 120 min; after this period, euthanasia was performed by exsanguination, under anesthesia.

METHODS Animals Male Wistar rats (RattusnorvegicusAlbinus), with ages between 90 and 120 days, and average weight of 319±26g, were used.

All animals were handled according to the “Guide for the Care and Use of Laboratory Animals” (Institute of Laboratory Animal Resources, National Academy of Sciences, Washington, D.C., 1996) and the animal experimental ethical principles of the National Council for the Control of Animal Experimentation (CONCEA).Study protocol approved by the Research Ethics Committee of Universidade Federal de São Paulo, Protocol No. 1712/11.

Anesthesia and operative procedure The animals were weighed and anesthetized with ketamine (50 mg/Kg) + xylazine (15 mg/kg) by intraperitoneal injection. They were considered anesthetized after being in deep sleep without reaction to mechanical stimuli,

Euthanasia and organ removal After euthanasia, median thoracotomy was performed and the heart was collected. Part of the left ventricle was

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immediately frozen in liquid nitrogen and stored at -70° C. Another fragment was fixed in 10% formaldehyde solution.

Next, this fragment was dehydrated in growing ethanol concentrations according to the histological techniques for inclusion in paraffin. The tissue fragment was cut in sections of 4 μm and stained with hematoxylin and eosin solution.

was washed three times with wash buffer. Then a block reaction was performed by adding 200 μL/well of 2% bovine serum albumin (BSA) in PBS and incubation for one hours at room temperature (20 to 26° C).The plate was again washed three times with wash buffer. It was added in duplicate 100 μL/well of standard and samples and incubating the plate for two hours at room temperature. For standard curves, recombinant IL-6 or IL-10 were used in the concentrations of 62.50; 125; 250; 500; 1000; 2000; 4000 e 8000 pg/mL. After repeating the plate washing procedure, 100 μL/well of biotinylated detection anti-IL-6 (400 ng/mL) or anti-IL-10 (300 ng/mL) were added, and the plate was incubated for 2 hours at room temperature. At the end of incubation, the plate washing process was repeated and then 100 μL/well of streptavidin peroxidase enzyme were added in the proportion of 1:200 of enzyme: PBS with 0.05% of tween-20 and incubation for an hour at room temperature protected from light. Next, the plate wash cycle was repeated and the reaction revealed by adding 3.3’ tetramethylbenzidine in one well and incubation for 60 min at room temperature protected from light. The reaction was blocked by adding 50 μL/well of H2SO4 (1N) and the optical density of samples at 450 nm (Multiscan Ex, MTX Labsystems, Virginia, USA) was evaluated immediately after the reaction blocking. All analyses were made in duplicate.

Determination of Lactate and Serum Potassium In order to assess the metabolic changes caused by hemorrhagic shock and the effectiveness of treatments, arterial blood samples (0.3 mL/animal) were collected for evaluation of lactate and serum potassium, in pre-heparinized syringes, before the shock induction, at the end of the shock period, and at the end of the stabilization after volume reanimationphase (Radiometer ABL 555, Copenhagen, Denmark).

Determination of thiobarbituric acid reactive substances in cardiac tissue A fragment of the left ventricle was withdrawn after euthanasia and frozen at -70° C; subsequently, it was homogenized in 1 ml of KCl 1.15% with sonicator (PT3100 Polytron) and used to determine the TBARS. The lipid peroxidation of cardiomyocytes’ cell membranes caused by the formation of free radicals was established by means of the TBARS dosage method[18], which value was expressed as nanomoles per milligram of protein (nmol/mg of protein).For this purpose, after homogenization the aliquots were centrifuged at 10,000 rpm for 20 min at 4° C (5804® Centrifuge Eppendorf, Hamburg, Germany). For reaction, 100 μL of supernatant, 100 μL of 8.1% sodium dodecil sulphate, 750 µL of 20% acetic acid, and 750 μL of 0.8% thiobarbituric acid were added. The mixture was heated for 50 min at 95° C. After the period established, 200 µL samples were analyzed in the 532 mn spectrophotometer (Multiscan Ex, MTX Labsystems, Virginia, USA).The results were expressed as μg/mg of protein. All analyses were performed in duplicate.

Histopathological Analysis An experienced pathologist assessed the histology slides qualitatively on light microscopy (Zeiss Axio Image A2, Oberkochen, Germany), blind to the groups. At least twenty cutting areas were randomly chosen and analyzed. The severity of histological lesions was assessed through parameter-based scores: myocardial damage, assessed by the presence of contraction bands and eosinophils; leukocyte infiltration, assessed by the presence of neutrophils, macrophages and lymphocytes; and interstitial edema. Each parameter was assessed by a score using the following scale: 0 – absent; 1 – slight; 2 – moderate; 3 – severe; and 4 - very severe[19].

The total score corresponding to inflammatory lesions was performed by summing the values ascribed to each parameter for each animal (total ranging from 0 to 12).

Determination of protein Interleukin 6 and 10 (IL-6), (IL-10) in cardiac tissue The determination of IL-6 and IL-10 in cardiac tissue previously frozen in liquid nitrogen was performed using the Duo-set ELISA method (R & D Systems, Inc., Minneapolis, MN, EUA).Initially, the tissue samples were macerated and homogenized in PBS at a concentration of 1 mg/ mL. After this procedure, the samples were centrifuged at 2600 rpm (Eppendorf 5804R Hamburg, Germany) for 15 min at 6° C.The collected supernatant was used in the measurements.

On the 96 well plate, 100 μL/well of capture antibody anti-IL-6 or anti-IL-10 were added. After incubation for one night at 4° C, the supernatant was discarded and the plate

Statistical Analysis The data are presented as mean ± standard deviation.

The data were analyzed by means of the SigmaStat Statistical program version 3.1 (Systat Software, San Jose, USA).

The groups were compared by Variance Analysis (Oneway Variance Analysis - ANOVA) or ANOVA on ranks (Kruskal-Wallis One-way Analysis of Variance on Ranks), after normality and equality variance tests. In the event of statistical difference (P<or=0.05) the ANOVA was complemented with the appropriate post-hoc test. Differences among groups were considered statistically significant when P< 0.05.

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Linear regression analysis was also performed to assess the correlation between the studied TBARS and interleukins’ dosages.

nmol/mg protein); however, TBARS values decreased in RLNAC group in relation to the RL group (P=0.014).

Protein dosage of pro- and anti-inflammatory interleukins in cardiac tissue Figures 2 and 3 show the results concerning the quantification of IL-6 e IL-10 in cardiac tissue for study groups.

It may be seen that the IL-6 dosages at the end of the post-treatment stabilization period were higher in RL (1.870±303.68 pg/mg protein) and RLNAC (2.138±316.89 pg/mg protein) groups, in relation to the control group (GC) (462.28±70.24 pg/mg protein), without any differences among treated groups (P=0.091). Likewise, IL-10 dosages presented increases in treated groups (848.58±106.48 and 1.019±262.51 pg/mg protein, respectively) in relation to the GC (247.31±39.82 pg/mg protein), without any differences among treated groups (P=0.169).

The linear regression analysis suggests positive association between dosages of TBARS and IL-6 (r2=0.744, P<0.001) and TBARS and IL-10 (r2=0.638, P<0.001).

RESULTS Metabolic Analysis At the end of the shock period, the RL and RLNAC groups showed significant lactate levels increases compared to the control group (7.23±1.03 vs 6.85±1.03 vs 1.15±0,25 mmol/L respectively; P=0.002).There were no significant differences at the end of the stabilization after volume reanimationphase in lactate levels between the three groups (2.89±0.94 vs 2.75±0.99 vs 1.75±1.09 mmol/L, respectively; P=0.101).

Serum potassium levels also showed significant increase in groups RL and RLNAC when compared with the control group after the shock period (6.68±0.44 vs 6.86±0.84 vs 4.95±0.39 mmol/L, respectively; P<0.001).However, at the end of the experiment, group RL presented the highest potassium level in comparison with the RLNAC group (5.95±0.75 vs 5.02±0.59 mmol/L, respectively; P=0.026).

Histopathology of heart tissue Animals in the RLNAC group presented significantly lower myocardial damage when compared with the RL group (score 1 (1-2) vs. 2.5 (2-5), P=0.049), as well as for edema scores (score 0 (0-1) vs. 2 (1-2), P=0.016).There were no differences on edema scores between the RLNAC groups and the control group (P=0.935) (Figure 4 A-C).

The evaluation of myocardial inflammatory infiltrate showed similarities between the three groups (P=0.427).

Oxidative stress in cardiac tissue Figure 1 shows the results concerning the quantification of TBARS in cardiac tissue for study groups. The TBARS dosage in cardiac tissue at the end of the stabilization after volume reanimation presented statistically significant increases in RL groups (0.27±0.05 nmol/mg protein) and RLNAC (0.20±0.05 nmol/mg protein) in relation to the control group (0.03±0.02

Fig. 1 - Thiobarbituric acid reactive substances (TBARS) values in cardiac tissue in the control group (GC), Ringer Lactate (RL) and Ringer lactate with N-acetylcysteine group (RLNAC). GC < RL, RLNAC; RLNAC < RL, P< 0.05.

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Fig. 2 - Interleukin 6 expression in cardiac tissue for the control group (CG), Ringer Lactate group (RL) and Ringer lactate with N-acetylcysteine group (RLNAC). * Significant difference when compared to CG, (P<0.05) .

Fig. 3 - Interleukin 10 expression in cardiac tissue for the control group (CG), Ringer Lactate group (RL) and Ringer lactate with N-acetylcysteine group (RLNAC). * Significant difference when compared to CG, (P<0.05).

Fig. 4 - Photomicrographs of heart tissue stained with HE of animals subjected to hemorrhagic shock and fluid resuscitation with Ringerâ&#x20AC;&#x2122;s lactate (RL Group, photomicrograph B) or Ringer Lactate associated with N-acetylcysteine (RLNAC Group, photomicrography C), compared to a control group (Group GC, A photomicrograph). It is observed in A, normal myocardium; B, myocardial damage by the presence of cardiomyocyte hipereosinophilic (more intense pink); C, myocardial preserved.

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DISCUSSION

However, in our study, the TBARS dosage in the cardiac tissue at the end of the stabilization after volume reanimation presented significant increases, describing the lipid peroxidation injury, which was attenuated by NAC. NAC effects on IR injuries were dose-dependent. While studying lung pre-conditioning with different doses of NAC to prevent IR injury after liver injury by reflow, Weinbroum et al.[17] noted that the 100 mg/kg dose attenuated the liver injury but not the lung one. High doses, such as 225 mg/kg, could imply a suppression of the properties that protect macrophages and monocytes residing in lungs, resulting in a decrease in lungs defense. The authors have concluded that the 150 mg/kg dose was more effective to reduce accumulation of xanthine oxidase in the liver tissue, reducing the tissue damages caused by ROS. Although this study shows the protecting effect of NAC on the oxidative stress in cardiac tissue, and that there is a positive correlation between oxidative stress and increase in the inflammatory cytokines, it did not show tissue reduction of pro-inflammatory IL-6.

Experimental studies have shown that the expression of the ribonucleic acid messenger of IL-6 (RNAm IL-6) is increased based on hypoxia conditions, mainly in the lungs, liver, and intestines of rats submitted to hemorrhage, inducing the cardiomyocytes to produce IL-6.Kupffer cells are the most important producers of systemic IL-6 after the shock[23].

Such increase in the genic expression and IL-6 levels in the cardiomyocytes occurs mainly two hours after the hemorrhagic shock has begun and is correlated to the cardiac dysfunction[24].

The mechanism whereby IL-6 promotes cardiac dysfunction has not been completely explained. Studies[24,25] suggest that IL-6 could act in activating the κB (NF- κB) nuclear factor that, in turn, would activate the transcription of inflammatory cytokines, chemotaxins, and adhesion molecules, notably the ICAM-1 in the heart. Such cascade of events would favor neutrophils adhesion and migration processes through the endothelial barrier to the interstitial space and parenchymatous tissue, with consequent myocardial damage.

Despite the increased levels of IL-6 noted in the hearts of both groups submitted to hemorrhagic shock, there was no difference in the scores for leucocitary infiltration for all study groups, including the GC group. The experimental protocol follow-up of this study is considered short to be able to verify myocardium infiltrate, because the increase in interleukins dosages takes place before inflammatory cells are present in the tissue.

In this study, we noted that the shock protocol activated the inflammatory cascades with significant increase of IL-6 and IL-10; nevertheless, there was no interference in the modulation with NAC in reducing IL-6 and increasing the expression of the IL-10.Mukherjee et al.[26] reported that the NAC treatment caused decreased dosage of serum IL-6 and

The results suggest that the NAC plays a promising role in the pharmacological therapy combined with fluid replacement in treating hemorrhagic shock, reducing tissue damage, edema, and oxidative stress on the cardiac tissue. To the extent of our knowledge, this is the first study that assessed the NAC effect on heart injury in a controlled hemorrhagic shock model in rats.

With regard to biochemistry data, the lactate – an important tissue stress predictor – presented a significant increase during the shock, followed by normalization after volume reanimation, although without NAC’s intervening. Nevertheless, the treatment with NAC reduced the potassium levels.

After the beginning of the ischemia that follows the shock, the oxidative phosphorylation is exhausted and the anaerobic metabolism becomes the primary source of ATP production. Such break down in the cell’s energetic condition leads to an accumulation of extra-cell potassium. The mechanism that causes potassium accumulation is not fully explained. The Na-K pump is inhibited in ischemic muscle cells models, contributing to reduce the K influx parallel to ATP-sensitive potassium channels, and it may be the main mechanism through which potassium efflux increases during muscle cell ischemia[20].

In an experimental study assessing secondary systemic changes to a prolonged hemorrhage hypertension condition, Torres et al.[21] noted that the potassium increase was related to mortality and could explain sudden and early death of some animals during the experiment. While evaluating the role potassium plays as a marker of tissue hypoxia in an experimental model, Rocha Filho et al.[20] noted that the increase in potassium serum levels complied with hemodynamic deterioration, finding a strong correlation between potassium and lactate levels. NAC, by acting on microcirculation and improving tissue perfusion, may take part in potassium washout restoring the aerobic metabolism. However, an in-depth evaluation is necessary to clarify whether this findings may be ascribed or not to the NAC’S protection role. No data have been found in literature to corroborate such fact.

In this study, it was noted that the myocardium damage and edema induced by hemorrhagic shock were lessened by volume replacement reanimation and NAC. Although the hemorrhagic shock was maintained for 60 minutes, no leucocitary infiltrated in the cardiac tissue was noticed. Such results agree with the studies performed by Meurs et al.[22], who evaluated the neutrophil recruitment in several organs in hemorrhagic shock protocols. The authors pointed out that, in the heart, the early expression of adhesion molecules in the microvascular bed was not accompanied by the leucocitary recruitment, different from lungs, liver, and kidneys, in which the expression of adhesion molecules was accompanied by an expressive leucocyte migration to tissues.

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increased plasma dosage of IL-10 in neonatal rats after two hours of induced septic shock. However, the authors state that, after 4 hours from the beginning of the experiment, the serum levels of IL-6 and IL-10 were similar in the groups, showing that the effect of the administration of NAC on interleukins expression is time-dependent. Therefore, they suggested once again that longer experimental protocols are needed to elucidate the effect of NAC on the expression of interleukins in hemorrhagic shock.

4. Lefèvre G, Beljean-Leymarie M, Beyerle F, Bonnefont-Rousselot D, Cristol JP, Thérond P, et al. Evaluation of lipid peroxidation by measuring thiobarbituric acid reactive substances. Ann Biol Clin (Paris). 1998;56(3):305-19.

5. Zweier JL, Talukder MA. The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res. 2006;70(2):181-90.

6. Garlid AO, Jaburek M, Jacobs JP, Garlid KD. Mitochondrial reactive oxygen species: which ROS signals cardioprotection?

Am J Physiol Heart Circ Physiol. 2013;305(7):H960-8.

CONCLUSION

7. Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res. 2004;61(3):481-97.

NAC showed a protective role in the cardiac tissue of rats submitted to hemorrhagic shock, mainly in lessening oxidative stress and histologic injury. Nevertheless, new studies must be performed that should consider the use of larger NAC doses associated with longer observation protocols in order to allow analyzing data regarding the late stage of the shock.

8. Santry HP, Alam HB. Fluid resuscitation: past, present, and the future. Shock. 2010;33(3):229-41.

9. Sochman J. N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know?! J Am Coll Cardiol. 2002;39(9):1422-8.

Authors’ roles & responsibilities LDOF KRS PFS MKK SMS EFSM

10. Cailleret M, Amadou A, Andrieu-Abadie N, Nawrocki A, Adamy C, Ait-Mamar B, et al. N-acetylcysteine prevents the deleterious effect of tumor necrosis factor-(alpha) on calcium transients and contraction in adult rat cardiomyocytes. Circulation.

2004;109(3):406-11.

Analysis and/or interpretation of data, final approval of the manuscript, design and study design, operations and/or experiments conduct Final approval of the manuscript, conception and design of the study, operations and/or experiments conduct, manuscript writing or critical review of its content Analysis and/or interpretation of data, final approval of the manuscript, study design, manuscript writing or critical review of its content Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript, manuscript writing or critical review of its content Analysis and/or interpretation of data, final approval of the manuscript, operations and /or experiments conduct Analysis and/or interpretation of data, final approval of the manuscript, study design, manuscript writing or critical review of its content

11. Glantzounis GK, Rocks SA, Sheth H, Knight I, Salacinski HJ, Davidson BR, et al. Formation and role of plasma S-nitrosothiols in liver ischemia-reperfusion injury. Free Radic Biol Med. 2007;42(6):882-92.

12. Saad KR, Saad PF, Dantas Filho L, Brito JM, Koike MK, Zanoni FL, et al. Pulmonary impact of N-acetylcysteine in controlled hemorrhagic shock model in rats. J Surg Res. 2013;182(1):108-15.

13. Saad PF, Saad KR, Oliveira Filho LD, Ferreira SG, Koike MK, Montero EF. Effect of N-acetylcysteine on pulmonary cell death in a controlled hemorrhagic shock model in rats. Acta Cir Bras.

2012;27(8):561-5.

14. Portella AO, Montero EF, Poli de Figueiredo LF, Bueno AS, Thurow AA, Rodrigues FG. Effects of N-acetylcysteine in hepatic ischemia-reperfusion injury during hemorrhagic shock.

Transplant Proc. 2004;36(4):846-8.

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24. Yang S, Zheng R, Hu S, Ma Y, Choudhry MA, Messina JL, et al. Mechanism of cardiac depression after trauma-hemorrhage: increased cardiomyocyte IL-6 and effect of sex steroids on IL-6 regulation and cardiac function. Am J Physiol Heart Circ Physiol.

2004;287(5):H2183-91.

20. Rocha Filho JA, Nani RS, D'Albuquerque LA, Malbouisson LM, Carmona MJ, Rocha-E-Silva M, et al. Potassium in hemorrhagic shock: a potential marker of tissue hypoxia. J Trauma. 2010;68(6):1335-41.

25. Yang S, Hu S, Hsieh YC, Choudhry MA, Rue LW 3rd, Bland KI, et al. Mechanism of IL-6-mediated cardiac dysfunction following trauma-hemorrhage. J Mol Cell Cardiol. 2006;40(4):570-9.

21. Torres LN, Torres Filho IP, Barbee RW, Tiba MH, Ward KR, Pittman RN. Systemic responses to prolonged hemorrhagic hypotension.

Am J Physiol Heart Circ Physiol. 2004;286(5):H1811-20.

26. Mukherjee R, McQuinn TC, Dugan MA, Saul JP, Spinale FG. Cardiac function and circulating cytokines after endotoxin exposure in neonatal mice. Pediatr Res. 2010;68(5):381-6.

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Murad JuniorORIGINAL JA, et al. - Predictors of mortality in cardiac surgery: brain ARTICLE natriuretic peptide type B

Predictors of mortality in cardiac surgery: brain natriuretic peptide type B Preditores de mortalidade em cirurgia cardíaca: peptídeo natriurético cerebral tipo B

Jamil Alli Murad Junior1, MD; Marcelo Arruda Nakazone1, MD; Mauricio de Nassau Machado1, PhD; Moacir Fernandes de Godoy2, PhD

DOI 10.5935/1678-9741.20150008

RBCCV 44205-1630

Abstract Objective: We evaluated whether the preoperative serum concentration of brain natriuretic peptide (BNP) is a predictor of in-hospital mortality in patients that underwent cardiac surgery.

Methods: We continuously evaluated 488 patients that underwent cardiac valve surgery or coronary artery bypass grafting (CABG) between January of 2009 and July of 2012. Follow up of these patients were done prospectively for 30 days postoperatively.

Results: Data analysis showed that the overall mortality rate was equal to 9.6%, Receiver Operating Charactheristic (ROC) curve analysis found the optimal cut-off value of BNP equal to 382 pg/mL for overall mortality (AUC=0.73, 95% CI=0.66 to 0.81, P<0.001). Multivariate analysis showed that the value of BNP higher than 382 pg/mL (P=0.033, HR=2.05, 95% CI=1.6 to 3.98) was an independent predictor of overall mortality at 30 days postoperatively.

Conclusion: We concluded that the preoperative serum concentration of BNP is an independent predictor of mortality in patients undergoing valve surgery or coronary artery bypass graft.

Resumo Objetivo: Avaliar se a concentração sérica pré-operatória de peptídeo natriurético cerebral tipo B (BNP) é preditora de mortalidade intra-hospitalar em pacientes submetidos à cirurgia cardíaca.

Métodos: Foram avaliados 488 pacientes consecutivamente submetidos à cirurgia cardíaca valvar ou à cirurgia de revascularização do miocárdio no período de janeiro de 2009 a julho de 2012. Estes foram seguidos, prospectivamente, por 30 dias de pós-operatório.

Resultados: Em nossa casuística, a mortalidade geral foi igual a 9,6% e 52% dos pacientes foram submetidos a cirurgia de revascularização do miocárdio. Análise de curva ROC (Receiver Operating Charactheristic) encontrou o valor de corte ótimo de BNP igual a 382 pg/mL para mortalidade geral (AUC=0,73, IC95%=0.66 a 0,81, P<0.001). Análise multivariada mostrou que o valor de BNP > 382 pg/mL (P=0,033, HR=2,05, IC 95%=1,06 a 3,98) foi preditor independente de mortalidade geral em 30 dias de pós-operatório.

Conclusão: A concentração sérica pré-operatória do BNP é um preditor independente de mortalidade em pacientes submetidos à cirurgia valvar ou de revascularização do miocárdio.

Descriptors: Natriuretic Peptides. Hospital Mortality. Cardiovascular Surgery Procedures. Prospective Studies.

Descritores: Peptídeos Natriuréticos. Mortalidade Hospitalar. Procedimentos Cirúrgicos Cardiovasculares. Estudos Prospectivos.

Hospital de Base (HB)/Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil and specialist in cardiology by Brazilian Society of Cardiology/Brazilian Medical Association 2 Division of Cardiology and Post Graduation in Health Sciences of Faculdade de Medicina de São José do Rio Preto, SP, Brazil.

Correspondence address: Jamil Alli Murad Junior Hospital de Base de S. José do Rio Preto Av. Brigadeiro Faria Lima, 5544 – São José do Rio Preto, SP, Brazil Zip code: 15090-000 E-mail: jmuradjr@gmail.com

1

This work was performed at Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.

Article received on September 9th, 2013 Article accepted on February 2nd, 2015

No financial support.

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tality from all causes within 30 days postoperatively. All variables were defined according to the latest guidelines published by the American Heart Association and European Society of Cardiology.

The serum concentration of BNP was measured in the preoperative period immediately before all operations, by the method of electrochemiluminescence using the Siemens ADVIA Centaur equipment (Siemens Medical).

Categorical variables were presented as absolute numbers (percentages) and continuous variables as median and interquartile range.

Statistical analysis was performed with SPSS software (version 20.0). The discriminating power of the value of preoperative serum concentration of BNP to predict mortality from all causes in 30 days after surgery was determined with the aid of statistical C by calculating the area under the ROC curve (“Receiver Operating Characteristic”), with the value > 0.60 considered not determined by chance.

In this study, proportional regression risk analysis of Cox was used to establish the relationship between the dependent variable (mortality from all causes) and the exploratory variables. Single variables associated with mortality (P value ≤0.05) were considered for multivariate regression analysis.

The Spearman test was used to correlate continuous variables when two or more variables were closely correlated, the one with the highest statistical value of Wald was selected for multivariate analysis. Independent predictors of mortality were established for variables with P≤0.05 in multivariate analysis.

The stepwise logistic regression method with likelihood ratio was used to determine independent predictors of mortality from all causes in the multivariate analysis. The probability of survival, as well as risk functions were estimated by the Kaplan-Meier method. The log rank test was used to compare the probability of survival between groups.

Values with P ≤ 0.05 were considered statistically significant.

Abbreviations, acronyms & symbols AUC BNP CABG CI HR LV ROC

Area under ROC curve Brain natriuretic peptide Coronary artery bypass grafting Confidence interval Hazard ratio Left ventricle Receiver Operating Charactheristic

INTRODUCTION In the last decade, the interest in the use of brain natriuretic peptide (BNP) levels as a risk stratification tool in patients undergoing cardiac surgery has increased[1-3]. In the clinical setting, risk scoring systems are widely validated and used as the gold standard method of evaluation of risk of perioperative mortality.

On the other hand, these systems were proved to be complex with limited accuracy for certain cohorts of patients[4,5]. Consequently, new markers able to stratify risk and predict higher mortality rate in cardiac surgery are being investigated.

In addition to be used as a parameter to assess and validate the prognosis in several clinical situations, the measurement of BNP serum concentration has low cost, is easily performed and highly available, and has good reproducibility[6-8]. Up to this the moment, few studies have evaluated the serum concentration of preoperative BNP as a predictor of mortality in cardiac surgery, mainly due to the heterogeneity of small sample size, making it impossible to consistently assess its relation to mortality[1-3]. Thus, additional studies have become necessary to demonstrate the correlations between BNP levels and mortality in cardiac surgery. In this study, the aim was to assess whether the preoperative BNP can be used as an independent predictor of mortality in cardiac surgery.

METHODS

RESULTS

The study evaluated 488 patients admitted to the Postoperative Cardiac Intensive Care Unit in the Medical School of Sao Jose do Rio Preto/Hospital of Base for heart valve surgery or coronary artery bypass grafting between January of 2009 and June of 2012. Exclusion criteria included patients younger than 18 years old, with advanced malignancy or who had undergone combined cardiac procedures. Data were collected prospectively by consulting the computerized database Hospital de Base of São José do Rio Preto - SP - Brazil. This hospital is a reference center for the treatment of cardiovascular diseases and serves a region of about 1.5 million people. The study was approved by the Ethics Committee of the Medical School of São José do Rio Preto (Protocol Number 6079/2010) and due to the nature of the study,no informed consent was required.

The data included demographic, comorbidities, degree of left ventricular systolic dysfunction, intraoperative variables and mor-

Baseline characteristics of patients From January of 2009 to June of 2012, 488 consecutive patients undergoing coronary artery bypass grafting or isolated valve surgery were included in the study.

The baseline characteristics evaluated in this study are summarized in Table 1. The median age was 57 (49-65) years and 58% were men. From the 488 patients, 92 (19%) were diabetic, 328 (67%) had systemic arterial hypertension. One hundred twenty-six patients (26%) had emergency surgery, 70 patients (14%) had at least one previous cardiac surgery and 80 patients (16%) had left moderate or severe ventricular dysfunction, the preoperative serum creatinine concentration and the preoperative clearance of creatinine were 1.1 mg/dl (0.9 to 1.3) and 68.5 mL/min/1.73 m2 (52.6 to 87.4), respectively. Isolated valve surgery was performed in 236 patients (48%) and coronary artery bypass surgery in 252 patients (52%), with 457 operations

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Table 1. Baseline characteristics of patients included in the study (n = 488).

(94%) performed with cardiopulmonary bypass, with the median of cardiopulmonary bypass time equal to 98 (81-120) minutes. The median value of addictive EuroSCORE was 3 (2-5). Â Mortality from all causes at 30 days postoperatively The area under the ROC curve was 0.74 (95% CI 0.66 to 0.81) for preoperative serum BNP with a cut-off value of 382 pg/mL, with a sensitivity of 72% and specificity equal to 64% for predicting death from all causes in 30 days after surgery (Figure 1).

In univariate analysis, age (P<0.001), urgency or emergency surgery (P<0.001), left moderate or severe ventricular dysfunction (P=0.026), previous surgery (P<0.001), preoperative serum BNP>382 pg/mL (P<0.001), clearance of preoperative creatinine (P<0.001) and cardiopulmonary bypass time (P<0.001) were retained to multivariate analysis. The age (P<0.001, HR = 1.05; 95% CI 1.02 to 1.09), urgent or emergency surgery (P=0.027, HR=1.98, 95% CI 1.08 to 3.64), preoperative serum BNP> 382 pg/mL (P=0.033, HR=2.05, 95% CI 1.06 to 3.98), clearance of preoperative creatinine (P<0.001, HR=0.97; 95% CI 0.96 to 0.99) and cardiopulmonary bypass time (P<0.001, HR=1.02, 95% CI 1.01 to 1.02) variables were retained as predictors independent of death from all causes after multivariate Cox regression analysis (Table 2).

Variables Age, years, median (Q1-Q3) Male, n (%) Systemic Arterial Hypertension, n (%) Chronic Obstructive Pulmonary Disease Diabetes Mellitus, n (%) Urgent or emergency surgery, n (%) Body mass index, median (Q1-Q3) Moderate or severe LV dysfunction, n (%) Previous Surgery, n (%) Preoperative serum creatinine (mg/dl) Preoperative creatinine clearence (ml/ min/1.73m2) Preoperative BNP, pg/ml, median (Q1-Q3) Additive EuroSCORE, median (Q1-Q3) Coronary Artery Bypass Surgery, n (%) Valve surgery, n (%) Preparative troponin I, median (Q1-Q3) Use of intra-aotic balloon, n (%) Number of coronary grafts, median (Q1-Q3) Use of extracorporeal circulation, n (%) Extracorporeal circulation time, min, median (Q1-Q3)

Values 57 (49-65) 284 (58) 328 (67) 16 (3.3) 92 (19) 126 (26) 26 (23-29) 80 (16) 70 (14) 1.1 (0.9-1.3) 68.5 (52.6-87.4) 239 (80-786) 3 (2-5) 252 (52) 236 (48) 0.1 (0.01-1.1) 31 (6.4) 3 (2-3) 457 (94) 98 (81-120)

LV=Left ventricle; BNP=brain natriuretic peptide

Fig. 1 - ROC (Receiver Operating Characteristic) curve relating preoperative serum brain natriuretic peptide (BNP) and mortality from all causes.

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Table 2. Uni and multivariate analysis of the variables in relation to mortality.

Variables Univariate model Age Male Systemic Arterial Hypertension Chronic Obstructive Pulmonary Disease Diabetes Mellitus Urgent br emergency surgery Body mass index Moderate or severe LV dyfunction Previous Surgery BNP preoperative > 382 pg/ml Preoperative creatinine clearence Extracorporeal circulation time, minutes Multivariate model Age Urgent or emergency surgery Extracorporeal circulation time, minutes Preoperative creatinine clearence BNP preoperative > 382 pg/ml

P value

Hazard Ratio

95%CI

<0.001 0.317 0.286 0.213 0.406 <0.001 0.908 0.026 <0.001 <0.001 <0.001 <0.001

1.074 0.075 1.429 2.104 1.332 3.882 1.003 2.067 3.025 3.89 0.96 1.017

1.043-1.105 0.421-1.323 0.742-2.752 0.653-6.776 0.678-2.616 2.184-6.900 0.948-1.062 1.091-3.917 1.638-5.586 2.082-7.270 0.94-0.97 1.012-1.021

<0.001 0.02 <0.001 <0.001 0.034

1.081 2.039 1.017 0.97 2.059

1.050-1.114 1.116-3.726 1.012-1.023 0.96-0.99 1.056-4.015

LV=Left ventricle; BNP=brain natriuretic peptide; CI=confidence interval

Fig. 2 - Kaplan-Meier’s curve for survival at 30 days postoperatively. BNP=brain natriuretc peptide

Figure 2 illustrates the 30-day survival probability of patients who were divided into groups according to the BNP values being lower than or equal to 382 pg/ml or greater than 382 pg/ml, respectively, with the values being 95.6% and 82.5 % at 30 days after surgery (P<0.001).

DISCUSSION In this prospective and contemporary study of patients undergoing cardiac surgery the preoperative serum concentration of BNP was correlated to postoperative mortality. Al-

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though there are several known risk factors of mortality in cardiac surgery, the association between preoperative BNP and mortality in cardiac surgery is still under investigation[1].

We found that preoperative BNP is an independent predictor of postoperative mortality in cardiac surgery. This assertion is based on the P value obtained by Cox regression analysis, in addition to the significant difference in the probability of survival between the groups stratified according to BNP. This finding demonstrates a role for BNP regarding the evaluation of preoperative risk in cardiac surgery.

Few studies have described the prognostic significance of preoperative BNP in the heart surgery setting[1-3]. In a meta-analysis recently published the preoperative BNP was evaluated as a predictor of adverse outcomes in cardiac surgery, among 819 relevant studies identified in the literature, only four associated preoperative serum BNP with mortality and of these, only one has examined this relationship with the help of multivariate analysis[1]. In this small study mentioned (n=209), BNP was an independent predictor of adverse cardiac events, described as combined event of death and non-fatal events (malignant ventricular arrhythmia, myocardial infarction and heart failure)[9]. In the present study, we found that preoperative BNP was an independent predictor of mortality from all causes with methodology specifically geared to this goal to become a pioneering study in relation to its results.

Our group believes that the prognostic value of preoperative BNP is due to its ability to measure ventricularhemodynamic changes even in asymptomatic patients[10]. Discovered in 1988, only in 1994 a study was performed to assess the site and mechanism of secretion of BNP, showing that higher BNP levels were significantly correlated with increased pulmonary capillary wedge pressure, increased diastolic and end systolic ventricular volume of the left ventricle, lower left ventricular ejection fraction and a lower cardiac index[11-14].

Consequently, it was concluded that secretion is stimulated by increased ventricular wall stress and correlates with increased cardiovascular risk variables[10,11,15]. Our group believes that this pathophysiological mechanism intrinsically related to secretion of BNP is the explanation for the higher levels of preoperative BNP are independently associated with increased mortality in cardiac surgery.

Score systems are widely used in preoperative risk stratification with emphasis on choosing the best method of treatment according to the risk found, and performed an uniform comparative analysis between different surgeons and centers specialized in heart surgery[16,17]. However, conducts aiming to reduce perioperative risk are rarely adopted based on these risk scores because they are made up of a large number of variables, and do not have a progressive nature to assess pre-surgical procedures[18]. Therapies guided by BNP levels have been effective in reducing hospitalization and death in patients with heart failure[19]. Therefore, BNP can provide a noninvasive indicator to evaluate the effectiveness of

perioperative hemodynamic reductions in stress related to blood volume status of these patients aiming at better risk stratification and optimization of surgical outcomes.

This study was designed to assess the association between the value of preoperative serum BNP and mortality in patients undergoing valve replacement surgery or coronary artery bypass graft surgery. Compared to the other existing studies in this area, this study has the highest number of participants with clinically relevant result to demonstrate that preoperative BNP was an independent predictor of the outcome of isolated postoperative mortality in cardiac surgery. However, our study has limitations, such as the fact that it was performed at a single medical center with short-term follow-up.

Further studies are needed to assess the association between preoperative serum BNP and mortality in cardiac surgery, because the data are limited regarding this issue. Our study adds information to the limited literature and suggests that the BNP preoperative serum concentration should be included in all future studies that assess mortality in cardiac surgery as a clinical outcome.

CONCLUSION It was demonstrated that the high levels of preoperative BNP were an independent predictor of 30-day mortality after surgery for patients undergoing heart valve surgery or coronary artery bypass graft. This finding raises the possibility that targeted therapy for the reduction of BNP can be effective in reducing mortality in cardiac surgery.

Authorsâ&#x20AC;&#x2122; roles & responsibilities JAMJ

MAN MNM MFG

Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; study design Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; writing of the manuscript or critical review of its content

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2. Patel UD, Garg AX, Krumholz HM, Shlipak MG, Coca SG, Sint K, et al; Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury (TRIBE-AKI) Consortium. Preoperative serum brain natriuretic peptide and risk of acute kidney injury after cardiac surgery. Circulation. 2012;125(11):1347-55.

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5. 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.

14. Gabriel EA, Locali RF, Matsuoka PK, Almeida LS, Silva PS, Ishigai MM, et al. Pulmonary artery perfusion does not improve brain natriuretic peptide (BNP) levels in suine experimental research. Rev Bras Cardiovasc. 2010;25(4):516-26.

6. Struthers AD. Ten years of natriuretic peptide research: a new dawn for their diagnostic and therapeutic use? BMJ. 1994;308(6944):1615-9.

15. Mukoyama M, Naka K, Hosoda K, Suga S, Saito Y, Ogawa Y, et al.

Brain natriuretic peptide as a novel cardiac hormone in humans.

Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest.

1991;87(4):1402-12.

7. Suzuki S, Yoshimura M, Nakayama M, Mizuno Y, Harada E, Ito T, et al. Plasma level of B-type natriuretic peptide prognostic marker after the acute myocardial infarction: a long-term followup analysis. Circulation. 2004;110(11):1387-91.

16. Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G. Risk of assessing mortality risk in elective cardiac operations: age, creatinine, ejection fraction, and the law of parsimony.

Circulation. 2009;119(24):3053-61.

8. Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P, Rouleau JL, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation.

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17. Parsonnet V, Dean D, Bernstein AD. The method of uniform stratification of risk factors for evaluating the results of surgery in acquired adult heart disease. Circulation. 1989;79(6 Pt 2):I3-12.

18. Tu JV, Sykora K, Naylor CD. Assessing the outcomes of coronary artery bypass graft surgery: how many risk factors are enough?

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9. Fellahi JL, Daccache G, Rubes D, Massetti M, Gerard JL, Hanouz JL. Does preoperative B-type natriuretic peptide better predict adverse outcome and prolonged length of stay than the standard European System for Cardiac Operative Risk Evaluation after cardiac surgery? J Cardiothorac Vasc Anesth 2011;25(2):256-62.

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Franco SS, etORIGINAL al. - A propose of pulmonary dysfunction stratification afther ARTICLE valve surgery by physiotherapeutic assistance level

A propose of pulmonary dysfunction stratification after valve surgery by physiotherapeutic assistance level Proposta de estratificação da disfunção pulmonar após cirurgia valvar segundo níveis de assistência fisioterapêutica

Satiko Shimada Franco1, Ft; Luiz Marcelo Sá Malbouisson2, PhD; Max Grinberg1, PhD; Maria Ignêz Zanetti Feltrim1, PhD

DOI 10.5935/1678-9741.20150006

RBCCV 44205-1631

Abstract Objective: a) to propose and implement an evaluation system; b) to classify the pulmonary involvement and determine levels of physical therapy; c) to check the progress postoperatively.

Methods: Patients underwent physiotherapy assessment preoperatively, postoperatively and after 5 days of intervention.

They were classified into three levels of care: level 1 - low risk of complication; Level 2 - medium risk; Level 3 - high risk. We used analysis of variance and Kruskal-Wallis and analysis of variance for repeated measures or Friedman. Chi-square test or Fisher for proportions. We considered statistical significance level P<0.05.

Results: We studied 199 patients, 156 classified within level 1, 32 at level 2 and 11 at level 3. Thoracoabdominal motion and auscultation changed significantly postoperatively, persisting at levels 2 and 3 (P<0.05). Oxygenation and respiratory rate changed at levels 2 and 3 postoperatively (P<0.05) with recovery at the end. Significant decrease in lung volumes occurred in three levels (P<0.05) with partial recovery at level 1, lung collapse occurred at all levels, with recovery by 56% at level 1, 47% at level 2, 27% at level 3.

Conclusion: The proposed assessment identified valve surgery patients who require differentiated physical therapy. Level 1 patients had rapid recovery, while the level 2 showed signifi-

cant changes with functional gains at the end. Level 3 patients, more committed and prolonged recovery, should receive greater assistance.

Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil.

2 Anestesiology Department of Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil.

Correspondence address: Satiko Shimada Franco Instituto do Coração do Hospital das Clínica da Faculdade de Medicina da Universidade de São Paulo InCor-HCFMUSP Av. Dr. Enéas de Carvalho de Aguiar, 44, 2o andar - Cerqueira Cesar – São Paulo, SP, Brazil Zip code: 05403-000 E-mail: satiko.shimada@incor.usp.br

Descriptors: Thoracic Surgery. Physical Therapy Modalities.

Vital Capacity.

Resumo Objetivo: a) propor e aplicar um sistema de avaliação; b) classificar o comprometimento pulmonar e determinar os níveis de assistência fisioterapêutica; c) verificar a evolução no pós-operatório de cirurgia valvar.

Métodos: Pacientes realizaram avaliação fisioterapêutica no pré-operatório, pós-operatório e após 5 dias de intervenção.

Foram classificados em três níveis de atenção: nível 1 - baixo risco de complicação; nível 2 - médio risco; nível 3 - alto risco. Utilizou-se Análise de Variância e Kruskal-Wallis e Análise de Variância para medidas repetidas ou Friedmann. Teste quiquadrado ou Fisher para as proporções. Considerou-se nível de significância estatística P<0,05.

Resultados: Foram estudados 199 pacientes, 156 classificados no nível 1, 32 nível 2 e 11 nível 3. Movimento toracoabdominal e ausculta pulmonar alteraram significantemente no pós -operatório, persistindo nos níveis 2 e 3 (P<0,05). Oxigenação

1

Work carried out at Instituto do Coração (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil and Anestesiology Department of Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil.

Article received on September 4th, 2014 Article accepted on January 26th, 2015

No financial support.

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(P<0,05), com recuperação parcial no nível 1. Colapso pulmonar ocorreu em todos os níveis, com recuperação em 56% no nível 1, 47% no nível 2, 27% no nível 3.

Conclusão: A avaliação proposta identificou pacientes de cirurgia valvar que necessitam de assistência fisioterapêutica diferenciada. Pacientes do nível 1 tiveram rápida recuperação, enquanto os do nível 2 mostraram alterações significativas, com ganhos funcionais no final. Pacientes do nível 3, mais comprometidos e com recuperação prolongada, devem receber maior assistência.

Abbreviations, acronyms & symbols ECC ICU PA PFC SpO2 TxAbM

Extracorporeal circulation Intensive care unit Pulmonary auscultation Peak flow cough Peripheral oxygen saturation Thoracoabdominal motion

e frequência respiratória se modificaram nos níveis 2 e 3 no pós-operatório (P<0,05), com recuperação no final. Diminuição significante dos volumes pulmonares ocorreu nos três níveis

Descritores: Cirurgia Torácica. Modalidades de Fisioterapia.

Capacidade Vital.

INTRODUCTION

tee of the Hospital das Clinicas at the Faculty of Medicine, University of São Paulo (approval No. 011/09). The informed consent was obtained from all of the subjects, who had undergone valve surgery.

The inclusion criteria for this study were as follows: patients of both sexes, patients aged 18 to 80 years, and patients hospitalized to undergo elective valve surgery who had no signs or symptoms of respiratory distress. Patients who had difficulty performing the functional tests, who were receiving oxygen therapy, or who required noninvasive ventilation in the preoperative period were excluded, as well as patients whose conditions progressed to cerebrovascular accident, who showed hemodynamic instability and worsening of clinical condition, or who died immediately after operation. Personal, anthropometric, and clinical data were collected from the patients who were hospitalized to undergo elective valve surgery.

A physical therapy evaluation that comprised eight parameters was conducted as follows: 1. Thoracoabdominal motion (TxAbM): With the patient placed in the dorsal position, the thoracoabdominal movement was evaluated during 1 minute. The TxbAM was classified as normal when the abdominal displacement predominated; mixed, when no thoracic or abdominal displacement predominated; thoracic, with predominant displacement of the rib cage; and paradoxical, when the thoracic or abdominal movements were inverted.

2. Pulmonary auscultation (PA): PA was verified based on lung sound and presence of adventitious sounds.

3. Mobility: Mobility was classified according to the degree of independence the patient had while sitting down and moving around.

4. Oxygenation: Peripheral oxygen saturation (SpO2) was measured by using pulse oximetry (Dixtall®), with the patient breathing environment air, after 5 minutes[15] in the dorsal position, with the headrest at 45º and the sensor placed in the middle finger of the right hand.

5. Respiratory frequency (f): Respiratory frequency was defined as the number of inspiratory incursions occurring in 1 minute, in the dorsal position.

The presence of postoperative respiratory dysfunction in patients after cardiovascular surgery with extracorporeal circulation (ECC), under general anesthesia, range from 50% to 100%[1-4]. Alterations in lung mechanics, such as decreased functional residual capacity, contribute to the occurrence of pulmonary collapse, increased shunt, decreased gas diffusion, and consequently, hypoxemia[5,6]. In this context, the presence of pain and chest tubes are directly implicated in keeping low lung volumes[7,8].

The use of techniques to remove bronchial secretions, as well as respiratory and early mobilization exercises, promote improvement of pulmonary function, support the correction of hypoxemia, and stimulate functional independence. However, despite that therapeutic protocols are widely used after cardiac surgery, the benefits of these protocols are not yet well established[9-16].

Evaluation and application of a classification system based on differentiated levels of physical therapy assistance comprise an alternative strategy for optimizing postoperative patient care[17-19]. The challenge is to differentiate patients according to the degree of pulmonary alterations present and to recommend appropriate therapies, with consideration of the available resources and application timing.

The use of physical therapy strategies adjusted to the severity level of respiratory dysfunction in individual patients may be beneficial in terms of inhibiting the clinical progression of respiratory dysfunction, and the organization and standardization of physical therapy assistance. Therefore, we designed this study with the following objectives: a) to propose and apply a postoperative evaluation system for patients undergoing cardiac valve surgery; b) to classify pulmonary impairment and to determine recommendable levels of physical therapy assistance; c) to monitor the postoperative clinical progress of patients who have been classified.

METHODS Patients and Methods This study was approved by the Research Ethics Commit-

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6. Pulmonary function: Pulmonary function was assessed by measuring forced vital capacity (FVC) in milliliters, obtained by using a ventilometer (Wright Mark 8®).

While in the sitting position, the patient was guided to inhale deeply and, subsequently, to expire as fast as far he/she can through mouth piece, with the nose closed with a clip to prevent air leakage. During the procedure, the patient was encouraged to optimize performance. The procedure was repeated three times, recording the highest value.

7. Peak flow cough (PFC): PFC was measured by using a peak flow meter (Assess®), with the patient in the sitting position and the nose closed with a nose clip. The patient was encouraged to inhale deeply and, subsequently, to cough through the mouth piece. The procedure was repeated three times, recording the highest value, as long as the difference between the measurements was not greater than 20 L/min.

8. Chest radiography: Chest radiographs were analyzed by a radiologist blinded to the study. Pulmonary collapse was assessed by using the Jenkins scale as follows[11]: 0, without alteration; 1, minimum collapse; 2, pronounced collapse or consolidation at one pulmonary base; and 3, bilateral alteration.

The physical therapy evaluations were performed in the ward unit at the following time points: preoperatively (basal), when the patient returned to the unit (postoperatively), and on the fifth day of the study (final of the protocol).

In the postoperative time, the patients who were assessed were classified according to degree of risk of pulmonary impairment by using the criteria shown in Table 1.

Each evaluation parameter corresponded to a point in the column. The preponderance of points in each column determined the type and level of assistance applied to the patient.

At level 1, patients with low risk of complications received minimum assistance; at level 2, patients with moderate risk of complications received intermediary assistance; at level 3, patients with high risk of complications received full assistance. In cases when the number of points was equal in 2 columns, the SpO2 criterion was used to differentiate.

When paradoxical movement, tachypnea, and hypoxemia were present, level 3 assistance was provided to the patient.

In the postoperative hospitalization period in the intensive care unit (ICU), the patient was attended to according to the ICU routine, without influence of this study. During this period, data on the surgical procedure, times of extracorporeal circulation (ECC), orotracheal intubation, and length of stay in the ICU were collected.

Level of Physical Therapy Assistance The patients received differentiated physical therapy assistance according to their classification. Patients with low risk of pulmonary complication (level 1) received physical therapy assistance for 20 minutes, once daily, with direct supervision by the physiotherapist. In this event, 3 series of 10 repetitions of therapeutic breathing exercises were performed, followed by coughing. In addition, general mobilization and walking exercises were performed. The patient was guided to repeat the breathing exercises every 2 hours, recording the results in a spreadsheet.

Table 1. Parameters for clinical and functional evaluations to define the degree of pulmonary impairment.

Parameters Thoracoabdominal motion (TxAbM)

Level 1

Level 2

Level 3

Normal

Normal/mixed

Thoracic/paradoxical

Standard pre or (sound ↓; RA+)

Abnormal sound (breathing; ↓ ↓; RA++)

Abnormal sound (breathing; ↓ ↓ ↓; RA+++)

Sits with little help, able to walk around

Requires help to sit and walk around

Requires a lot of help to sit and walk around

≥92%

88% ≥SpO2 <92%

<88%

f >15 < 25 rpm

25≥f<32

>32

Forced vital capacity (FVC)

≥50% of pre

30% ≥ FVC < 49%

<30%

Peak flow cough (PFC)

≥50% of pre

30% ≥ FVC < 49%

<30%

Normal Minimum collapse/atelectasis

Pronounced collapse or consolidation at one base

Bilateral alteration

Pulmonary auscultation Mobility Oxygenation (SpO2) Respiratory frequency (f)

Chest radiography (Jenkins, 1989)

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The patients classified at level 2 were treated with continuous positive airway pressure (CPAP) or intermittent positive pressure associated with positive end-expiratory pressure (IPPV + PEEP) for 20 minutes, twice daily. These patients also performed breathing exercises similar to those performed by the patients at level 1, maneuvers for bronchial secretion removal, assisted coughing, and mobility exercises.

The duration of the complete therapy was 40 minutes.

The patients at level 3 were treated with positive pressure at two levels of pressure (bilevel) for 60 minutes, 3 times daily. In addition, the physiotherapist applied breathing exercises, maneuvers for bronchial secretion removal, assisted coughing, and mobility exercises twice daily. The time required to assist these patients was approximately 80 minutes per session.

Five days after applying each protocol, the final evaluation was performed. The patients who remained at the same level continued to receive the same therapy until improvement or until hospital discharge. Those whose level of assistance required changed received the treatment that was proposed for the new level of assistance. The day of hospital discharge was recorded, and that was when the patients received standardized guidance of respiratory and motor care.

cardiac surgery. More than 90% of the patients were in the functional classes II or III. In our study sample, mitral valve lesions (79%) were the most common cases, with valve replacement being the most frequent surgical procedure (47%), followed by mitral commissurotomy (18.5%).

The mean durations of mechanical ventilation, and ICU and hospital stay were longer for the patients at levels 2 and 3. However, no statistically significant difference was observed between the groups.

Classification of physiotherapeutic assistance level Data regarding the TxAbM evaluation and pulmonary auscultation are shown in Table 3. The number of cases with the TxAbM altered increased significantly in the postoperative period at level 2, decreasing at the end of the study. Meanwhile, at level 3, the number of patients with this alteration increased from 64% to 82%. Pulmonary auscultation was altered in more than 85% of the cases, in all of the groups in the postoperative period. At the end of the study, a high percentage of patients at levels 2 and 3 still had significant alterations when compared with the patients at level 1.

The quantitative parameters of the physical therapy evaluation are shown in Table 4. In the analysis over time, the patients at level 1 did not show significant alterations in SpO2 and f. The pulmonary function data revealed statistically significant reductions in the postoperative period, with strong improvement at the end of the study, though not returning to the original values. The radiological data shown in Figures 2â&#x20AC;&#x201C;4 demonstrate that in this group, the patients had minimum collapse, with collapse in one of the lung bases predominating, which was significantly reduced on the fifth day of the study. The behaviour of the patients at levels 2 and 3 were similar. All of the parameters showed significant reductions during the postoperative period, with the pulmonary function value not returning to its original value. The relevance of lung collapse was higher in both groups. At level 2, collapse occurred in 41% of the patients, and bilateral alterations occurred in 9% of the patients, with strong reductions in these alterations by the end of the study. In level 3, collapse occurred in 64% of the patients.

In the comparison between the groups, we observed that patients at level 1 showed a significant improvement in pulmonary function by the end of the study, whereas the patients at levels 2 and 3 had the most severe respiratory impairment. In these groups, only oxygenation and respiratory frequency data showed significant improvements by the end of the study when compared with the postoperative period.

After the end of the study, all the patients continued to receive assistance until hospital discharge, and no complications were reported during this period.

Statistical Analysis The quantitative data were presented as mean and SD values; and the qualitative data, as absolute and relative frequencies. For a comparative analysis between the groups according to age, height, weight, and body mass index, the single-factor analysis of variance and Kruskal-Wallis were used to analyze the length of hospital stay. Homogeneity among the proportions was tested by using the chi-square or Fisher test. The comparison of mean values between the groups over time was performed by using the repeated-measures analysis of variance. For the analysis of the radiographic data, the Friedman nonparametric test was used. The level of statistical significance was considered as P<0.05.

RESULTS Between June 2009 and October 2013, 288 patients hospitalized in the General Valve Diseases Patient Care Unit were evaluated. Among these patients, 89 were excluded and 199 were included and completed the study, of whom 156 were allocated at level 1,32 at level 2, and 11 at level 3, as shown in the flowchart in Figure 1.

The anthropometric characteristics and length of hospital stay of the patients as described above are shown in Table 2.

A predominance of female patients and level 1 classification (78%) was observed, including the younger group of patients in the study.

Most of the patients did not smoke (63%) or consume alcohol (87%), and 64% of the patients did not have previous

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Franco SS, et al. - A propose of pulmonary dysfunction stratification afther valve surgery by physiotherapeutic assistance level

Fig. 1 - The flowchart of patients in the study protocol.

Table 2. Anthropometric characteristics and length of hospital stay of the patients classified according to level of physical assistance required.

Characteristics N Sex (M/F) Age (years) Height (m) Body weight (kg) BMI (kg/m2) ECC (min) MV (min) Discharged from ICU (day) Hospital discharge (day)

Level 1 156 (78%) 52/104 46±14 1.61±0.09 63±14 24.1±4.6 78.3±27 495.3±231 4.7±3 14.2±10

Level 2 32 (16%) 10/22 53±15 1.59±0.09 66±13 25.8±4.6 87.5±25 620.4±583 5.1±3 16±10

Level 3 11 (6%) 2/9 58±18 1.55±0.07 60±11 24.9±5.6 78.8±25 1131±1636 6.8±4 18.1±9

P <0.05(1) 0.073(1) 0.396(1) 0.165(1) 0.074(2) 0.141(2) 0.328(2) 0.099(2)

M=male; F=female; BMI=body mass index; ECC=extracorporeal circulation; MV=mechanical ventilation; ICU=intensive care unit.

(1) Probability descriptive levels of single-factor analysis of variance (2) Descriptive level of probability of non-parametric test and Kruskal-Wallis

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Table 3. Qualitative variables of the classification system in the 3 levels of assistance.

TxAbM (pre) Altered TxAbM (post) Altered TxAbM (discharge) Altered PA (pre) Altered PA (post) Altered PA (discharge) Altered

Level 1 156 (%)

Level 2 32 (%)

Level 3 11 (%)

P

26 (17)

7 (22)

3 (27)

0.5631

45 (29)

22 (69)#

7 (64)#

<0.0001

30 (19)

14 (44)#

9 (82)#

<0.0001

35 (23)

8 (25)

5 (45)

0.2301

35(87)

30 (94)

11 (100)

0.3748

86(55)

24 (75)#

11 (100)#

0.0029

P< 0.05 versus level 1 TxAbM=thoracoabdominal motion; PA=pulmonary auscultation. #

Table 4. Quantitative variables of the classification system of level 3 assistance.

Level 1 (n=156)

Level 2 (n=32)

Level 3 (n=11)

P

96.7±1.5 94.8±2.5 96.5±1.5

96±2.2 90.9±3.4* 94.8±3.4†

96.1±2.2 88.4±2.9* 94±2.9 †

GxT: P<0.001 G2 and 3: P=0.067

19±4 20±4 20±4

19±4 23±5* 22±4†

21±6 28±7* 25±6†

GxT: P<0.001 G2 and 3: P=0.217

2.63±0.89 1.82±0.62* 2.02±0.69*†

2.34±0.85 1.2±0.37* 1.59±0.58*†

2.28±1.17 0.90±0.43* 1.05±0.39*

GxT: P<0.001 G: P<0.001

FVC (%) FVC% (pre) FVC% (post) FVC% (discharge)

75±18 52±14* 58±15*†

72±17 37±10* 49±15*

79±35 30±12* 36±11

GxT: P<0.001 G: P<0.001

Peak Flow Cough PF (pre) PF (post) PF (discharge)

(n=107) 383±130 303±126* 350±142†

(n=32) 358±148 228±90* 297±127*

(n=11) 330±137 141±72* 177±90*

GxT: P<0.001 G: P<0.001

Oxygenation SpO2 (pre) SpO2 (post) SpO2 (discharge) Respiratory Function f (pre) f (post) f (discharge) FVC (L) FVC (pre) FVC (post) FVC (discharge)

* P<0.05 versus preoperative period; † P<0.05 versus postoperative period.

G=group; T=time, SpO2=peripheral oxygen saturation; f=respiratory frequency; FVC=forced vital capacity; FVC%=forced vital capacity in percentage predictive; PF=peak flow cough.

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Fig. 2 - Percentage of radiological changes of level 1 in the pre, post and discharge of study.

Fig. 3 - Percentage of radiological changes of level 2 in the pre, post and discharge of study.

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Fig. 4 - Percentage of radiological changes of level 3 in the pre, post and discharge of study.

DISCUSSION

regardless of the type of valve lesion[21]. This was observed in our present study again. However, in the postoperative period, the TxAbM was altered, particularly in the patients at levels 2 and 3. At the end of the study, the patients at level 2 showed a normal TxAbM, and this was partially attributed to the resolution of the pulmonary collapse observed on chest radiograph. In the patients at level 3, alterations in the TxAbM (63%) were mainly associated to the diaphragmatic dysfunction, which is a complication of cardiac surgery, occurring at an incidence of 2% to 54%[22,23], depending on the research method. The lower diaphragmatic mobility increases the area of pulmonary collapse and can be triggered through rapid superficial breathing. These patients receive intensive physical therapy support and require more time for recovery, which justifies the small improvements observed at the end of the protocol for level 3.

Pulmonary function was reduced until approximately 25% at level 1, 35% at level 2, and more than 50% at level 3. At the end of the study, the patients in all the groups showed recovery but did not achieve the preoperative values. The lower decline observed at level 1 allowed a faster recovery. In previous studies[10,14,24], FVC and/or FEV1 showed reductions of approximately 40% to 50% in regard to the expected values. Among these parameters, only age affected the results, as the younger patients presented less severe pulmonary impairment. Pain remained at the levels

Our results showed that the surgical event altered the pulmonary conditions in the patients who underwent valve surgery. The pulmonary volumes decreased, with smaller diaphragmatic mobility, which increased auscultatory alterations and reduced oxygenation. Moreover, the radiological images showed pulmonary collapse. After 5 days of study, pulmonary function improved; however, the preoperative values were not reached.

Our data showed that most of the patients were allocated into level 1 (78%), with a younger mean age. This may be justified by the fact that the patients with valve disease of rheumatic etiology and a first surgical intervention was most prevalent among the younger individuals[20]. Advanced age has been pointed out as a factor associated to a higher incidence of postoperative pulmonary complications (CPPO), which has observed in our study, as patients older than 50 years were included at levels 2 and 3.

In this structured evaluation, the respiratory mechanics was confirmed by the TxAbM analysis, palpation of the diaphragmatic movement, and generation of pulmonary volumes, which help the physiotherapist in detecting alterations in the muscle mobility. Our group previously observed that patients with stenosis and mitral regurgitation in the preoperative period showed normal TxAbM and breathing patterns,

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slight or very slight and thus did not affect the patients’ clinical progress.

Hypoxemia was present in the postoperative period, probably due to the surgical stress and reduction in the pulmonary volumes, with decreased area of gas exchange. The patients at level 1 were those with lower deoxygenation and those who recovered the original values in 5 days. The patients at levels 2 and 3, who showed higher degrees of hypoxemia, had a partial recovery but had persistent gas exchange alterations at the end of this study.

The factors that contributed to pulmonary impairment are reportedly multivariate. The presence of median sternotomy, drains, inhibition of deep breaths, hypervolemia, signs of congestive heart failure, lower complacency of the rib cage through manipulation, and diaphragmatic dysfunction may justify these pulmonary alterations[1-8]. All of these factors were present in our patients. Nevertheless, the presence of pleural changes, with consequent collapse and diaphragmatic dysfunction, was an important element in the reduction of pulmonary function.

For evaluation of pulmonary collapse, we adopted the same classification system used by Jenkins et al. [11] in patients with cardiac surgery. The authors observed the presence of collapse in 50% of the patients on the fifth day after coronary artery bypass graft surgery (CABG). In valve surgery, this incidence was 35% [14]. In our country, Vargas et al.[25] found a collapse incidence of 76% among patients on the seventh day after CABG. Our findings are not different from those reported in the literature, and we observed pulmonary collapse in the postoperative period in all of the patient groups.

Among the patients who were discharged from the hospital, 56% of the patients at level 1 achieved normal radiographic data compared with 47% and 27% of the patients at levels 2 and 3, respectively. Thus, the chest radiographic parameter was useful in differentiating patients with a higher degree of impairment, as evident in the lower functional recovery.

The application of physical therapy assessment to classify patients according to lung impairment, patients requiring smaller alterations are expected to be allocated into level 1. In fact, in our study, such patients had lower pulmonary function impairment, oxygenation, and pulmonary collapse incidence. In level 2, patients who showed a greater extent of pulmonary changes were included. Meanwhile, in level 3, only 11 patients who presented with lower variation in functional gains and had longer hospital stay were included. With the classification system used in this study, it was possible to characterize the severity of pulmonary alterations and differentiate the clinical progress of the patients.

In conclusion, the proposed evaluation method was useful in identifying from among patients who underwent valve surgery, those who developed pulmonary impairment and require different levels of physical therapy assistance. The patients at level 1 showed lower decrease in pulmonary function and

had rapid recovery. The patients at level 2 showed significant changes in their evolution but had functional improvement due to the treatment applied. The patients at level 3 showed higher levels of impairment, recovered slowly, and required a higher level of physical therapy assistance.

Limitations of the study Our study has some limitations. The main limitation was the different number of patients in each group, which was due to the random distribution of the clinical cases at the valve disease group Another limitation was that the study was performed in 5 days; thus, improvements achieved by the patients until hospital discharge were not registered.

Our study sample was a convenience sample and included patients indicated for surgery at the valve disease group and those who underwent postoperative follow-up. Most of the patients showed lesions in the mitral valve, with a small number of patients with aortic lesion, which did not allow us to perform a statistical analysis among them. This fact did not allow to evaluate the impact of valve disease on the patients’ progress.

Potential Conflict of Interest The authors declare no conflict of interest.

Sources of Funding No external funding was received for the completion of this study.

Academic Level This study is linked to the postgraduate program of anesthesiology of the Faculty of Medicine, University of São Paulo.

Authors’ roles & responsibilities SSF LMSM MG MIZF

Analysis and/or interpretation of data; operations and/or experiments conduct; writing of the manuscript or critical review of its content Analysis and/or interpretation of the data Conception and design Analysis and/or interpretation of data; statistical analysis; study design; writing of the manuscript or critical review of its content

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Kozak MF, et al. - Factors associated with moderate or severe left ORIGINAL ARTICLE atrioventricular valve regurgitation within 30 days of repair of incomplete atrioventricular septal defect

Factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of repair of incomplete atrioventricular septal defect Fatores associados à insuficiência moderada ou grave da valva atrioventricular esquerda nos primeiros 30 dias de correção de defeito de septo atrioventricular incompleto

Marcelo Felipe Kozak1, MD; Ana Carolina Leiroz Ferreira Botelho Maisano Kozak1, MD; Carlos Henrique De Marchi1, MD; Moacyr Fernandes de Godoy2, MD, PhD; Ulisses Alexandre Croti1, MD, PhD; Airton Camacho Moscardini1, MD

DOI 10.5935/1678-9741.20150026

RBCCV 44205-1632

Abstract Introduction: Left atrioventricular valve regurgitation is the most concerning residual lesion after surgical correction of atrioventricular septal defect.

Objective: To determine factors associated with moderate or greater left atrioventricular valve regurgitation within 30 days of surgical repair of incomplete atrioventricular septal defect.

Methods: We assessed the results of 51 consecutive patients 14 years-old and younger presenting with incomplete atrioventricular septal defect that were operated on at our practice between 2002 and 2010. The following variables were considered: age, weight, absence of Down syndrome, grade of preoperative left atrioventricular valve regurgitation, abnormalities on the left atrioventricular valve and the use of annuloplasty. The median age was 4.1 years; the median weight was 13.4 Kg; 37.2% had Down syndrome. At the time of preoperative evaluation, there were 23 cases with moderate or greater left atrioventricular valve regurgitation (45.1%). Abnormalities on the left atrioventricular valve were found in 17.6%; annuloplasty was performed in 21.6%.

Results: At the time of postoperative evaluation, there were

12 cases with moderate or greater left atrioventricular valve regurgitation (23.5%). The variation between pre- and postoperative grades of left atrioventricular valve regurgitation of patients with atrioventricular valve malformation did not reach significance (P=0.26), unlike patients without such abnormalities (P=0.016). During univariate analysis, only absence of Down syndrome was statistically significant (P=0.02). However, after a multivariate analysis, none of the factors reached significance.

Conclusion: None of the factors studied was determinant of a moderate or greater left atrioventricular valve regurgitation within the first 30 days of repair of incomplete atrioventricular septal defect in the sample. Patients without abnormalities on the left atrioventricular valve benefit more of the operation.

Department of Pediatrics and Pediatric Surgery, Hospital de Base, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil.

2 Department of Cardiology, Hospital de Base, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil.

Correspondence address: Marcelo Felipe Kozak 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: marcelo.f.kozak@uol.com.br

Descriptors: Endocardial Cushion Defects. Mitral Valve Insufficiency. Heart Defects, Congenital. Postoperative Period.

Resumo Introdução: A insuficiência da valva atrioventricular esquerda é a lesão residual mais preocupante após o tratamento cirúrgico do defeito de septo atrioventricular.

1

Work carried out at Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil and Hospital de Base (HB), São José do Rio Preto, SP, Brazil.

Article received on November 26th, 2014 Article accepted on April 6th, 2015

No financial support.

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valva atrioventricular foram encontradas em 17,6% dos casos; anuloplastia foi realizada em 21,6% dos pacientes.

Resultados: Após a correção cirúrgica, 12 casos apresentaram insuficiência da valva atrioventricular esquerda pelo menos moderada (23,5%). A variância entre os graus de insuficiência da valva atrioventricular esquerda pré e pós-operatória nos pacientes com anormalidades na valva atrioventricular não teve significância estatística (P=0,26), ao contrário daqueles sem tais anormalidades (P=0,016). Pela análise univariada, apenas a ausência de síndrome de Down teve significância estatística (P=0,02). Porém, após análise multivariada, nenhum dos fatores teve significância.

Conclusão: Nenhum dos fatores estudados foi determinante de insuficiência da valva atrioventricular esquerda de grau moderado ou importante nos primeiros 30 dias após a correção de defeito de septo atrioventricular incompleto na população avaliada. Pacientes sem anormalidades na valva atrioventricular se beneficiam mais da operação.

Abbreviations, acronyms & symbols AV Atrioventricular AVSD Atrioventricular septal defect LAVVR Left atrioventricular valve regurgitation

Objetivo: Determinar fatores associados à insuficiência da valva atrioventricular esquerda de grau moderado ou importante nos primeiros 30 dias após correção de defeito de defeito de septo atrioventricular.

Métodos: Avaliamos os resultados em 51 pacientes consecutivos menores de 14 anos com defeito de septo atrioventricular incompleto, operados em nosso serviço entre 2002 e 2010. Avaliamos as seguintes variáveis: idade, peso, ausência de síndrome de Down, grau de insuficiência da valva atrioventricular esquerda antes da correção, anormalidades na valva atrioventricular e uso de anuloplastia. A mediana da idade foi de 4,1 anos e a do peso de 13,4 Kg; 37,2% tinham síndrome de Down; antes da operação, 23 apresentavam insuficiência da valva atrioventricular esquerda pelo menos moderada (45,1%); anormalidades na

Descritores: Coxins Endocárdicos. Insuficiência da Valva Mitral. Cardiopatias Congênitas. Período Pós-Operatório.

INTRODUCTION

struction, and those who had a previous pulmonary banding were excluded.

The reports of the transthoracic echocardiograms performed before and after operation were reviewed. These exams were performed by one of two physicians using commercially available machines, HDI 5000CV (ATL Ultrasound), Envisor-C and HD11 (Philips Ultrasound, Bothell, WA, USA), with 3 to 8 MHz probes. For further analysis, there were considered the exam before surgery and the exam closer to the 30th postoperative day, while still being within 1 month of the repair.

These were the factors assessed: preoperative (age, weight, absence of Down syndrome and grade of LAVVR), intraoperative (abnormalities on the AV valve morphology and the need for use of annuloplasty). Abnormalities on the AV valve morphology were subjectively described by the surgeon. Transesophageal echocardiography was not available during the period in which the patients were operated on.

Pre- and post-surgical LAVVR was graded based on the appearance of the color Doppler jets in relation to the left atrium (8): I=absent or trivial; II=mild; III=moderate; IV=severe. The categorizations were based just on official written summaries of the exams. Images stored on tapes or in digital media were not assessed.

A non negligible number of patients who undergo surgical repair of incomplete atrioventricular septal defect (AVSD) are discharged from hospital with residual left atrioventricular valve regurgitation (LAVVR)[1,2]. Reoperation rates for LAVVR are still relatively high, varying between 7% and 22%[1,3-6]. Many factors associated to reoperation have been proposed[1,2,4,6], but there is a lack of data reporting factors associated with immediate postoperative LAVVR, although the reports of valve replacement and of in-hospital deaths due to significant residual LAVVR within 30 days of operation[1,5,7].

To improve these statistics, a clear outline of the predisposing factors leading to a worse immediate surgical outcome is essential. The goal of this study was to assess whether some of the previous risk factors published in the literature would be associated to an at least moderate LAVVR within 30 days of surgical repair at our practice, in Brazil.

METHODS This study was approved by the ethics committee of our institution (protocol CEP 3802/2010), a tertiary-care hospital with a division of pediatric cardiology and cardiovascular surgery in Brazil, which waived the need for patient consent.

The medical records of all patients 14 years old and younger who had undergone repair of incomplete (partial or transitional) AVSD at our practice between March 2002 and April 2010 were reviewed. Patients with any right ventricle ob-

Statistical Analysis Continuous variables were expressed as mean or median, and comparisons were made using the two-sided Mann-Whitney test. Categorical variables were expressed using frequency distribution and percentages, and comparisons were made

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using the Fisher exact test. For the analyses of variances, the Kruskal-Wallis test was used. Univariate odds ratios and their 95% confidence intervals (95% CI) were estimated for variables found to have a statistically significant (P≤0.05) or borderline significant (P≤0.2) relationship with moderate or greater post-operative LAVVR. These variables were included in the multivariate analysis, which was completed using logistic regression. A P-value of 0.05 or less was considered significant. All statistical analyses were conducted using the software StatsDirect, version 2.7.2. 2008 (Cheshire, UK).

Operative management The atrial septal defect was closed with a preserved bovine pericardium patch in 50 of the 51 cases, and with direct suture in 1 case. The ventricular septal defect was not found in 8 of the 16 patients with transitional AVSD. Among the 8 other cases with ventricular septal defect, this defect was closed with direct suture in 3, with a preserved bovine pericardium patch in 2, with the same patch used for the closure of the atrial septal defect in 2, and it was closed using implantation of the superior bridging left on the superior rim of the defect in another one.

The cleft was completely closed with interrupted 6-0 polypropilene sutures in 49 patients (96.1%). For those 11 patients (21.6%) who presented annular dilation based on the surgeon’s judgment, both cleft closure and posterior annuloplasty were used. There were no statistically significant differences in the preoperative grade of LAVVR of these 11 patients when comparing to those who had not undergone annuloplasty (P=0.94).

Among the nine patients in whom abnormalities on the AV valve were diagnosed, the cleft was left untouched in one patient with a dysplastic valve. In one of the cases with an accessory cleft, the attempt of closing it caused worsening of regurgitation, thus this cleft was left intact. Another patient presented a big atrial septal defect and a severe LAVVR; the choice for this case was to close de cleft and to leave a small residual atrial septal defect. Annuloplasty was performed in four out of these nine patients.

Patient Population We included 51 patients (27 females and 24 males): 35 with partial AVSD and 16 with transitional AVSD, 32 without Down syndrome (62.7%). Age at the time of repair ranged from 4.2 months to 12.8 years (median=4.1 years). Weight varied between 3.8 and 44.3 Kg (median=13.4 Kg). At the time of preoperative evaluation, there were 4 cases with grade I LAVVR (7.9%), 24 with grade II (47%), 15 with grade III (29.4%), and 8 with grade IV (15.7%) (Table 1). Less than 50% of the patients presented minor associated heart defects (Table 2). Patients with Down syndrome had lower grades of preoperative LAVVR than those without Down syndrome, but it did not reach statistical significance (P=0.17).

Table 1. Pre- and intraoperative characteristics of the patients enrolled in the study.

Characteristic Age at the time of repair in years (median) Female Weight in Kg (median) Down syndrome Grade I LAVVR Grade II LAVVR Grade III LAVVR Grade IV LAVVR Atrioventricular valve abnormalities Annuloplasty

RESULTS

n (%) 4.1 27 (52.9%) 13.4 19 (37.2%) 4 (7.9%) 24 (47%) 15 (29.4%) 8 (15.7%) 9 (17.6%) 11 (21.6%)

The cardiopulmonary bypass time was longer in patients with AV valve malformation: mean=83±24.13 (median 94.5 min) vs. 64.7±20.2 (median 70 min); P=0.03. The postoperative time on a mechanical ventilator ranged from 2.6 to 44.7 hours (mean=9.4±7.1 hours, median=7.2 hours) and the time of inotropic support varied between 10 and 157 hours (mean=49.9±26 hours, median=46 hours). The length of hospital stay ranged from 1 to 22 days (mean=7.9±4.6 days, median=7 days). There were two deaths (3.9%), one within the first 24 hours due to a 3rd degree AV block not properly treated and another due to low cardiac output syndrome on the 2nd postoperative day. The postoperative LAVVR grades on these patients were II and I, respectively, and none of them presented AV valve malformation. Before treatment, both of these patients had a grade I LAVVR. Postoperative echocardiographic exams were performed between zero and 30 days after surgery (mean=12.6±9.4 days). There were 8 cases with grade I LAVVR (15.7%), 31 with grade II (60.8%), 11 with grade III (21.5%), and 1 with grade IV (2%) (Figure 1). The mechanisms of valve regurgitation were not available on the medical reports. The variance between pre- and postoperative grades of valvar regurgitation was statistically significant (P=0.01).

LAVVR=left atrioventricular valve regurgitation.

Table 2. Associated minor heart defects* noted before surgery.

Defect Ostium secundum atrial septal defect Common atrium Additional ventricular septal defect Patent ductus arteriosus Left superior caval vein Left atrium isomerism Coarctation of the aorta Subaortic stenosis

N 15 3 2 1 1 1 1 1

% 29.4 5.8 3.9 2 2 2 2 2

*Defects not mutually exclusive.

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Fig. 1 - Change in left atrioventricular valve regurgitation from pre-operation to post-operation.

Nine cases (17.6%) of abnormalities on the AV valve morphology were found and they were described according to the surgeonâ&#x20AC;&#x2122;s report: dysplastic valve leaflets (n=5), accessory cleft (n=2), tendinous cordae rupture (n=1), and small left AV valve orifice (n=1). Six of these 9 patients presented with moderate or severe LAVVR before operation (66.7%), a rate greater than that seen in patients without such abnormalities (40.5%) (P=0.27). After repair, 4 of these 9 patients presented the same grade of preoperative LAVVR; there was worsening in 1, and improvement in 4. The variance between pre- and postoperative grades of LAVVR in this group of patients with AV valve malformation did not reach significance (P=0.26), unlike patients without such abnormalities (P=0.016). Among the 19 patients with Down syndrome, 2 (10.5%) presented AV valve abnormalities; whereas among the 32 without Down syndrome, 7 (21.9%) presented it (P=0.7).

In 17 patients, the trivial or mild LAVVR found before operation was maintained after the procedure. In 15 of the 23 (65.2%) patients with moderate or severe pre-operative LAVVR, the postoperative LAVVR was found to be trivial or mild. A one-grade worsening on the LAVVR was found in 8 patients (15.7%). Of the 2 cases in which the cleft was

left open, the grade of LAVVR didnâ&#x20AC;&#x2122;t change. Regarding the improvement on the grade of LAVVR, there was no statistical significance comparing those patients who had undergone annuloplasty, with those who had not undergone it (P=0.84).

Other findings on postoperative echocardiograms: 12 cases (23.5%) of insignificant residual ventricular septal defect, which is defined as a ventricular septal defect < 3 mm (8 of them were not seen during surgery, confirming that they were too small); four cases (7.8%) of insignificant residual atrial septal defect, which is defined as an atrial septal defect < 3 mm; two (3.9%) cases of mild left AV valve stenosis; and one (2%) case of a fistula from the left ventricle to the right atrium.

Univariate analysis revealed that absence of Down syndrome was associated with moderate or severe post-operative LAVVR (P=0.02; OR=9.43). Severe preoperative LAVVR and AV valve abnormalities were only marginally significant (P=0.07 and 0.19, respectively) (Table 3). However, none of the factors were found to be associated with moderate or severe postoperative under multivariate analysis. Absence of Down syndrome reached only a borderline significance (P=0.06; OR=8.4) (Table 4).

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Table 3. Univariate relations between variables and moderate or severe postoperative left atrioventricular valve regurgitation (LAVVR).

Age in months (median) Weight in Kg (median) Abscence of Down syndrome Grade IV pré-operative LAVVR AV valve abnormality Annuloplasty

LAVVR ≤ II n=39 53.3 13.1 21 (53.8%) 4 (10.2%) 5 (12.8%) 8 (20.5%)

LAVVR ≥ III n=12 45.3 15.4 11 (91.7%) 4 (33.3%) 4 (33.3%) 3 (25%)

OR

Univariate 95% CI

9.43 4.4 3.4

1.12-427.9 0.64-28.31 0.53-19.7

P 0.97 0.87 0.02 0.07 0.19 0.7

LAVVR=left atrioventricular valve regurgitation; AV=atrioventricular; CI=confidence interval; OR=odds ratio.

Table 4. Multivariate relations between variables and moderate or severe postoperative left atrioventricular valve regurgitation (LAVVR).

Abscence of Down syndrome Grade IV Preoperative LAVVR AV valve abnormality

LAVVR ≤ II n=39 21 (53.8%) 4 (10.2%) 5 (12.8%)

LAVVR ≥ III n=12 11 (91.7%) 4 (33.3%) 4 (33.3%)

OR 8.4

Multivariate 95% CI 0.9-79.5

P 0.06 0.25 0.32

LAVVR=left atrioventricular valve regurgitation; AV=atrioventricular; CI=confidence interval; OR=odds ratio.

DISCUSSION

study, which was performed without the use of intraoperative transesophageal echocardiography, a decrease of the number of patients with moderate or greater LAVVR from 45.1% to 23.5% was similar to that reported by Kaza et al.[22] in a study evaluating data from seven centers in North America. These results show that all techniques that were used, including cleft closure and annuloplasty, had an impact, but not enough of an impact to completely avoid early post-operative LAVVR in some patients.

These patients, if previously identified, might receive an alternative approach to minimize the grade of LAVVR. As for the Down syndrome factor, AVSD is a real model to study the impact of Down syndrome on outcomes, since there are no other situations in congenital heart diseases in which there is such a high prevalence of a chromosomal disorder. Statements such as “In Down patients valve tissue is more abundant and allows for an easier reconstruction”[11] are often seen. It suggests that patients without Down syndrome would have a higher risk of worse surgical outcomes, as found by some authors[6,13]. However, not all studies confirm this relationship. Murashita et al.[4] and Al-Hay et al.[3], for instance, did not find any significant differences between individuals with or without Down syndrome in their studies. In the aforementioned study by Kanani et al.[18], there was no mention if hearts of patients with Down syndrome were included. Perhaps, histopathological comparisons of the valve and subvalvar apparatus of patients with and without Down syndrome might answer this question. In our study, the absence of Down syndrome tended to have some statistical significance.

Despite different ages, different weight at repair, and different physiology, patients with both complete and incomplete AVSD present a similar risk of reoperation for LAVVR[1,3-6,9-14].

What both variations of the same disease have in common are the typical anatomical landmarks of AVSD (common AV junction, a common 5-leaflet AV valve, distinct papillary muscle displacement and a narrow and elongated left ventricle outflow tract)[15,16], as well as a high prevalence of individuals with Down syndrome[17]. Therefore, the clue to understanding this frequent complication may be related more to these two aspects than to another factor such as age, weight, or AV valve malformation.

In the study by Kanani et al.[18], in which the anatomy of the subvalvar apparatus of normal hearts was compared to those of hearts with complete and incomplete AVSD with an intact left AV valve, the structural and geometric disarray of the tendinous cords of those hearts with AVSD defect was clearly visible, along with its possible rule on the mechanisms of valve regurgitation. Moreover, in the work by Bharucha et al.[19], with the use of three-dimensional echocardiography, it was found that a more acute angle of the components of the common AV valve against the plane of the common AV junction would be a predictor of postoperative valve function.

Performing an intraoperative transesophageal exam is routine in many centers[5,10,20]; though, there is often too much discrepancy between its findings and those obtained through transthoracic exams in the days or weeks after repair[12,21]. In our

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Some studies found the AV valve malformation to be associated with reoperation or valve replacement[9,14]. In the present study, the results could not prove any relationship between the presence of malformation and moderate or severe postoperative LAVVR. However, it was found that the operation for patients with such abnormalities did not produce the same benefits as it was seen for patients without them. The longer cardiopulmonary bypass time and the impossibility of closing the cleft in two out of nine patients demonstrate how difficult these cases can be. The diagnosis of these valvar abnormalities can be difficult. Ando et al.[21] found a weak correlation between preoperative echocardiographic findings and the surgeonâ&#x20AC;&#x2122;s judgment in regard to the diagnosis of these malformations.

Moreover, one should know that little consistency between the findings of two- and three-dimensional Echocardiography, considering the presence of AV valve malformation, has been shown by some authors. In the study by Takahashi et al.[23], for instance, the correlation between the findings of both methods was lower than 46% in the evaluation of the mural leaflet and in the evaluation of the commissural abnormalities of the left AV valve leaflets. The three-dimensional echocardiogram was more accurate and more reliable.

In conclusion, for this sample we were not able to identify any risk factor for early moderate or severe postoperative LAVVR at our center, but we could observe that patients with AV valve abnormalities may be a challenge for surgeons.

REFERENCES 1. Aubert S, Henaine R, Raisky O, Chavanis N, Robin J, Ecochard R, et al. Atypical forms of isolated partial atrioventricular septal defect increase the risk of initial valve replacement and reoperation. Eur J Cardiothorac Surg. 2005;28(2):223-8.

2. Minich LL, Atz AM, Colan SD, Sleeper LA, Mital S, Jaggers J, et al.; Pediatric Heart Network Investigators. Partial and transitional atrioventricular septal defect outcomes. Ann Thorac Surg. 2010;89(2):530-6.

3. Al-Hay AA, Lincoln CR, Shore DF, Shinebourne EA. The left atrioventricular valve in partial atrioventricular septal defect: management strategy and surgical outcome. Eur J Cardiothorac Surg. 2004;26(4):754-61.

4. Murashita T, Kubota T, Oba J, Aoki T, Matano J, Yasuda K. Left Atrioventricular valve regurgitation after repair of incomplete atrioventricular septal defect. Ann Thorac Surg.

2004;77(6):2157-62.

5. Chowdhury UK, Airan B, Malhotra A, Bisoi AK, Kalaivani M, Govindappa RM, et al. Specific issues after surgical repair of partial atrioventricular septal defect: actuarial survival, freedom from reoperation, fate of the left atrioventricular valve, prevalence of left ventricular outflow tract obstruction, and other events. J Thorac Cardiovasc Surg. 2009;137(3):548-55.

6. Welke KF, Morris CD, King E, Komanapalli C, Reller MD, Ungerleider RM. Population-based perspective of long-term outcomes after surgical repair of partial atrioventricular septal defect. Ann Thorac Surg. 2007;84(2):624-9.

Study Limitations It was a retrospective study, and was therefore subject to limitations in terms of how correctly the information in the medical records was filed. The small number of patients may, in some ways, account for the lack of statistical significance among the factors studied. There were no pre- and postoperative echocardiographic information about the mechanisms of valve regurgitation (residual cleft, mobility of the leaflets, etc), precluding its impact on results.

7. Stulak JM, Burkhart HM, Dearani JA, Cetta F, Barnes RD, Connolly HM, et al. Reoperations after repair of partial atrioventricular septal defect: a 45-year single-center experience. Ann Thorac Surg. 2010;89(5):1352-9.

8. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al.; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with twodimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.

Authorsâ&#x20AC;&#x2122; roles & responsibilities MFK

Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; writing of the manuscript or critical review of its content ACLFBMK Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript or critical review of its content CHM Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript or critical review of its content MFG Statistical analysis UAC Analysis and/or interpretation of data; final approval of the manuscript; operations and/or experiments conduct; writing of the manuscript or critical review of its content ACM Analysis and/or interpretation of data; final approval of the manuscript; study design; writing of the manuscript or critical review of its content

9. Al-Hay AA, MacNeill SJ, Yacoub M, Shore DF, Shinebourne EA. Complete atrioventricular septal defect, down syndrome, and surgical outcome: risk factors. Ann Thorac Surg.

2003;75(2):412-21.

10. Crawford FA. Atrioventricular canal: single-patch technique.

Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu.

2007;11-20.

11. Dodge-Khatami A, Herger S, Rousson V, Comber M, Knirsch W, Bauersfeld U, et al. Outcomes and reoperations after total correction of complete atrioventricular septal defect. Eur J Cardiothorac Surg. 2008;34(4):745-50.

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12. Dragulescu A, Fouilloux V, Ghez O, Fraisse A, Kreitmann B, Metras D. Complete atrioventricular canal repair under 1 year: Rastelli one-patch procedure yields excellent long-term results.

Ann Thorac Surg. 2008;86(5):1599-606.

RH. Late incompetence of the left atrioventricular valve after repair of atrioventricular septal defects: the morphologic perspective. J Thorac Cardiovasc Surg. 2006;132(3):640-6.

19. Bharucha T, Sivaprakasam MC, Haw MP, Anderson RH, Vettukattil JJ. The angle of the components of the common atrioventricular valve predicts the outcome of surgical correction in patients with atrioventricular septal defect and common atrioventricular junction. J Am Soc Echocardiogr. 2008;21(10):1099-104.

13. Lange R, Guenther T, Busch R, Hess J, Schreiber C. The presence of Down syndrome is not a risk factor in complete atrioventricular septal defect repair. J Thorac Cardiovasc Surg.

2007;134(2):304-10.

14. Suzuki T, Bove EL, Devaney EJ, Ishizaka T, Goldberg CS, Hirsch JC, et al. Results of definitive repair of complete atrioventricular septal defect in neonates and infants. Ann Thorac Surg.

2008;86(2):596-603.

20. Cope JT, Fraser GD, Kouretas PC, Kron IL. Complete versus partial atrioventricular canal: equal risks of repair in the modern era. Ann Surg. 2002;236(4):514-21.

15. Ho SY, Rigby ML, Anderson RH. Echocardiography in congenital heart disease made simple. London: Imperial College Press; 2005.

21. Ando M, Takahashi Y. Variations of atrioventricular septal defects predisposing to regurgitation and stenosis. Ann Thorac Surg.

2010;90(2):614-21.

16. Mahle WT, Shirali GS, Anderson RH. Echo-morphological correlates in patients with atrioventricular septal defect and common atrioventricular junction. Cardiol Young. 2006;16 Suppl 3:43-51.

22. Kaza AK, Colan SD, Jaggers J, Lu M, Atz AM, Sleeper LA, et al.; Pediatric Heart Network Investigators. Surgical interventions for atrioventricular septal defect subtypes: the pediatric heart network experience. Ann Thorac Surg. 2011;92(4):1568-75.

17. Torfs CP, Christianson RE. Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Gen. 1998;77(5):431-8.

23. Takahashi K, Guerra V, Roman KS, Nii M, Redington A, Smallhorn JF. Three-dimensional echocardiography improves the understanding of the mechanisms and site of left atrioventricular valve regurgitation in atrioventricular septal defect. J Am Soc Echocardiogr. 2006;19(12):1502-10.

18. Kanani M, Elliott M, Cook A, Juraszek A, Devine W, Anderson

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Dias RR, et al.ORIGINAL - Surgical treatment of complex aneurysms and thoracic aortic ARTICLE dissections with the Frozen Elephant Trunk technique

Surgical treatment of complex aneurysms and thoracic aortic dissections with the Frozen Elephant Trunk technique Tratamento cirúrgico dos aneurismas complexos e dissecções da aorta torácica utilizando a técnica "Frozen Elephant Trunk"

Ricardo Ribeiro Dias1, MD, PhD; José Augusto Duncan1, MD; Diego Sarty Vianna1, MD; Leandro Batisti de Faria1, MD; Fábio Fernandes1, MD, PhD; Félix José Álvares Ramirez1, MD, PhD; Charles Mady1, MD, PhD; Fábio Biscegli Jatene1, MD, PhD

DOI 10.5935/1678-9741.20140119

RBCCV 44205-1633

Abstract Objective: Report initial experience with the Frozen Elephant Trunk technique.

Methods: From July 2009 to October 2013, Frozen Elephant Trunk technique was performed in 21 patients (66% male, mean age 56 ±11 years). They had type A aortic dissection (acute 9.6%, chronic 57.3%), type B (14.3%, all chronic) and complex aneurysms (19%). It was 9.5% of reoperations and 38% of associated procedures (25.3% miocardial revascularization, 25.3% replacement of aortic valve and 49.4% aortic valved graft). Aortic remodeling was evaluated comparing preoperative and most recent computed tomography scans. One hundred per cent of complete follow-up, mean time of 28 months.

Results: In-hospital mortality of 14.2%, being 50% in acute type A aortic dissection, 8.3% in chronic type A aortic dissection, 33.3% in chronic type B aortic dissection and 0% in complex aneurysms. Mean times of cardiopulmonary bypass (152±24min), myocardial ischemia (115±31min) and selective cerebral perfusion (60±15min). Main complications were bleeding (14.2%), spinal cord injury (9.5%), stroke (4.7%), prolonged mechanical

ventilation (4.7%) and acute renal failure (4.7%). The need for second-stage operation was 19%. False-lumen thrombosis was obtained in 80%.

Conclusion: Frozen Elephant Trunk is a feasible technique and should be considered. The severity of the underlying disease justifies high mortality rates. The learning curve is a reality. This approach allows treatment of more than two segments at once.

Nonetheless, if a second stage is made necessary, it is facilitated.

Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP (InCor HC-FMUSP), São Paulo, SP, Brazil.

Correspondence address: Ricardo Ribeiro Dias Instituto do Coração Avenida Dr. Enéas de Carvalho Aguiar, 44 Bloco II 2º andar - Sala 13 - Pinheiros - São Paulo, SP, Brazil - Zip Code: 05403-900 E-mail: ricardo.dias@incor.usp.br

Descriptors: Aortic Diseases. Aorta, Thoracic. Cardiovascular Surgical Procedures. Aortic Aneurysm, Thoracic. Aneurysm, Dissecting. Endovascular Procedures.

Resumo Objetivo: Relatar experiência inicial com a técnica “Frozen Elephant Trunk”.

Métodos: Entre julho de 2009 e outubro de 2013, 21 pacientes, 66% homens, média de idade de 56±11 anos, 66,7% portadores de dissecção da aorta tipo A de Stanford (9,6% agudas e 57,1% crônicas), tipo B (14,3%, todas crônicas) e aneurismas

1

This study was carried out at the Heart Institute of the University of São Paulo Medical School, São Paulo, SP, Brazil.

Article received on July 18th, 2014 Article accepted on October 13th, 2014

No financial support.

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Tempos médios de CEC (152±24min), isquemia miocárdica (115±31min) e perfusão cerebral seletiva (60±15min). Principais complicações pós-operatórias foram sangramento (14,2%), acidente vascular encefálico (4,7%), paraplegia (9,5%), intubação>72h (4,7%) e insuficiência renal aguda (4,7%). Houve necessidade de complementação do tratamento (distal ao stent) em 19%. Houve trombose da falsa luz em 80%.

Conclusão: Frozen Elephant Trunk é opção técnica a ser utilizada. A gravidade e extensão da doença justificam mortalidade mais elevada. A curva de aprendizado é uma realidade. Esta abordagem permite abordar mais de dois segmentos de aorta em um estágio, mas se necessário segundo estágio, este é facilitado.

Abbreviations, acronyms & symbols CPB CT FET

Cardiopulmonary bypass Computed tomography Frozen elephant trunk

complexos (19%), foram operados pela técnica Frozen Elephant Trunk. Foram 9,5% de reoperações e 38% com procedimentos associados (25,3% revascularizações do miocárdio, 25,3% troca da valva aórtica e 49,4% tubos valvulados). Remodelamento da aorta foi avaliado com a comparação de angiotomografia pré-operatória e pós-operatória mais recente. Seguimento 100% dos pacientes, tempo médio de 28 meses.

Resultados: Mortalidade hospitalar de 14,2%, sendo 50% nas dissecções do tipo A agudas, 8,3% nas tipo A crônicas, 33,3% nas tipo B crônicas e 0% nos aneurismas complexos.

Descritores: Doenças da Aorta. Aorta Torácica. Procedimentos Cirúrgicos Cardiovasculares. Aneurisma da Aorta Torácica.

Aneurisma Dissecante. Procedimentos Endovasculares.

INTRODUCTION

sequently, all patients underwent antegrade implantation of the endovascular prosthesis through the aortic arch.

The choice of prosthesis was due to it being the only one available in the Brazilian market. A series of previously published cases using this prosthesis have shown satisfactory perioperative and mid-term results in terms of the extent of the aneurysm, false lumen thrombosis, and aortic remodeling[6,7].

The patients who were treated had complex diseases of the thoracic aorta involving the aortic arch. A complex disease of the aorta was defined as simultaneous involvement of three or more aortic segments.

Operations performed in the distal aorta were defined as new surgical approaches involving treatment of any segment distal to the stent in order to supplement the primary treatment or because of the evolution of the disease.

Cardiopulmonary bypass was maintained with arterial cannulation of the right subclavian artery in 5 patients and innominate # 16 patients. Venous drainage was performed with double-stage cannula through the right atrium.

Brain protection was performed by antegrade cerebral perfusion by both carotid arteries, with monitoring of the right upper limb perfusion pressure (invasive blood pressure in the right radial artery), associated with moderate hypothermia (25°C), hypothermia with ice and sodium thiopental (spinal cord protection exclusively by 25ºC hypothermia associated with systemic circulatory arrest).

The reconstruction of the supra-aortic vessels was made from reimplantation in island anastomosed to the polyester tube for all cases.

All operations were performed in conventional operating

The treatment of complex diseases of the aorta that involve the aortic arch using a hybrid procedure aims at reconstructing several segments within a single intervention. The “Frozen Elephant Trunk” (FET) surgical technique has been used for the treatment of complex aneurysms and chronic dissections of the thoracic aorta since 1996[1]. The prostheses used in these procedures consist of a proximal segment made of polyester (used to reconstruct the ascending aorta and aortic arch segment) distally attached to a self-expanding endovascular prosthesis (used to treat the proximal segment of the descending thoracic aorta). The main purpose of this technique is to potentially avoid a second procedure required after the classic elephant trunk technique[2]. Over time, indications for the use of the FET have extended to patients with acute aortic dissections. This surgical approach was established to expand aortic treatment as well as to favor thrombosis of the false lumen or the aneurysm, since the false lumen that remains patent (and, therefore, pressurized) is a risk factor for dilation and rupture of the aorta and subsequent need for a new surgical treatment[3-5].

The aim of this study is to report an initial experience with the FET technique to treat complex diseases of the thoracic aorta with involvement of the aortic arch.

METHODS Between July 2009 and October 2013, 21 patients underwent surgery with the FET technique, all with the E-vita Open® prosthesis (Jotec GmbH, Hechingen, Germany). Con-

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room, without use of scopes or guidewire. The introduction of the prosthesis was performed through direct identification of the true light for patients with aortic dissection.

The FET technique was used in type A acute or chronic dissections with inlet port located in the distal aortic arch or descending thoracic aorta, and patients with these aorta segments greater than than four centimeters.

During the study period, all patients with involvement of the ascending aorta, aortic arch and proximal descending aorta underwent this technique.

There were 21 patients, 66% male, with a mean age of 56Âą11 years (ranging from 27 to 70 years-old).

Out of the 21 patients, 67% had Stanford type A aortic dissections (10% acute and 57% chronic), 14% had Stanford type B chronic aortic dissections, and 19% had complex aneurysms.

In 9.5% of the patients, there was a reoperation (all had previous surgery in the aortic root and ascending aorta), and 38% required associated procedures (50% underwent aortic root reconstruction with composite-graft valve replacement, 25% underwent aortic valve replacement, and 25% underwent myocardial revascularization).

In addition, 28% were urgency or emergency surgeries, 10% of which were Stanford type A acute dissections.

Radiological assessment was carried out taking into consideration preoperative angiotomographies of the aorta and comparing it to the last postoperative exam (Figures 1A and 1B).

Patient data were retrospectively analyzed from a database prospectively built. Full clinical follow-up was done up to November 30, 2013. Follow-up was performed at the institutionâ&#x20AC;&#x2122;s outpatient facility or via telephone.

Fig. 1A - Tridimensional reconstruction of angiotomography of the aorta: preoperative.

Fig. 1B - Tridimensional reconstruction of angiotomography of the aorta: postoperative.

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This study was approved by the Research Ethics Committee of the institution (No. 837) for specific database creation of the aforementioned patients and the consent form is not required by the retrospective feature of the research.

dominal aorta open reintervention and 84% were free from additional endovascular treatments[10].

Our experience has shown that, in less than a 3-year follow-up period, there was 20% of reinterventions, all of them as a consequence of the inability to fully approach the disease of the aorta through the FET procedure. None of the reinterventions was due to progression of the initial disease or to the appearance of a new disease in the distal segment of the aorta.

The percentage of reoperations, the high number of associated procedures required as well as procedures characterized as urgency or emergency attest the high surgical complexity and high surgical risk of patients included in this study.

This study states the initial experience of the Heart Institute of the University of São Paulo Medical School with this operation. Follow-up time is still short (average of 28 months, ranging from 1 to 54 months), with hospital mortality compatible with that reported in the international literature[11].

In the last 10 years, the use of the FET technique has spread to include the treatment of acute aortic dissections and mega-aorta syndrome. As a result, the need for second-stage surgery is real, since the approach of the aorta has to be extended distally to the segment associated with the stent. Thus, the FET stent facilitates the second stage of surgery while complementing the treatment, in cases of open thorax or endovascular operations, and providing a better region for new endoprosthesis anchoring, especially when compared to the classic elephant trunk technique or with the diseased native aorta initially untreated[11,15,16].

Likewise, in patients with chronic aortic dissection, a second stage is likely to be required since the possibility of excluding false lumen is lower. In this disease, the delaminated membrane is thicker than in acute dissections and true lumen is lower, which increases the risk of leakage and progression of aneurysmatic dilation. Consequently, a large number of publications have shown high percentage of false lumen thrombosis around the endoprosthesis, but inferior outcomes in the distal segments of the aorta without stent and no improvement throughout follow-up[9,17,10]. Therefore, we believe that the need for second stage surgery is not related to the failure of the prosthesis used in the FET, but rather to the characteristics of the primary disease.

Some authors have shown that the prevalence of aortic reinterventions distally to the original surgery is higher in patients with chronic aortic dissection when compared to patients with acute dissection[11]. Conversely, in acute dissections, the FET technique prevented late dilation of the proximal segment of the descending aorta, stabilized the dissected membrane, and promoted true lumen expansion, even in segments distal to the stent[11]. As a result, knowing that in these patients the distal portion of the dissected aorta tends to dilate over time when only a conduit interposition in the ascending aorta is performed, especially the proximal segment of the

RESULTS Hospital mortality was 14.2%. According to etiology, mortality rates for Stanford type A acute dissections, Stanford type A chronic dissections, and Stanford type B chronic dissections were 50%, 8.3%, and 33.3%, respectively.

There was no mortality in patients with complex thoracic aortic aneurysms.

Mean CPB time was 152 min±24 min, mean myocardial ischemia time was 115 min±31 min, and mean time of selective cerebral perfusion at 25°C was 60 min±15 min.

The main complications observed were reoperation due to bleeding in three patients, stroke in one patient, paraplegia in two patients, prolonged intubation (longer than 72 hours) in one patient, and acute renal failure requiring dialysis in one patient.

Four patients (19%) required a second surgical time for intervention in the descending thoracic aorta. Most of them (three patients) underwent implantation of vascular endoprosthesis in the segment distal to the one first treated during the same hospital stay whereas one patient, while recovering from the first stage and awaiting thoracoabdominal reconstruction, was admitted to another facility four months after hospital discharge and underwent open surgery, leading to death.

Angiotomographies for postoperative control of patients diagnosed with dissection showed false lumen thrombosis in 80% of the aortic segments with vascular endoprosthesis and in 60% of the aortic segments without endoprosthesis. All of the patients with aneurysm had thrombosis around the stent.

DISCUSSION The use of a hybrid approach to complex diseases of the thoracic aorta allows for the treatment of long segments of the aorta in a single stage.

Some authors have questioned the possibility of treating complex aortic diseases in a single stage through median sternotomy using the FET technique[12], giving preference to other approaches, such as bithoracotomy[13,14]. However, the FET technique has shown fewer pulmonary complications as well as similar survival rates in 5-year follow-ups[11,14].

Shimamura et al.[8] and Uchida et al.[9] demonstrated survival free from reintervention in the distal segment of the aorta of 75% and 92%, respectively, in up to 10 years of follow-up, and with mortality ranging from 46% to 25%.

The first mid-term results obtained with the use of the E-vita Open® prosthesis showed 5-year survival rates of 79%, where 96% of the patients were free from thoracoab-

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descending aorta[3-5], the FET technique has become the technique of choice for the treatment of Stanford type A acute dissections in some centers[11]. This technique has been used even in patients with connective tissue diseases[18].

Lastly, when compared to other series of cases[19,20], the prevalence of spinal injury in this study was equal or lower to what has been reported in the international literature and it was present only in the first cases, in particular, when systemic circulatory arrest time was longer due to initial difficulties to perform the procedure.

2. Borst HG, Walterbusch G, Schaps D. Extensive aortic replacement using ‘elephant trunk’ prosthesis. Thorac Cardiovasc Surg.

1983;31(1):37-40.

Limitations of the study Main limitations of the study are the reduced number of patients and short, though complete, follow-up period.

5. Kim JB, Lee CH, Lee TY, Jung SH, Choo SJ, Lee JW, et al.

Descending aortic aneurysmal changes following surgery for acute DeBakey type I aortic dissection. Eur J Cardiothorac Surg.

2012;42(5):851-6.

3. Halstead JC, Meier M, Etz C, Spielvogel D, Bodian C, Wurm M, et al. The fate of the distal aorta after repair of acute type A aortic dissection. J Thorac Cardiovasc Surg. 2007;133(1):127-35.

4. Song SW, Chang BC, Cho BK, Yi G, Youn YN, Lee S, et al. Effects of partial thrombosis on distal aorta after repair of acute DeBakey type I aortic dissection. J Thorac Cardiovasc Surg. 2010;139(4):841-7.

CONCLUSION

6. Di Bartolomeo R, Di Marco L, Armaro A, Marsilli D, Leone A, Pilato E, et al. Treatment of complex disease of the thoracic aorta: the frozen elephant trunk technique with the E-vita open prosthesis. Eur J Cardiothorac Surg. 2009;35(4):671-5.

The FET technique has been shown to be an option in the surgical treatment of complex diseases of the thoracic aorta.

High mortality is warranted in view of the severity of primary diseases and the complexity of the patients.

The learning curve is a reality in these operations.

This technique can treat complex diseases of the thoracic aorta in a single stage. When required, FET simplifies reintervention in the distal segments, providing a more appropriate region both for surgical manipulation and for new endoprosthesis anchoring.

7. Gorlitzer M, Weiss G, Moidl R, Folkmann S, Waldenberger F, Czerny M, et al. Repair of stent graft-induced retrograde type A aortic dissection using the E-vita open prosthesis. Eur J Cardiothorac Surg. 2012;42(3):566-70.

8. Shimamura K, Kuratani T, Matsumiya G, Kato M, Shirakawa Y, Takano H, et al. Long-term results of the open stent-grafting technique for extended aortic arch disease. J Thorac Cardiovasc Surg. 2008;135(6):1261-9.

9. Uchida N, Katayama A, Tamura K, Sutoh M, Kuraoka M, Murao N, et al. Long-term results of the frozen elephant trunk technique for extended aortic arch disease. Eur J Cardiothorac Surg.

2010;37(6):1338-45.

Authors’ roles & responsibilities RRD

JAD DSV LBF FF FJAR CM FBJ

Analysis and/or interpretation of data, statistical analysis, final approval of the manuscript, conception and study design study, carried out procedures and/or experiments, writing of the manuscript or review of its content Analysis and/or interpretation of data, carried out procedures and/or experiments, writing of the manuscript or review of its content Analysis and/or interpretation of data, carried out procedures and/or experiments, writing of the manuscript or review of its content Analysis and/or interpretation of data, statistical analysis, carried out procedures and/or experiments Conception and study design Conception and study design Conception and study design Conception and study design

10. Jakob H, Dohle DS, Piotrowski J, Benedik J, Thielmann M, Marggraf G, et al. Six-year experience with a hybrid stent graft prosthesis for extensive thoracic aortic disease: an interim balance. Eur J Cardiothorac Surg. 2012;42(6):1018-25.

11. Ius F, Fleissner F, Pichlmaier M, Karck M, Martens A, Haverich A, et al. Total aortic arch replacement with the frozen elephant trunk technique: 10-year follow-up single centre experience. Eur. J Cardiothorac Surg. 2013;44(5):949-57.

12. Kouchoukos NT. Frozen elephant trunk technique for extensive chronic thoracic aortic dissection: is the final answer? Ann Thorac Surg. 2011;92(5):1557-8.

REFERENCES

13. Beaver TM, Martin TD. Single-stage transmediastinal replacement of the ascending, arch, and descending thoracic aorta. Ann Thorac Surg. 2001;72(4):1232-8.

1. Kato M, Ohnishi K, Kaneko M, Ueda T, Kishi D, Mizushima T, et al. New graft-implanting method for thoracic aortic aneurysm or dissection with a stented graft. Circulation. 1996;94(9 Suppl I):II188-93.

14. Kouchoukos NT, Masetti P, Mauney MC, Murphy MC, Castner CF. One-stage repair of extensive chronic aortic dissection using the arch-first technique and bilateral anterior thoracotomy. Ann Thorac Surg. 2008;86(5):1502-9.

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15. Pichlmaier MA, Teebken OE, Khaladj N, Weidemann J, Galanski M, Haverich A. Distal aortic surgery following arch replacement with a frozen elephant trunk. Eur J Cardiothorac Surg. 2008;34(3):600-4.

18. Sun L, Li M, Zhu J, Chang Q, Zheng J, Qi R. Surgery for patients with Marfan syndrome with type A dissection involving the aortic arch using total arch replacement combined with stented elephant trunk implantation: the acute versus the chronic. J Thorac Cardiovasc Surg. 2011;142(3):e85-91.

16. Uchida N, Kodama H, Katayama K, Takasaki T, Katayama A, Takahashi S, et al. Endovascular aortic repair as second-stage surgery after hybrid open arch repair by the frozen elephant trunk technique for extended thoracic aneurysm. Ann Thorac Cardiovasc Surg. 2013;19(3):257-61.

19. Flores J, Kunihara T, Shiiya N, Yoshimoto K, Matsuzaki K, Yasuda K. Extensive deployment of the stented elephant trunk is associated with an increased risk of spinal cord injury. J Thorac Cardiovasc Surg. 2006;131(2):336-42.

17. Sun LZ, Qi RD, Chang Q, Zhu JM, Liu YM, Yu CT, et al. Surgery for acute type A dissection using total arch replacement combined with stented elephant trunk implantation: experience with 107 patients. J Thorac Cardiovasc Surg. 2009;138(6):1358-62.

20. Pacini D, Tsagakis K, Jakob H, Mestres CA, Armaro A, Weiss G, et al. The frozen elephant trunk for the treatment of chronic dissection of the thoracic aorta: a multicenter experience. Ann Thorac Surg. 2011;92(5):1663-70.

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Leão SC, et ORIGINAL al. - AnalysisARTICLE of immunostaining and western blotting of endothelin 1 and its receptors in mitral stenosis

Analysis of immunostaining and western blotting of endothelin 1 and its receptors in mitral stenosis Análise da expressão imunohistoquímica e de western blotting da endotelina 1 e seus receptores na estenose mitral

Sydney Correia Leão1, MD; Michael R. Dashwood2, PhD; Mateus Santana de Andrade3; Nicolas Nascimento Santos3; Olivia Regina Lins Leal Teles3; Williasmin Batista de Souza3; Tania Maria de Andrade Rodrigues3, MD; MSc; PhD

DOI 10.5935/1678-9741.20150004

RBCCV 44205-1634

Abstract Introduction: Rheumatic Fever represents a serious public health problem in developing countries, with thousands of new cases each year. It is an autoimmune disease, which occurs in response to infection by streptococcus A. Objective: The aim of this study was to evaluate the immunolabeling and protein expression for endothelin-1 and 3 (ET-1, ET-3) and its receptors (ETA, ETB) in rheumatic mitral valves.

Methods: Immunohistochemistry was used to identify ET-1/ ET-3 and ETA/ETB receptors in rheumatic and control mitral valves. Quantitative analysis of immunostaining for ET-1/ET-3 and ETA/ETB receptors was performed. In addition, western blot analysis was carried out to assess protein levels in tissue samples.

Results: ET-1 and ETA receptor immunostaining predominated in stenotic valves, mainly associated with fibrotic regions, inflammatory areas and neovascularization. Quantitative analysis showed that the average area with positive expression of ET-1 was 18.21±14.96%. For ETA and ETB, the mean expressed areas were respectively 15.06±13.13% and 9.20±11.09%. ET-3

did not have a significant expression. The correlation between the expression of both endothelin receptors were strongly positive (R=0.74, P=0.02), but the correlation between ET-1 and its receptor were negative for both ETA (R=-0.37, P=0.25), and ETB (R=-0.14, P=0.39). This data was supported by western blot analysis.

Conclusion: The strong correlation between ET-1 and its receptors suggests that both play a role in the pathophysiology of rheumatic mitral valve stenosis and may potentially act as biomarkers of this disease.

Universidade Federal de São Paulo (UNIFESP), São Paulo,SP, Brazil.

Department of Clinical Biochemistry, University College London Medical School, London, UK. 3 Group of Molecular Anatomy, Universidade Federal de Sergipe, São Cristóvão, SE, Brazil.

Correspondence address: Sydney Correia Leao Group of Molecular Anatomy- Universidade Federal de Sergipe Marechal Rondon Avenue b.b - Rosa Elze neighborhood - São Cristóvão, SE, Brazil Zip code: 49100-000 E-mail: sydneyleao@hotmail.com

Descriptors: Rheumatic Fever. Mitral Valve Stenosis. Endothelin-1. Immunohistochemistry. Blotting, Western.

Resumo Introdução: A febre reumática representa um sério problema de saúde pública em países em desenvolvimento, com milhares de novos casos a cada ano. Ela é uma doença autoimune que ocorre em resposta à infecção por estreptococos do grupo A. Objetivo: O objetivo deste estudo foi avaliar a expressão

1 2

This study was carried out at Universidade Federal de Sergipe (UFS), São Cristovão, SE, Brazil.

Article received on April 25th, 2014 Article accepted on January 26th, 2015

Financial support CNPq and Fapitec.

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toquímica para receptores de ET1/ET3 e ETA/ETB foi também efetuada. Adicionalmente, foi feita análise do western blot para mensurar níveis de proteínas em extratos tissulares.

Resultados: A expressão imunohistoquímica de ET-1 e de seu receptor predominou em valvas estenóticas, estando associada com regiões fibróticas, áreas inflamatórias e neovascularização. A análise quantitativa mostrou que a área média com expressão positiva para ET-1 foi de 18,21±14,96%. Para o ETA e o ETB, as áreas médias expressas foram, respectivamente, 15,06±13,13% e 9,20±11,09%. ET-3 não teve uma expressão significante. A correlação entre a expressão dos dois receptores de endotelina foi fortemente positiva (R=0,74, P=0,02); mas a correlação entre ET-1 e o seu receptor foi negativa tanto para ETA (R=-0,37, P=0,25) como para ETB (R=-0,14, P=0,39). Estes dados foram confirmados pela análise do western blot.

Conclusão: A forte correlação entre ET-1 e seus receptores sugere que ambos têm papel importante na fisiopatologia da estenose mitral reumática, podendo potencialmente atuar como biomarcadores desta doença.

Abbreviations, acronyms & symbols BSA Bovine serum albumin DMEM Dulbecco’s modified Eagle’s medium ET-1 Endothelin-1 ET-3 Endothelin-3 ETA Endothelin receptor A ETB Endothelin receptor B MPS Mucopolysaccharides PBS Phosphate buffered saline RF Rheumatic fever RNA Ribonucleic acid UFS Universidade Federal de Sergipe VA Valve area

proteica e imunohistoquímica para a endotelina-1 e 3 (ET-1 e ET-3) e seus receptores (ETA e ETB) em valvas mitrais reumáticas.

Métodos: Imunohistoquímica foi utilizada para identificar receptores de ET1/ET3 e ETA/ETB em valvas mitrais reumáticas e controles. A análise quantitativa da expressão imunohis-

Descritores: Febre Reumática. Estenose da Valva Mitral.

Endotelina-1. Imunoistoquímica. Western Blotting.

INTRODUCTION

ciated with endothelin-induced vasodilation via nitric oxide and prostacyclin release[10].

Some studies show gene expression of endothelin in heart valves of patients who underwent surgical valve replacement[2,5,11,12]. The expression and synthesis of ET-1 is increased by shear and turbulent forces that are likely to occur in various forms of valvular dysfunction that impact on tissue structure and function[5]. This study aims to confirm the presence and determine endothelin and its receptor levels in rheumatic mitral valves, the importance of this peptide and how it might act as a biomarker in inflammatory processes associated with cardiovascular diseases.

Mitral stenosis is an obstruction to blood inflow between left atrium and left ventricle caused by some structural abnormality of the mitral valve, such as annular calcification and chordal fusion[1,2]. Usually, mitral stenosis is of rheumatic origin (more than 99% of cases). Rheumatic fever (RF) is a recurring, inflammatory and autoimmune disease as a result of complications of infections by Lancefield group A β-hemolytic Streptococcus pyogenes. RF is rare in developed countries but remains a disease with high prevalence in developing countries, and is a major cause of acquired heart diseases in children and young adults, such as mitral or aortic stenosis[3-6]. It is estimated that more than 125000 people are hospitalized per year in Brazil because of acute RF[7].

Endothelins are a family of peptides of which there are 3 isoforms: ET-1, ET-2 and ET-3, acting on 2 receptors: ETA and ETB. ET-1 is the form most produced by cardiac endothelium, being normally detected in low concentration in serum. It is related to the regulation of physiological functions including cardiovascular homeostasis[8]. However, in higher concentrations, it acts as pathogenic mediator causing vasoconstriction, fibrosis, inflammation and vascular hypertrophy[9]. ETA receptors have a greater affinity for ET-1 and are expressed in several cells in the cardiovascular system, including smooth muscle cells and fibroblasts, whereas ETB receptors are mainly expressed on endothelial cells and have the same affinity for all three endothelin isoforms. The main effects of ET-1 on ETA receptors are vasoconstriction, increased inotropism and mitogenesis; ETB receptors are asso-

METHODS This study focused on the quantitative analysis of immunostaining and western blotting of eleven mitral valves collected at Aracaju, SE, Brazil under local Ethics Committee approval (CAAE 2344.0.000.107.10). Additionally, we performed calcium determination on the mitral valves.

Seven mitral valve samples were obtained during heart valve surgeries in association with two major cardiovascular Surgery services located in the city of Aracaju. The control group consists of four samples from victims of fatal motorcycle accidents which were obtained at the local Institute of Legal Medicine. At autopsy, valvular changes were not evidenced; nor other signs that could be suggestive of acute or chronic rheumatic disease.

After gathering the samples, they were submerged in RNA stabilization solution made by BioAgency® and stored

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in a -80°C freezer at the Morphology Department of UFS. The samples were prepared as 5 μm sections that were mounted on silanized microscope slides.

haematoxylin, tapwater was rinsed for 5 minutes, washed in distilled water 2 times, then dehydrated in increasing concentration alcohol (50% to 100%) and dewaxed in histoclear for 3 times of 5 minutes each. Vector® red substrate was used as the chromogen of this reaction.

Antibodies and their dilution: Mouse anti-human monoclonal antibody against endothelial cells (CD31, clone JC70A, 1:100, DakoCytomation, Denmark); rabbit anti-human monoclonal antibody against ET-1 and ET-3 (1:250, R & D Labs), rabbit anti-human monoclonal antibodies against ETA and ETB receptors (both 1:200, Alomone Labs, Israel) and AS02/Thy-1 for fibroblasts (1:200, DakoCytomation, Denmark). Representative sections from each sample were also stained using haematoxylin and eosin.

Epidemiological profile All the 7 patients who underwent surgical treatment between the months of June 2012 and August 2012 were male, with documented evidence of rheumatic mitral stenosis, diagnosed by echocardiographic exams associated with serological tests (ASO) and clinical history of rheumatic fever.

The mean age of the patients was 33±11.56 years. There were no deaths during surgery. Echocardiographic data from the valve area (VA) and pulmonary artery systolic pressure (PASP) were obtained. The findings showed a mean valve area of 1.0±0.38 cm2 and a mean PASP of 52.71±13.64 mmHg, as shown in Table 1. The mean age of the control group (four males) is 27±1.41 years old and the average mitral valve area measured at autopsy was 4.55±0.36 cm2.

Endothelin quantification Stained area measurement of each sample was performed using ImageJ software (National Institute of Health, Bethesda, MD, USA). The method of measurement was based on calculating the mean value derived from the red channel of a red-green-blue (RGB) digital microphotograph of the stained sections. Using a color histogram module and the statistics of the red color distribution, the specimens under examination were compared. The higher the mean intensity on a scale of 0 to 255, the more positive the specimen is. Quantification was performed obtaining the mean intensity value of each section stained by immunohistochemistry at 200x magnification, including the samples stained with ASO2/Thy-1 to identify fibroblasts. Thereafter, a ratio between the mean value in each sample for endothelins and the fibroblast was used as a constitutive control. The measurement of stained areas was repeated by a second observer.

Immunohistochemistry Standard immunohistochemistry was performed on slide-mounted tissue sections using the Avidin-Biotin Complex Alkaline Phosphatase method (ABC-Alkaline Phosphase kit, Vector Laboratories Inc, USA) following the manufacturer’s instructions as previously described[13].

The samples were dewaxed in xylene for 10 minutes, rehydrated in decreasing concentration alcohol (100% to 50%) and immersed in distilled water. Then the slides were heated in full power microwave for 10 minutes in citrate buffer solution pH 6 and washed in phosphate buffered saline (PBS).

The histological sections were circled by wax pen to contain incubation solution. Blocking normal horse serum (10 minutes) and primary antibody (30 minutes), both in PBS solution, were added. After that, slides were gently washed in PBS for 3 times. Secondary antibody in PBS solution was added for 10 minutes and then the slides were gently washed for 3 times again. Sections were incubated in Vectastain® ABC-AP reagent for 5 minutes. The sections were washed in PBS 3 times and incubated in alkaline phosphatase substrate solution 20 minutes. The slides were counterstained with

Western blot analysis To examine biochemical and functional differences between control and ET-1 fibroblasts in mitral valves, we performed some western blot experiments, according previous protocols[14,15]. Fibroblasts were cultured and treated with ET-1 in floating or fixed collagen gels as described above.

Alternatively, fibroblasts were grown to confluence in Dul-

Table 1. Epidemiological profile of patients and controls.

Patients Sex Age VA (cm2) PSAP Controls P1 M 28 0.8 33 C1 P2 M 32 1.8 35 C2 P3 M 42 0.6 54 C3 P4 M 24 1.1 67 C4 P5 M 55 0.8 55 P6 M 24 1 60 P7 M 26 0.9 65 Mean 33 1 52,71429 Std. Dev 11.56 0.38 13.64 VA=valve area; PASP=pulmonary artery systolic pressure.

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Age 26 27 26 29

VA(cm2) 4.2 4.7 4.3 5.0

PSAP -

27 1.41

4.55 0.36

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becco’s modified Eagle’s medium (DMEM) with 10% fetal calf serum and then serum starved in DMEM with 0.5% bovine serum albumin (BSA) for 24 h. After serum starvation, cells were stimulated with 100 nM ET-1 for 24 h with 0.5% BSA .Cell layer lysates were examined. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed on 12% polyacrylamide gels, and the separated proteins were transferred onto nitrocellulose membranes at 30 V for 90 min. Membranes were blocked by incubation for 1 h with 5% nonfat milk in PBS containing 0.2% Tween 20, and antigens were detected using specific antibodies. Cell layer lysates (10 μg/sample) were probed using antibodies directed against ET-1, ET-3 (R & D Labs) ETA and ETB (Alomone Labs, Israel), followed by incubation with appropriate horseradish peroxidase-conjugated bound secondary antibody (Jackson ImmunoResearch Laboratories).Signal was detected using the enhanced chemiluminescence protocol (Amersham Biosciences, Piscataway, NJ) as described by the manufacturer.

was particularly evident at inflammatory regions and also in close proximity to calcified areas (Figure 1). At higher magnification more discrete, localized, immunostaining was observed where ET-1 and ETA/B receptors were associated with regions of fibrosis (ASO2/Thy-1 immunostaining), inflammation and neovascularization (CD31 immunostaining) (Figure 2). In most samples there was no (or very weak) positive immunostaining for ET-3. Endothelial ET-1 staining was observed in regions of neovascularization (Figure 2).

Quantitative analysis Figure 3 shows the quantitative analysis for stained area measurement data as a ratio between mean values for ET and fibroblast. The results of this quantitative analysis for rheumatic versus control samples: ET-1 122%±13% vs.

129%±12; ETA 121%±7% vs. 118%±20%; ETB 121%±12% vs. 110%±16% (one control sample did not express ETB receptor). While quantitative analysis for ET showed that the average area with positive expression of ET-1 was 18.21±14.96%. For ETA and ETB, the mean expressed areas were respectively 15.06±13.13% and 9.20±11.09%. ET-3 had none or very weak expression. The correlation between the expression of both endothelin receptors were strongly positive (R=0.74, P=0.02), but the correlation between ET-1 and its receptor were negative for both ETrA (R= -0.37, P=0.25), and ETrB (R=-0.14, P=0.39).

Here, quantitative data is expressed at ET/ET receptor staining as a proportion of fibrotic regions. Where staining is >100% additional staining was associated with other areas such as neovascularization and inflammation; there are cases where these regions overlap (e.g. neovascularization within fibrotic regions).

Calcium determination The valve fragments were sent to the Laboratory of Analytical Chemistry, Department of Chemistry (UFS) to determine their inorganic calcium content. We also analyzed the control group. HCl was used to digest the samples, and the quantitative analysis of the inorganic calcium was performed via atomic absorption spectrometer (Varian® Atomic Absorption 240FS, Mulgrave, AUS).

Statistics Statistical calculus was performed by measures of central tendency and variation. We also examined the correlation between expression of ET1 and its receptors. For correlation analysis, we used Pearson’s correlation, with the significance level of 5% (P value< 0.05). The results obtained was analyzed by the software Microsoft Excel® 2007.

Western blot analysis The western blot analysis data generally supported the quantitative immunohistochemistry where ET-1 and ETA receptor protein expression were shown to be raised in RF/ stenotic mitral valves compared with controls. ETB receptor protein levels were low and a small rise in stenotic valves was observed while ET-3 expression was low and there was no difference between RF patients and controls (Figure 4).

RESULTS Immunohistochemistry There was dense immunostaining in stenotic mitral valves, mainly for ET-1 and ETA receptors. This staining

Fig. 1 - ET-1 and ETA receptor immunostaining at inflammatory and calcified regions of stenotic mitral valve. Neg=negative control

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Fig. 2 - Immunostaining of sections of stenotic valve from a patient with rheumatic fever.

Top left. ET-1 staining associated with fibrotic regions and neovascularization. Top middle. ETA receptor staining of fibrotic region and neovascularization.

Top right. H + E-stained section.

Lower left. No ET-3 immunostaining.

Lower middle. ETB receptor immunostaining of fibrotic region and neovascularization.

Lower right. Negative control.

ET=endothelin; ETA=endothelin receptor A; ETB=endothelin receptor B

Fig. 3 - Results of quantitative analysis of ET-1 and ET receptors in mitral valves.

Data presented as ET/Thy ratio (percent ET/ET receptor staining associated with fibrosis) in mitral valves from patients with RF undergoing valve replacement (n=7) and control tissue (n=4).

RF=rheumatic fever; ET=endothelin

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Fig. 4 - Western blot analysis of RF versus control mitral valve tissue extracts.

Left. Representative blots for ET-1, ET-3, ETA and ETB receptors from control (Co) and rheumatic (Rh) mitral valve extracts. Right. Histograms of mean ± SD of pooled data from control and rheumatic tissue.

Calcium determination In fact, the group with mitral stenosis showed high levels of inorganic calcium, with an average of twenty-six times higher than the control group (Mitral Stenosis Group=8.1±1.6 vs. Control Group=0.3±0.2; P<0.05).

concentration did not differ between the two groups of patients, plasma ET-1 levels in the pulmonary artery and right atrium were significantly higher in patients with high pulmonary artery pressure than those with normal pulmonary artery pressure. Before cardiopulmonary bypass there was a significant pulmonary extraction of plasma ET-1 in patients with high pulmonary artery pressure but this was not seen after bypass. Since there was no transpulmonary difference of plasma ET-1 concentration in patients with normal pulmonary artery pressure either before or after bypass the authors concluded that high levels of ET-1 in the pulmonary circuit and the pulmonary extraction of the ET-1 in patients with high pulmonary artery pressure might be a protective mechanism for rheumatic valvular patients with elevated pulmonary artery pressure.

A study investigating the expression levels of ET-1 and ET(A) and ET(B) receptors in porcine mitral valves and associating transcription levels to age, leaflet location and deposition of mucopolysaccharides (MPS) has been described[19] where transcription levels of ET-1 and ET(A)-R were significantly higher in leaflets from the ‘old’ compared with ‘young’ pigs whereas gene expression of ET(B)-R was not associated with age, but increased in chordal insertion areas compared with inter-chordal areas. It was concluded that an age-related valvular degeneration occurs in porcine mitral valve leaflets and that ET-1 is involved via an action on both ET(A) and ET(B) receptors.

Regarding a potential role of ET-1 in calcification, there is evidence that this peptide is involved in vascular calcifi-

DISCUSSION In this study we have shown that ETs and their receptors are present in mitral valves obtained from patients with RF undergoing valve replacement surgery. Early indications for a role of ET-1 in patients with mitral valve stenosis were described by Kinoshita and colleagues[16] where plasma ET-1 concentrations were higher in patients with mitral stenosis than in healthy volunteers. More recently, Chen et al.[17] measured plasma concentrations of ET-1 in patients with moderate-to-severe rheumatic mitral stenosis before and after percutaneous transluminal mitral valvuloplasty. While circulating ET-1 levels were elevated in patients with mitral stenosis the authors proposed that ET-1 release was due largely to increased systemic venous pressure and mechanical damage of the endothelium.

A protective role for ET-1 in rheumatic valvular patients with elevated pulmonary artery pressure has been proposed based on data from Huang et al.[18]. Here, patients who underwent cardiac valvular replacement were studied to determine the perioperative changes of plasma ET-1 levels and disposition of ET-1 in the pulmonary and systemic vasculature between patients with elevated pulmonary artery pressure and patients with normal pulmonary artery pressure. While ET-1

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cation based on a study using both an in vivo model and in vitro calcification of vascular smooth muscle cells (VSMCs) induced by beta-glycerophosphate[20]. In vitro, calcium content and Ca(2+) uptake were increased in calcified VSMCs, compared with controls, but were decreased, compared with calcified VSMCs in the presence of BQ123. In addition, ET-1 content in the medium and ET-1 mRNA in VSMCs was elevated compared with normal VSMCs. These results indicated an upregulated ET-1 gene expression as well as an increased production of ET-1 in calcified aorta and VSMCs with BQ123 and bosentan significantly reducing vascular calcification suggesting that ET-1 might be involved in pathogenesis of vascular calcification. Our study revealed marked ET-1 immunostaining of microvessels in rheumatic mitral valves that was paralleled by staining of both ETAR and ETBR, an observation that may be of particular relevance to the calcification occurring in these patients[21,22].

According other studies which found a positive correlation between ET-1 and ETA receptors with mitral stenosis in rheumatic patients, our study showed higher levels of ET-1 in rheumatic replaced valve samples in comparison to control samples. But it should be understood that the results fit to more complex valve situations to the point of not allowing the plastic; with this, we can not assert that the results can be assumed as a general rule during the natural history of mitral stenosis.

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

4. Leão SC, Lima MR, Nascimento HM, Octacilio-Silva S, Rodrigues TM. IL-10 and ET-1 as biomarkers of rheumatic valve disease.

Rev Bras Cir Cardiovasc. 2014;29(1):25-30.

5. Costa LP, Domiciano DS, Pereira RMR. Características demográficas, clínicas, laboratoriais e radiológicas da febre reumática no Brasil: revisão sistemática. Rev Bras Reumatol. 2009;49(5):617-22.

6. Carapetis JR. Rheumatic heart disease in developing countries. N Engl J Med. 2007;357(5):439-41.

7. Spina GS. Doença reumática: negligenciada, mas ainda presente e morta. Rev Med (São Paulo). 2008;87(2):128-41.

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

9. Mayes MD. Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum.

2003;48(5):1190-9.

10. Masaki T. Historical review: Endothelin. Trends in Pharmacol Sci. 2004;25(4):219-24.

11. Porto CC. Doenças do coração: prevenção e tratamento. 2ª ed.

Rio de Janeiro: Guanabara Koogan; 2005.

Authors’ roles & responsibilities SCL MRD MSA NNS ORLLT WBS TMAR

12. Veinot JP. Pathology of inflammatory native valvular heart disease.

Cardiovasc Pathol. 2006;15(5):243-51.

Final approval of the manuscript; conception and design; manuscript writing or critical review of its content Analysis and/or interpretation of data; conception and design; operations and/or experiments conduct Analysis and/or interpretation of data; statistical analysis Operations and/or experiments conduct; manuscript writing or critical review of its content Operations conduct and/or experiments conduct; manuscript writing or critical review of its content Analysis and/or interpretation of data; operations and/or experiments conduct; manuscript writing or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript; conception and design; operations and/or experiments conduct; manuscript writing or critical review of its content

13. Haque SU, Dashwood MR, Heetun M, Shiwen X, Farooqui N, Ramesh B, et al. Efficacy of the specific endothelin a receptor antagonist zibotentan (ZD4054) in colorectal cancer: a preclinical study. Mol Cancer Ther. 2013;12(8):1556-67.

14. Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, et al. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/ Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell. 2004;15(6):2707-19.

REFERENCES

15. Shi-Wen X, Denton CP, Dashwood MR, Holmes AM, BouGharios G, Pearson JD, et al. Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. J Invest Dermatol. 2001;116(3):417-25.

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.

16. Kinoshita O, Yoshimi H, Nagata S, Ishikura F, Kimura K, Yamabe T, et al. Rapid increase in plasma endothelin concentrations during percutaneous balloon dilatation of the mitral valve in patients with mitral stenosis.Br Heart J. 1993;69(4):322-6.

2. Carabello BA, Paulus WJ. Aortic stenosis. Lancet. 2009;373(9667): 956-66.

17. Chen MC, Wu CJ, Yip HK, Chang HW, Chen CJ, Yu TH, et al.

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irrelevance to left atrial and pulmonary artery pressures.Chest.

2004;125(2):390-6.

Endothelin-1 is a potent regulator in vivo in vascular calcification and in vitro in calcification of vascular smooth muscle cells.

Peptides. 2003;24(8):1149-56.

18. Huang CH, Huang HH, Chen TL, Wang MJ. Perioperative changes of plasma endothelin-1 concentrations in patients undergoing cardiac valve surgery. Anaesth Intensive Care. 1996;24(3):342-7.

21. Rajamannan NM, Nealis TB, Subramaniam M, Pandya S, Stock SR, Ignatiev CI, et al. Calcified rheumatic valve neoangiogenesis is associated with vascular endothelial growth factor expression and osteoblast-like bone formation. Circulation.

2005;111(24):3296-301.

19. Pedersen LG, Offenberg H, Moesgaard SG, Thomsen PD, Pedersen HD, Olsen LH. Transcription levels of endothelin-1 and endothelin receptors are associated with age and leaflet location in porcine mitral valves. J Vet Med A Physiol Pathol Clin Med. 2007;54(3):113-8.

22. Mariscalco G, Lorusso R, Sessa F, Bruno VD, Piffaretti G, Banach M, et al. Imbalance between pro-angiogenic and anti-angiogenic factors in rheumatic and mixomatous mitral valves. Int J Cardiol.

2011;152(3):337-44.

20. Wu SY, Zhang BH, Pan CS, Jiang HF, Pang YZ, Tang CS, et al.

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Pinto Júnior VC, et al. - Epidemiology ORIGINAL ARTICLEof congenital heart disease in Brazil

Epidemiology of congenital heart disease in Brazil Epidemiologia da cardiopatia congênita no Brasil

Valdester Cavalcante Pinto Júnior1,MD, MSc; Klébia Magalhães P. Castello Branco2, PhD; Rodrigo Cardoso Cavalcante3; Waldemiro Carvalho Junior4, MD; José Rubens Costa Lima5, PhD; Sílvia Maria de Freitas6, PhD; Maria Nazaré de Oliveira Fraga7, PhD; Nayana Maria Gomes de Souza8 DOI 10.5935/1678-9741.20150018

RBCCV 44205-1635

Abstract Introduction: Congenital heart disease is an abnormality in the structure or cardiocirculatory function, occurring from birth, even if diagnosed later. It can result in intrauterine death in childhood or in adulthood. Accounted for 6% of infant deaths in Brazil in 2007.

Objective: To estimate underreporting in the prevalence of congenital heart disease in Brazil and its subtypes.

Methods: The calculations of prevalence were performed by applying coefficients, giving them function rates for calculations of health problems. The study makes an approach between the literature and the governmental registries. It was adopted an estimate of 9: 1000 births and prevalence rates for subtypes applied to births of 2010. Estimates of births with congenital heart disease were compared with the reports to the Ministry of Health and were studied by descriptive methods with the use of rates and coefficients represented in tables.

Results: The incidence in Brazil is 25,757 new cases/year,

distributed in: North 2,758; Northeast 7,570; Southeast 10,112; South 3,329; and Midwest 1,987. In 2010, were reported to System of Live Birth Information of Ministry of Health 1,377 cases of babies with congenital heart disease, representing 5.3% of the estimated for Brazil. In the same period, the most common subtypes were: ventricular septal defect (7,498); atrial septal defect (4,693); persistent ductus arteriosus (2,490); pulmonary stenosis (1,431); tetralogy of Fallot (973); coarctation of the aorta (973); transposition of the great arteries (887); and aortic stenosis 630. The prevalence of congenital heart disease, for the year of 2009, was 675,495 children and adolescents and 552,092 adults.

Conclusion: In Brazil, there is underreporting in the prevalence of congenital heart disease, signaling the need for adjustments in the methodology of registration.

Specialist in Cardiovascular Surgery. Master’s Degree in Evaluation of Public Policies at Federal University of Ceará (UFC). Head of Pediatric Cardiovascular Surgery at Hospital Messejana and InCor Criança of Fortaleza, CE, Brazil.

Head of the Pediatric Cardiovascular Surgery – Hospital Messejana).

2 University of São Paulo. Head of Pediatric Cardiology of the Hospital Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, CE, Brazil.

3 Medicine student at UniChristus, Fortaleza, CE, Brazil.

4 Specialist in cardiovascular surgery by BSCCV. Cardiovascular Surgeon at Hospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, CE, Brazil.

5 Epidemiologist Physician of Epidemiological Surveillance Cell of Fortaleza, Municipal Health Department, CE, Brazil. Master’s Degree in Public Health from Unicamp, Campinas, SP, Brazil.

6 Professor of Master’s Degree Course of Vocational Assessment of Public Policies by the UFC, Fortaleza, CE, Brazil.

7 Professor of Professional Master’s Degree Course in Public Policy Evaluation by the UFC, Fortaleza, CE, Brazil.

8

Descriptors: Heart Defects, Congenital. Epidemiology.

Health Policy. Brazil.

Nurse at the Hospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, CE, Brazil.

1

This study was carried out at Heart Institute for Children and Adolescents InCor Criança, Fortaleza,CE, Brazil.

No financial support.

Correspondence address: Valdester Cavalcante Pinto Júnior Rua Núbia Barrocas, 125, Parque Manibura Fortaleza - Ceará - Brazil Zip code: 60821-775 E-mail: incorcrianca@yahoo.com.br Article received on July 21st, 2013 Article accepted on February 24th, 2015

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nascimentos e taxas de prevalências para subtipos, aplicadas aos nascimentos de 2010. As estimativas de nascimentos com cardiopatia congênita foram comparadas com as notificações ao Ministério da Saúde. Foram estudados por métodos descritivos com uso de taxas e coeficientes, representados em tabelas.

Resultados: A incidência, no Brasil, é de 25.757 novos casos/ ano, distribuídos em: Norte 2.758; Nordeste 7.570; Sudeste 10.112; Sul 3.329; e Centro-Oeste 1.987. Em 2010, foram notificados ao SINASC/MS 1.377 casos de nascidos com cardiopatias congênitas, o que representa 5,3% do estimado para Brasil. No mesmo período, os subtipos mais frequentes foram: comunicação interventricular (7.498); comunicação interatrial (4.693); persistência do canal arterial (2.490); estenose pulmonar (1.431); tetralogia de Fallot (973); coarctação da aorta (973); transposição das grandes artérias (887); e estenose aórtica 630. A prevalência de cardiopatias congênitas, para o ano de 2009, foi 675.495 crianças e adolescentes e 552.092 adultos.

Conclusão: Há, no Brasil, subnotificação na prevalência das cardiopatias congênitas, sinalizando para a necessidade de adequações na metodologia de seu registro.

Abbreviations, acronyms & symbols AoCo ASD CHD MOH PDA T4F TGA VSD

Aortic coarctation Atrial septal defect Congenital heart disease Ministry of Health Persistent ductus arteriosus Tetralogy of Fallot Transposition of the great arteries Ventricular septal defect

Resumo Introdução: Cardiopatia congênita é uma anormalidade na estrutura ou função cardiocirculatória, ocorrente desde o nascimento, mesmo que diagnosticada posteriormente. Pode resultar em morte intraútero, na infância ou na idade adulta. Foi responsável por 6% dos óbitos infantis, no Brasil, em 2007.

Objetivo: Estimar a subnotificação na prevalência das cardiopatias congênitas no Brasil e seus subtipos.

Métodos: Os cálculos das prevalências foram realizados aplicando-se coeficientes, atribuindo-lhes função de taxas para cálculos dos agravos. O estudo faz aproximação entre a literatura e os registros governamentais. Adotou-se estimativa de 9:1000

Descritores: Cardiopatias Congênitas. Epidemiologia. Política de Saúde. Brasil.

INTRODUCTION

congenital heart defects corresponding to 9.58:1,000 births and equal to 87.72:1,000 between stillbirths[16]. Rivera, in Alagoas, Brazil, for the same age group, found prevalence in 13.2:1,000 births[17].

Study review and meta-analysis on the global prevalence of congenital heart disease included 114 studies, with a study population of 24,091,867 births. The prevalence rate estimated at 9.1 per 1,000 births remains stable over the last 15 years. This corresponds to 1.35 million newborns with CHD each year[18].

In this study, prevalence is the greatness of the event at any given time[19], adopting the coefficient of 9:1000 births as the basis for calculation of CHD in Brazil and in each federal unit.

The scarcity of specific bibliography and reliable statistics on the Brazilian population with congenital heart disease forces the approximation to the international literature, in order to estimate the prevalence of CHD in Brazil and compare it to the official notifications, serving therefore as basis for formulation of public policies, based on more realistic data.

Congenital Heart Disease (CHD) is an abnormality in the structure or cardiocirculatory function that occurs from birth, even if subsequently diagnosed[1]. It varies in severity, occurring from communications between cavities that spontaneously regress up to major malformations that even require several procedures, surgical or catheterization. It can result in intrauterine, childhood or adulthood death[2].

Globally, 130 million children are born each year. Of these, four million die in the neonatal period, or that is, in the first 30 days of life[3] and 7% of the fatalities are related to CHD[4].

In 2007, in Brazil, 6% of deaths in children under one year of age were by CHD[5]. Among the congenital malformations, cardiovascular abnormalities are the most common cause of infant mortality, 40% under study in São Paulo/Brazil[6] and 26.6% and 48.1% in the US[7,8]. Delays in the development and cognitive deficits are associated with a congenital heart disease of 20% to 30%[9-11].

Hoffman & Kaplan reported a variation in prevalence rate of 4:1000 to 50:1000 births. The highest one is related to the occurrence of low severity injuries that are solved without medical intervention[12].

In Brazil, studies on the epidemiology of congenital heart disease with different cuts, express coefficients ranging from 5.494[13] to 7.17 per 1,000 births[14]. For a group with low birth weight, the prevalence rate ranged from 10.7 to 40.7:1,000 births[15].

Amorim, in Minas Gerais, Brazil, from 1990 to 2003, analyzing data on 29,770 newborns, found prevalence rate of

Objective The aim of this study was to estimate underreporting in the prevalence of congenital heart disease in Brazil and its most frequent subtypes.

METHODS We adopted for the test under report, the prevalence rate of congenital heart disease equal to 9:1000 births, defined in a review and meta-analysis study for births worldwide [18].

Population and birth registries in Brazil, regions and federated

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units, were obtained by consulting the Demographic Census of 2010, published in 2012, and made available on the DATASUS/ Ministry of Health (MOH) website[20].

Secondary data relating to the distribution by age group, the Brazilian population of 2009, published by the Demographic Census of 2010[20], were divided into two groups: the first with children under 18 years of age and the second formed by adults, aged 18 and more.

Rates for the prevalence of congenital heart disease by age group, were defined in the study on the population of Canada. For children under 18, 11.89 CHD per 1,000 individuals and 4.09 CHD per 1,000 adults[21].

The prevalence of congenital heart disease in 2010, recorded in SINASC (System of Live Birth Information), was obtained by consulting the DATASUS/MOH website.

The estimated prevalence of congenital heart disease in

Brazil, was generated when the prevalence rate equal to 9: 1000 births was applied to quantitative births.

Estimated prevalence of congenital heart disease was compared with notifications from SINASC/MOH, revealing the disease registration percentage in Brazil and the federal units.

The estimated prevalence of the eight most frequent subtypes of CHD was achieved by applying to the quantitative of birth the prevalence rates per 1,000 births of each subtype, namely: Ventricular septal defect (VSD) 2.62; Atrial septal defect (ASD) 1.64; Persistent ductus arteriosus (PDA) 0.87; Pulmonary stenosis 0.5; Tetralogy of Fallot (T4F) 0.34; Aortic Coarctation (AoCo) 0.34; Transposition of the great arteries (TGA) 0.31 and Aortic Stenosis, 0.22[18].

The CHD prevalence rates among age groups were estimated when applied to population groups their respective relative rates of prevalence[21].

Table 1. Distribution of the number of births, prevalence of Congenital Heart Disease (CHD), birth notification with (CHD) - SINASC/Ministry of Health (MOH) and notification percentage for Brazil, regions and federated units in 2010.

Region/State BRAZIL North Rondônia Acre Amazonas Roraima Pará Amapá Tocantins Northeast Maranhão Piauí Ceará Rio Grande do Norte Paraíba Pernambuco Alagoas Sergipe Bahia Southeast Minas Gerais Espírito Santo Rio de Janeiro São Paulo South Paraná Santa Catarina Rio Grande do Sul Midwest Mato Grosso do Sul Mato Grosso Goiás Distrito Federal

Born 2,861,868 306,422 25,835 16,495 74,188 9,738 140,687 15,008 24,471 841,160 119,566 49,424 128,831 47,668 58,699 136,591 54,164 34,016 212,201 1,123,593 255,126 51,853 215,262 601,352 369,905 152,051 84,611 133,243 220,788 40,132 48,929 87,476 44,251

Prevalence (CHD) 9:1.000 births 25,757 2,758 233 148 668 88 1,266 135 220 7,570 1,076 445 1,159 429 528 1,229 487 306 1,910 10,112 2,296 467 1,937 5.412 3,329 1,368 761 1,199 1,987 361 440 787 398

Notification to (CHD) SINASC/MS 1.377 51 3 0 19 3 19 3 4 162 14 3 31 8 8 45 13 8 32 837 99 12 58 668 277 80 74 123 50 10 6 14 20

Source: MoH/SVS/DASIS - Live Births Information System - SINASC – 2010.

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% of Notification 5.3 1.8 1.3 0 2.8 3.4 1.5 2.2 1.8 2.1 1.3 0.67 2.7 1.9 1.5 3.7 3 2.6 1.7 8.3 4.3 2.6 3.0 12 8.3 5.8 9.7 10 2.5 2.8 1.4 1.8 5

Pinto JĂşnior VC, et al. - Epidemiology of congenital heart disease in Brazil

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The data were evaluated by descriptive methods using rates and ratios represented in tables.

It is common to find in the scientific literature that large differences in epidemiological calculations, which stems in part of the variation in sample selection in which the studies are performed[12,15,16]. Studies on the prevalence of CHD after the first year of life underestimate the occurrence of the disease in the fetus and newborn, considering that 20% of children die in their first year of life[23]. Another aspect that implies inaccuracies is related to the fact that 30% of CHD can not be diagnosed in the first weeks of life[24].

CHD prevalence rate equal to 9:1000 births, defined in the study review and meta-analysis to births worldwide[18], was defined as basis for calculation of CHD estimates for this study.

Thus, estimates for Brazil point to 25,757 new cases of CHD/year, distributed by regions North 2,758; Northeast 7,570; Southeast 10,112; South 3329; and Midwest 1,987.

The notifications published by DATASUS/MS have shown 1,377 births with CHD in 2010, corresponding to 5.3% of the estimate of 9:1,000 births used for this study.

Therefore, the public policies in this segment are supported by a reality of underreporting. Thus, assumptions of the Unified Health System; as universality, comprehensiveness and equity, principles of health-inducing public policies with quality[25], remain outside of care to this group of patients.

Knowing that 25% of births with CHD require invasive treatment in the first year of life[26], in order to meet the demand, it would be needed 6,439 procedures per year in Brazil. In 2008, however, 1919 procedures were performed[5].

There is, therefore, for this age group, deficit of procedures is about 70%.

A quantitative explanation of congenital heart disease, its territorial distribution and classification by subtypes associated with the determination of risk for disease, allows establishing planning for the health care of this population.

Thus, considering all the variables, it is possible to direct investments equally to this group that, in 2009 amounted to 675,495 children and adolescents and 552,092 adults with CHD, with expected annual growth rate of 1% to 5%, depending on age and the distribution of[21,27] injuries.

RESULTS In 2010, in Brazil, 2,861,868 births were reported. When applied the prevalence rate of congenital heart disease of 9:1,000 births, an estimate of 25,757 new cases for the year under study was found. The occurrence of CHD in the Brazilian regions, for the same year, was as follows: North 2758; Northeast 7,570; Southeast 10,112; South 3329; and Midwest 1,987 new cases Table 1.

In the same period, 1,377 cases of births with CHD were reported to the Ministry of Health/SINASC, representing 5.3% of estimated for Brazil. The distribution by federal unit is visualized in Table 1.

In this study, the prevalence for the year 2010, from the eight most frequent subtypes of CHD were: Ventricular septal defect (VSD) 7498; Atrial septal defect (ASD) 4693; Persistent ductus arteriosus (PDA) 2490; Pulmonary stenosis 1,431; Tetralogy of Fallot (T4F) 973; Aortic coarctation (CoA) 973; Transposition of the great arteries (TGA) 887 and Aortic Stenosis 630 Table 2.

In 2009, to a Brazilian population of 191,795,000, divided into 56,809,000 under 18 and 134 986 000 adults was estimated a prevalence of 675,495 children and adolescents and 552,092 adults with congenital heart disease.

DISCUSSION Pinto Jr et al.[22] propose, in a study on regionalization of Brazilian pediatric cardiovascular surgery, the implementation of a support network for patients with congenital heart disease, of fair range for all regions of Brazil. Therefore, it becomes important to define the prevalence and distribution of the disease and its subtypes for each territory.

The lack of national studies forces the approximation of the numbers with specific international literature and thus, through estimates, it reveals a scenario that best describes the reality.

Table 2. Distribution of the prevalence of the eight CHD subtypes in Brazil and in the regions for the year 2010.

Region BRAZIL North Northeast Southeast South Midwest

Births 2,861,868 306,422 841,160 1,123,593 369,905 220,788

VSD 2.62* 7,498 803 2,204 2,944 969 578

ASD 1.64* 4.693 503 1.380 1.843 607 362

PDA 0.87* 2.490 267 732 978 322 192

Pulm. Stenosis 0.5* 1.431 153 421 562 185 110

T4F 0.34* 973 104 286 382 126 75

AoCo 0.34* 973 104 286 382 126 75

TGA 0.31* 887 95 261 348 115 68

Ao Stenosis 0.22* 630 67 185 247 81 49

Source: MoH/SVS/DASIS - Live Births Information System - SINASC â&#x20AC;&#x201C; 2010. *Prevalence of types of CHD per 1,000 births. CHD=congenital heart deseases; VSD=ventricular septal defect; ASD=atrial septal defect; PDA=persistent ductus arteriosus; Pulm Stenosis=pulmonary stenosis; T4F=tetralogy of Fallot; AoCo=aortic coarctation; TGA=transposition of the great arteries; Ao Stenosis=aortic stenosis

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Transposition of the gap between standards, Ordinances 1169/GM and 210/SAS-MS[28,29] and the assistance requires political will and planning aimed at improving access to pediatric cardiovascular surgery centers, financing of Cardiology and Cardiovascular Surgery Pediatric; database feeding; promote management for quality and establish continuing education programs[5,6].

Failure to observe these points, which are fundamental in the design and implementation of health care policy for CHD patients, blames the Brazilian system of health care, public and supplementary, to leave outside the surgical treatment of 62% of infants with congenital heart disease, reaching in some regions of Brazil to 76 and 91%[5].

Gomes[30], in an editorial, “the debt to the nation’s health: the case of congenital heart disease,” translates numbers into words and says: [...] became untenable the acceptance of the quality of health care of the Brazilians. Felt by the population, but mainly affecting patients, their families, doctors and all other professionals involved, and even more so when it involves children with congenital heart disease, excluded from the basic right of adequate treatment and the chance to be alive.

Facing such problem requires the participation of civil society in the development of social policies and it is mandatory for the elaboration of issues in the social area, the intervention of agents who experience difficulties, either as carriers of disease, either as family components, either as professionals[31].

Authors’ roles & responsibilities VCPJ

KMPCB RCC WCJ JRCL SMF MNOF NMGS

Coordinator of the study; planning and review of the final version; analysis and/or interpretation of the data; final approval of the study; conception and design; study writing or critical review of its contents Study writing or critical review of its contents; text review Data survey from IBGE; performance of surgeries and/or experiments; study writing or critical review of its contents; references Text review and translation into english; performance of surgeries and/or experiments; study writing or critical review of its contents Analysis and epidemiological calculations; analysis and/or interpretation of the data; statistical analysis; conception and design of the study Supervisor of Master’s Degree thesis which led to this study; analysis and/or interpretation of the data Co-supervisor of the Master’s Degree dissertation which led to this study; analysis and/or interpretation of the data; study writing or critical review of its contents Data survey from IBGE and references; statistical analysis; performance of surgeries and/or experiments

REFERENCES 1. Friedman WF. Congenital heart disease in infancy and childhood.

In: Braunwald E, org. Heart disease. A textbook of cardiovascular medicine. Pennsylvania: Saunders; 1997. p.877-962.

2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics−2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245.

Study limitations The calculation of the prevalence of congenital heart disease and their most frequent subtypes was anchored in study review and meta-analysis that proposed to estimate the prevalence of this disease in the world[18]. One of the limitations of this meta-analysis is not cover the entire world population, in addition to using only studies with summaries in English and make use of government records available online, a fact that leads to underreporting error, as demonstrated in this study. In this study we found differences in prevalence rates between the continents, ranging from 1.9 to 9.3/1000 births in Africa and Asia, respectively. The author states that data from developing countries were scarce, and studies often did not include indigenous peoples and tribes.

Records to consider the entire population of births are needed to determine the true prevalence of congenital heart disease.

3. Zupan J, Aahman E. Perinatal mortality for the year 2000: estimates developed by WHO. Geneva: World Health Organization; 2005.

4. Lawn JE, Cousens S, Zupan J; Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: when? Where? Why? Lancet. 2005;365(9462):891-900.

5. Pinto Jr VC. Avaliação da política nacional de atenção cardiovascular de alta complexidade com foco na cirurgia cardiovascular pediátrica [Dissertação de mestrado]. Fortaleza: Universidade Federal do Ceará; 2010.

6. Caneo LF, Jatene MB, Yatsuda N, Gomes WJ. Uma reflexão sobre o desempenho da cirurgia cardíaca pediátrica no Estado de São Paulo. Rev Bras Cir Cardiovasc. 2012;27(3):457-62.

7. Centers for Disease Control and Prevention, National Center for Health Statistics. Compressed Mortality File 1999-2009.

CDC WONDER Online Database, compiled for Compressed Mortality File 1999-2009 Series 20, No 20, 2012. Underlying cause-of-death 1999-2009. Available at: http://wonder .cdc . gov/mortSQl .html. Acessed on: 5/6/2013

CONCLUSION In Brazil, there is underreporting in the prevalence of congenital heart disease, signaling the need for adjustments in the methodology of registration.

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8. Gilboa SM1, Salemi JL, Nembhard WN, Fixler DE, Correa A. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006.

Circulation. 2010;122(22):2254-63.

saúde. 7ª ed. Rio de Janeiro: MedBook; 2013. p.25-64.

20. Brasil. IBGE. Censo demográfico 2010. Rio de Janeiro, 2012 [Accessed: Jul. 21, 2013]. Available from: http://www.ibge.gov. br/home/presidencia/noticias/imprensa/ppts/000000084731041 22012315727483985.pdf

9. Miller A, Riehle-Colarusso T, Alverson CJ, Frías JL, Correa A. Congenital heart defects and major structural noncardiac anomalies, Atlanta, Georgia, 1968 to 2005. J Pediatr.

2011;159(1):70-78.e2.

21. Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007;115(2):163-72.

10. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr. 2000;137(5):638-45.

22. Pinto Jr VC, Fraga MNO, Freitas SM, Croti UA. Regionalização da cirurgia cardiovascular pediátrica brasileira. Rev Bras Cir Cardiovasc. 2013;28(2):256-62.

11. Shillingford AJ, Glanzman MM, Ittenbach RF, Clancy RR, Gaynor JW, Wernovsky G. Inattention, hyperactivity, and school performance in a population of school-age children with complex congenital heart disease. Pediatrics. 2008;121(4):e759-67.

23. Cabo JM. Problemas sociales del niño cardiopata. In: Sanchez PA, eds. Cardiología pediátrica: clínica e cirurgía. Barcelona: Salvat; 1986.

24. Abu-Harb M, Hey E, Wren C. Death in infancy from unrecognized congenital heart disease. Arch Dis Child.

1994;71(1):3-7.

12. Hoffman JI, Kaplan S. The incidence of congenital heart disease.

J Am Coll Cardiol. 2002;39(12):1890-900.

13. Guitti JCS. Aspectos epidemiológicos das cardiopatias congênitas em Londrina, Paraná. Arq Bras Cardiol. 2000;74(5):395-9.

25. Pinto Jr VC, Fraga MNO, Freitas SM. Análise das portarias que regulamentam a Política Nacional de Atenção Cardiovascular de Alta Complexidade. Rev Bras Cir Cardiovasc. 2012;27(3):463-8.

14. Nogueira AG. Avaliação da prevalência da cardiopatia congênita no município de Florianópolis/SC [Dissertação de mestrado].

Florianópolis: Universidade Federal de Santa Catarina, Centro de Ciências da Saúde. Programa de Pós-Graduação em Ciências Médicas; 2012.

26. Moller J. Prevalence and incidence of cardiac malformation.

Perspectives in Pediatric Cardiology: Surgery of Congenital Heart Disease: Pediatric Cardiac Care Consortium, 1984 -1995.

Armonk: Futura; 1998. p.19-26.

15. Sadeck LSR, Azevedo R, Barbato AJG, Calil VMLT, Latorre MRDO, Leone CR, et al. Indicações clínico-epidemiológicas para investigação ecocardiográfica no período neonatal: valor dos grupos de risco. Arq Bras Cardiol. 1997;69(5):301-7.

27. Warnes CA, Liberthson R, Danielson GK, Dore A, Harris L, Hoffman JI, et al. Task force 1: the changing profile of congenital heart disease in adult life. J Am Coll Cardiol.

2001;37(5):1170-5.

16. Amorim LF, Pires CA, Lana AM, Campos AS, Aguiar RA, Tiburcio JD, et al. Apresentação das cardiopatias congênitas diagnosticadas ao nascimento: análise de 29.770 recémnascidos. J Pediatr. 2008;84(1):83-90.

28. Brasil. Portaria no 1169/GM em 15 de junho de 2004. Institui a Política Nacional de Atenção Cardiovascular de Alta Complexidade, e dá outras providências. Diário Oficial 2004; seção 1, n.115, p.57.

29. Brasil. Portaria 210 SAS/MS de 15 de junho de 2004. Serviços de cirurgia cardiovascular pediátrica. Diário Oficial 2004; seção 1, n.117, p.43.

17. Rivera IR, Silva MAM, Fernandes JMG, Thomaz ACP, Soriano CFR, Souza MGB. Cardiopatia congênita no recém-nascido: da solicitação do pediatra à avaliação do cardiologista. Arq Bras Cardiol. 2007;89(1):6-10.

30. Gomes WJ, Grupo de Trabalho da SBCCV no Programa Nacional para o Tratamento Integral de Crianças com Diagnóstico de Cardiopatia Congênita. A dívida com a saúde da nação: o caso das cardiopatias congênitas. Rev Bras Cir Cardiovasc. 2013;28(2):VI-VII.

18. van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ, at al. Birth prevalence of congenital heart disease worldwide. A systematic review and meta-analysis.

J Am Coll Cardiol. 2011;58(21):2241-7.

31. Pinto Jr VC, Rodrigues LC, Muniz CR. Reflexões sobre a formulação de política de atenção cardiovascular pediátrica no Brasil. Rev Bras Cir Cardiovasc. 2009;24(1):73-80.

19. Costa-Lima JR, Pordeus AMJ, Rouquayrol MZ. Medida da saúde coletiva. In: Rouquayrol MZ, Silva MGC, eds. Epidemiologia &

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Yuan SM & Humuruola - Stroke of a cardiac myxoma origin REVIEWGARTICLE

Stroke of a cardiac myxoma origin Acidente vascular cerebral com origem em mixoma cardíaco

Shi-Min Yuan1, MMed, PhD; Gulimila Humuruola2, MD

DOI 10.5935/1678-9741.20150022

RBCCV 44205-1636

Abstract Objective: The clinical features of cardiac myxoma stroke have not been sufficiently described. Debates remain concerning the options and timing of treatment and the clinical outcomes are unknown. This article aims to highlight the pertinent aspects of this rare condition.

Methods: Data source of the present study came from a comprehensive literature collection of cardiac myxoma stroke in PubMed, Google search engine and Highwire Press for the year range 2000-2014.

Results: Young adults, female predominance, single cerebral vessel (mostly the middle cerebral artery), multiple territory involvements and solitary left atrial myxoma constituted the outstanding characteristics of this patient setting. The most common affected cerebral vessel (the middle cerebral artery) and areas (the basal ganglion, cerebellum and parietal and temporal regions) corresponded well to the common manifestations of this patient setting, such as conscious alteration, ataxia, hemiparesis and hemiplegia, aphasia and dysarthria. Initial computed tomography scan carried a higher false negative rate for the diagnosis of cerebral infarction than magnetic resonance imaging did. A delayed surgical resection of cardiac myxoma was associated with an increased risk of potential consequences in particular otherwise arterial embolism. The mortality rate of this patient population was 15.3%.

Conclusion: Cardiac myxoma stroke is rare. Often does it affect young females. For an improved diagnostic accuracy,

magnetic resonance imaging of the brain and echocardiography are imperative for young stroke patients in identifying the cerebral infarct and determining the stroke of a cardiac origin. Immediate thrombolytic therapy may completely resolve the cerebral stroke and improve the neurologic function of the patients.

An early surgical resection of cardiac myxoma is recommended in patients with not large territory cerebral infarct.

Descriptors: Embolism. Middle Cerebral Artery. Myxoma.

Stroke.

The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, People’s Republic of China.

2 Department of Internal Medicine, People’s Hospital of Jimunai County, Jimunai, Altay Prefecture, Xinjiang Uygur Autonomous Region, People’s Republic of China.

No financial support.

Resumo Objetivo: As características clínicas do acidente vascular cerebral causado por mixoma cardíaco não foram descritas suficientemente. Debates permanecem sobre as opções e o momento de tratamento e os resultados clínicos são desconhecidos. Este artigo tem como objetivo destacar os aspectos pertinentes desta condição rara.

Métodos: Os dados do presente estudo foram levantados em uma revisão abrangente de literatura sobre acidente vascular cerebral causado por mixoma cardíaco no PubMed, no sistema de buscas do Google e no Highwire Press, abrangendo ao anos entre 2000 e 2014.

Resultados: Adultos jovens, predominância do sexo feminino, vaso cerebral único (principalmente a artéria cerebral mediana), envolvimentos de territórios múltiplos e mixoma atrial esquerdo solitário são características marcantes destes pacientes. O vaso

1

Correspondence address: Shi-Min Yuan Longdejing Street, 389 - Chengxiang District, Putian, Fujian Province, People’s Republic of China E-mail: shi_min_yuan@yahoo.com

Work carried out at Department of Cardiothoracic Surgery, First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, Fujian Province, People’s Republic of China and Department of Internal Medicine, People’s Hospital of Jimunai County, Altay Prefecture, Xinjiang Uygur Autonomous Region, People’s Republic of China.

Article received on January 19th, 2015 Article accepted on March 23th, 2015

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forma de embolia arterial. A taxa de mortalidade dessa população de pacientes foi de 15,3%.

Conclusão: Acidente vascular cerebral causado por mixoma cardíaco é raro. Frequentemente, afeta mulheres jovens. Para um diagnóstico mais preciso, exames de ressonância magnética e ecocardiográficos são imperativos para pacientes jovens com acidente vascular cerebral para determinar a localização do enfarte cerebral e se houve origem cardíaca. Terapia trombolítica imediata pode resolver completamente o acidente vascular cerebral e melhorar a função neurológica dos pacientes. Ressecção cirúrgica precoce de mixoma cardíaco é recomendada em pacientes com acidente vascular cerebral de pequena extensão.

Abbreviations, acronyms & symbols CT MRI

Computed tomography Magnetic resonance imaging

cerebral afetado mais comum (artéria cerebral média) e áreas (o gânglio basal, cerebelo e regiões parietais e temporais) corresponderam bem com as manifestações comuns destes pacientes, como alteração da consciência, ataxia, hemiparesia e hemiplegia, afasia e disartria. Tomografia computadorizada inicial mostrou taxa de falso negativo mais alta para o diagnóstico de acidente vascular cerebral do que a imagem por ressonância magnética. A ressecção cirúrgica tardia de mixoma cardíaco foi associada com risco aumentado de potenciais consequências, em particular, de outra

Descritores: Embolia. Artéria Cerebral Média. Mixoma.

Acidente Vascular Cerebral.

INTRODUCTION

quencies were made by Fisher exact test. P-P plot was used to test normal distribution. Logistic regression was taken to assess the possible predisposing risk factors of mortality.

P<0.05 was considered statistically significant.

Cardioembolic stroke accounts for 14-30% of ischemic strokes with a predilection of early and later recurrences[1].

Atrial fibrillation, acute myocardial infarction, valvular heart disease, infective endocarditis and cardiac myxoma are major sources of cerebral emboli[2]. Of them, atrial fibrillation is the most important one responsible for 45% of cardiogenic embolism[3]. Cardiac myxoma, the most common primary cardiac tumor, is a rare cause, but an important etiology as well for stroke in the young[4]. However, the diagnosis of a cardiac myxoma is often elusive in young stroke patients[5].

A delayed diagnosis and untimely treatment may mean laissez-faire of progression of stroke and development of certain critical consequences like systemic and peripheral embolic events. The clinical features of stroke of a cardiac myxoma origin have not been sufficiently described. In addition, debates remain concerning the options and timing of treatment and the clinical outcomes are unknown. This article aims to highlight the pertinent aspects of this rare condition.

RESULTS A total of 83 reports were obtained with 133 patients involved[4-86]. Eighty-two (98.8%) articles reported only sporadic single case and one (1.2%) article described a small series. There were 71 (53.4%) females and 62 (46.6%) males with a female-to-male ratio of 1.2:1. Patients’ ages were 42.3±18.6 (range, 4-84; median, 43.5) years (n=118), in a normal distribution. Ages of 67 (56.8%) patients were ≤45 years while ages of 51 (43.2%) patients were ≥46 years (χ2=4.3, P=0.051). Ages of male and females patients were 40.1±16.1 (range, 10-57; median, 40) years (n=57) and 45.0±20.5 (range, 4-84; median, 47) years (n=64), respectively (P=0.093). The onset time was described in 54 patients with an acute onset in 53 (98.1%) and a chronic onset in 1 (1.9%) patient, respectively (χ2=100.1, P=0.000). Time interval from onset to physician consultation was 1413.1±3581.6 (range, 0.5-17280; median 24) hours (n=30) with 17 (56.7%) of them presented within 24 hours, and the remaining 13 patients were admitted 3 days-2 years after the onset.

Their initial symptoms were reported in 108 patients: neurological in 97 (89.8%), constitutional in 3 (2.8%), neurological with constitutional 3 (2.8%), neurological with circulatory in 3 (2.8%), circulatory in 1 (0.9%) and all three triad symptoms in 1 (0.9%) patient. Eleven (8.3%) patients had precursory symptoms including headache in 5 (50%), transient ischemic attack in 2 (20%) and a skin rash/spot in 3 (30%) patients. Totally 104 patients developed neurological symptoms. Hemiparesis, aphasia and conscious alteration were the three most common symptoms (Table 1). Forty-two (31.6%) patients had one or more predisposing risk factors of stroke with hypertension being the most common (Table 2).

METHODS A comprehensive literature collection of cardiac myxoma stroke was made in PubMed, Google search engine and Highwire Press for the year range 2000-2014. The search terms included “cardiac myxoma”, “atrial myxoma”, “valvular myxoma” and “stroke”. The search ended on June 30, 2014. Articles describing transient ischemic attack, cerebral vascular aneurysm without stroke, or stroke caused by other cardiac tumors than myxomas were excluded from this study.

Data were extracted from the text or tables, including details of the study subjects, demographics, cerebral infarct, cardiac myxoma, complications, follow-up length and mortality. The main outcomes were complications and mortality.

Quantitative data were expressed in mean ± standard deviation with range and median values. Comparisons of fre-

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Table 1. 228 neurological symptoms in 104 patients.

Neurological symptom Hemiparesis Aphasia Conscious alteration Hemiplegia Dysarthria Ataxia Vision disturbance Dysesthesia Seizures Collapse Dizziness Dysphagia Hemianopsia Mental disturbance Transient ischemic attack Vertigo Diplopia Facial paresis Disorientation Syncope Nausea/vomiting Cognitive impairment Convulsion Epilepsy Hypomnesis Memory loss Paraparesis Ptosis Quadriparesis

septal defect (incidental finding during cardiac surgery), patent ductus arteriosus, acute renal impairment, posttraumatic seizure, synovial sarcoma of the right hand, internal carotid artery aneurysm, non-ST segment elevation myocardial infarction, pregnancy, Raynaud’s disease plus multiple cerebral aneurysms, NAME syndrome and systemic vasculitis with antiphospholipid antibody syndrome in 1 (4.3%) patient each.

Erythrocyte sedimentation rate was detected in 25 (18.8%) patients: 23 (92%) were positive and 2 (8%) were negative (χ2=35.3; P=0.000) with a quantitative value of 57.4±19.7 (range, 30-85; median, 60) mm/h (n=15). C-reaction protein was detected in 16 (12.0%) patients: positive in 10 (62.5%) and negative in 6 (37.5%) patients (χ2=2.0; P=0.289) with a quantitative value of 8.5±13.0 (range, 0.09-35; median, 1.8) mg/dL (n=10).

Cardiac myxoma was diagnosed ahead of the diagnosis of stroke in 8 (11.8%), delayed until after the diagnosis of stroke in 59 (86.8%) and simultaneously with the diagnosis of stroke in 1 (1.5%) patient.

The diagnostic techniques for stroke were given in 81 (60.9%) patients with magnetic resonance imaging (MRI) being the most commonly and computed tomography (CT) more commonly used technique (Table 3).

n (%) 51 (49.0) 29 (27.9) 24 (23.1) 18 (17.3) 17 (16.3) 11 (10.6) 10 (9.6) 9 (8.7) 7 (6.7) 6 (5.8) 6 (5.8) 4 (3.8) 4 (3.8) 4 (3.8) 4 (3.8) 4 (3.8) 3 (2.9) 3 (2.9) 2 (1.9) 2 (1.9) 2 (1.9) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0)

Table 3. Diagnostic tools for cerebral infarct in 81 patients.

Table 2. Predisposing risk factors of stroke.

Risk factor Hypertension Hyperlipidemia Smoking Atrial fibrillation Coronary artery disease Hypertension, hyperlipidemia Hypertension, diabetes mellitus Alcohol Mitral regurgitation Neurosurgery for temporooccipital cavernoma Raynaud’s disease Transient ischemic attack Unknown

n (%) 39 (48.1) 23 (28.4) 7 (8.6) 4 (4.9) 3 (3.7) 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2) 1 (1.2)

Diagnostic tool MRI CT CT, MRI MRI, MRA MRA Autopsy CT, MRA CT, MRI, angiogram Computed tomographic angiography MRI, autopsy

n (%) 13 (9.8) 5 (3.8) 5 (3.8) 4 (3.0) 4 (3.0) 3 (2.3) 2 (1.5) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8) 1 (0.8)

CT=computed tomography; MRI=magnetic resonance imaging; MRA=magnetic resonance angiography.

Table 4. Results of computed tomography and time of scanning, n (%).

Computed tomography Positive Negative χ2 P value

Except for cardiac myxoma and stroke, an additional diagnosis was established in 23 (17.3%) patients including Carney’s syndrome in 7 (30.4%), infected cardiac myxoma in 3 (13.0%) (associated with disseminated intravascular coagulation, kidney and spleen infarcts and urinary tract infection in 1 patient each), patent fossa ovalis in 2 (8.7%), and atrial

Initial 5 (26.3) 14 (73.7) 8.5 0.009

Subsequent 40 (87.0) 6 (13.0) 50.3 0.000

Sixty-five CT scans were examined in 53 patients with a false negative rate of 30.8% (20/65) in overall and of 73.7% (14/19) in initial CT scans taken within 3 hours after the stroke onset (Table 4). Sixty MRIs were taken in 58 patients: 58 (96.7%) MRIs illustrated a positive result and only 2 (3.3%) were negative, both of which were taken within 7 hours after

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the onset. The false negative rate of MRI was much lower than that of CT scan (χ2=15.2, P=0.000). Magnetic resonance angiography was investigated in 14 (10.5%) patients: positive in 12 (85.7%) and unremarkable in 2 (14.3%) patients (χ2=14.3, P=0.000). Cerebral angiogram was performed in only one patient 3 hours after the onset and it revealed a normal result.

The affected cerebral artery was reported in 54 patients and the infarct region could be tracked in 62 patients. The most common affected vessel was the middle cerebral artery (Table 5) and the most common infarct regions were the basal

ganglion, cerebellum and parietal and temporal regions (Table 6). An old cerebral infarct was noted in 6 (4.5%) patients.

Patients were more with unilateral cerebral infarct than with bilateral (χ2=14.1, P=0.000), and more with multiple infarcts than solitary. No prevalence was noted between leftand right-sided infarcts (Table 7).

Nineteen (14.3%) patients had other than cerebral artery embolisms, with systemic multiple emboli in 4 (21.1%)[55,63,71,80], peripheral multiple emboli in 3 (15.8%)[19,72,85] and solitary arterial embolus in 12 (63.2%) patients[9,11,13,16,21,35,41,43,60,76,84]. The 39 affected arteries in 18 patients were listed in Table 8.

Table 5. The affected cerebral artery in 54 patients. n (%) 35 (64.8) 21 (60) 12 (34.3) 2 (5.7) 6 (11.1) 3 (5.6) [1 (33.3) with aneurysm and 1 (33.3) with stenosis)] Basilar artery 2 (3.7) MCA, anterior cerebral artery 2 (3.7) Internal carotid artery + vertebrobasal artery 1 (1.9) MCA, posterior inferior cerebellar artery 1 (1.9) MCA, posterior cerebral artery 1 (1.9) MCA, basilar artery 1 (1.9) Posterior inferior cerebellar artery 1 (1.9) Superior cerebellar artery 1 (1.9) Affected cerebral artery MCA Left Right Unknown Internal carotid artery Posterior cerebral artery

Table 7. Comparisons of site and number of cerebral infarcts.

Infarct side Left Right Bilateral Not given Total

Multiple 14 (22.6) 6 (9.7) 26 (41.9) 16 (25.8) 62 (100)

χ2 0.069 6.40 -3.92 11.52

P value 1.000 0.026 -0.089 0.001

Table 8. The 39 affected arteries other than cerebral artery in 18 patients.

Affected artery Extremity artery Brachial Radial Ulnar Dorsalis pedis Peroneal Popliteal Tibial Tibio-peroneal trunk Unknown Visceral artery Hepatic Mesenteric Renal Splenic Coronary Circumflex Ramus intermedius Unknown Other peripheral artery Carotid Femoral Iliac, internal Retinal Great vessel Abdominal aorta Infrarenal aorta Pulmonary

MCA=middle cerebral artery.

Table 6. Locations of cerebral infarcts in 62 patients.

Location of infarct Basal ganglion Cerebellum Parietal Temporal Cerebral Frontal Occipital Capsula interna Thalamic Frontoparietal Brainstem Lacunar Pons Corpus callosum Corona radiate Frontotemporal Insular cortex Medulla Perisylvian Periventricular Sylvian fissure Watershed

Single 15 (39.5) 14 (36.8) -9 (23.7) 38 (100)

n (%) 28 (45.2) 23 (37.1) 17 (27.4) 12 (19.4) 10 (16.1) 9 (14.5) 9 (14.5) 7 (11.3) 6 (9.7) 5 (8.1) 3 (4.8) 3 (4.8) 3 (4.8) 2 (3.2) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6) 1 (1.6)

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n (%) 14 (35.9) 1 (7.1) 1 (7.1) 1 (7.1) 1 (7.1) 1 (7.1) 2 (14.2) 2 (14.2) 1 (7.1) 4 (28.6) 13 (23.1) 1 (7.7) 2 (15.4) 3 (23.1) 3 (23.1) 4 (10.3) 1 (25) 1 (25) 2 (50) 8 (20.5) 3 (37.5) 2 (25) 2 (25) 1 (12.5) 4 (10.3) 2 (50) 1 (25) 1 (25)

Reference [72] [72] [72] [85] [72] [80] [72,85] [72] [13,76,84] [63] [16,80] [55,63,80] [55,63,80] [41] [35] [63,80] [11,19,63] [21,80] [55,80] [9] [60,80] [19] [43]

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On admission, an immediate thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) was given in 9 (6.8%) patients with an onset-to-treatment interval of 104.2±36.9 (range, 65-160; median, 92) minutes (n=5). The thrombolytic therapy was successful in 7 (77.8%), failed in 1 (11.1%) and the effect unavailable in 1 (11.1%) patient. However, one of the successful patients died of diffuse cerebral edema in spite of an urgent decompressive craniectomy[21].

On admission, the Glasgow Coma Scale of the patients was 10±2.6 (range, 7-15; median, 9) (n=13) and NIH Stroke Scale was 16.7±5.8 (range, 10-26; median, 15.5) (n=10). The latter was decreased to 9.7±7.6 (range, 0-21; median, 9) (n=6) after treatment (P=0.055).

Timing of the diagnosis of cardiac myxoma was described in 33 (24.8%) patients. A patient had been diagnosed with a cardiac myxoma 7 years earlier during which time she declined to all treatments. The remaining 32 (97.0%) patients had their cardiac myxomas diagnosed at a mean of 342.7±744.6 (range, 1-3240; median, 7.5) days after admission.

The diagnostic techniques of cardiac myxoma were described in 114 (85.7%) patients. Transthoracic echocardiography was the most common diagnostic technique, which was used in 90 (78.9%) patients. It was the only diagnostic tool in 79 (87.8%) patients and as an adjunctive to other imaging in 11 (12.2%) patients (Table 9). In one patient, the pathology of the aspirated materials by catheterized thrombectomy on day 5 after admission revealed platelet thrombus and myxomatous tissue, which aroused the suspicion of a cardiac myxoma origin[41]. Both transthoracic and transesophageal echocardiography showed a respective false negative result in one patient each[10,19], the cause of the latter was a complete detachment of the cardiac myxoma[19].

The left atrium was the most common location of cardiac myxoma. There were more solitary myxomas than multiple (Table 10). The attachments of myxomas were reported in 32 myxomas of 31 (23.3%) patients: 25 (78.1%) myxomas were pedunculated and 7 (21.9%) were sessile (χ2=20.3, P=0.000).

Prolapse of atrial myxoma into the ventricle was described in 45 (33.8%) patients with a complete prolapse in 43 (95.6%), a partial prolapse in 1 (2.2%) and no prolapse in 1 (2.2%) patient. Gross appearance of the myxoma was reported in 52 (39.1%) patients: irregular in 48 (92.3%) and smooth in 4 (7.7%) (χ2=74.5, P=0.000). The tumor size was 40.0±19.7 (range, 2-92; median, 40.4) mm (n=71).

Table 10. Locations of 112 cardiac myxomas.

Location Single LA LV Left heart Atrium Infrarenal aorta (complete detachment to) RA Multiple LA, RA LA, LV, RA, RV Multiple chambers LA, pulmonary vein orifice, mitral annulus LA, mitral annulus LA, RV

1 (14.3) 1 (14.3) 1 (14.3)

LA=left atrium; LV=left ventricle; RA=right atrium; RV=right ventricle.

Timing of cardiac myxoma resection was reported in 48 (36.1%) patients. Seven (14.6%) patients underwent operation urgently without giving an exact time interval from admission to surgery. In the remaining 41 (85.4%) patients, the interval from admission to surgery was 140.5±439.9 (range, 1-2550; median, 21) days. The causes of a delayed operation in 3 patients were requirement of heparin therapy for 1 week[61], minimizing the risks from cardiopulmonary bypass and heparinization[25] and avoidance of exacerbation of cerebral hemorrhage[33] in one patient each, and the operations were delayed for 7, 21 and 28 days, respectively.

The interval between the diagnosis and surgical operation of cardiac myxoma was 194.2±798.5 (range, 0-4302; median, 12) days (n=38). One (2.6%) patient was operated on immediately, 2 (5.3%) patients, within 24 hours, and 14 (36.8%) patients, within one week. A delayed myxoma resection was performed in 42.1% (8/19) patients with alternative embolic events in comparison to 25.4% (29/114) patients without alternative embolic events. The interval from diagnosis to treatment of the former was significantly longer than that of the latter (872.5±1644.2 days vs. 13.3±11.2 days, P=0.005).

The treatment methods were unavailable in 28 (21.1%) patients. Nine (6.8%) patients did not receive a cardiac myxoma resection due to sudden death in 3 (33.3%)[18,60,67], patient decline in 2 (22.2%)[4,35], and poor patient condition only indicated for anticoagulant therapy[40], rapid deterioration in spite

Table 9. Diagnostic means of cardiac myxoma.

Diagnostic means TTE TTE, TEE, 3D TEE TEE TTE, MRI Autopsy Computed tomography, TTE TTE, TEE, MRI Computed tomography, TTE, TEE Computed tomography angiography, TTE

n (%) 105 (93.8) 93 (88.6) 8 (7.6) 1 (1.0) 1 (1.0) 1 (1.0) 1 (1.0) 7 (6.3) 2 (28.6) 1 (14.3) 1 (14.3)

n (%) 79 (69.3) 12 (10.5) 9 (7.9) 4 (3.5) 3 (2.6) 2 (1.8) 2 (1.8) 1 (0.9) 1 (0.9)

MRI=magnetic resonance imaging; TEE=transesophageal echocardiography; TTE= transthoracic echocardiography

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of peripheral embolectomies and herniation decompressive hemicraniectomy[19], unfit for cardiac surgery but only cranial decompression[63] and extensive metastasis in the lungs[73] in 1 (12.5%) patient each. The surgical operations performed in 98 (73.7%) patients, 82 (83.7%) of which were isolated cardiac myxoma resection and 2 (2.0%) of which received an operation other than cardiac myxoma resection, were listed in Table 11. Patients without a myxoma resection showed an increased mortality (44.4%, 4/9) than those receiving a myxoma resection (2.1%, 2/95) (χ2=27.1, P=0.000). Of the 9 patients receiving a myxoma resection on an urgent basis, 1 patient died with a mortality of 11.1%, while no patient died among the 45 patients with a delayed surgical resection of cardiac myxoma. No difference was found in the mortality between patients receiving an urgent and a delayed myxoma resection (χ2=5.1, P=0.167). Moreover, a staged cardiac myxoma resection was performed subsequent to other operations in 3 patients with an interval between operations of 1[64], 2[41] and 4[80] weeks, respectively. Patients were followed up for 24.3±27.8 (range, 1-132; median, 12) months (n=59).

Prognosis was reported in 72 patients: a full recovery in 41 (56.9%), an improvement in 13 (18.1%), unchanged in 2 (2.8%), cardiac myxoma recurrence in 5 (6.9%) and death in 11 (15.3%) patients.

By multivariant analysis, none of the independent variables including gender, age, comorbidities, multiplicity of stroke, peripheral embolic events, middle cerebral artery occlusion, basal ganglion infarct, left atrial myxoma, multiplicity of cardiac myxoma and surgical resection of cardiac myxoma was a predisposing risk factor for patient’s mortality. Logistic regression analysis showed peripheral embolic

events (P=0.024) and non-surgical resection of cardiac myxoma (P=0.033) correlated significantly with mortality.

DISCUSSION Cardiac myxoma is an important cause of stroke in young patients. Lee et al.[46] reported that the stroke patients aged 48.5 (range, 17-70) years. Ekinci & Donnan’s[25] patient series aged between 6 and 82 years. The present study revealed young children at the age of 4 years can be a victim of cardiac myxoma stroke.

Aziz et al.[5] reported a female predominance with a female-male ratio of 2:1 in cardiac myxoma, and the present study also revealed a female predominance but with a smaller gender ratio. The classic symptom triad of cardiac myxoma patients includes obstructive, embolic and constitutional manifestations[13]. Cardiac myxoma stroke is often of an acute onset, whereas tumor embolization including myxoma-induced cerebral aneurysm and myxomatous metastasis may show a delayed presentation[46]. However, cardiac myxoma is responsible for only 0.5% of stroke, with females at the age of 50 years at greatest risk[87]. Embolic manifestations occur in 20-45% of patients with a cardiac myxoma, sometimes as the onset symptom[75], as a result of cerebral ischemia and less commonly hemorrhage[18]. In a series of 113 atrial myxoma patients with neurologic presentations, 83% presented with ischemic stroke, most often at multiple sites (41%). Other manifestations included syncope (28%), psychiatric symptoms (23%), headache (15%) and seizures (12%)[72]. Alvarez-Sabín et al.[13] reported 11 of 28 (39.3%) cardiac myxoma patients had embolic phenomena, which affected the cerebral arteries in 6 (54.5%), peripheral arteries in 2 (18.2%) and both cerebral and peripheral arteries in 3 (27.3%) patients. Lee et al.[45] reported 13 of 59 (22.0%) patients with a cardiac myxoma developed embolic events, 11 (18.6%) of which were in the brain, 2 (3.4%) in the limb and 1 (1.7%) in the eye. Furthermore, Yuan[85] reported a patient with a delayed cardiac myxoma resection developed multiple embolic events in the lower extremities. Bajraktari et al.[16] reported one cardiac myxoma patient who declined to all treatments for 7 years eventually developed mesenteric embolism.

The size of the atrial myxoma was variable with a mean of 2.7 (range, 0.4-6.5) cm as reported by Lee et al.[46], and was 4.8±1.9 cm by Lee et al.[45]. Cardiac myxoma was classified into two types according to their gross appearances: type 1, with an irregular or a villous surface and a soft consistency; and type 2, with a smooth surface and a compact consistency[45]. Porapakkham et al.[88] reported that cardiac myxomas with an irregular surface exceeded those with a smooth surface in number (62.2% vs. 37.8%). Embolic potential usually depends on the mobility other than on the size of the myxoma[46]. Neurologic complications of atrial myxoma are most frequently cerebral infarcts caused by detached thrombus from the myxoma; while rarely by tumor fragments[46].

Active illness is often accompanied by elevation of erythrocyte sedimentation rate and C-reactive protein, hyperglobulin-

Table 11. Surgical operations in 98 patients with cardiac myxoma stroke.

Surgical operation Isolated myxoma resection Myxoma resection with concurrent heart operation Mitral valve repair Mitral valve replacement Aortic valve replacement Patent fossa ovalis/atrial septal defect closure Coronary artery bypass grafting Myxoma resection with other operation Peripheral embolectomy Peripheral embolectomy and amputation Peripheral embolectomy, fasciotomies and amputation Decompression craniotomy Endovascular coiling of internal carotid artery aneurysm No myxoma resection Embolectomies and herniation decompressive hemicraniectomy Cranial decompression

n (%) 82 (83.7) 8 (8.2) 3 (37.5) 1 (12.5) 1 (12.5) 2 (25) 1 (12.5) 6 (6.1) 2 (33.3) 1 (16.7) 1 (16.7) 1 (16.7) 1 (16.7) 2 (2.0) 1 (50) 1 (50)

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emia and anemia. Constitutional symptoms may be mediated by interleukin-6 produced by the myxoma itself[89]. MRI is more sensitive than CT in identifying subtle abnormalities of the brain[49].

Transthoracic and/or transesophageal echocardiography can be options for the screening of stroke of a cardiac source[31].

The timing of treatment in such patient is always a matter of intense debate. Soleimanpour et al.[74] proposed that the patients with a delayed presentation of more than 3-4.5 hours were not indicated for intravenous thrombolysis. Al-Said et al.[11] disagreed the use of recombinant tissue plasminogen activator for intravenous thrombolysis due to probable myxoma source infarct. Vogel et al.[80] suggested a 4-week delay of surgical resection of cardiac myxoma concerning the risk of intracerebral hemorrhage following cerebral infarction. Da Silva & de Freitas[21] advocated a delayed surgery after a large stroke.

However, Sethi[90] carried out emergent peripheral vascular and cardiac surgeries in a patient with an acute large infarct of a cardiac myxoma origin and the patient did well.

Young adults, female predominance, single cerebral vessel (mostly the middle cerebral artery) and multiple territory involvements and solitary left atrial myxoma epitomize the outstanding characteristics of the patients with cardiac myxoma stroke. The most common affected cerebral vessel (the middle cerebral artery) and areas (the basal ganglion, cerebellum and parietal and temporal regions) correspond well to the common manifestations of conscious alteration, ataxia, hemiparesis and hemiplegia, aphasia and dysarthria. Initial CT scan carries a higher false negative rate in diagnosing cerebral infarction, and thus MRI should take the place of it, especially in patients with an immediate presentation. Echocardiography is a reliable means for determining the cardiogenic origin of stroke.

Limited patient information concerning the timing of onset, presentation and treatment as well as survival constitutes the main drawbacks of the present study. Multicenter prospective studies on this particular patient population are anticipated in the future.

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65 Rathore KS, Hussenbocus S, Stuklis R, Edwards J. Novel strategies for recurrent cardiac myxoma. Ann Thorac Surg.

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52 Namura O, Saitoh M, Moro H, Watanabe H, Sogawa M, Nishikura K, et al. A case of biatrial multiple myxomas with glandular structure. Ann Thorac Cardiovasc Surg. 2007;13(6):423-7.

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69 Sawhney S, Agarwal M, Roy S, Buxi S, Sud S, Singh S. A patient with rashes and limb weakness. Indian Pediatr.

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56 Nijmeh G, Tatooles A, Zelinger A. Utilizing three-dimensional echocardiography in cardioscopic left ventricular myxoma resection. Echocardiography. 2013;30(2):E44-6.

57 Novendstern SL, Silliman SL, Booth RP. Cerebrovascular co m p l i c a t i o n s o f atria l my x o ma. H o s p P h y s ic ia n.

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71 Sigurjonsson H, Andersen K, Gardarsdottir M, Petursdottir V, Klemenzson G, Gunnarsson G, et al. Cardiac myxoma in Iceland: a case series with an estimation of population incidence. APMIS 2011;119(9):611-7.

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72 Singh PK, Sureka RK, Sharma AK, Bhuyan S, Gupta V. Recurrent stroke in a case of left atrial myxoma masquerading vasculitis. J Assoc Physicians India. 2013;61(12):912,917-20.

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Passaroni AC, etREVIEW al. - Cardiopulmonary ARTICLE bypass: development of John Gibbon's heart-lung machine

Cardiopulmonary bypass: development of John Gibbon's heart-lung machine Circulação extracorpórea: desenvolvimento da máquina de coração-pulmão de John Gibbon

Andréia Cristina Passaroni1, MSc, PhD; Marcos Augusto de Moraes Silva2, MD, PhD; Winston Bonetti Yoshida3, MD, PhD

DOI 10.5935/1678-9741.20150021

RBCCV 44205-1637

Abstract Objective: To provide a brief review of the development of cardiopulmonary bypass.

Methods: A review of the literature on the development of extracorporeal circulation techniques, their essential role in cardiovascular surgery, and the complications associated with their use, including hemolysis and inflammation.

Results: The advancement of extracorporeal circulation techniques has played an essential role in minimizing the complications of cardiopulmonary bypass, which can range from various degrees of tissue injury to multiple organ dysfunction syndrome. Investigators have long researched the ways in which cardiopulmonary bypass may insult the human body. Potential solutions arose and laid the groundwork for development of safer postoperative care strategies.

Conclusion: Steady progress has been made in cardiopulmonary bypass in the decades since it was first conceived of by Gibbon. Despite the constant evolution of cardiopulmonary bypass techniques and attempts to minimize their complications, it is still essential that clinicians respect the particularities of each patient’s physiological function.

Resumo Objetivo: Relatar de forma simples e resumida o desenvolvimento da circulação extracorpórea.

Métodos: Realizada revisão de literatura sobre a evolução da circulação extracorpórea, seu papel fundamental para cirurgia cardiovascular e as complicações que podem surgir após o seu uso, dentre elas, a hemólise e a inflamação.

Resultados: O processo de desenvolvimento da circulação extracorpórea foi fundamental, diminuindo as complicações desencadeadas por ela, que acabam por repercutir no paciente, variando de lesões de graus variados até falência de múltiplos órgãos. Os pesquisadores estudaram quais as agressões que a circulação extracorpórea poderia suscitar no organismo humano. Possíveis soluções surgiram e, consequentemente, meios mais adequados para uma condução mais segura do pós-operatório foram propostas.

Conclusão: A circulação extracorpórea progrediu a passos firmes e seguros ao longo destas últimas décadas desde a sua concepção por Gibbon. Apesar da sua evolução e das condutas realizadas na tentativa de amenizar as complicações, o respeito aos detalhes das funções fisiológicas do paciente é fundamental.

Descriptors: Cardiopulmonary Bypass. Oxygenation. Postoperative Complications.

Descritores: Circulação Extracorpórea. Oxigenação. Complicações Pós-Operatórias.

PhD in General Basis of Surgery (nurse-perfusionist), Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (FMB-UNESP), Botucatu, SP, Brazil.

2 Cardiovascular surgeon; study co-coordinator, Associate Professor, Department of Surgery and Orthopedics, Faculdade de Medicina de Botucatu (UNESP), Botucatu, SP, Brazil.

3 Vascular surgeon; study coordinator, Full Professor, Department of Surgery and Orthopedics, Faculdade de Medicina de Botucatu (UNESP), Botucatu, SP, Brazil.

No financial support.

1

Correspondence address: Andréia Cristina Passaroni Av. Prof. Montenegro, s/n - Distrito de Rubião - Botucatu, SP Brazil Zip code: 18618-970 E-mail: andreia@fmb.unesp.br

Work carried out at Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (FMB-UNESP), Botucatu, SP, Brazil.

Article received on November 4th, 2014 Article accepted on March 23th, 2015

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As a tool for circulatory support during cardiovascular surgery, CPB is a contemporary notion. On May 6, 1953, Gibbon – who devoted his life’s work to obtaining a working heart-lung machine – performed an atrial septal defect repair that became a landmark in the development of this technology.

At the time, the University of Minnesota was considered the cradle of cardiovascular surgery, where innovative techniques made it a destination of choice for heart surgeons worldwide. Concepts such as hypothermic circulatory arrest, cross-circulation, and the bubble oxygenator, which became commonplace in the field, were first investigated at Minnesota[17]. This combined advent of cardiac surgery and cardiopulmonary bypass techniques constituted a major advance in the history of healthcare, as it enabled direct manipulation of the heart, thus providing a possibility of cure for a variety of conditions that were hitherto considered incurable[17,18].

In the meantime, Brazilian heart surgeons had started to exchange experiences with their foreign peers, ringing in a “Golden Age” for cardiovascular surgery at Hospital das Clínicas in São Paulo. One of the pioneering researchers in this field was Professor Hugo João Felipozzi, who was responsible for the very first heart-lung machine and for the first on-pump open-heart procedure in Brazil, performed in October 1955[17,19,20].

This watershed moment marked the start of a new age in Brazilian cardiac surgery. In São Paulo, the group headed by surgeon Euryclides Zerbini built Hospital das Clínicas into the largest cardiovascular surgery center in the country[17].

Mere months after Christiaan Barnard performed the first human heart transplant in December 1967, he assisted Professor Zerbini in conducting the first such procedure in Brazil, in May 1968, thus giving rise to the era of transplantation in Brazil[20].

However, such progress was not without its challenges. Supplies for surgery had to be imported at a high cost. This, compounded by the fear of being unable to match the pace of U.S. and European development in the field of cardiovascular surgery equipment, prompted Brazilian surgeons to design and construct their own devices so that procedures could continue unimpeded.

Surgeons such as Adib Jatene, Domingos de Morais, and Otoni M. Gomes began developing domestic heart-lung machines, oxygenators, prosthetic valves, and pacemakers. Particular attention is warranted to the dedication of cardiovascular surgeon Domingo M. Braile, who established his own manufacturing plant to produce CPB circuits and machines, prosthetic valves, and endoprosthetic devices of the highest quality, building a reputation for Brazil at cardiovascular surgery centers the world over. The dedication of these professionals in the operating theater and in the laboratory, improving their surgical techniques through experimentation so as to contribute to the advancement of the field and ensure safer and more efficient care of patients with heart disease, speaks for itself.

This evolution also brought progress to CPB, making the procedure even more complex. Within this context, profes-

Abbreviations, acronyms & symbols ANC CP CPB IL LDH MCV RP TNFα

Absolute neutrophil count Centrifugal pump Cardiopulmonary bypass Levels of interleukin Lactate dehydrogenase Mean corpuscular volume Roller pump Tumor necrosis factor-alpha

THE ADVENT OF CARDIOPULMONARY BYPASS In the 19th century, the interest of physiologists in the circulation of blood turned to the study of isolated organs. Many of the studies conducted at this time laid the foundation for the future development of cardiopulmonary bypass (CPB).

In 1813, Le Gallois formulated the first concept of what would constitute an artificial circulation[1]. In 1828, Kay showed that the contractility of muscle could be restored by perfusing with blood[2]. Between 1848 and 1858, BrownSéquard obtained “oxygenated” blood by agitating it with air, highlighting the importance of blood in the perfusate solution to obtain neurologic activity in isolated mammalian heads[2-4]. In 1868, Ludwig and Schmidt built a device that could infuse blood under pressure, thus enabling better perfusion of isolated organs for study[5,6]. In 1882, Von Schroeder developed and built the first prototype of a primitive bubble “oxygenator”, which consisted of a chamber containing venous blood; air was bubbled into the chamber and converted the venous blood to arterial blood[7].

In 1885, Von Frey and Gruber developed an artificial heartlung system whereby the perfusate solution could be oxygenated without interrupting blood flow, an achievement that had not been attempted by their predecessor Von Schroeder.

Other discoveries played essential roles in the further development of research that would ultimately contribute to CPB. One such achievement was the discovery of the ABO blood group system by Landsteiner in 1900, which enabled prevention of many inconveniences related to incompatibility[8]. In 1916, Howell and McLean (the latter a medical student) serendipitously discovered heparin while studying animal liver extracts. This discovery would assist both in vivo and in vitro studies, which were made successful by inhibition of coagulation[9,10].

The later work of Gibbon, starting in 1937, piqued the curiosity of many other investigators, who were prompted to start similar projects and follow in his footsteps[11,15].

To Crafoord, who would later perform the first successful atrial myxoma removal surgery with CPB[16], artificial circulation was a necessity, as correction of intracardiac defects required that the surgeon be able to open the heart while maintaining blood flow to all organs and carrying out gas exchange.

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sionals responsible for CPB operation (i.e., perfusionists) needed new knowledge to enable rapid and appropriate decision-making. Experienced professionals such as perfusionist Maria Helena L. Souza and cardiovascular surgeon Décio O. Elias wrote peerless textbooks that provide a comprehensive, up-to-date overview of the techniques and methods required of those who devote themselves to restoring the health and quality of life of patients with cardiovascular disease[18].

Happy were – and still are – those who, by absorbing hard-won knowledge through years of sacrifice and experimentation, had the privilege of reading about the evolution of cardiovascular surgery in recent decades and witnessing the complete devotion of these providers, whose love and dedication have carved their feats in stone. Words cannot express the importance of their work.

Fig. 1 - Cylinder (drum) oxygenator, 1957. Source: Correa Neto, 1988.

EXTRACORPOREAL OXYGENATORS DEVELOPED FOR CARDIOPULMONARY BYPASS The need for adequate oxygenation led Gibbon to continue his search for an enhanced method of blood arterialization. He noted many issues that occurred during the oxygenation process, such as foaming, hemolysis, and synthesis and release of vasoactive substances[21,22]. The first oxygenator models developed were classified according to the method used for oxygenation.

Film oxygenators performed gas exchange on a surface onto which blood was flowed in thin films, over a substrate exposed to an oxygen-rich atmosphere[3,23,24].

In 1885, von Frey and Gruber had developed a rotating cylinder that is considered the precursor of cylinder or drum oxygenators. Venous blood was spread over the inner wall of the rotating cylinder, where it came into contact with a stream of oxygen, thus accomplishing gas exchange. In 1957, Crafoord, Norberg, and Senning[25] developed a new oxygenator consisting of multiple spinning rollers, the rotation of which facilitated the exposure of filmed blood to oxygen (Figure 1).

In screen oxygenators, venous blood was flowed over a support containing mesh screens. Much of Gibbon’s work used such a model of oxygenator, in which venous blood flowed down a series of vertical screens (Figure 2)[16,22,26,27].

Disc oxygenators were the next development. Briefly, these oxygenators consisted of a horizontal axis around which a series of metal discs were arranged. These discs rotated within a glass cylinder, through which venous blood was circulated and exposed to oxygen. Bjork[28] worked on the first disc oxygenator in 1948, but Kay and Cross[29] were the ones to enhance it and improve its effectiveness in 1956 (Figure 3). Disc oxygenators were an important landmark in the evolution of CPB, and their efficiency ensured they remained in use well into the 1970s.

The development of bubble oxygenators was plagued by the occurrence of bubbling and foaming, with the inherent

Fig. 2 - Screen oxygenator, 1946. Source: Correa Neto, 1988.

Fig. 3 - Disc oxygenator, 1956. Source: Souza & Elias, 2006.

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risks they pose, during the arterialization process. In these oxygenators, venous blood is exposed to an oxygen stream at the reservoir inlet, forming a cascade of bubbles of varying sizes that arterialized the deoxygenated blood. In 1950 and 1952, Clark[30] designed and built bubble oxygenators that incorporated a dispersion chamber, facilitating control of oxygenation.

In 1956, DeWall developed a helical bubble oxygenator based on concepts learned from other surgeons that was innovative both for its simplicity and for a disposable version that was developed soon thereafter[31,32]. A smaller, more compact oxygenator with a bolder design – which also contributed to ease of assembly – had been developed by Gollan[33] in 1952.

In 1955, Kolff[34] constructed the first prototype of a membrane oxygenator, using polyethylene tubing wrapped around a central axis, which gave the oxygenator a coil-like appearance. In 1958, Clowes and Neville[35] developed a flat Teflon membrane oxygenator specifically for use in cardiac surgery, and published a series of case reports describing the use of their apparatus. Other oxygenators later entered clinical use, such as that designed by Bramsen, Peirce, and Landè-Edwards and known as the “sandwich-type” oxygenator, which was quite similar to the Clowes and Neville model[36-38]. In 1965, Kolobow[39] modified the Kolff oxygenator by adding long silicone strips with spacers that prevented membrane collapse.

The continued development of new technologies contributed to the production of capillary membranes, ushering in the latest generation of modern membrane oxygenators with increased efficiency and safety, which remain in use to this day.

Fig.4 - Sigmamotor® pump. Source: Correa Neto, 1988.

BLOOD PUMPS FOR CARDIOPULMONARY BYPASS The search for pumps capable of displacing large volumes of blood deserves its own chapter in the history of CPB, as it demonstrates investigators’ constant concern with obtaining safe ways to accomplish artificial blood circulation.

The pumps used by early physiologists displaced small volumes of blood; however, the trauma they inflicted on blood components was already apparent. Flow velocity was the main culprit implicated in hemolysis.

The search for better CPB pumps led to a discussion that persists to this day: pulsatile or continuous flow? Since no consensus emerged, studies focused on the occluding mechanism, as output could be maintained during blood pumping.

Overall, pumps are classified according to the mechanism that transfers energy to the fluid. Using this criterion, pumps can be classified into two categories: displacement (roller) pumps and kinetic (centrifugal) pumps.

Displacement pumps impel the fluid progressively forward. One example is the well-known Sigmamotor® finger pump, which Lillehei used from 1954 before replacing it with a roller pump (Figure 4). This pump was traumatic to blood components and was intolerably loud while in operation[40,41].

The roller pump design, introduced in 1955, remains in

Fig. 5 - Modern roller pump. BEC Heart Lung Machine. Source: Braile Biomédica®.

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use for all types of cardiovascular surgical procedures. Briefly, on the horseshoe-shaped rigid console of the pump, a segment of silicone tubing is bent into a semicircle within which two cylinders (rollers) are placed opposite to each other, equidistant from the central axis. As the axis rotates, the rollers compress this segment of tubing and impel the blood forward[42].

The first roller pump was patented in 1855 by Porter and Bradley[43]. In 1934, DeBakey made some modifications that enabled its use for blood transfusion. The two-roller DeBakey design was further modified before being applied to CPB (Figure 5).

Kinetic pumps impart energy generated by the rotation of an element known as an impeller. The first centrifugal pump was developed in the late 17th century, when Denis Papin built a centrifugal fan with straight vanes, which he named the Hessian bellows in honor of his patron, the Landgrave of Hesse. However, only in the 19th century were centrifugal pumps first manufactured and used in the United States.

The rotary vane design was developed in England by John Appold, in 1851.

Although the operating principle of centrifugal pumps dates back to the early days of fluid engineering, it was not until the 1970s that the first such pumps were designed specifically for use in CPB circuits. In these pumps, forward movement of the blood was accomplished by imparting kinetic energy produced by a rotating element.

The most common type, the vortex pump, featured a set of concentric cones, with the outermost cone containing a central inlet and a lateral outlet. The innermost cone was magnetically coupled to the outer rotor, which made it spin at a high RPM, causing rotation of the other cones and thus creating a centrifugal force that drove blood flow through the circuit (Figure 6).

Despite the advantages and disadvantages of both major pump types for CPB in cardiovascular surgery, the optimal design in terms of minimizing patient complications remains unclear[44,45].

COMPLICATIONS OF CARDIOPULMONARY BYPASS Due to its mechanical components and their interaction with blood, CPB can produce significant changes in the body.

All organs were affected by CPB systems, due to factors such as contact between blood and artificial materials, continuous flow, hemodilution, hypothermia, and anticoagulation. These complications could arise immediately after surgery or later in the intensive care unit. Despite improvements in equipment, it was clear that longer durations of CPB were associated with increased risk and severity of complications[46].

Other issues were identified as contributing factors for the development of CPB-related complications, including age, the presence of multiple or complex injuries, the presence of comorbidities, and reoperation.

The main complications of CPB are hemorrhage, low cardiac output, arrhythmias, respiratory failure, renal failure, neurological or neuropsychiatric changes, fluid and electrolyte imbalances, abdominal changes, hemolysis, and inflammation.

MARKERS OF HEMOLYSIS Markers of hemolysis are capable of demonstrating acute tissue injury during its acute phase. These markers were measured at centers that had the laboratory capacity to do so using specific kits for the marker of interest, thus enabling diagnosis of hemolysis and investigation of its etiology (hemolytic anemia, CPB, prosthetic valve dysfunction, acute myocardial infarction, etc.).

One acute phase marker specific to hemolysis (detectable even in surgical trauma) is the serum concentration of haptoglobin, a protein that binds hemoglobin to form a complex that prevents renal loss of hemoglobin, thus decreasing its levels in the bloodstream[47,48]. A reduction in haptoglobin levels is indicative of hemolysis.

Lactate dehydrogenase (LDH) in an enzyme that catalyzes the conversion of pyruvate to lactate in the Krebs cycle. It can also be measured as a nonspecific marker of hemolysis: when cell lysis occurs, LDH is released from within the ruptured cells and remains in the bloodstream at high concentrations[49].

Fig. 6 - Modern centrifugal pump module. Centripump. Source: Braile BiomĂŠdicaÂŽ.

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Reticulocyte counts are also used as a nonspecific marker of hemolysis, but infrequently so, as their levels increase not only in hemolysis but in the presence of hypoxia as well[50].

As reticulocytes are larger than erythrocytes, when the reticulocyte count increases, so does the mean corpuscular volume (MCV), including in hemolysis.

Bilirubin can also be used as a marker of hemolysis. Jaundice develops when bilirubin levels are elevated, and it may be a consequence of liver disease or hemolysis.

MARKERS OF INFLAMMATION Markers of inflammation are chemicals released by certain cells that act on tissue injury in the acute or chronic phases of the inflammatory process. Specific kits can be used to measure the concentration of inflammatory mediators. However, the high cost of some of these kits precludes their routine use.

The human body maintains constitutive cytokine production, whereby specialized cells contain a baseline level

Table 1. Comparative analyses of roller vs. centrifugal pumps for cardiopulmonary bypass, using markers of hemolysis as outcome measures.

Author

Marker of hemolysis

Statistical analysis RP CP 1.2 99000 67.9

Mean

1.3 121846 45.5

P value

Pêgo-Fernandes et al. [57]

Haptoglobin (g/dL) Platelet count (103/mm3) Hemoglobin (mg/dL)

Berki et al. [58]

Platelet count (103/mm3) Hematocrit (%)

Mean ± standard deviation 9.66±3.4 13.02±6.8 23.14±4.2 36±4.8

<0.01 RP <0.05 RP & CP

Yoshikai et al. [59]

LDH (U/L) Platelet count (103/mm3)

Mean ± standard deviation 1475.9±490.5 3814.2±1125.0 14.4±4.1 15.8±55

>0.05 >0.05

Morgan et al. [60]

Hematocrit (%) *Haptoglobin (g/dL)

Mean ± standard deviation 32±0.06 31±0.05 -

>0.05 -

Andersen et al. [61]

Platelet count (103/mm3) Hemoglobin (mg/dL) Hematocrit (%)

Mean ± standard deviation 222±12 221±13 11.2±0.4 11.1±0.3 33±0.01 32±0.01

>0.05 >0.05 >0.05

Keyser et al. [62]

Platelet count (103/mm3) Hematocrit (%) LDH (U/L) Bilirubin (mg/dL)

Saczkowski et al. [63]

Platelet count (103/mm3) Hemoglobin (mg/dL)

150000 32 160 1.2

Mean

170000 34 180 0.9

Meta-analysis

>0.05 >0.05 >0.05

>0.05 >0.05 >0.05 >0.05 >0.05 >0.05

CP=centrifugal pump; RP=roller pump. *Haptoglobin: after the start of CPB, the haptoglobin levels in nearly all samples exceeded the limit of quantitation (0.1g/L) and could not be measured.

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of these substances in normal situations. Cytokines must bind to specific cell membrane receptors to exert their effects. In most cases, the action of one or more cytokines is required for an immune response to mount; therefore, these substances form a complex network in which production of one cytokine influences the production or response of others.

Levels of interleukin (IL)-1β are usually increased after CPB[47]. However, this cytokine is often undetectable due to the hemodilution inherent to CPB[47]. IL-1β is also responsible for inducing synthesis of IL-6, and acts synergistically with tumor necrosis factor-alpha (TNFα) in a feedback loop that ensures continuity of the inflammatory process. Alongside TNFα, these are the first interleukins to play a role in the inflammatory response to CPB. Another widely studied interleukin is IL-6, levels of which increase 2 to 4 hours after any surgical incision. The intensity of the IL-6 response correlates with the duration of the surgical procedure, which makes this factor extremely important in the inflammatory process[47]. The IL-6 response pattern is consistent with the role of a major mediator of the acute-phase reaction to CPB; therefore, IL-6 may be a more precise indicator of the progression of inflammatory states[19].

IL-8 is a potent chemotactic agent involved in the homing of neutrophils and leukocytes to sites of infection[47,48-54]. It may be present in any tissue, and its effects may occur during infection, ischemia, trauma, and other disorders of homeostasis[54].

TNFα is implicated in several systemic complications and severe infections, inducing a febrile state that is often detectable in the immediate postoperative period of CPB. High concentrations of TNFα in plasma may induce low cardiac output, decrease vascular smooth muscle tone, and cause intravascular thrombosis[55]. High levels of this cytokine after acute myocardial infarction have been associated with increased risk of recurrent infarction[56].

The most important determinant of the erythrocyte sedimentation rate (ESR) is fibrinogen, an acute-phase protein, levels of which increase two- to fourfold in the presence of acute inflammation. Fibrinogen is also a known risk factor for coronary artery disease, peripheral artery disease, and stroke.

Immunoglobulins are also implicated in this phenomenon, and play an important role in chronic inflammatory processes.

the two pump types. This corroborates a meta-analysis by Saczkowski et al.[63] that also failed to find any difference between roller and centrifugal pumps in terms of hemolysis. Quite a wide variety of markers were used, which favored this result.

Comparative studies of the inflammatory response to cardiopulmonary bypass Table 2 lists studies that have compared roller vs. centrifugal pumps for CPB, using markers of hemolysis as the measures of interest.

In these comparative analyses of roller vs. centrifugal pumps, with the exception of two studies[59,62] that found no significant differences, the remaining studies reported significant differences between the two pump types in terms of inflammatory response, as assessed by measurement of markers of inflammation. However, results were variable and sometimes controversial, and the evidence remains inconclusive.

CONCLUSION Steady progress has been made in CPB techniques in the years since modern extracorporeal circulation was first conceived of by Gibbon. Over essentially seven decades, many changes were made, not only to CPB apparatuses and circuits but also to protocols and standards of work. The patient population has also changed: patients undergoing CPB are now in much more severe condition, due to such factors as comorbidities, advanced age, adverse lifestyles, and, many times, limited access to healthcare services.

The constant evolution of CPB and attempts to minimize its complications notwithstanding, it is essential that clinicians respect the particularities of each patient’s physiological function. Patients undergoing CPB require constant care and attention, as the complications of this procedure still pose a very severe threat.

Hemolysis and inflammation were cited in the majority of studies addressing the complications of CPB with roller and centrifugal pumps, but these two phenomena were generally studied separately. Some investigators found no significant differences between these two types of pumps in terms of hemolysis. Nevertheless, it has been suggested empirically that centrifugal pumps be used in prolonged bypass to mitigate hemolysis. In practice, however, this decision should rest with the perfusion team.

Only one of seven studies reviewed reported significant changes (in platelet count and hematocrit) with roller pumps.

Conversely, regarding inflammation, five of the seven studies reviewed reported significant differences between roller and centrifugal pumps. IL-6 was the marker of inflammation most commonly cited in these studies, particularly when centrifugal pumps were used.

Comparative studies of the hemolytic response to cardiopulmonary bypass Table 1 lists studies that have compared roller vs. centrifugal pumps for CPB, using markers of hemolysis as the measures of interest.

In these comparative analyses of roller vs. centrifugal pumps, with the exception of one study[62] that reported significant differences in platelet count and hematocrit respectively, the remaining studies found no significant differences in the most reliable markers of hemolysis between

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Table 2. Comparative analyses of roller vs. centrifugal pumps for cardiopulmonary bypass, using markers of inflammatory response as outcome measures.

Marker of inflammation

Statistical analysis CP RP

Fibrinogen (mg/dL)

Mean ± standard deviation 258±160 216±148

<0.01 RP

Yoshikai et al. [59]

C3 (mg/dL) C4 (mg/dL) IgA (mg/dL) IgG (mg/dL) IgM (mg/dL)

Mean ± standard deviation 36.4±10.4 41.1±7.3 13.7±3.0 19.3±2.3 172.8 191.95 1011.4 836.81 126.7 78.0

>0.05 >0.05 >0.05 >0.05 >0.05

Morgan et al. [60]

IL-6 (pg/dL)

Mean ± standard deviation 329±59 392±57

<0.05 CP

Author Berki et al. [58]

IL-1β (pg/dL) IL-6 (pg/dL) IL-8 (pg/dL) TNFα (pg/dL) C5b-9 (ng/mL) ANC(x109)

341 143 765 8.15

Baufreton et al. [65]

IL-6 (pg/dL) IL-8 (pg/dL) TNFα (pg/dL)

770 115 160

Braulio [66]

IL-6 (pg/dL) TNFα (pg/dL)

904.4 1648.0

Fibrinogen (mg/dL)

250

Ashraf et al. [64]

Keyser et al. [62]

Mean

Mean

Mean

Mean

P value

260 150 509 6.2

<0.05 CP >0.05 <0.05 CP <0.05 CP

600 122 130

<0.01 CP <0.05 CP <0.01 CP

393.2 1255.8

<0.05 RP <0.05 RP

230

>0.05

ANC=absolute neutrophil count; CP=centrifugal pump; RP=roller pump.

Although the complications of CPB have many postoperative repercussions, including a direct influence on the duration of mechanical ventilation and length of intensive care unit stay, pump designs meant to mitigate these complications are not yet based on scientific evidence. Further studies are required to compare roller and centrifugal CPB pumps and their association with hemolysis and inflammatory response.

Authors’ roles & responsibilities ACP MAMS WBY

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Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript and critical review of its content Final approval of the manuscript; conception and design; Manuscript writing and critical review of its content Final approval of the manuscript; conception and design; manuscript writing and critical review of its content

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Oliveira MAB,SPECIAL et al. - Endnote Web tutorial for BJCVS/RBCCV ARTICLE

Endnote Web tutorial for BJCVS/RBCCV Tutorial do Endnote Web para o BJCVS/RBCCV

Marcos Aurélio Barboza de Oliveira1, MD, PhD; Carlos Alberto dos Santos2, MD, PhD; Antônio Carlos Brandi2, MD; Paulo Henrique Husseini Botelho2, MD; Adília Maria Pires Sciarra2, MSc; Domingo Marcolino Braile3, MD, MSc, PhD

DOI 10.5935/1678-9741.20150023

RBCCV 44205-1638

Abstract At present, many useful tools for reference management are available for use. They can be either off-line softwares or accessible Websites to all users in the internet. Their target is to facilitate the production of scientific text. But, to accomplish that, the featured bibliographic style should be effectively inserted, and the program has to be free. Here in this tutorial, we present Endnote Web®, a bibliographic reference management program comprising these two requirements: it contains the Brazilian Journal of Cardiovascular Surgery reference format and its use is free for charge after sign-in in IP registered terminal in Web of Science®.

Resumo Diversas ferramentas de gerenciamento de referências bibliográficas estão disponíveis tanto por meio de softwares quanto websites acessíveis para todos utilizadores da Internet. Todas têm um só objetivo: facilitar a produção do texto científico, mas para que isso seja possível necessitam que o estilo bibliográfico da revista em questão esteja disponível e o programa seja grátis. Apresentamos neste tutorial o Endnote Web®, um programa de gerenciamento de referências bibliográficas que cumpre esses dois quesitos: possui o formato de referências exigido pela Revista Brasileira de Cirurgia Cardiovascular e tem utilização grátis, após cadastro em terminal com IP cadastrado na Web of Science®.

Descriptors: Periodicals as Topic. Bibliography as Topic.

Electronic Journals.

Descritores: Publicações Periódicas como Assunto. Bibliografia como Assunto. Revistas Eletrônicas.

INTRODUCTION

Endnote Web® is a publishing program of references based on the Web. Features of this program will be the subject of our tutorial. At present, Endnote Web® also comprises the bibliographic style for both the Brazilian Journal of Cardiovascular Surgery/Revista Brasileira de Cirurgia Cardiovascular (BJCVS/RBCCV) and the Postgraduate course of São José do Rio Preto Medical School (FAMERP).

Currently tools editing and organizing references have been growing in the Web since their use provides feasible production of papers[1]. There are many programs which create a list of references, such as Reference Manager®, RefWorks®, SciRef®, and EndNote® to name some. The

PhD in Health Sciences - Faculdade de Medicina de São José do Rio Preto, Cirurgião Cardiovascular adulto e pediátrico, Professor de Estatística e Metodologia Científica da UNIFEV de Votuporanga, SP, Brazil.

2 Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, SP, Brazil.

3 Emeritus Professor of Famerp and Unicamp Editor in Chief Brazilian Journal of Cardiovascular Surgery President: Board of Trustees Braile Biomédica Ltda.

Correspondence address: Marcos Aurélio Barboza de Oliveira 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: m_aurelio@sbccv.org.br

1

Article received on February 23th, 2015 Article accepted on March 24th, 2015

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This tutorial content is divided into the following topics: • Sign-in and consecutive accesses; • Inserting items in the Endnote Web®; Via Pubmed Via Endnote Web® Manually • Favorite Formatting Styles • Set “Cite While You Write®” in Word® • Inserting and editing references in the scientific text Our goal is to present basic instructions to the user on how to use the Endnote Web®. More detailed instructions for each available function can be obtained from the Endnote Web® site by clicking “help”[2].

file created in the previous step, select filter (import option) “PubMed (NLM)”, target “new group” and “import”. The program asks the name of the new group, in this case, can be “heart failure”, completing the process.

These previous steps can be repeated indefinitely up to the author should be satisfied with all local database.

Via Endnote Web® Surveying directly the Endnote Web® site can be another way to do research. Doing this, one needs to select “collect” from the main menu followed by “online research”. Select the database “PubMed (NLM)” and “connect”. The user interface is similar to the “advanced search” of Pubmed. After the search is performed, the results are presented as in Pubmed. Select items of interest and click “add to group”, as shown in Figure 4. This method is fast, but it requires the researcher makes the bibliographic survey directly by the Endnote Web® site.

SIGN-IN AND CONSECUTIVE ACCESSES At first, the user has to sign-in to Endnote Web® (www. myendnoteweb.com) with an authenticated terminal to find out fully functional accesses; that is, IP registered in the Web of Science®. The majority of Post-Graduation, Master and Doctorate Programs, is registered in CAPES program, and home computers with remote access to these institutions have this authentication.

After the site register is finished, subsequent accesses can be obtained in any computer connected to the Internet since they occur within the subsequent 12 month-authenticated access to the current time. The 12-month period of renewal occurs every time the account is logged through authenticated access, subsequently the use of the program is long-lasting period.

Manually Undoubtedly, this is the most laborious way to insert a citation to the local database. Different from the previous methods, while including all the search at one time; manually we can include only one article at a time. This method is particularly useful regarding chapters, books, and internet sites which cannot be found in Pubmed.

To include a reference manually; click “collect”, followed by “new reference”. Change “type of reference” to the desired type, such as book chapter, book, thesis, dictionary, etc. Then just fill the form with required information. At the bottom of the page you can select the folder that the article will occupy. Do not forget to save typing.

INSERTING ITEMS IN ENDNOTE WEB® Before we use Endnote Web® as reference manager software, it is necessary to feed it with all research references.

These references may be obtained by searching Pubmed website, for researching directly into Endnote Web® or manually inserting articles.

FAVORITE FORMATTING STYLES Before using the Endnote Web® in Word®, it is advisable to restrict the bibliographic styles to make its use easier. Access the main menu of Endnote Web® select “format” and “bibliography”. Click “favorites” and select ABNT, FAMERP and BJCVS/RBCCV, for example. These styles can be changed at any time.

Via Pubmed Research in Pubmed website (http://www.ncbi.nlm. nih.gov/pubmed/) should be commonly performed. After the entire bibliography is collected, change the display format for MEDLINE, as shown in Figure 1. After this, the browser will display the results into text format, as it is shown in Figure 2. Save the page as is shown in Figures 3.a for Internet Explorer and 3.b for Firefox and choose txt format. If you are using Google Chrome you have to copy all text and paste it to word and save it in txt format.

Thus we created a text file with the work list with all the required fields to Endnote Web®, but we have to import the txt database to use it in the Endnote Web®. To do this, click on “collect” and “import references”. Then select the txt

CONFIGURE CITE WHILE YOU WRITE® For the use of Endnote Web® directly in Word® you have to install a program obtained by clicking “options” and, then “download installers”. Download and install “cite while you write” Windows® or Mac® version as appropriate (Word® has to be closed). Open Word®, click “endnote” and enter login and password. They are the same as in the Endnote Web®. In “style” select “RBCCV” (Figure 5). Note that the style options are restricted to those selected as favorites in the Endnote Web® site.

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Fig. 1 - PUBMED homepage. After inserting the bibliography, change the display format for MEDLINE.

Fig. 2 - The text display after procedure described in Figure 1.

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Fig. 3 - Save the page for Internet Explorer (3A) or for Firefox (3B) and choose txt format.

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Fig. 4 - Research display in PUBMED database into Endnote Web site. Choose the items of interest and click “add to group”.

Fig. 5 - Bibliographic style display. Select “RBCCV”.

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You do not have to enter username and password each time the Word® is open, if you click on “preferences”, “application”; “enter your Endnote Online Subscription” type “http://www.myendnoteweb.com:80/” login and password and click “remember my address and password” (Figure 6).

more than one result, the program will find them all. The author has to double-click on what interest him. Subsequently, the citation can already be seen in the text (usually number) and the list of references at the end of the text right on the shape of the desired journal (in case BJCVS/RBCCV).

If you need to update the numbering of references due to the text rearrangement; click on “update citations and bibliography” (Figure 8). The program will make all the adjustments, even if you have modified all the text and the reference list exceeds a hundred. After no more than a few seconds, the text are properly referenced again.

INSERT AND EDIT REFERENCES IN A SCIENTIFIC TEXT After configuring the bibliographic styles and inserting all the bibliography needed in the Endnote Web® site, we draw some explanation of Word® functioning. It is worth remembering that all the literature necessary for the work must be stored in the Endnote Web® site, if you need complete database just take the steps previously described.

The author should write the text normally, and when he needs to cite an article, click “insert citation”, as shown in Figure 7. As soon as the search field opens, one can enter any data of the reference in question. The year, title, journal, authors or any word inside abstract can be searched. If there is

CONCLUSION Endnote Web® as reference manager software is a very useful and feasible alternative for authors who submit scientific papers to both BJCVS/RBCCV and Postgraduate course of São José do Rio Preto medical school (FAMERP). The numbering and references sequencing become faster; moreover, reducing format mistakes considerably by means of this program.

Fig. 6 - How to register password and automatic login in the Endnote Website.

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Fig. 7 - “Insert citations” display to look up for specific paper in your local database.

Fig. 8 - “Update citations and bibliography” for updating numbers of references in the text and the total references at the end of the article.

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Authors’ roles & responsibilities MABO CAS ACB PHHB AMPS DMB

Analysis and interpretation of data; final approval of the manuscript; study design; writing of the manuscript or critical review of its content Drafting of the manuscript and critical review of its content Drafting of the manuscript and critical review of its content Manuscript writing and critical review of its content Analysis and interpretation of data; study design; drafting of the manuscript and critical review of its content Final approval of the manuscript; study design; writing of the manuscript or critical review of its content

REFERENCES

1. Oliveira MAB. BJCVS/RBCCV and Endnote. Rev Bras Cir Cardiovasc. 2015;30(1):127-8.

2. Reuters T. 2015. Índice da ajuda do EndNote on-line [cited Mar 3, 2015]. Available from: http://www.myendnoteweb.com/help/ pt_br/ENW/help.htm

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Bienert IRC, etSPECIAL al. - Bibliometric indexes, databases and impact factors in ARTICLE cardiology

Bibliometric indexes, databases and impact factors in cardiology Índices bibliométricos, bases de dados e fatores de impacto em cardiologia

Igor R C Bienert1,2, MD; Rogério Carvalho de Oliveira2, MD; Pedro Beraldo de Andrade1, MD; Carlos Antonio Caramori2, MD, PhD

DOI 10.5935/1678-9741.20150019

RBCCV 44205-1639

Abstract Bibliometry is a quantitative statistical technique to measure levels of production and dissemination of knowledge, as well as a useful tool to track the development of an scientific area. The valuation of production required for recognition of researchers and magazines is accomplished through tools called bibliometricindexes, divided into quality indicators and scientific impact. Initially developed for monographs of statistical measures especially in libraries, today bibliometrics is mainly used to evaluate productivity of authors and citation repercussion. However, these tools have limitations and sometimes provoke controversies about indiscriminate application, leading to the development of newer indexes. It is important to know the most common search indexes and use it properly even acknowledging its limitations as it has a direct impact in their daily practice, reputation and funds achievement.

Resumo A bibliometria é uma técnica quantitativa estatística para medir índices de produção e disseminação do conhecimento, assim como ferramenta útil para acompanhar o próprio desenvolvimento de uma determinada área científica. A avaliação da produção necessária para reconhecimento de investigadores e de revistas é realizada com o uso de ferramentas chamadas índices bibliométricos, divididos em indicadores de qualidade e de impacto científico. Inicialmente desenvolvida para medidas estatísticas de monografias, especialmente em bibliotecas, hoje a bibliometria é utilizada principalmente para avaliar produtividade de autores e estudos de citações. Contudo, tais ferramentas por vezes têm limitações e controvérsias surgem acerca da aplicação indiscriminada das mesmas, levando ao desenvolvimento de índices mais recentes. É importante para o pesquisador conhecer os índices mais comuns, utilizá-los adequadamente e reconhecer suas limitações, pois sua utilização correta tem impacto direto na prática diária, reputação e obtenção de recursos.

Descriptors: Impactfactor. Databases as topic.Bibliometrics.

Descritores: Fator de impacto. Bases de Dados como Assunto. Bibliometria.

INTRODUCTION

pact factor). Such indicators are applied from the indexing of research (primary data source) in the database (secondary source)[1]. Several databases provide their assessment results of bibliometric analysis and quantification of citations.

The most referenced is the Web of Science (WoS), owned

by Thomson Reuters, however there are databases that also

Although there are several ways to analysis of production, scientific impact indicators are mainly of two types: research impact indicators (such as the number of citations received) and impact indicators of the sources (the magazine itself im-

Faculdade de Medicina de Marília (FAMEMA), Marília, São Paulo, Brazil.

Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (FMB UNESP), Department of Clinical Medicine, Postgraduate Course Discipline of Information Technologies in Education and Research, Botucatu, SP, Brazil.

Correspondence address: Igor Bienert Hospital das Clínicas de Marília – Department of Interventional Cardiology R. Aziz Atallah, S/N, 1º andar – Fragata – Marília, SP, Brazil Zip code: 17514-410 E-mail: bienert@famema.br

1 2

Work carried out at Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (FMB UNESP), Botucatu, São Paulo, Brazil.

No financial support.

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it more visible and giving to the publication a quality label[4].

The impact factor is calculated by setting the number of times an article from a given journal published in the previous two years was cited, divided by the total number of articles published by this journal in the same period. The Impact factor is published annually as part of the Journal Citation Report (JCR) serving as a beacon of the periodic exposure.

IF 2015 = (citations 2013 + citations 2014) / (articles 2013 + articles 2014) However, some limitations regarding the IF refer to the calculation method itself, to enter as “citations” not only original articles, but also letters, editorials, reports and summaries, while the definition of “articles” are only original articles, review articles and reports[5], amplifying the IF using a variety of communications, including for example communications challenging the article itself. All citations have equal weight in the IF calculation. In addition, the citations counts only if it is in the own database (SCI), which is estimated to be half of the existing peer-reviewed publications[6,7] and varies according to the publication area[5], the nature of the research (articles about basic research, revisions or updates are often most cited and amplify the journal impact)[8] and even with the publication language, being difficult to obtain an IF for non-English language publications[9,10]. It is important to remember also that IF is not intended to individual article impact analysis, but for journal impact analysis. Still, the IF is often mistakenly used in academic researchers rating process[11].

Even the absolute value of the IF of a journal has less comparative value than intuitively attributed, because different areas have different volume of publications. As an example, an IF of 1.5 would not be too high in a generic cardiology journal, but it would be much in very specialized magazines (for example in a molecular diagnostic cardiology journal) because its articles are most read and cited by a small and specialized target population[12]. Also, journals dedicated to very specific areas, usually have the a higher impact due to natural restriction of the attention focus. One point still to consider is the probability of self-citations and cross citations[13] from research groups, institutions or individual authors,relevant topic in the publications universe. Despite all the criticism, the IF is the most worldwide used journal impact reference within the scientific field today.

Abbreviations, acronyms & symbols GSM IF ISI JCR SCI SJR SNIP WoS

Google Scholar Metrics Impact Factor Institute for Scientific Information Journal Citation Report Science Citation Index SCImago Journal Rank Source Normalized Impact per Paper Web of Science

come in increasing development in citation analysis, such as Scopus, owned by Elsevier and the latest Google Scholar Metrics (GSM), owned by Google.

Impact of Bibliometric indexes The scientific production is the final line of all academic activities and research being the instrument by which the scientific community shows the results and submit your work to the external riddle. The search result should be credible, be accessible and after published should not be modified. Also, different analyzes of primary research database should be clearly identified. In addition, the scientific production must have clear evaluation criteria such as peer-review process[2].

The importance for bibliometric indexeshas repercussions in the assignment of weight that give it research and funding institutions. In Brazil such directions from the scientific production base (Universities, CAPES, CNPq, FAPESP, etc.) provide an orientation on directing the publication of the scientific paper according to the indexes[3]. The most visible magazines are most read and consequently referenced, generating a higher request for papers evaluation and competition for recognition. This competition works as quality enhancer of published research and the number of citations resulting from this increases the prestige of the reporting agency and researcher. Thus, production and incentive institutions itself develops publishing rules where the brunt of the impact factor from a journal becomes criteria of production quality, closing the circle.

Impact Factor (thomsonreuters.com/journal-citation-reports) The IF is the most used worldwide and is available online through a paid subscription. It is a source impact indicator (e.g. periodic, journal) and determines how often this is referred to an article. It was created by Eugene Garfield in 1955 to evaluate the journals indexed in Science Citation Index (SCI), a multidisciplinary database in science and technology of the Institute for Scientific Information (ISI), founded by Garfield in 1960 and acquired in 1992 by Thomson Reuters.

SCI is now offered by this database, Web of Science (WoS).

This database allows researchers to identify which articles are most often cited and who cited. Moreover, the very disclosure of the database seems to increase its impact, making

Other impact measurement indexes and databases The IF reigned supreme for decades in the evaluation of periodicals, however, alternative indicators of important validity have been designed with rankings with good correspondence between rating quartiles, although the choice of a specific indicator can impact a lot in the classification of a particular journal[14,15].Two other indexes also widely used are the SNIP (Source Normalized Impact per Paper) and the SJR (SCImago Journal Rank), developed respectively by professor Henk-

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Moed at the University of Leiden, Netherlands and professor Felix de Moya at the University of Granada, Spain. These indexes refer also to source evaluation. Unlike the IF they are based not in WoS database but in Scopus database, owned by the dutch company Elsevier, and include more publications in non-English language. These indexes seek to circumvent the criticism directed to the IF. The SNIP measures the impact of a journal citation weighing it against the total number of citations in a particular area of interest and the SJR corrects the weight of a citation according to the area of interest and the also according the reputation and quality from the journal that performed the citation.

In evaluation of databases, a study compared PubMed, Scopus, Web of Science, and Google Scholar and concluded that PubMed remains an optimal tool in biomedical electronic research. Scopus covers a wider journal range but it is currently limited to recent articles (published after 1995) compared with Web of Science. PubMed and Google Scholar have the advantage of free access and Scopus offers about 20% more coverage than Web of Science. The study refers results of relative inconsistent accuracy from Google Scholar[16].

research most cited papers and the number of citations that they have received in other publications. Was developed in 2005 by the physicist Jorge E. Hirsch[18] and corresponds to the number of articles by a particular author with at least the same number of citations. In other words, if an author has in his body of publications 50 articles and among its most cited articles has 5 articles with 8 citations and 7 articles with 7 citations, his h-index will be 7. Besides the advantage of merge impact (citations) and production (publications) the h-index can also be applied to institutions and research groups.

However, some criticism is also directed to its indiscriminate application. For example, highly cited papers have relative importance. Researchers with lower h-index can be a result of more selective publications or only a smaller time of productive career. In Table 4, there is an example for a research group: the researcher “A” has more impact papers than the researcher “D”, although they have the same h-index. In addition, the h-index does not differentiate the primary authorship from co-authorship nor the citation context (e.g. defense citations from negative ones) and still is influenced by self-citations, whether from the researcher himself or from the research group.

SNIP index (Source Normalized Impact per Paper) (http://www.journalindicators.com) The SNIP index can be quickly checked online and it is free. SNIP is calculated in such way the citations are equalized for a specific field, correcting the variations found in the IF giving different weights to citations. So the impact of a single citation receive a higher value in little citations research areas and vice versa, becoming a more reliable indicator than the IF to compare journals across disciplines[17].

Table 1. Journal ranking – Impact factor.

Rank 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

The SJR index (SCImago Journal Rank) (http://www.scimagojr.com) As SNIP, the SJR is also a free index. SJR incorporates the concept of quality in its construction, taking into account the weight of each journal individually in citations. Thus, the SJR indicates which journals have articles cited by the most prestigious periodicals (calculated through a PageRank algorithm), and not simply which periodicals are cited more often. A citation from a source with a higher SJR has greater weight than a citation with a lower SJR. Also, the SJR records the period of 3 years prior to the current in the calculation and reduces the influence of self-citations. Additionally, JRS counts in the denominator all articles from a journal, not just the “citable” as described in the IF. The journals classification in cardiovascular medicine is presented in Tables 1 to 3, according to each index.

H-index H-index attempts to measure both the productivity and citation impact of the published body of work of a researcher, a research group or a institution, not primarily intended to evaluate a journal. The index is based on the set of the

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Title Journal of the American College of Cardiology Circulation European Heart Journal Circulation Research Nature Reviews Cardiology JACC: Cardiovascular Interventions JACC: Cardiovascular Imaging Circulation: Cardiovascular Interventions JACC: Cardiovascular Imaging European Journal of Heart Failure International Journal of Cardiology Heart Basic Research in Cardiology Circulation: Heart Failure Cardiovascular Research European Heart Journal Supplements Journal of Heart and Lung Transplantation Circulation: Arrhythmia and Electrophysiology Circulation: Cardiovascular Genetics Journal of Molecular and Cellular Cardiology Journal of Cardiovascular Magnetic Resonance Circulation: Cardiovascular Quality and Outcomes Heart Rhythm American Heart Journal Journal of Cardiovascular Computed Tomography Clinical Research in Cardiology AJP: Heart and Circulatory Physiology Heart Failure Reviews Journal of Thoracic and Cardiovascular Surgery Journal of the American Society of Echocardiography

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IF 15.343 14.948 14.723 11.089 10.154 7.440 6.986 6.982 6.752 6.577 6.175 6.023 5.955 5.945 5.808 5.640 5.611 5.417 5.337 5.218 5.112 5,040 4.918 4.555 4.506 4.167 4.012 3.991 3.991 3.987

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Table 2. Journal ranking – SJR index.

Rank 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Table 3. Journal ranking –SNIP index.

Title Journal of the American College of Cardiology Circulation European Heart Journal Circulation Research JACC: Cardiovascular Interventions Circulation: Cardiovascular Quality and Outcomes Circulation: Heart Failure European Journal of Heart Failure Circulation: Cardiovascular Interventions Circulation: Arrhythmia and Electrophysiology Stroke JACC: Cardiovascular Imaging Circulation: Cardiovascular Imaging American Heart Journal Chest Circulation: Cardiovascular Genetics Heart Rhythm Arteriosclerosis, Thrombosis, and Vascular Biology Journal of Heart and Lung Transplantation Journal of Cerebral Blood Flow and Metabolism Cardiovascular Research Heart Journal of Cardiovascular Magnetic Resonance Journal of Molecular and Cellular Cardiology Basic Research in Cardiology Current Opinion in Lipidology Journal of the American Society of Echocardiography Resuscitation Nature Reviews Cardiology Journal of Cardiovascular Electrophysiology

SJR 9.179 8.202 6.983 6.355 5.275 4.515 4.358 4.347 4.193 3.968 3.893 3.505 3.459 3.457 3.432 3.337 3.335 3.026 2.881 2.823 2.799 2.793 2.737 2.703 2.659 2.585 2.571 2.491 2.371 2.351

Rank 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Some variations have been created to improve the performance of the index, for example, the “M index” developed

by Hirsch himself, calculated by dividing the H index by the number of years of researcher productive life[18,19].

Despite the criticism, the h-index is considered a good bibliometric indicator and preferable to the use of individual parameters such as total of published articles, total of citations or more cited articles alone. Currently the h-index is available in the Lattes Platform[20] automatically as production indicator from the Wos and Scopus databases. To researchers not included in Lattes, it can be directly found in the databases described above.

Title SNIP European Heart Journal 5.19 Circulation 4.62 Journal of the American College of Cardiology 4.61 Chest 2.93 Stroke 2.71 Circulation Research 2.49 JACC: Cardiovascular Interventions 2.49 European Journal of Heart Failure 2.14 Circulation: Cardiovascular Interventions 2.14 Journal of the American Society of Echocardiography 2.13 JACC: Cardiovascular Imaging 2.10 Circulation: Arrhythmia and Electrophysiology 2.08 Circulation: Cardiovascular Imaging 2.02 Circulation: Cardiovascular Quality and Outcomes 2.00 Circulation: Heart Failure 1.96 Nature Reviews Cardiology 1.96 Progress in Cardiovascular Diseases 1.84 Heart 1.83 Journal of Heart and Lung Transplantation 1.81 American Heart Journal 1.78 Journal of Vascular Surgery 1.75 Heart Rhythm 1.74 Journal of Thoracic and Cardiovascular Surgery 1.74 Resuscitation 1.72 Journal of Cerebral Blood Flow and Metabolism 1.70 Arteriosclerosis, Thrombosis, and Vascular Biology 1.69 European J. of Vascular and Endovascular Surgery 1.67 Cerebrovascular Diseases 1.66 Cardiovascular Research 1.64 Current Opinion in Lipidology 1.61

Table 4. H-index comparative analysis.

Researcher A B C D

Papers published 5 10 100 1000

Citations 1000 100 10 5

h-index 5 10 10 5

of qualification, also including different levels of qualification for the same publication according each research area (Figure 1). Classification criteria for the area are available on the portal itself and have as general characteristics various impact factors in global databases. Other criteria that can influence this classification are the number of articles published by the last three years, periodicity, accessibility and the publication of articles by authors from different institutions not direct related to the journal edition. Although the classification system receives criticism mainly on the referential adopted[21] and its weight given between different areas[22], it is one of the main criteria used for evaluation of post graduate programs in Brazil.

The WEBQUALIS (http://qualis.capes.gov.br) The CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) is a Brazilian government agency for research support and offers its own system of journals qualification where can be found Brazilian post graduation programs scientific production. This system put the journals into groups (A1, A2, B1 to B5 and C), in descending order

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Fig. 1 - WebQualis classification for the Brazilian Journal of Cardiovascular Surgery.

CONCLUSION

REFERENCES 1. Michán L, Llorente-Bousquets J. [Bibliometry of biological systematics in Latin America during the twentieth century in three global databases]. Rev Biol Trop. 2010;58(2):531-45.

The basic understanding of the most common bibliometric tools aiming at a better understanding of its importance and limitations in the scientific production chain is vital to the researcher, journals and to institutions. Several new indicators are emerging and constantly being improved and may be more widespread in the near future. It is important an appropriate use of impact measures and the recognition of its limitations, as this practice has a direct impact on performance measures and consequently in raising of research funding.

2. Halliday L. Scholarly communication, scholarly publication and status of emerging formats. Inf Res. 2001;6(4) [Accessed Mar 17 2015]. Available at: http://InformationR.net/ir/paper111.html 3. Bicas HEA, Rother ET, Braga MER. Fatores de impacto, outros índices bibliométricos e desempenhos acadêmicos. Arq Bras Oftalmol. 2002;65(2):151-2.

4. Varela D. The contribution of ISI indexing to a paper’s citations: results of a natural experiment. Eur Polit Sci. 2012;12(2):245-53.

Authors’ roles & responsibilities IRCB RCO PBA CAC

Bibliographic research, data collection, writing Bibliographic research, data collection, writing Writing and English version Guidance, theme proposition, general review

5. Fernandéz-Llimós F. Análisis de la cobertura del concepto de Pharmaceutical Careenfuentes primarias y secundarias de información. [Dissertation]. Granada: Universidad de Granada; 2003.

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6. Ietto-Gillies G. The evaluation of research papers in the XXI century. The Open Peer Discussion system of the World Economics Association. Front Comput Neurosci. 2012;6:54.

15. Falagas ME, Kouranos VD, Arencibia-Jorge R, Karageorgopoulos DE. Comparison of SCImago journal rank indicator with journal impact factor. FASEB J. 2008;22(8):2623-8.

7. Committee HoCSaT. Peer review in scientific publications [Accessed Mar 17 2015]. Available at: http://www.publications. parliament.uk/pa/cm201012/cmselect/cmsctech/856/856.pdf

16. Falagas ME, Pitsouni EI, Malietzis GA, Pappas G. Comparison of PubMed, Scopus, Web of Science, and Google Scholar: strengths and weaknesses. FASEB J. 2008;22(2):338-42.

8. Falagas ME, Alexiou VG. The top-ten in journal impact factor manipulation. Arch Immunol Ther Exp (Warsz). 2008;56(4):223-6.

17. Moed HF. The source normalized impact per paper is a valid and sophisticated indicator of journal citation impact. J Am Soc Inf Sci Tec. 2011;62(1):211-3.

9. Sevinc A. Manipulating impact factor: an unethical issue or an Editor’s choice? Swiss Med Wkly. 2004;134(27-28):410.

18. Hirsch JE. An index to quantify an individual’s scientific research output. Proc Natl Acad Sci U S A. 2005;102(46):16569-72.

10. Smith R. Journal accused of manipulating impact factor. BMJ. 1997;314(7079):463.

19. Hirsch JE. Does the H index have predictive power? Proc Natl Acad Sci U S A. 2007;104(49):19193-8.

11. Seglen PO. Why the impact factor of journals should not be used for evaluating research. BMJ. 1997;314(7079):498-502.

20. Brasil. Ministério da Ciência, Tecnologia e Inovação. Plataforma Lattes. CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico; 2014 [cited 2014 Dec 10]. Available from: http:// lattes.cnpq.br/

12. Sloan P, Needleman I. Impact factor. Brit Dent J. 2000;189(1):1.

13. Van Noorden R. Brazilian citation scheme outed. Nature.

2013;500(7464):510-1.

21. Rocha-e-Silva M. [Open letter to the president of CAPES: the new Qualis, which has nothing to do with the science of Brazil.].

Pró-Fono. 2009;21(4):275-8.

14. Kianifar H, Sadeghi R, Zarifmahmoudi L. Comparison Between Impact Factor, Eigenfactor Metrics, and SCimago Journal Rank Indicator of Pediatric Neurology Journals. Acta Inform Med. 2014;22(2):103-6.

22. Rocha-e-Silva M. [The new Qualis, or the announced tragedy].

Clinics (São Paulo). 2009;64(1):1-4.

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Mesquita ET, et ARTICLE al. - Andreas Vesalius 500 years - A Renaissance that SPECIAL - HISTORICAL RECOVERY revolutionized cardiovascular knowledge

Andreas Vesalius 500 years - A Renaissance that revolutionized cardiovascular knowledge Andreas Vesalius 500 anos - Um renascentista que revolucionou o conhecimento cardiovascular

Evandro Tinoco Mesquita1, MD; Celso Vale de Souza Júnior, MD1; Thiago Reigado Ferreira1

DOI 10.5935/1678-9741.20150024

RBCCV 44205-1640

Abstract The history of medicine and cardiology is marked by some geniuses who dared in thinking, research, teaching and transmitting scientific knowledge, and the Italian Andreas Vesalius one of these brilliant masters. His main scientific work “De Humani Corporis Fabrica” is not only a landmark study of human anatomy but also an artistic work of high aesthetic quality published in 1543. In the year 2014 we celebrated 500 years since the birth of the brilliant professor of Padua University, who with his courage and sense of observation changed the understanding of cardiovascular anatomy and founded a school to date in innovative education and research of anatomy. By identifying “the anatomical errors” present in Galen’s book and speech, he challenged the dogmas of the Catholic Church, the academic world and the doctors of his time. However, the accuracy of his findings and his innovative way to disseminate them among his students and colleagues was essential so that his contributions are considered by many the landmark of modern medicine. His death is still surrounded by mysteries having different hypotheses, but a certainty, suffered sanctions of the Catholic Church for the spread of their ideas. The cardiologists, cardiovascular surgeons, interventional cardiologists, electrophysiologists and cardiovascular imaginologists must know the legacy of genius Andreas Vesalius that changed the paradigm of human anatomy.

Resumo A história da medicina e da cardiologia é marcada por alguns gênios que ousaram na forma de pensar, investigar, ensinar e transmitir o conhecimento científico, sendo o italiano Andreas Vesalius um desses brilhantes mestres. A sua principal obra científica “De Humani Corporis Fabrica” não é apenas um marco do estudo da anatomia humana, mas também uma obra artística de elevada qualidade estética publicada no ano de 1543. No ano de 2014, comemoraram-se 500 anos do nascimento do genial professor da universidade de Pádua, que com sua coragem e senso de observação mudou o entendimento da anatomia cardiovascular e fundou uma escola até hoje inovadora no ensino e na investigação da anatomia. Ao identificar “os erros anatômicos” presentes nos livros e discurso de Galeno, desafiou os dogmas da Igreja Católica, o mundo acadêmico e os médicos do seu tempo. No entanto, a exatidão de seus achados e sua forma inovadora de disseminá-los junto aos seus alunos e colegas foi fundamental para que suas contribuições sejam consideradas por muitos o marco da moderna medicina. A sua morte ainda hoje é cercada de mistérios, havendo diferentes hipóteses, porém uma certeza, sofreu sansões da Igreja Católica pela difusão de suas ideias. O cardiologista clínico, cirurgiões cardiovasculares, hemodinamicistas, eletrofisiologistas e imaginologistas cardiovasculares devem conhecer os legados do gênio Andreas Vesalius, que mudou o paradigma da anatomia humana.

Descriptors: Anatomy. History of Medicine. Cardiology.

Descritores: Anatomia. História da Medicina. Cardiologia.

Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil.

Correspondence address: Celso Vale de Souza Júnior Rua Doutor Mário Vianna, 734, Bloco 5, Apto 402 - Santa Rosa - Niterói, RJ, Brazil. Zip code: 24241-001 E-mail: celsovsouzajunior@hotmail.com

1

This study was carried out at Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil.

Article received on March 4th, 2015 Article accepted on March 23th, 2015

No financial support.

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INTRODUCTION

GALEN OF PERGAMUM AND HIS INFLUENCE ON CARDIOVASCULAR ANATOMY AND PHYSIOLOGY

The history of medicine is marked by men and scientific discoveries that have transformed how medical pratice is conducted and knowledge of biological phenomena in the human body both in health and in disease, the professor of anatomy and physician Andreas Vesalius was one of these geniuses.

The medieval world was gradually giving rise to a new thinking present in arts, music, literature, science and medicine, where the human body became worshiped, studied and thus better understood its aesthetic, functional and anatomical value.

In addition, the observation followed by experimentalism and critical thinking were central to change the way how we search for solutions and see the world. Galen’s ideas that influenced for 15 centuries teaching and medical practice were progressively challenged and replaced front of new evidence from the observational method and systematic experimentation.

The Italian peninsula, the cradle of the Renaissance, was where were consolidated two important universities -Bolonha and Pádua- that enabled new knowledge in the academic environment, broadened the knowledge and promote the free debate of ideas, allowing that a new scientific research model, the Scientific Method, could advance over the dogmatic knowledge that influenced medical education from Galen’s texts.

Cardiology and Cardiovascular Surgery, as medical specialties that emerged centuries later, have large debts to Vesalius as he questioned and shown through his systematic study of the heart, Galen’s errors concerning this organ, and formed the basis for that years later, Harvey -also a student in Pádua University- demonstrates the role of circulation involving the heart and blood vessels.

The story of Vesalius combines a revolutionary approach to anatomy, innovative teaching method through the execution of dissection by the professor of medicine alongside the students and an innovative technique of publication. Those were made possible by the university environment of Padua in the Venetian Renaissance setting and, this way, a testament to the history of medicine of the importance and benefits between science and art, in particular with the publication of his important book “De Humani Corporis Fabrica” becoming certainly the father of modern anatomy. Besides, due to his ideas ahead of time and the content of his literary works he suffered persecution of religious and political attitude that contributed to his tragic end.

Free will, critical thinking and freedom of expression, which still in the contemporary world faces challenges and threats, in the Renaissance period was through him that we began to consolidate a new paradigm of looking at scientific phenomena - the scientific method.

The aim of this review is to present a summary of his career as a physician and anatomist and his important anatomical contributions as a legend of Medicine.

Claudius Galenus, also known as Galen of Pergamum, was one of the most influential Roman physicians of Greek origin, his theories dominated the practice and medical science for over 15 centuries. Galen made important contributions to distinguish veins, arteries and the venous blood from the arterial blood, besides the concept of the brain controlling the body and the role of the kidneys in the urine formation[1,2].

In his treatise “De usu Partium” he expresses his theory about blood circulation. According to his concept venous blood present the function of nourishing the body, as this would be secondary to the absorption of the useful part of the food and its subsequent transformation in the liver, an organ which has key role in maintaining the circulatory system[2].

This venous blood reaches the heart and lungs, where in addition to the nutrients being consumed, a portion of it would pass through the pores in the interventricular septum and in the process it would get in touch with the pneuma from the lungs and the very center of the innate heat, leading to the formation of the arterial blood which is responsible for distributing the vital heat around the living body.

Therefore, according to this view both venous and arterial blood circulate together and were governed by repelling properties by the heart and liver, and the attraction of other body organs[2].

PARADIGM SHIFT IN MEDICINE In many societies, formerly, the dissection was a prohibited act to be performed in human bodies, animals were the only source for some of these, which provided poor anatomical knowledge or misapplication of it by trying to interpret these findings to humans. The first anatomists, properly, probably emerged only in the Hellenistic Alexandria, with Herophilus and Erasistratus, being considered the medical school founders in the region and performed dissections in public. Herophilus, in particular is considered the father of anatomy, accounting for important descriptions of the structure and functioning of nerves and vessels[3].

Only in the mid-twelfth century, with the rediscovery of Aristotle’s works, it was found that some studies were based on the dissection of animals and vivisection of these, which somehow legitimized the practice at this time, being an important driver to beginning of a new ideology that would allow less restricted execution of human dissection. Those subject to dissection varied during the historical context, from a private investigation because of a noble death, the ultimate form of humiliation for criminals during public practice, until the Renaissance in which the dissection of

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bodies is progressively introduced to medical universities and reaches a status of academic importance.

The Renaissance had an important scientific milestone to Medicine fostering research on the organizer components of the human body through dissection of cadavers, process which won not only public notoriety due to the associated status, as well as its relation to teaching in universities.

However, even before the descriptions made by Vesalius another important name in human history has contributed significantly to medicine in the field of anatomical research.

Leonardo Da Vinci, and his numerous projects in the areas of math, engineering and aerodynamics, made several anatomical drawings with detail and often his questions with regard to the physiological functioning became the basis for numerous other researchers after him, being one of the inspirations for Vesalius.

After a study phase in Louvain, where he learned classical languages, went to medical degree in Paris in 1533, where he was student of the first French anatomist Johannes Quinterus of Andernach and Jacobus Sylvius. The latter was very committed to Galen’s ideas, making the study of anatomy frustrating in Paris. The lack of anatomy practical classes at the University of Paris took him in with his peers to visit at night, cemeteries outside the city in search of human bones.

This set of difficulties did the young man to return to Louvain in search for completing his studies in medicine[4,5].

In 1537, after completing his bachelor’s degree, he sought the University of Padua to perform his doctorate, since it was the birthplace of Renaissance science and provided the best opportunity to advance his studies in the anatomy area. The influence of many other icons of this institution -as Pietro d`Abano, Alessandro Benedetti, Ermolao Barbaro and Giorgio Valla- allowed the advent of medical humanism with critical thinking. At 23, after completing his doctorate, he was appointed Professor of Surgery at the University of Padua, which at that time was also linked to the teaching of anatomy[4-6].

As a teacher promoted a major change in the teaching of anatomy by assuming the role of dissecting the corpses instead of assistants and barbers, common practice in major medical universities in Europe, making his lessons increasingly attractive to his students and colleagues. He liked to communicate directly with his pupils and never as an authority figure, but as someone that encourages them to examine, to perform experiments and to judge for themselves. The second major innovation promoted by the teacher Vesalius was the development of anatomical drawings with didactic purpose and six of them were published as the Tabulae Sex, with the help of artist Jan Stefan van Kalkar, a disciple of the great Italian Renaissance painter Titian. It can be said that the academic life contributed to instigate the constant search for knowledge of Vesalius as can be seen in one of his notes after students request that he prepare a draft of the venous circulation “that claim proved to be so pleasurable for doctors and students that they strongly encouraged me to describe the arteries and nerves”[4-7].

Vesalius was gradually becoming a more critical observer and, in his “Letter of Venesection,” he abandons his beliefs in traditional and authorized teachings emanated from the influence of Galen, who built a human anatomy extrapolated from the dissection of animals, especially chimpanzees, and incorporates the principle that scientific knowledge should be based solely by the facts derived from observation. According to his observations Galen’s errors occurred because he never dissected a human and for thinking that the information found on dissected animals could be applied to humans, and the very words of Vesalius, Galen was “fooled by his monkeys, and compared the similarities between the human body and monkeys, barely noticed they ended in the presence of fingers and knee bend”[4-6].

TRAJECTORY OF ANDREAS VESALIUS Andreas Vesalius was born on December 31, 1514 in Brussels, Belgium, being the son of a family of physicians where both his father and his grandfather had served the emperor of the Holy Roman Empire. (Figure 1)

Fig. 1 - Painting showing Andreas Vesalius in his dissection activity (Adapted[11]).

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Thus, the Letter of venesection, published in 1539, is an important document that allows us to identify the transition from Vesalius knowledge of the traditional method for the method of direct observation which is consolidated in his masterpiece De Humani Corporis Fabrica, considered a pioneer mark of modern medical science. Even as a renowned teacher and anatomist he suffered strong opposition from those who still defended Galen’s ideas, taking a wear in his academic life in the long run and one of the reasons for accepting to be a doctor of Emperor Charles V of Spain[4-8].

universities and libraries across Europe and the United States showing the rarity and historical importance that the work has even after 459 years of its publication[4,5,7-9]. (Figure 3)

THE GREAT WORK - DE HUMANI CORPORIS FABRICA Modern medicine can be marked by the production of the work De Humani Corporis Fabrica, published in 1543, this book is by far the largest single contribution to medical science, being a magnificent example of creative art, with a perfect combination of form, typography and illustration, as described by Saunders and O`Malley, important Vesalius’ biographers. His work was so important that after a few weeks of publication was named Emperor Charles V’s doctor[4,5,7-9].

It was composed of seven volumes, and the third volume was dedicated to the vasculature in which we find a detailed description of the arteries and veins that was possibly essential for the future work of William Harvey in his description of circulation. It was also through his experiments that it was able to link the relationship between pulse and heart contraction[4,5,7-9].

The VI volume refers to the anatomy of the heart and a small part about the lungs, this first edition despite the description of the heart to be well detailed it is not noted as exceptional to the point that is still rooted in the concepts of Galen, although refute the existence of pores that communicate the right side with the left side of the heart allowing blood to pass through the septum, a concept that helped to better understand the system[4,5,7-9]. (Figure 2) The illustrations drawn attention at the time because they were larger and closer to reality than any previous publication, and were very well applied didactically, as Vesalius often correlated visual content with text.

The second edition was published in 1555, having numerous improvements in the text, and expanded the chapter on his physiological experiments, including the report given on the effect of nerve section on laryngeal paralysis and recurrent laryngeal nerve section, besides adding the description of the venous valves and two new chapters. The illustrations were better due to the print quality in a thicker paper. In this edition, an important quote from Vesalius confirms the absence of pores invisible to the naked eye in the interventricular septum, moving away permanently from Galen’s vision.

A 2009 study found that there were a total of 113 copies of the second edition of De Humani Corporis Fabrica at major

Fig. 2 - Cover of his work De Humani Corporis Fabrica (Adapted[11]).

Fig. 3 - Illustration of Andreas Vesalius’s work in an amphitheater (Adapted[11]).

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CONTRIBUTIONS TO CARDIOVASCULAR SURGERY AND ANATOMICAL-CLINICAL CORRELATION

The death of Vesalius is still controversial, different sources point that he would have been the target of the Inquisition and had to exchange his penalty for a pilgrimage to the Holy Land. At the time of his departure from Madrid to his pilgrimage he clearly had a desire to return to the intellectual and scientific environment of the University of Padua according to a letter sent to his great disciple Fallopius. In return, in 1564, was the victim of a shipwreck and his body found by a goldsmith and later buried on the Greek island of Zakynthos where a tomb was found presenting an epitaph written the following sentence: “The genius lives forever, everything else is mortal - Andreas Vesalius of Brussels”[4,5].

An important acknowledgment of the legacy of Vesalius in Cardiology was the tribute by the American College of Cardiology. It’s logo created in 1965 is a modified heart figure designed by Andreas Vesalius in his Tabulae anatomicae sex. As it was chosen by Franz Maximilian Groedel, he aimed that this logo would have a strong identification with the scientific knowledge, a “learning seal”[10,11] (Figure 4).

The genius of Vesalius’s work has been recognized not only by the scientific community, but by the different nations, whether in the form of stamps, notes, cultural or scientific events (Figure 5).

Vesalius’ power of observation allowed him to describe quite accurately the pericardial anatomy: “The heart as a whole is covered by a membranous envelope which is not attached to any point. This wrap is much broader than the heart and has in its interior an aqueous humor ...”.

The prototype of anatomopathological methodology was performed by Andreas Vesalius in 1557, by correlating the signs and symptoms of a patient with pathological changes consistent with aortic aneurysm revealed in postmortem examination. This kind of research allowed in 1707 in Bologna, Giovanni Morgagni to describe the possibility of diagnosis based on findings of the “Anatomy of morbid corpses”, this clinicopathological project culminated in the publication of his iconic work “The Seats and Causes of Diseases Investigated by Anatomy” in which approximately 700 dissection reviews were described to accurately identify the injury giving rise to the symptoms observed in patients while they were alive, consolidating a new way of thinking and teach medicine, the anatomoclinical correlation[5,7-9].

There has been evidence that Vesalius was preparing a third edition of his De Humani Corporis Fabrica work because they found in his works, thousands of notes and corrections of all kinds, from deletions, additions and transpositions phrases to footnotes. Particularly the first three quarters of his work contained many modifications and to this day it is not know why this third edition was never released. Still, these changes demonstrate an admirable concern for the quality of his work and a willingness to correct even the smallest details[4,5,7-9].

DEATH OF ANDREAS VESALIUS AND THE RECOGNITION OF HIS LEGACY During his career as a doctor of the emperor he poorly attended teachings of anatomy, he rarely did dissections in Padua and Pisa, as he spent most of the time attending royalty in the Netherlands and later in Spain. With no intention of returning to academic life soon he burned many of his books including the notes he had made during the years. Remained as a doctor of Charles V and, 12 years later, his successor Philip II. After a while he regretted the incident and returned to his hometown - Brussels - with a fortune conquered by his services to the most important monarch of his time and it was then that his desire for dissections resurfaced. There are few records of its activities after 1555, but it is known that he participated in the treatment and autopsy of famous names like Ferrante Gonzaga of Mantua and Henri II of France[4,5].

His last publication was Anatomicarum Gabrielis Falloppii Observationum Examen dated May 24, 1564, and since 1559 he moved with his wife to Spain, which stated to be a place where he had few opportunities to perform dissection and lived there until the event of his death.

Fig. 4 - Seal of the American College of Cardiology (Adapted[11]).

Fig. 5 - Commemorative bill to 500 years of Vesalius (Adapted[11]).

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CONCLUSIONS

3. Bay NS, Bay BH. Greek anatomist herophilus: the father of anatomy. Anat Cell Biol. 2010;43(4):280-3.

All the works of Andreas Vesalius places him as a genius with multiple skills as an artist, naturalist, humanist and the first modern medical scientist thus included among the giants of the history of medicine. His scientific contributions and his legacy as a teacher and artist promoted a profound impact also in Cardiology and Cardiovascular Surgery.

4. O’Malley CD. Andreas Vesalius 1514-1564: In memoriam. Med Hist. 1964;8:299-308.

5. Haas LF. Andreas Vesalius (1514-64). J Neurol Neurosurg Psychiatry. 1992;55(1):3.

6. Castiglioni A. Andreas Vesalius: Professor at the Medical School of Padua. Bull N Y Acad Med. 1943;19(11):766-77.

Authors’ roles & responsibilities ETM CVSJ TRF

7. Nutton V. Vesalius revised. His annotations to the 1555 Fabrica.

Med Hist. 2012;56(4):415-43.

Final approval of the manuscript; study design; writing of the manuscript and critical review of its contents Final approval of the manuscript; design and study design; writing of the manuscript or critical review of its content Drafting of the manuscript and critical review of its content

8. Joffe SN. A census of the edition of 1555 of Andreas Vesalius’ De Humani Corporis Fabrica. Int Arch Med. 2009;2(1):26.

9. Dunn PM. Andreas Vesalius (1514-1564), Padua, and the fetal “shunts”. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F157-9.

REFERENCES

10. Zampieri F, Basso C, Thiene G. Andreas Vesalius’ Tabulae anatomicae sex (1538) and the seal of the American College of Cardiology. J Am Coll Cardiol. 2014;63(7):694-5.

1. Haas LF. Claudius Galen 131-201 AD. J Neurol Neurosurg Psychiatry. 1991;54(4):287.

11. Saunders JBDCM, O’Malley CD. Andreas Vesalius de Bruxelas De Humani Corporis Fabrica. Epitome. Tabulae Sex. Campinas, São Paulo: Editora Unicamp, Imprensa Oficial; 2003.

2. Fullerton JB, Silverman ME. Claudius Galen of Pergamum: authority of medieval medicine. Clin Cardiol. 2009;32(11):E82-3.

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Jeremic N, EXPERIMENTAL et al. - Effects of ischemia and omeprazole preconditioning on WORK functional recovery of isolated rat heart

Effects of ischemia and omeprazole preconditioning on functional recovery of isolated rat heart Efeitos da isquemia e pré-condicionamento com omeprazol na recuperação funcional do coração isolado de rato

Nevena Jeremic1, Mr Pharm; Anica Petkovic2; Ivan Srejovic2, MD; Vladimir Zivkovic2, MD, PhD; Dragan Djuric3, MD, PhD; Vladimir Jakovljevic2, MD, PhD

DOI 10.5935/1678-9741.20150020

RBCCV 44205-1641

Abstract Objective: The aim of this study was to compare protective effects of ischemic and potential protective effects of pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/reperfusion.

Methods: The hearts of male Wistar albino rats were excised and perfused on a Langendorff apparatus. In control group (CG) after stabilization period, hearts were subjected to global ischemia (perfusion was totally stopped) for 20 minutes and 30 minutes of reperfusion. Hearts of group II (IPC) were submitted to ischemic preconditioning lasting 5 minutes before 20 minutes of ischemia and 30 minutes of reperfusion. In third group (OPC) hearts first underwent preconditioning lasting 5 minutes with 100µM omeprazole, and then submitted 20 minutes of ischemia and 30 minutes of reperfusion.

Results: Administration of omeprazole before ischemia induction had protective effect on myocardium function recovery especially regarding to values of systolic left ventricular pressure and dp/dt max. Also our findings are that values of coronary flow did not change between OPC and IPC groups in last point of reperfusion.

Conclusion: Based on our results it seems that ischemic preconditioning could be used as first window of protection after ischemic injury especially because all investigated parameters showed continuous trend of recovery of myocardial function.

On the other hand, preconditioning with omeprazole induced sudden trend of recovery with positive myocardium protection, although less effective than results obtained with ischemic preconditioning not withstand, we must consider that omeprazole may be used in many clinical circumstances where direct coronary clamping for ischemic preconditioning is not possible.

Department of Pharmaceutical chemistry, Faculty of Medical Sciences, University of Kragujevac, Serbia.

2 Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Serbia.

3 Institute of Medical Physiology “Richard Burian”, School of Medicine, University of Belgrade, Serbia.

No financial support.

Descriptors: Coronary circulation. Ischemic Preconditioning, Myocardial. Omeprazole.

Resumo Objetivo: O objetivo deste estudo foi comparar os efeitos protetores de efeitos protetores isquêmicos e potenciais de précondicionamento farmacológico com omeprazol no coração isolado de rato submetido à isquemia/reperfusão.

Métodos: Os corações de ratos albinos Wistar machos foram excisados e perfundidos em um aparelho de Langendorff.

No grupo controle (grupo I), após o período de estabilização, os corações foram submetidos à isquemia global (a perfusão foi totalmente interrompida) por 20 minutos e 30 minutos de reperfusão. Corações do grupo II (IPC) foram submetidos a précondicionamento isquêmico com duração de 5 minutos antes de 20 minutos de isquemia e 30 minutos de reperfusão. No terceiro grupo (OPC), corações foram submetidos a pré-condiciona-

1

Correspondence address: Vladimir Jakovljevic Svetozara Markovica 69, P.O.Box 124, 34000 Kragujevac E-mail: drvladakgbg@yahoo.com

Work carried out at Department of Physiology, Faculty of Medical Sciences, University of Kragujevac, Serbia.

Article received on September 9th, 2014 Article accepted on March 9th, 2015

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sistólica ventricular esquerda e dp/dt max. Também os nossos achados são de que os valores de fluxo coronário não se alteraram entre os grupos OPC e IPC no último ponto de reperfusão.

Conclusão: Com base nos nossos resultados, o pré-condicionamento isquêmico poderia ser usado como primeira janela de proteção após a lesão isquêmica, especialmente porque todos os parâmetros analisados ​​apresentam tendência contínua de recuperação da função do miocárdio. Por outro lado, o pré-condicionamento induzido com omeprazol apresenta tendência repentina de recuperação com proteção miocárdio positiva, embora menos efetiva da obtida com o pré-condicionamento isquêmico.

Devemos considerar que o omeprazol pode ser usado em muitas circunstâncias clínicas em que o pinçamento coronariano direto para pré-condicionamento isquêmico não é possível.

Abbreviations, acronyms & symbols CF DLVP HCl HR ICP PPI ROS SLVP

Coronary flow Diastolic left ventricular pressure Hydrochloride acid Heart rate Ischemic preconditioning Proton pump inhibitors Reactive oxygen species Systolic left ventricular pressure

mento com duração de 5 minutos com 100 µM de omeprazol, e, então, submetidos a 20 minutos de isquemia e 30 minutos de reperfusão.

Resultados: A administração de omeprazol antes da indução da isquemia teve efeito protetor sobre a recuperação funcional do miocárdio especialmente em relação aos valores de pressão

Descritores: Circulação Coronária. Precondicionamento Isquêmico Miocárdico. Omeprazol

INTRODUCTION

and CP (creatine phosphate) which results in decreased activity of ATP reliant ion pumps including Na+/K+ ATP-ase pump and exacerbation of contractile function. Inactivation of Na+/ K+ ATP-ase contributes to intracellular Na+ overloading. Lower intracellular pH induces the Na+/H+ exchanger to extrude H+ and results in intracellular accumulation of Na+, which leads to activation of the 2Na+/Ca2+ exchanger in order to extrude Na+ and accumulate intracellular Ca2+[6-9]. All these facts and generation of reactive oxygen species (ROS) can lead to cell death induced by ischemic episodes[10].

Furthermore, reperfusion is restoration of blood flow after an ischemic episode and it may result in paradoxical cardiomyocite dysfunction caused by ROS, intracellular and mitochondrial Ca++ overload and accumulation of inflammatory cells. This phenomenon is called “reperfusion injury”, where prompt changes in intracellular ions and normalization of pH can occur cell death and greater damage than it can be induced by pre-reperfusion ischemia[6,8,11].

Besides ischemic preconditioning, which represents an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion, the same response can be induced with pharmacological agents[3-5]. Proton pump inhibitors (PPI) have been one of most important advances in the field of gastroenterology in past 15 years. These medications showed significant progress in acid-related diseases over other acid reducing medications. Most commonly used PPI are omeprazole, lansoprazole and pantoprazole[12,13]. Omeprazole was first introduced into clinical practice and it is commonly used for treatment of gastroesophageal reflux and erosive esophagitis in children. The main mechanism of action of these drugs is suppression of acid secretion by binding to H+/K+ ATP-ase known as “proton pump” or “acid pump”[14,15]. Proton pump is enzymatic pump expressed in different tissues like parietal cells where hydrochloride acid (HCl) is secreted. The main physiological effect of this pump is H+ exchange for K+ ions.

Myocardial preconditioning represents exposure of myocardium to sublethal stimulus in order to protect it from a subsequent normal lethal stress[1]. Myocardium can be preconditioned by two basic techniques such as ischemic and pharmacological preconditioning. Ischemic preconditioning (ICP) is a concept introduced by Murry et al. in 1986 by using canine models. He showed that single or multiple brief periods of myocardial ischemia that produce reversible myocyte injury can limit the size of the infarct and the degree of reperfusion injury after a subsequent and more prolonged period of myocardial ischemia[2].

These protective effects of ICP on heart can be consequence of reduction in reactive oxygen species generation, delay in ATP depletion, reduction of: infarct size, apoptosis and neutrophil accumulation, as well as improvement of endothelial function and reduction of intracellular Ca++ overload[3-5]. Two different time frames have been reported for pre-conditioning, early or ’’classical preconditioning’’ phase and late or ’’second window’’ phase. Duration of first phase, which involves the activation of different membrane receptors, is from several seconds and to 3h and for second phase from 12-72 h which represents changes in gene expression leading to production cardioprotective stress proteins[4].

Ischemia is characterized by an absolute or relative decrease in the blood supply of tissue or organ due to blockage of blood vessels. Blood vessel can be occluded by thrombus, atherosclerotic plaque, vasoconstriction or inflammation.

During myocardial ischemia absence of oxygen and metabolic substrates to cardiomyocite can cause functional, structural and metabolic diseases. As a consequence, cell switches metabolism to anaerobic, resulting in accumulation of lactate and generation of acidosis. Hypoxic conditions lead to diminished intracellular concentrations of ATP (adenosine triphosphate)

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Due to existence of proton pump in myocardial tissue, which was first proven by Nagashima et al.[16], mechanical and electrical properties can be changed by using PPI[6]. Recently proton pump inhibitors had showed protective effects in treatment of myocardial ischemia in patients with coronary artery disease and gastroesophageal reflux[17].

Regarding all above presented data, the aim of this study was to compare protective effects of ischemic and potential protective effects of pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/reperfusion.

hearts were subjected to global ischemia (perfusion was totally stopped) for 20 minutes and 30 minutes of reperfusion. Twelve hearts of group II (IPC) were submitted to ischemic preconditioning lasting 5 minutes before 20 minutes of ischemia and 30 minutes of reperfusion. In third group (OPC) hearts first underwent preconditioning lasting 5 minutes with 100ÂľM omeprazole, then submitted 20 minutes of ischemia and 30 minutes of reperfusion. In control group after 20 minutes of global ischemia during period of reperfusion (30 minutes) all cardiodynamic parameters and coronary flow were measured in intervals of 5 minute (RP1-RP7). In IPC group, after short period of ischemia (5 minutes) during period of reperfusion (10 minutes), all cardiodynamic parameters and coronary flow were measured in intervals of 1 minute (PR1-PR10), while during second period of ischemia (20 minutes)/reperfusion (30 minutes) cardiodynamic parameters and coronary flow were measured in intervals of 5 minute (RP1-RP7).

In OPC group (after 5 minutes preconditioning with omeprazole), during period of reperfusion all cardiodynamic parameters and coronary flow were measured during second period of ischemia (20 minutes)/reperfusion (30 minutes) in intervals of 5 minute (RP1-RP7). When the flow was considered stable (three measurements of the same values), coronary flow was recorded. Only the properly performed experiments were included in the study (i.e., the groups of the hearts in which the CPP/CF relationship was studied twice in the absence of any drug).

After placing the sensor in the left ventricle, the following parameters of myocardial function have been continuously registered: 1. Maximum rate of pressure development in the left ventricle (dp/dt max) 2. Minimum rate of pressure development in the left ventricle (dp/dt min) 3. Systolic left ventricular pressure (SLVP) 4. Diastolic left ventricular pressure (DLVP) 5. Heart rate (HR) Coronary flow (CF) was measured flowmetrically.

METHODS Preparation of isolated rat hearts The hearts of male Wistar albino rats (n=36, 12 in each experimental group, body mass 180â&#x20AC;&#x201C;200 g) were excised and perfused on a Langendorff apparatus (Experimetria Ltd,1062 Budapest, Hungary). After a short-term ketamine/xylasin narcosis, animals were killed by cervical dislocation (Schedule 1 of the Animals/ Scientific Procedures, Act 1986, UK), and premedicated with heparin as an anticoagulant. After emergency thoracotomy and rapid cardiac arrest by superfusion with ice-cold isotonic saline, rapidly excised, the aortas were cannulated and retrogradely perfused under a constant perfusion pressure (CPP).

The composition of the non-recirculating Krebs-Henseleit perfusate was as follows (mM): NaCl 118, KCI 4.7, CaCI2x2H2O 2.5, MgSO4x7H2O 1.7, NaHCO3 25, KH2PO4 1.2, glucose 11, pyruvate 2, equilibrated with 95 % O2 plus 5% CO2 and warmed to 37 oC (pH 7.4). Immediately after the restoration of normal heart rhythm, through the created entrance to the left atrium of the heart and damaged mitral valve, the sensor (transducer BS473-0184, Experimetria Ltd, Budapest, Hungary) was inserted into the left ventricle for continuous monitoring of cardiac function (Figure 1).

Physiological assay and experimental protocol All study groups underwent 30 min perfusion at CPP of 70 cm H2O. In control group (CG) after stabilization period,

Fig. 1 - Immediately after the restoration of normal heart rhythm, through the created entrance to the left atrium of the heart and damaged mitral valve, the sensor was inserted into the left ventricle for continuous monitoring of cardiac function.

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Drugs All drugs were purchased from Sigmaâ&#x20AC;&#x201C;Aldrich Chemie GmbH, Germany.

01-12149 and by Ministry of Agriculture, Forestry and Water Management, Authority for Veterinary of Serbia number 323-07-09426/2013-05.

Statistical analysis For statistical analysis we examined three measured points, first point was stabilization, second was the first minute of reperfusion and third was the 30 minute of reperfusion.

Values are expressed as mean Âą SE. Statistical analysis was performed by ANOVA test. P values lower than 0.05 were considered to be significant.

The experimental protocol was approved by the Faculty of Medical Sciences Ethics Committee for the welfare of experimental animals, University of Kragujevac, number

RESULTS Maximum Rate of Left Ventricular Pressure Development (dp/dt max) There were no significant differences among groups in the values of point of stabilisation and first minute of reperfusion.

In control and IPC group there were no significant difference between periods of stabilisation an first minute of reperfusion, however there were high statistical significant increase (P<0.01**) of values of dp/dt max between these

Fig. 2 - The influence of ischemic preconditioning (5 min ischemia/10 min reperfusion) on cardiodynamic parameters of the isolated rat heart during subsequent ischemia (20 minutes)/reperfusion (30 minutes): 2a) dp/dtmax, 2b) dp/dtmin, 2c) SLVP, 2d) DLVP, 2e) HR, 2f) CF.

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points in OPC group. Trend of values in period of reperfusion was the same in all investigated groups. Furthermore, there were statistical significant changes between control group and IPC group in values of the last point of reperfusion (P<0.05*) but in comparison with mentioned groups, OPC group has statistical different values (P<0.01**) which were very similar with values before omeprazole administration (Figures 2a, 3a and 4a).

In control, IPC and OPC groups there were no significant difference between periods of stabilisation an first minute of reperfusion. Trend of values in period of reperfusion was the same in OPC, IPC and control group without any statistical difference. Furthermore, there were changes between control group and OPC group in values of the last point of reperfusion (P<0.01**) in comparison between control group with IPC group values were statistical different (P<0.05*) at the end; in comparison OPC group with IPC group values were statistical different (P<0.01**) but in OPC group values were similar with values before omeprazole administration (Figures 2b, 3b and 4b).

Minimum Rate of Left Ventricular Pressure Development (dp/dt min) There were no significant differences among groups in the values of point of stabilisation and first minute of reperfusion.

Fig. 3 - The influence of ishemia (20 minutes)/reperfusion (30 minutes) on cardiodynamic parameters of the isolated rat heart: 3a) dp/dtmax, 3b) dp/dtmin, 3c) SLVP, 3d) DLVP, 3e) HR, 3f) CF.

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Systolic Blood Pressure in the Left Ventricle (SLVP) There were no significant differences among groups in the values of point of stabilisation and first minute of reperfusion.

In control and IPC group there were no significant difference between periods of stabilisation an first minute of reperfusion, however there were high statistical significant increase (P<0.01**) of values of SLVP between these points in OPC group. Trend of values in period of reperfusion was the same in OPC and control group on the other hand trend in IPC group was statistical significantly lower than in mentioned groups (PË&#x201A;0.05*). Furthermore, there were statistical significant changes between control group and IPC group in values of the last point of reperfusion (P<0.05*) but in comparison with

mentioned groups, OPC group has statistical different values (P<0.01**) which were very similar with values before omeprazole administration (Figures 2c, 3c and 4c).

Diastolic Blood Pressure in the Left Ventricle (DLVP) There were no significant differences among groups in the values of point of stabilisation and first minute of reperfusion.

In control and IPC group there were no significant difference between periods of stabilisation at the first minute of reperfusion, however there were high statistical significant increase (P<0.05*) of values of DLVP between these points in OPC group. Trend of values in period of reperfusion was different among groups, in

Fig. 4 - The influence of preconditioning with omeprazole (5 minutes) on cardiodynamic parameters of the isolated rat heart during subsequent ischemia (20 minutes)/reperfusion (30 minutes): 4a) dp/dtmax, 4b) dp/dtmin, 4c) SLVP, 4d) DLVP, 4e) HR, 4f) CF.

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control group values of DLVP in period of reperfusion increased compared with period before ischemia. In IPC and OPC groups values of DLVP in period of reperfusion decreased compared with period before preconditioning.

Furthermore, there were statistical significant changes between control group and IPC group. Compared with values in control group, IPC and OPC groups values were statistical different in last point of reperfusion (P<0.05*) (Figures 2d, 3d and 4d).

OPC group. Trend of values in period of reperfusion was the same in OPC, IPC and control group without any statistical difference. Furthermore, there were no changes among control, IPC and OPC group in last point of reperfusion (Figures 2f, 3f and 4f).

Summary table shows all cardiodynamic parameters compared between the groups (Table 1).

Heart Rate (HR) There were no significant differences between IPC group and control group and also between OPC and control group, but there were significant difference between IPC and OPC at the point of stabilisation.

In control and IPC group there were no significant difference between periods of stabilisation at the first minute of reperfusion, however there were high statistical significant drop (P<0.01**) of values of HR between these points in OPC group. Trend of values in period of reperfusion was the same in IPC and control group on the other hand trend in OPC group was the same as in mentioned groups but with statistical significant lower decrease. Furthermore, there were no changes between control group and OPC group in values of the last point of reperfusion but in comparison with IPC group those values were statistically different (P<0.05*) (Figures 2e, 3e and 4e)

Acute myocardial infarction is leading cause of morbidity and mortality worldwide each year. Consequence of acute myocardial infarction, a diminished blood supply to the heart exceeds a critical threshold and overwhelms myocardial cellular repair mechanisms designed to maintain normal operating function and homeostasis[18]. The treatment of acute myocardial infarction has been prospering in last few decades and new methods such as preconditioning, post-conditioning and pharmacological agents have been examined to protect the heart[19,20].

Preconditioning (PC) involves reduction of necrotic tissue mass, improvement of cardiac contractile performance after ischemia and reperfusion, and reduction of arrhythmias. Although the ischemic preconditioning is not entirely clarified, recently parts of the signal transduction cascade of ischemic preconditioning have been identified. According to different species, the organism increases the production of several chemical mediators that trigger the cardio protection process[21]. To avoid the problems which can cause ischemic preconditioning in clinical use, administration of pharmacological agents could be ideal solution. Pharmacological agents such as a cardio-selective β1-blocker and the adenosine triphosphate-sensitive potassium channel openers have been shown the ability to protect the heart but none has been widely accepted[19].

DISCUSSION

Coronary Flow (CF) There were no significant differences among groups in the values of point of stabilisation and first minute of reperfusion.

In control and IPC group there were no significant difference between periods of stabilisation and first minute of reperfusion however there were high statistical significant increase (P<0.01**) of values of CF between these points in

Table 1. Summary table of statistically significant difference between groups in points of interest.

Groups Dp/dt max Dp/dt min SLVP DLVP CF [mmHg/s] [mmHg/s] [mmHg] [mmHg] [ml/min] CG vs. IPC P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05* P>0.05 P>0.05 P>0.05* P>0.05* P>0.05* P>0.05* P>0.05 CG vs. OPC P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.01** P>0.05 P>0.05 P>0.05 P>0.05* P>0.01** P>0.01** P>0.05* P>0.05 IPC vs. OPC P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.05 P>0.01** P>0.05* P>0.05 P>0.05 P>0.05* P>0.01** P>0.01** P>0.05 P>0.05 *Statistically significant **High statistically significant CG=control group; IPC=ischemic preconditioning; OPC=preconditioning whit omeprazole

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Point of interest Stabilisation First point of reperfusion Las point of reportfusion Stabilisation First point of reperfusion Las point of reportfusion Stabilisation First point of reperfusion Last point of reperfusion

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Model of isolated rat heart is one the most convenient experimental tool for preclinical investigations of mammalian heart, and also very reliable for connection between animal and human studies. Generally, viewed morphology of the rat heart is very similar with human one[22]. Namely, structure of the left ventricular, wall thickness and properties of the papillary muscles are almost the same as in the human heart[22].

In addition, examination of nodal cells showed that they are very similar to human T cells, and begin with the functioning during the early embryogenesis[23]. Moreover, both ventricular and atrial cardiomyocites are showed to possess high percent of histological similarity[24]. In this sense, we can assume that there are significant analogy between cardiac (patho) physiological events in rat and human heart.

In that sense, data collected from these experimental studies could be of great interest in improving knowledge about ischemic and especially pharmacological form of preconditioning.

The present study aimed to compare potential protective effects of ischemic and pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/ reperfusion. Considering the fact that myocardial tissues have H+/K+ - ATPase[19], we examined the effects of one of clinically most used H+/K+-ATPase inhibitor (omeprazole) in isolated rat heart.

Proton pump inhibitors may be a particularly important in patients with intrinsic cardiac disease however their safety has not been well studied. Omeprazole was first introduced into clinical practice and it is commonly used for treatment of gastroesophageal reflux and erosive esophagitis but some studies pioneering demonstrated the protective effect of omeprazole on myocardial contractility in isolated rat hearts[25].

Considering the fact that H+/K+-ATPase exists in myocardial tissues it could be expected that specific proton pump inhibitors might change the mechanical and electrical properties of the myocardium and might cause intracellular acidification via decreasing the extracellular H+ transport and membrane depolarization through intracellular K+ import[6,16].

Gomes et al.[25] have shown that administration of omeprazole before ischemia induction had protective effect on myocardium function recovery and our results were very similar especially regarding to values of SLVP and dp/ dt max. These results are coherent with findings in studies where only ischemic preconditioning was induced[2].

On the other hand, in case of coronary flow (CF), in the present study there were no difference between OPC and IPC groups in last point of reperfusion (Figures 2a and 4a), which was very close to findings of Gomes et al.[25].

It has been shown, that ischemic preconditioning can reduce the magnitude of ischemia/reperfusion injury via activation of K+ adenosine triphosphate (ATP)-sensitive (K(ATP)) channels[26]. Concerning this fact, Kersten et al.[27] found that left-ventricular pressure and coronary flow, respectively,

were recovered to a greater extent after inducing ischemic preconditioning. In our study, results are very similar (Figures 2a, 2b, and 2f).

A study evaluating animal model of frog by Gautam et al.[28], showed interesting results. They found that PPI in minimal used dose did not change heart rate, but when they increased doses twice, they noticed bradycardia. However, Gomes et al., on rat model did not show any effect on heart rate[25]. In this investigation, we found high statistical significant drop of values of HR between period of stabilisation and first minute of reperfusion in OPC group (Figure 4e).

Birnbaum et al.[29] showed that induction of ischemic preconditioning on isolated rabbit heart leads to slower heart rate then in control group as we also demonstrated (Figures 2e and 3e).

In our study, omeprazole decreased tension and complete inhibition of cardiac contractility (Figure 4d) and these results correlate with studies of other authors who investigated another PPI on similar models[6,30,31]. In OPC group we remarked that values of every parameter was significantly increased in first minute of reperfusion compared to point of stabilisation (Figures 4a to 4f).

Based on findings by Murry et al.[2], we investigated ischemic preconditioning using similar procedure and we also concluded that in IPC group there was recovery of all measured parameters.

Furthermore, based on our results it seems that ischemic preconditioning could be used as first window of protection after ischemic injury especially due to all investigated parameters showed continuous trend of recovery of myocardial function. On the other hand, after administration of omeprazole we noticed sudden trend of recovery with positive myocardium protection, although less effective than results obtained with ischemic preconditioning not withstand we must consider that omeprazole may be used in many clinical circumstances where direct coronary clamping for ischemic preconditioning is not possible.

CONCLUSION Although there is lack of data regarding the events occurring during cellular adaptation to stressful stimuli, ischemic preconditioning may be powerful means in protection of ischemic myocardium, and the results of this investigation also confirmed the important preconditioning effect of the omeprazole in the protection against reperfusion lesions of the myocardium ischemia. However, current research on the different aspects of preconditioning seems to diverge more and the possibility of pharmacological manipulation of the pathways involved becomes reality. Therefore, this study is meant as another contribution for many other investigations, with emphasis on pharmacological preconditioning.

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ACKNOWLEDGMENTS

9. Jennings RB, Reimer KA. The cell biology of acute myocardial ischemia. Annu Rev Med. 1991;42:225-46.

This study is supported by Grant no. 175043 from the Ministry of Science and Technical Development of the Republic of Serbia.

10. Sommerschild HT, Kirkebøen KA. Preconditioning - endogenous defense mechanisms of the heart. Acta Anaesthesiol Scand. 2002;46(2):123-37.

11. Verma S, Fedak PW, Weisel RD, Butany J, Rao V, Maitland A, et al. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation. 2002;105(20):2332-6.

Authors’ roles & responsibilities NJ AP IS VZ DD VJ

Analysis and/or interpretation of data; statistical analysis; study design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; operations and/or experiments conduct Conception and design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Final approval of the manuscript; study design; operations and/or experiments conduct; writing of the manuscript or critical review of its content Final approval of the manuscript; study design Final approval of the manuscript; study design

12. Richardson P, Hawkey CJ, Stack WA. Proton pump inhibitors.

Pharmacology and rationale for use in gastrointestinal disorders.

Drugs. 1998;56(3):307-35.

13. Fock KM, Ang TL, Bee LC, Lee EJ. Proton pump inhibitors: do differences in pharmacokinetics translate into differences in clinical outcomes? Clin Pharmacokinet. 2008;47(1):1-6.

14. Monzani A, Oderda G. Delayed-release oral suspension of omeprazole for the treatment of erosive esophagitis and gastroesophageal reflux disease in pediatric patients: a review.

Clin Exp Gastroenterol. 2010;3:17-25.

15. Lindberg P, Nordberg P, Alminger T, Brändström A, Wallmark B. The mechanism of action of the gastric acid secretion inhibitor omeprazole. J Med Chem. 1986;29(8):1327-9.

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16. Nagashima R, Odashiro K, Morita S. Evidence for the existence of myocardial H+-K+ATP and its electrophysiological effects. Jpn Heart J. 1994; 35(suppl):473-4.

2. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.

Circulation. 1986;74(5):1124-36.

17. Dobrzycki S, Baniukiewicz A, Korecki J, BachórzewskaGajewska H, Prokopczuk P, Musial WJ, et al. Does gastroesophageal reflux provoke the myocardial ischemia in patients with CAD? Int J Cardiol. 2005;104(1):67-72.

3. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning.

Am J Physiol Heart Circ Physiol. 2003;285(2):H579-88.

18. Xia A, Xue Z, Li Y, Wang W, Xia J, Wei T, et al. Cardioprotective effect of betulinic acid on myocardial ischemia reperfusion injury in rats. Evid Based Complement Alternat Med. 2014;2014 [Acessed on: Set 1, 2014]. Available from: http://www.hindawi. com/journals/ecam/2014/573745/

4. Sanada S, Komuro I, Kitakaze M. Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. Am J Physiol Heart Circ Physiol. 2011;301(5):H1723-41.

5. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121-35.

19. Li J, Iorga A, Sharma S, Youn JY, Partow-Navid R, Umar S, et al.

Intralipid, a clinically safe compound, protects the heart against ischemia-reperfusion injury more efficiently than cyclosporine-A. Anesthesiology. 2012;117(4):836-46.

6. Bacaksiz A, Teker ME, Buyukpinarbasili N, Inan O, Tasal A, Sonmez O, et al. Does pantoprazole protect against reperfusion injury following myocardial ischemia in rats? Eur Rev Med Pharmacol Sci. 2013;17(2):269-75.

20. Ghyasi R, Sepehri G, Mohammadi M, Badalzadeh R, Ghyasi A. Effect of mebudipine on oxidative stress and lipid peroxidation in myocardial ischemic-reperfusion injury in male rat. J Res Med Sci. 2012;17(12):1150-5.

7. Gomes OM, Magalhães Mde M, Abrantes RD, Kallás E. Pantoprazole provides myocardial protection similar to ischemic preconditioning: experimental study of isolated hearts of rats.

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21. Schulz R, Cohen VM , Behrends M , Downey MJ , Heusch D. Signal transduction of ischemic preconditioning. Cardiovasc Res. 2001;52(2):181-98.

8. Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123(1):92-100.

22. Grimm AF, Katele KV, Klein SA, Lin HL. Growth of the heart.

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23. Domenech-Mateu JM, Boya-VeguĂŠ J. An ultrastructural study of sinuatrial node cells in the embryonic rat heart. J Anat.

1975;119(Pt 1):77-83.

DC. Role of adenosine in isoflurane-induced cardioprotection.

Anesthesiology. 1997;86(5):1128-39.

28. Gautam CS, Utreja A, Goel D, Sandhu G, Gogia N. Negative chronotropic effect of proton pump inhibitors on frog-heart preparation. Indian J Gastroenterol. 2009;28(4):147-9.

24. Anversa P, Loud AV, Vitali-Mazza L. Morphometry and autoradiography of early hyperthropic changes in the ventricular myocardium of adult rat: an electron microscopic study. Lab Invest. 1976;35(5):475-83.

29. Birnbaum Y, Hale SL, Kloner RA. Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation. 1997;96(5):1641-6.

25. Gomes OM, MagalhĂŁes MM, Abrantes RD. Myocardium functional recovery protection by omeprazole after ischemiareperfusion in isolated rat hearts. Rev Bras Cir Cardiovasc.

2010;25(3):388-92.

30. Novalija E, Fujita S, Kampine JP, Stowe DF. Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. Anesthesiology.

1999;91(3):701-12.

26. Schillinger W, Teucher N, Sossalla S, Kettlewell S, Werner C, Raddatz D, et al. Negative inotropy of the gastric proton pump inhibitor pantoprazole in myocardium from humans and rabbits: evaluation of mechanisms. Circulation. 2007;116(1):57-66.

31. Yenisehirli A, Onur R. Positive inotropic and negative chronotropic effects of proton pump inhibitors in isolated rat atrium. Eur J Pharmacol. 2005;519(3):259-66.

27. Kersten JR, Orth KG, Pagel PS, Mei DA, Gross GJ, Warltier

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Yuan SM -BRIEF Prognostic prediction of troponins in cardiac myxoma: case study COMMUNICATION with literature review

Prognostic prediction of troponins in cardiac myxoma: case study with literature review Previsão de prognóstico de troponinas em mixoma cardíaco: estudo de caso e revisão da literatura

Shi-Min Yuan1, MMed, PhD

DOI: 10.5935/1678-9741.20140087

RBCCV 44205-1642

Abstract Objective: It was supposed that troponins in cardiac myxoma patients might be in a same fashion as in the conditions without myocardial injury. In order to verify this hypothesis, troponins in cardiac myxoma patients were discussed by presenting a comprehensive retrieval of the literature with incorporating the information of a recent patient.

Methods: Postoperative detections of troponin I, creatine kinase isoenzyme MB (CK-MB) and N-terminal pro-B-type natriuretic peptide revealed elevated troponin I and CK-MB and normal N-terminal pro-B-type natriuretic peptide. Postoperative troponin I and CK-MB shared a same trend, reaching a peak value at postoperative hour 2, gradually decreased on postoperative day 1, and reached a plateau on postoperative days 7 and 13. A significant correlation could be noted between the postoperative values of the two indicators (Y=0.0714X + 0.6425, r2=0.9111, r=0.9545, P=0.0116). No significant linear correlation between troponin I and N-terminal pro-B-type natriuretic peptide were found. Literature review of troponins in cardiac myxoma patients revealed the uncomplicated patients had a normal or only slightly elevated troponin before open heart surgery. However, the complicated patients (with cerebral or cardiac events) showed a normal preoperative troponin in 3 (23.1%) and an elevated troponin in 10 (76.9%) patients (χ2=7.54, P=0.0169, Fisher’s exact test). The overall quantitative

result of troponin I was 2.45±2.53 μg/L, and that of troponin T was 3.10±4.29 mg/L, respectively.

Conclusion: Troponins are not necessarily elevated in patients with a cardiac myxoma without coronary syndrome. By contrast, patients with a cardiac myxoma with an elevated troponin may herald the presence of an associated coronary event.

An old cerebral infarct does not necessarily cause an elevation of troponin or B-type natriuretic peptide, or new neurological events, but might lead to a delayed awakening.

The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, China.

Correspondence address: Shi-Min Yuan Longdejing Street, 389 - Chengxiang District, Putian, Fujian Province, People’s Republic of China E-mail: shi_min_yuan@yahoo.com

Descriptors: Brain. Myxoma. Natriuretic Peptides. Troponin.

Resumo Objetivo: Supunha-se que troponinas em pacientes com mixoma cardíaco poderiam estar em uma mesma forma que naqueles sem lesão miocárdica. Para verificar essa hipótese, as troponinas em pacientes com mixoma cardíaco foram discutidas, em uma revisão abrangente da literatura com a incorporação das informações de um paciente recente.

Métodos: Detecções pós-operatórias de troponina I, creatina quinase isoenzima MB (CK-MB) e peptídeo natriurético tipo B N-terminal revelaram troponina I e CK-MB elevadas e pró-peptídeo natriurético tipo B N-terminal normais. Troponina I e CK -MB no pós-operatório tiveram a mesma tendência, chegando a

1

This study was carried out at First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, Fujian Province, People’s Republic of China.

Article received on March 28th, 2014 Article accepted on June 29th, 2014

No financial support.

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apenas ligeiramente elevada antes da cirurgia de coração aberto.

No entanto, nos pacientes com complicações (com eventos cerebrais ou cardíacos) três (23,1%) estavam com troponina normal e 10 (76,9%) com troponina elevada no pré-operatório (χ2=7,54, P=0,0169, teste exato de Fisher). O resultado quantitativo global de troponina I foi 2,45±2,53 μg/L, e o de troponina T foi 3,10±4,29 mg/L, respectivamente.

Conclusão: As troponinas não são necessariamente elevadas em pacientes com mixoma cardíaco sem síndrome coronariana.

Por outro lado, em pacientes com mixoma cardíaco a troponina elevada pode ser preditora de um evento coronariano associado.

Um infarto cerebral antigo não necessariamente causa elevação de troponina, do peptídeo natriurético tipo B, ou novos eventos neurológicos, mas pode levar a um atraso no despertar.

Abbreviations, acronyms & symbols BNP CK-MB NT-proBNP NYHA POD POH

Brain natriuretic peptide Creatine kinase isoenzyme MB N-terminal pro-B-type natriuretic peptide New York Heart Association Postoperative day Postoperative hour

um valor de pico na 2a hora de pós-operatório, diminuindo gradualmente no primeiro dia pós-operatório, chegando a um patamar nos dias 7 e 13 do pós-operatório. Correlação significativa pode ser observada entre os valores pós-operatórios de dois indicadores (Y=0,6425 + 0.0714X, r2=0,9111, r=0,9545, P=0,0116). Nenhuma correlação linear significativa entre troponina I e pró-peptídeo natriurético tipo B N-terminal foi encontrada. A revisão da literatura de troponina em pacientes com mixoma cardíaco revelou que os pacientes sem complicações tiveram troponina normal ou

Descritores: Encéfalo. Mixoma. Peptídeos Natriuréticos.

Troponina.

INTRODUCTION

result of multiple cerebral infarcts with a diagnosis of “top of the basilar” syndrome due to a left atrial myxoma. Later, she also developed multiple segmental embolism of her lower extremities involving the bilateral anterior tibial, bilateral posterior tibial, right popliteal and bilateral dorsal arteries.

Left atrial myxoma resection was performed under cardiopulmonary bypass. During the operation, the myxoma was found to be originated from the free wall of the left atrium.

The myxoma was resected en bloc, and the iatrogenic atrial free wall defect was repaired with an autologous pericardial patch. She had a delayed awakening until postoperative hour (POH) 13.5 without any new neurological sequelea. She had an uneventful postoperative course and was discharged home on postoperative day (POD) 19. Histopathology of the resected myxoma showed a glandular cardiac myxoma.

On admission, her C-reaction protein was 41.66 (normal range, 0-10) mg/L, hypersensitive C-reaction protein was >5 (normal range, 0-1) mg/L, and CK-MB 7.6 (normal range, 0-40) U/L. Her condition was gradually stable after prolonged treatment. She was recently referred to this hospital for surgical treatment of left atrial myxoma.

After admission, the diagnosis of left atrial myxoma was confirmed by echocardiography and chest computed tomography. Her preoperative troponin I and NT-proBNP values were normal.

Postoperative detections revealed elevated troponin I and CK-MB and normal NT-proBNP (Table 1). Troponin I values were moderately elevated at POH 2 and POD 1.

Postoperative CK-MB showed a same trend with cardiac troponin I, which reached a peak value at POH 2 (POD 0.08), gradually decreased on POH 24 (POD 1), and reached a plateau on PODs 7 and 13. The only difference between the two indicators was CK-MB recovered to normal values since POD 7, whereas troponin I did not, but

Troponins are a type of contractile protein produced in cardiac and skeletal muscles. They are composed of troponin subunits I, C and T, with the former two subunits being highly sensitive and specific for myocardial damage, especially implicated in the diagnosis of acute coronary syndrome[1].

Dynamics of troponins have been sufficiently described as to start to increase a few hours after myocardial ischemic damage, reach a plateau after 10-15 hours, and recover gradually to the baseline level[2]. Elevations of troponins T and I were also found in patients without myocardial injury. These situations included severe renal dysfunction[3], acute neurological events (with a peak troponin I value of 3.43±3.22 µg/L)[4], hepatic cirrhosis and portal hypertension[5], stroke, pulmonary embolism and sepsis[6].

Troponins were sporadically reported in cardiac myxoma patients. However, these results were actually anecdotal without being taken into a through investigation. It was supposed that troponins in cardiac myxoma patients might be in a same fashion as in the conditions without myocardial injury. In order to verify this hypothesis, a patient with cardiac myxoma, whose clinical and histopathological aspects have been reported elsewhere[7,8], is to be presented in terms of her serum troponin studies along with creatine kinase isoenzyme MB (CK-MB) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) by incorporating the results based on a comprehensive retrieval of the literature.

CLINICAL OBSERVATIONS Six months prior to current admission, a 51-year-old female had abrupt loss of vision and consciousness. She was in a state of cardiogenic shock, which was revealed to be a

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were 0.43 μg/L and 0.32 μg/L at PODs 7 and 13 (Figure 1). A significant correlation could be noted between the postoperative values of the two indicators (Y=0.0714X + 0.6425, r2=0.9111, r=0.9545, P=0.0116) (Figure 2). Ran-

dom NT-proBNP values were 243 and 448 pg/mL at POH 2 and on POD 7. No significant linear correlation between troponin I and NT-proBNP were found (Y=-0.0251X + 11.2760, r2=0.2846, r=-0.5335, P=0.6418) (Figure 3).

Table 1. Determinations of serum cardiac biomarkers.

Biomarker Troponi I (μg/L) CK-MB (U/L) N-terminal pro-B-type natriuretic peptide (pg/mL)

Normal range 0-0.1 0-40 0-900

Fig. 1 - A similar changing trend of troponin I and creatine kinase isoenzyme MB. CK-MB=creatine kinase isoenzyme MB.

Preoperation 0 7.6 261

0.08 9.47 126 243

Postoperative day 1 7 3.74 0.43 15 1 -448

13 0.32 1 --

Fig. 3 - Linear correlation between troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP). NT-proBNP=Nterminal pro-B-type natriuretic peptide.

DISCUSSION Troponin I is a popularly recognized sensitive biomarker in the diagnosis of postoperative myocardial damage and perioperative myocardial infarction[9]. Clinical observations revealed that troponin I, CK and CK-MB values peaked between POHs 6 and 18, troponin T between POHs 18 and 42, and myoglobin at the surgical closure. The values of all markers were higher in patients undergoing coronary surgery compared to those undergoing valve surgery[10]. Yuan et al.[11] discovered significant elevated serum troponin I during the early days after the onset or surgical repair of myocardial rupture, and they advocated the troponin I was valuable in judging the prognosis of the patients with myocardial injury.

Troponin I (as well as NT-BNP) can be helpful in the evaluation of the functions of the vital organs including heart

Fig. 2 - Linear correlation between troponin I and creatine kinase isoenzyme MB. CK-MB=creatine kinase isoenzyme MB.

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subjected to perioperative drug use, such as oral prophylactic metoprolol[12] and high-dose aprotinin[13].

Troponin levels in cardiac myxoma were reported in 18 sporadic patients[14-31], totally 19 patients including the present one (Table 2). Of them, 12 (63.2%) were troponin I and 7 (36.8%) were troponin T. Six (31.6%) patients were uncomplicated, and 13 (68.4%) were complicated (χ2=5.16, P=0.0502, Fisher’s exact test). Of the complicated patients, acute myocardial infarction developed in 10 (76.9%) patients, and ventricular fibrillation arrest, pulmonary embolism, and ischemic stroke developed in 1 (7.7%) patient, each (χ2=21.17, P=0.0001, Fisher’s exact test). The uncomplicated

patients had a normal or only slightly elevated troponin before open heart surgery. However, the complicated patients showed a normal preoperative troponin in 3 (23.1%) and an elevated troponin in 10 (76.9%) patients (χ2=7.54, P=0.0169, Fisher’s exact test). The overall quantitative result of preoperative troponin I was 2.45±2.53 (range, 0.0189-5.91; median, 1.47) μg/L (n=7), and that of troponin T was 3.10±4.29 (range, 0.31-9.37; median, 1.36) mg/L (n=4), respectively.

The troponin I was somewhat higher than the baseline value of coronary artery disease patients (1.0±6 μg/L)[9] or the baseline value of the patients with coronary and/or valvular disorders (0.16±0.05 μg/L)[10] reported in the literature.

Table 2. Preoperative troponin levels in the patients with a cardiac myxoma.

Year

Author

1. 2003

Gurlertop et al. [14]

Age (year) 90

2. 2005 3. 2006

Demir et al. [15] Balami et al. [16]

55 82

f f

Location of cardiac myxoma Left ventricular outflow tract myxoma Left atrial myxoma Left atrial myxoma

4. 2008 5. 2009

Özdoğru et al. [17] Yadav et al. [18]

38 62

m f

Left atrial myxoma Left atrial myxoma

6. 2009

Dalzell et al. [19]

59

m

7. 2010 8. 2010

Albouaini et al. [20] Shimada et al. [21]

70 68

m f

Left atrial myxoma, recurrent Left atrial myxoma Left atrial myxoma

9. 2011

Agarwal et al. [22]

22

f

Left atrial myxoma

10. 2011

Vogel et al. [23]

43

f

Left atrial myxoma

11. 2011

Weiss et al. [24]

14

m

12. 2012

Marta et al. [25]

57

f

Calcified right atrial myxoma Left atrial myxoma

13. 2012

Stępień et al. [26]

75

m

Left atrial myxoma

14. 2013 Haffner et al. [27] 15. 2013 Jung et al. [28] 16. 2013 Lazaros et al. [29] 17. 2013 Leo et al. [30] 18. 2013 Sadeghpour et al. [31]

58 76 35 58 73

f f f f f

Left atrial myxoma Right atrial myxoma Left atrial myxoma Left atrial myxoma Left atrial myxoma

19.

51

f

Left atrial myxoma with glandular structures

Present

Sex f

279

Complication A history of anterior myocardial infarction (2 years ago) Myocardial infarction Transient ischemic attack and acute coronary syndrome Acute unheralded neurological compromise, acute pulmonary edema, severe impairment of left ventricular function, total occlusion of abdominal aorta Ventricular fibrillation arrest

Troponin I (μg/l)

0.071

Non-ST elevation acute myocardial infarction Critical stenosis of several coronary arteries Myocardial infarction Pulmonary embolism Acute ST segment elevation, inferolateral myocardial infarction, multiple emboli

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0.31 Negative 2.4

4.5

Myocardial infarction Ischemic stroke (middle cerebral artery and posterior inferior cerebellar artery) Systemic embolization (acute posterior circulation territory ischemia) and myocardial infarction

Troponin T (mg/L) Positive

4.8

9.37 Slightly increased

0.32

Normal 0.0189 5.91 1.47 0.38 Normal Normal Very high 0

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The functional atrioventricular valve obstruction and embolic phenomena predisposing to myocardial infarction in the presence of a cardiac myxoma might be the explanations of the remarkable rise of the baseline troponin values[25].

It was proposed that troponin I levels measured on POD 1 may predict short-, medium- and long-term mortality. Troponin I levels of alive patients was 2.01 (range, 1.01-3.65) and 4.26 (range, 2.18-8.37) μg/L at POH 2 and on POD 1, while those of the deceased were 3.63 (range, 1.62-8.26) and 11.85 (range, 5.59-23.96) μg/L, respectively[14]. In a patient with a cardiac myxoma and associated coronary artery stenosis, his troponin I was 3.56 μg/L on POD 13[26]. The present patient with old cerebral infarct had an uneventful recovery after the resection of cardiac myxoma. She had compatible troponin I values during the early postoperative period to the maximal value of the survived surgical patients as reported by Croal et al.[32]. In addition, this patient had significantly decreased troponin I values on PODs 7 and 13, much lower than those of the patient reported by Stępień’s et al.[26]. This could be interpreted by the associated coronary artery disease in the latter patient[26].

Comparative studies between troponins and CK-MB have already been stated some decades ago. There were little differences among troponins I and T, and CK-MB after cardiac operation to diagnose myocardial damage[33]. However, troponins have a more prolonged release than CK-MB when the patient is subjected to myocardial damage; it is therefore more sensitive than CK-MB in indicating myocardial necrosis. A troponin I concentration <15 μg/L within PODs 1-2 was highly suggestive of the absence of perioperative myocardial necrosis[34]. The dynamic changes of troponin I and CK-MB in the present patient were quite identical. The incidental finding was a peak value at POH 2 and a gradual decrease on POD 1, contrary to a delayed peak appearing on POD 1 as reported by Croal et al.[32]. The disconformity warranted further investigations.

NT-proBNP is a pre-propetptide synthetized in the cardiomyocytes. When it is secreted, it splits into two parts: physiologically active brain natriuretic peptide (BNP) and biologically inactive NT-proBNP. Both can be significantly elevated when the patient is with an acute or congestive heart failure[35]. The normal range of BNP was <200 pg/mL[36]. Increased BNP values were discovered to be related to acute cerebrovascular events[37]. BNP >140 pg/mL could be helpful in distinguishing cardiogenic from non-cardiogenic embolism[38]. Clinical observations revealed BNP levels were loosely correlated with New York Heart Association (NYHA) functional class[36]. In the patients undergoing cardiac surgery including one patient with atrial myxoma, BNP was 62.8±68.1 pg/mL[39]. Patients with congestive heart failure had a mean BNP concentration of 1076±138 pg/mL, while the non-congestive heart failure patients had a mean BNP concentration of 38±4 pg/mL[40]. Links between BNP and

cardiac myxoma have rarely been discussed. Factors associated with high BNP levels other than congestive heart failure were age, gender, renal failure, lung disease and myocardial infarction; meanwhile, atrial myxoma was determined as a factor accounting for low BNP levels with congestive heart failure[41]. Plasma BNP level in 17 consecutive adult patients (including one patient with a left atrial myxoma) during the perioperative period were detected. Plasma BNP remained unchanged until 12, 24 and 48 hours after the termination of cardiopulmonary bypass, which were 149.5±43.0 pg/mL, 175.2±93.6 pg/mL and 146.2±59.4 pg/mL, respectively[42]. In a patient with right heart enlargement and severe pulmonary hypertension free of congestive heart failure, her BNP was 5,613.4 pg/mL[30]. A 53-year-old man with a large left atrial myxoma presented with biventricular heart failure. His BNP was as high as 4,800 pg/mL[43]. Lack of elevations of BNP has been reported in the event of acute congestive heart failure or with ventricular inflow obstruction (hypertrophic obstructive cardiomyopathy, mitral stenosis, or atrial myxoma)[36].

Top of the basilar artery refers to a 2-cm territory surrounding the five-forked junction at the top of the basilar artery formed by 2 posterior cerebral arteries, 2 superior cerebellar arteries and the top of basilar artery[44]. Cerebral infarction involving the rostral brainstem and cerebral hemisphere that are supplied by the distal basilar artery causes a clinical syndrome, known as rostral brainstem infarction or “top of the basilar” syndrome, characterized by visual, oculomotor, and behavioral abnormalities, often with insignificant motor dysfunction[45]. “Top of the basilar” syndrome occurs when the top of the basilar artery is subjected to thromboembolic occlusions, and results in bilateral thalamic ischemia due to occlusion of perforator vessels. Transient ischemic attack and stroke can present in 80% of patients with a cardiac myxoma[46]. Unexplained transient ischemic attack, cerebral infarction and syncope are common neurologic manifestations[47]. Clinical observations demonstrated that the patients with preoperative cerebral infarct took longer time to awaken than those without (6.5±5.0 hours vs. 4.6±2.9 hours, P<0.05)[48]. The incidence of confusion and cerebral infarction after operation in the preoperative infarct patients was higher than those without[48]. The anesthetic awareness in the present patient was 13.5 hours, even longer than reported. This phenomenon implicated that an old cerebral infarct may interfere anesthetic awareness, but not necessarily complicated with new postoperative sequelae.

The normal postoperative BNP values of the present patient offered a strong support to this argument.

CONCLUSION Troponins are not necessarily elevated in patients with a cardiac myxoma without coronary syndrome. By contrast, cardiac myxoma patients with an elevated troponin may herald the presence of an associated coronary event. An old

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cerebral infarct does not necessarily cause an elevation of troponin or BNP, or new neurological events, but might lead to a delayed awakening.

11. Yuan SM, Jing H, Lavee J. The implications of serum enzymes and coagulation activities in postinfarction myocardial rupture.

Rev Bras Cir Cardiovasc. 2011;26(1):7-14.

12. Rossi Neto JM, Gun C, Ramos RF, Almeida AF, Issa M, Amato VL, et al. Myocardial protection with prophylactic oral metoprolol during coronary artery bypass grafting surgery: evaluation by troponin I. Rev Bras Cir Cardiovasc. 2013;28(4):449-54.

Author role & responsibility SMY

Main Author

13. Ferreira CA, Vicente WV, Evora PR, Rodrigues AJ, Klamt JG, Carlotti AP, et al. High-dose aprotinin does not affect troponin I, N-Terminal pro-B-type natriuretic peptid and renal function in children submitted to surgical correction with extracorporeal circulation. Rev Bras Cir Cardiovasc. 2009;24(4):519-32.

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43. Hodkinson EC, Dixon LJ, Dalzell GW. Multimodal imaging of an atypical left atrial myxoma. QJM. 2015;108(1):51-3.

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33. Bonnefoy E, Filley S, Kirkorian G, Guidollet J, Roriz R, Robin J, et al. Troponin I, troponin T, or creatine kinase-MB to detect perioperative myocardial damage after coronary artery bypass surgery. Chest. 1998;114(2):482-6.

46. Ugurlu B, Oto Ö, Okutan H, Kutluk K, Silistreli E, Sariosmanoğlu N, et al. Stroke and myxoma. Asian Cardiovasc Thorac Ann. 2000;8(2):130-3.

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Stolf NAG, et al. MEMORY - Geraldo Verginelli, the search for elegance and perfectionism in cardiovascular surgery

Geraldo Verginelli, the search for elegance and perfectionism in cardiovascular surgery Geraldo Verginelli, a busca da elegância e do perfeccionismo em cirurgia cardiovascular

Noedir A. G. Stolf1, MD, MSc, PhD; Domingo M. Braile2, MD, MSc, PhD DOI 10.5935/1678-9741.20150030

RBCCV 44205-1643

Geraldo Verginelli, the son of Angelo Verginelli and Marianna Marchetti Verginelli, was born on May 8, 1920, in the city of Campinas, located in the countryside of the state of São Paulo.

From 1929 to 1931, he went to elementary school at Grupo Escolar Modelo and, from 1933 to 1937, he attended the prestigious “Culto à Ciência” school, where he graduated from junior high school, both schools being in Campinas.

After graduation, he moved to São Paulo, where he took the Pre-Med course at Colégio Universitário, an annex of the University of São Paulo Medical School (FMUSP), during the years of 1938 and 1939. In 1940, after passing the required test for admission, he enrolled in the University of São Paulo Medical School. As both a curricular and a volunteering activity, he attended Second Surgical Rotation under Prof. Alípio Corrêa Neto at Santa Casa de Misericórdia de São Paulo, which was the teaching hospital of the Medical School at the time.

After graduating in 1945 (Figure 1), Verginelli started his three-year surgical training, equivalent to the current medical residency, at the Clínicas Hospital of the University of São Paulo Medical School. In the first year, the rotation covered several specialties, and, in the second and third years, his rotation was under the service of Prof. Alípio Corrêa Neto. The Professor was a pioneer in the First Surgical Rotation and he divided the group into different specialties: Gastrointestinal Surgery, Thoracic Surgery, Endocrine Surgery, and Peripheral Vascular Surgery. Next, Verginelli acted as an intern and Assistant Physician. However, the specialized groups saw General Surgery patients. At last, he joined the Thoracic

Fig. 1 - Geraldo Verginelli at his Graduation from USP Medical School.

Surgery Group as an Assistant Physician. Thoracic surgery practice had been going through great advances, especially after the trip of Prof. Zerbini, the group’s chief, to Saint Louis and Boston, when surgery for tuberculosis was integrated into the lung resection surgery. Likewise, when the decision to start performing cardiac surgeries under cardiopulmonary bypass was made, the Artificial Lung-heart workshop station was set up in the basement of the Clínicas Hospital in order to produce the equipment that made the surgery possible.

The equipment was tested in a series of more than a hundred dogs. In 1957, Verginelli was one of the most active members of that experimental group. In the following year, the first surgery under cardiopulmonary bypass was performed in the Clínicas Hospital. The development of this specialty, with congenital heart disease and heart valve surgeries, was fastpaced, from valve replacement in the 1960s to coronary artery bypass grafting in the 1970s. Throughout those decades, Verginelli continued working almost full-time, becoming

Professor Emeritus and Senior Professor of the University of São Paulo Medical School (FMUSP).

2 Professor Emeritus of Famerp and Unicamp, Editor in Chief of the Brazilian Journal of Cardiovascular Surgery, President of the Board of Trustees of Braile Biomédica Ltda.

1

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Stolf NAG, et al. - Geraldo Verginelli, the search for elegance and perfectionism in cardiovascular surgery

an important asset in the workings of the service. His reputation as a skilled, elegant, and perfectionist surgeon was established in the Clínicas Hospital. Therefore, on January 26, 1965, when the first kidney transplant was performed by Prof. Geraldo Campos Freire, Verginelli was called to take care of the vascular anatomy. He remained with this transplant team for many years.

In addition, he participated in the first heart transplant on May 26, 1968 as well as in the following two transplants performed in 1968 and 1969. Similarly, he took part in the development of the dura mater bioprosthesis, where his contribution, in addition to his performance in the congenital heart disease surgery service, was crucial.

He was the point of contact for younger assistants, residents, and interns. Hundreds of them, from all over Brazil, Latin America (Argentina, Ecuador, Mexico, Peru, Uruguay, and Venezuela), Portugal, Spain, and even Japan, owe much of their training to Geraldo Verginelli. He followed a routine, arriving at the Clínicas Hospital, then going to the Heart Institute (Incor) to do postoperative rounds at 7:00 am sharp.

Afterwards, he participated in the meeting to discuss the daily surgical cases at Incor, where his presence was always a certainty, even when he started having health problems and using a wheelchair.

When interacting with Prof. Verginelli, two other remarkable characteristics stood out: his search for propriety in the use of language and his knowledge of the “Nomina Anatomica”. Regarding the former, unquestionably a legacy from Prof. Alípio Corrêa Neto, whether at formal or informal meetings, he was known for correcting inaccurate terms, such as pathology, synonyms of diseases as well as any language in disagreement with writing and style manuals. He was frequently asked to correct texts, articles, and even dissertations. As for the Nomina Anatomica, he would not compromise, not even when the term commonly used in medical language was not in accordance with the Nomina.

Regarding academics, most of his titles and positions were obtained through civil service examinations: • In 1972, Medical Doctor from the University of São Paulo Medical School; • In 1973, Full Professor of Surgical Rotation at the University of São Paulo Medical School; • In 1974, Full Professor of Thoracic Surgery at the Paulista Medical School; • In 1978, Assistant Professor of Thoracic Surgery at the University of São Paulo Medical School.

Those were his titles and positions. The University of São Paulo later extinguished the titles of Full Professor and Assistant Professor, which were then classified as Associate Professor. Verginelli retired as such compulsorily in 1990 at the age of 70. However, he continued to work at Incor (Figures 2, 3, and 4).

Fig. 2 – Examination board at USP Medical School. From left to right, professors: Domingo Braile, Adib Jatene, Geraldo Verginelli, Noedir Stolf, and Enio Buffolo.

Fig. 3 – In the Board of Directors room at Incor (Euclydes J. Zerbini standing; seated from left to right, Seigo Tsuzuki, Director of Bioengineering; Geraldo Verginelli, Assistant Professor; João Tranchesi, Chief of Electrocardiogram; Radi Macruz, Assistant Professor; Fulvio Pilleggi, Full Professor; and Noedir Stolf, Assistant Professor).

Fig. 4 - Prof. Verginelli, retired, in his room at Incor, receiving a visit from Full Professor and Chief of the Cardiovascular Surgery Subject.

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Prof. Verginelli was incredibly active on the scientific level. He coordinated and/or was an exhibitor in more than a hundred national and international conferences in addition to presenting more than 700 communications. He had an extensive list of publications. Besides two dissertations, he published more than 40 book chapters, almost 200 articles in Brazilian journals and about 50 articles in international journals.

He received approximately 40 national and international awards and honors.

Due to his almost exclusive dedication to the Thoracic Surgery Service, the Thoracic Surgery subject, the Clínicas Hospital as well as the Heart Institute, Verginelli was nominated to highly important administrative positions. At the Heart Institute, he was President of the Teaching Committee, member of the Scientific Committee, member of the Board of Directors, member of the Curators Committee of the Zerbini Foundation, and Director of the Surgery Department. The department was established in 1979, encompassing the Surgical, Bioengineering, and Experimental Surgery divisions as well as the Anesthesia Service. Subsequently, those became independent areas and the Surgery Department ceased to be a part of the Heart Institute.

Unlike many, Prof. Verginelli was able to successfully accomplish the triple mission of assisting patients, teaching, and conducting research. While assisting patients, he was crucial to the development of cardiovascular surgery in the Clínicas Hospital of the University of São Paulo Medical School, working and assisting in all areas and specialties. In addition, he participated in the development of innovations in this and other several areas. In terms of teaching, a huge number of cardiovascular surgeons in Brazil and abroad owe much of their training to Prof. Verginelli.

After undergoing an only partially successful hip surgery and suffering from a progressive neurological disease, Prof.

Verginelli passed away on July 10, 2014.

Paraphrasing the popular Antoine de Saint Exupéry: Those who pass us by go alone, as every individual is unique and unreplaceable. “Those who pass us by, do not go alone, do not leave us alone. They leave us a little of them and take a little of us.” There are those who take a lot and those who take nothing at all. There are those who leave a lot and those who leave nothing…

Prof. Verginelli fits the description of those that passed us by, left a lot of themselves and took a lot from us.

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REVIEWERS

Reviewers BJCVS 30.2 The Brazilian Journal of Cardiovascular Surgery (BJCVS) is grateful for the reviewers, listed below, which collaborate in this issue. Their work is essential to improve the high scientific level of our journal.

Domingo Braile Editor-in-Chief BJCVS

Charles Simão Filho

José Ernesto Succi

Dorotéia Souza

Leonardo Silva Roever Borges Luciano Cabral Albuquerque

Edmo Atique Gabriel Eduardo Keller Saadi Eliana Sotello Cabrera

Marcos Aurélio Barboza de Oliveira Max Grimberg Michel Pompeu B. de Oliveira Sá

Fabio Antonio Gaiotto Fernando Platania

Otoni Moreira Gomes

Gibran Roder Feguri Gilberto Goissis Guilherme Agreli

Roberto Gomes de Carvalho

Jarbas Jakson Dinkhuysen João Carlos Leal José Carlos Dorsa Vieira Pontes

Valquiria P. Campagnucci Victor Rodrigues Ribeiro Ferreira Vinicius José da Silva Nina

Tomas A Salerno

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Erratum

ERRATUM In the article "Determinants of peak VO2 in heart transplant recipients", published in the Brazilian Journal of Cardiovascular Surgery/Revista Brasileira de Cirurgia Cardiovascular 30.1, pages 9-15, the correct name of one of the co-authors is Marcelo Luiz Campos Vieira and not Marcelo Luiz Campos-Vieira.

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INFORMATION FOR AUTHORS BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY/ Revista Brasileira de Cirurgia Cardiovascular Editor Prof. Dr. Domingo M. Braile Av. Juscelino Kubitschek de Oliveira, 1.505 – Jardim Tarraf I 15091-450 – São José do Rio Preto – SP - Brasil E-mail: revista@sbccv.org.br

Electronic Submission Manuscripts should be compulsorily submitted electronically on site http://www.rbccv.org.br/sgp/. When entering this link, the system will ask for the username and password if the user have already registered. Otherwise, click on “I want to register” and register. Or, if the user have forgotten his password, the mechanism to remember the password can be used, which will generate an email containing such password.

The submission system is self-explanatory and includes eight steps: Step 1: Classification of the article Step 2: Adding title and keywords Step 3: Registering for authors Step 4: Inclusion of summary and Abstract Step 5: Inclusion of the manuscript itself with references Step 6: Sending images Step 7: Generation of copyright declarations, conflict of interest and copy of the Opinion of the Research Ethics Committee of the Institution 8th Step: Author’s approval / finalization of submission

The Brazilian Journal of Cardiovascular Surgery (BJCVS) is the official journal of the Brazilian Society of Cardiovascular Surgery (BSCVS). It is a bimonthly publication, with regular circulation since 1986. BJCVS is indexed in the Thomson Scientific (ISI), Medline/PubMed, SCOPUS, SciELO, LILACS, Scirus and SCImago database.

BJCVS aims to record the scientific production in cardiovascular surgery, encouraging the study, improving and updating the professional specialty.

Studies submitted for publication in BJCVS must deal with themes related to cardiovascular surgery and related fields. The journal publishes the following types of articles: original article, editorial, review article, special article, case report, how to do it, short communications, preliminary notes, clinical-surgical correlation, experimental study, multimedia and letter to editor.

Acceptance will be based on originality, significance and scientific contribution. Articles with merely propaganda or commercial purposes will not be accepted.

The authors are responsible for the content and information contained in their manuscripts.

BJCVS vehemently rejects plagiarism and self-plagiarism. On submission of manuscripts, the authors sign a statement declaring they are aware of the consequences of violation.

The texts must be edited in word format and figures and tables should be in separate files.

Keep your records updated because communication with authors is exclusively by e-mail.

When finishing the submission of the study, it will generate an e-mail stating that the submission was made correctly, another email will be generated after checking if it is within the standards.

If the article is “Out of Standard”, the author will be notified by email and can fix it into the SGP / BJCVS in www. bjcvs.org/sgp.

Authors may follow the course of their study at any time

by SGP/BJCVS through the flow code automatically generated by GSP, or even by the title of his study.

The journal will be published in full on the journal’s website (www.rbccv.org.br/www.bjcvs.org) and SciELO (www. scielo.br/rbbcv), with specific links in the BJCVS site (www. sbccv. org.br) and CTSnet (www.ctsnet.org).

EDITORIAL POLICY Standard BJCVS adopts the Standards of Vancouver - Uniform Requirements for Manuscripts Submitted to Biomedical Journals, organized by the International Committee of Medical Journal Editors, available at: www.icmje.org Submission and Publication Policy Only manuscripts whose data is not being assessed by other journals and/or have not been previously published will be considered for review.

Manuscripts accepted may only be reproduced in whole or in part, without the express consent of the editor of BJCVS.

Peer review All scientific contributions are reviewed by the Editor, Associate Editors, Editorial Board Members and/or Guests Reviewers. The reviewers answer a questionnaire in which they rated the manuscript, their rigorous examination on all items that compose a scientific study by assigning a score for each of the questionnaire items. At the end, general comments about the study and suggestion if it should be published, cor-

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rected according to the recommendations or definitively rejected are made. With these data, the Editor will make a decision. In case of discrepancies between the reviewers, a new opinion can be requested in order to provide a best judgment.

When modifications are suggested, they will be forwarded to the author and then the reviewers to verify that these requirements have been met. The authors have 30 days to make the changes requested by reviewers and resubmit the article.

In response to the comments/suggestions of the reviewers, authors should highlight the changes made in the text. The non-observance of this period will involve the removal of the article from the review process.

Once the article is approved, authors will be notified by e-mail registered on the site and shall forward an abstract of up to 60 words in Portuguese and English, of the article.

They are inserted into the electronic mailing and sent to all members when the BJCVS is available online.

Once accepted for publication, a proof of the edited article (PDF format) will be sent to the corresponding author for assessment and final approval.

whose addresses are available at the ICMJE website (http:// www.icmje.org/). The number should be recorded at the end of the abstract.

The statement of approval of the study by the Ethics and/ or Scientific Institutional Committee must be sent at the time of submission of the manuscript.

Copyright Transfer and Declaration of Conflict of Interest The authors should submit manuscripts at the time of submission, the copyright declaration signed by all authors.

All published manuscripts become the permanent property of the Brazilian Journal of Cardiovascular Surgery and can not be published without the written consent of the editor.

Likewise, for confirmation of the submission of the manuscript a statement of conflict of interest, signed by all authors should be sent.

Both documents, statement of copyright transfer and declaration of conflicts of interest, are standardized and generated by the SGP at the time of submission of the manuscript.

Authoring Criteria & Individual Contribution to Research We suggest the author to adopt the criteria for authorship of the articles according to the recommendations of the International Committee of Medical Journal Editors. Thus, only those people who contributed directly to the intellectual content of the study should be listed as authors.

Authors should meet all the following criteria in order to be able to take public responsibility for the content of the study: 1. have conceived and planned the activities that led to the study or interpreted the data it presents, or both; 2. have written the study or revised successive versions and took part in the review process; 3. have approved the final version.

Language Articles should be written in English, using easily and accurately language and avoiding informality of colloquial language. For those studies whose standard the English language is deemed inappropriate by the Editorial Board, the journal will provide correction. and costs should be assumed by the authors.

Research on human subjects must be submitted to the Ethics Committee of the institution, fulfilling the Declaration of Helsinki 1975, revised in 2008 (World Medical Association, available at: http://www.wma.net/en/30publications/10policies/b3/ 17c.pdf) and Resolution 196/96 of the National Health Council (available at: http://conselho.saude. gov.br/resolucoes/reso_96.htm).

In experimental study involving animals the guidelines established in the Guide for Care and Use of Laboratory Animals should be respected (Institute of Laboratory Animal Resources, National Academy of Sciences, Washington, DC, United States), 1996, and Ethical Principles Animal Experimentation (Brazilian College of Animal Experimentation COBEA, available at: www.cobea.org.br), 1991.

Randomized studies should follow the CONSORT guidelines (available at: www.consort-statement.org/consort-statement).

BJCVS supports policies for the registration of clinical trials of the World Health Organization (WHO) and the International Committee of Medical Journal Editors (ICMJE), recognizing the importance of these initiatives for the registration and international open access dissemination of information on clinical trials. Thus, only be accepted for publication, the clinical research articles that have received an identification number in one of the Clinical Trial Registers validated by the criteria established by WHO and ICMJE,

People who do not meet the above requirements and who had purely technical or of general support participation, should be mentioned in the acknowledgments section.

On submission, the kind of contribution of each author when performing the study and manuscript preparation in the following areas should be made explicit: 1. Study Design 2. Collection, analysis and interpretation of data 3. Drafting of the manuscript Abbreviations and Terminology The use of abbreviations should be minimal. When extensive expressions need to be repeated, it is recommended that their initial capital letters replace them after the first mention. It should be followed by the letters in parentheses. All abbreviations in tables and figures should be defined in the respective legends.

The use of abbreviations in the Summary and Abstract Should be avoided.

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Only the generic name of the drug used should be cited in the study, and we discourage the use of trade names.

BJCVS adopts Universal Official Anatomical Terminology, approved by the International Federation of Anatomists Associations (FIAA).

by the International Committee of Medical Journal Editors (ICMJE, available at: http://www.icmje.org).

References should be identified in the text with Arabic numerals in square brackets, following the order of citation in the text, overwritten. The accuracy of references is the responsibility of the author. If more than two references were cited in sequence, only the first and last must be typed, separated by a dash (Example: [6-9]). In case of alternate citation, all references should be typed, separated by commas (Example: [6,7,9]).

Publications with up to six authors, all authors should be cited; publications with more than six authors, the first 6 followed by the Latin phrase “et al.” should be cited.

Titles of journals should be abbreviated according to the List of Journals Indexed for MEDLINE (available at: http:// www.nlm.gov/tsd/serials/lji.html).

PREPARATION OF MANUSCRIPT Manuscript Sections Title and Authors. The study title, in Portuguese and English, should be concise and informative. The full names of authors, titles and their institutional affiliation should be provided.

Summary and Abstract. The abstract should be structured in four sections: Objective, Methods, Results and Conclusion. The Abstract (literal version, in English, of Abstract in Portuguese) should follow the same structure of the summary into four sections: Objective, Methods, Results and Conclusion. Abbreviations should be avoided. The maximum number of words should follow the recommendations in the table. In the Articles Case Reports and How-I-Do, the abstract should not be structured (informative or free). The Clinical and Surgical Correlations and sections Multimedia exempt summary and abstract.

Descriptors: From three to five descriptors (keywords) should also be included as well as their translation. The descriptors can be found at the website http://decs.bvs.br/, which contains terms in Portuguese, Spanish and English or www.nlm.nih.gov/mesh for terms in English only, or in the respective links available at the submission system of the journal.

Body of the manuscript. Original Articles and Experimental Study should be divided into the following sections: Introduction, Methods, Results, Discussion, Conclusion and Acknowledgements (optional). The Case Reports should be structured in sections: Introduction, Case Report and Discussion, and Clinical-surgical Correlations in Clinical Data, Electrocardiography, Radiogram, Echocardiogram, Diagnosis and Operation. The section Multimedia should have the following sections: Patient Characterization and Description of the Technique. The Review Articles and Special Articles can be structured into sections according the author’s criteria.

Letters to the Editor, in principle, should comment, discuss or criticize articles published in BJCVS, but it can also be about other topics of general interest. It is recommended a maximum size of 1000 words, including references - that should not exceed five, and they may or may not include title.

Whenever possible and appropriate, a response from the authors of the article in question will be published with the letter.

References Models Journal Article Issa M, Avezum A, Dantas DC, Almeida AFS, Souza LCB, Sousa AGMR. Fatores de risco pré, intra e pós-operatórios para mortalidade hospitalar em pacientes submetidos à cirurgia de aorta. Rev Bras Cir Cardiovasc. 2013;28(1):10-21.

Organization as Author Diabetes Prevention Program Research Group. Hypertension, insulin, and proinsulin in participants with impaired glucose tolerance. Hypertension. 2002;40(5):679-86.

No indication of authorship 21st century heart solution may have a sting in the tail.

BMJ. 2002;325(7357):184.

Article electronically published before the print version (“ahead of print”) Atluri P, Goldstone AB, Fairman AS, Macarthur JW, Shudo Y, Cohen JE, et al. Predicting right ventricular failure in the modern, continuous flow left ventricular assist device era.

Ann Thorac Surg. 2013 Jun 21. [Epub ahead of print] Online Journal Article Machado MN, Nakazone MA, Murad-Junior JA, Maia LN. Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center. Rev Bras Cir Cardiovasc [online]. 2013[cited 2013 Jun 25];28(1):29-35. Available from: <http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-76382013000100006&lng=en&nrm=iso> Book Chapter Chai PJ. Intraoperative myocardial protection. In: Mavroudis C, Backer C, eds. Pediatric cardiac surgery. 4th ed.

Chichester: Wiley-Blackwell; 2013. p.214-24.

References The references of the print and electronic records must be standardized according to the Vancouver standard, prepared

Book Cohn LH. Cardiac surgery in the adult. 4th ed. New York: McGraw-Hill;2012. p.1472.

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Thesis Dalva M. Estudo do remodelamento ventricular e dos anéis valvares na cardiomiopatia dilatada: avaliação anátomo-patológica [Tese de doutorado]. São Paulo: Universidade de São Paulo, 2011. 101p.

alphabetically at the bottom, with their forms in full. Likewise, the abbreviations employed in the figures should be explained in the legends.

The figures will be published in color only if the author agrees to bear the cost of printing color pages.

We will only accept images in TIFF or JPEG format with a minimum resolution according to the type of image, both for black and white and for color images.

BJCVS prompts the authors to archive their possession the original images, as if the images submitted online present any impediment to print, we will contact the author to send us these originals.

Legislation Conselho Nacional de Saúde. Resolução n. 196, de 10 de outubro de 1996. Dispõe sobre diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Bioética.

1996;4(2 Supl):15-25.

Other examples of references can be found at: http://www.nlm.nih.gov/bsd/uniform_requirements.html

Limits by Type of Article Aiming at streamlining the space of the journal and allow a higher number of articles per issue, the criteria below outlined should be met according the type of publication. The electronic counting of words should include the home page, abstract, text, references, and figure legends. The titles have a maximum of 100 characters (counting spaces) for Original Articles, Review and Update Articles and Experimental Study and 80 characters (counting spaces) for the other categories.

Tables and Figures Tables and Figures should be numbered according to the order of appearance in the text, with a title and be in separate files. Tables should not contain redundant data already cited in the text. They should be open on the sides and a totally white background.

The abbreviations used in the tables should be listed

Table example: Cardiovascular Risk Factors in Study Group Cardiovascular Risk Factors Hypertension (>140 mm Hg systolic and >90 mm Hg diastolic) Insulin-dependent diabetes mellitus Hypercholesterolemy ( 240 mg/dL) Hypertriglyceridemy ( 250 mg/dL) Cigarette smoking ( 10 cigarettes/d) Previous contraceptive therapy Previous myocardial infarction Family history of cardiovascular disease

Figure example

Number of Patients 11 6 12 6 12 2 11 12

Percentage of Patients 55 30 60 30 60 10 55 60

Checklist before sending the manuscript - Submission letter indicating category of manuscript - Declaration from authors and co-authors saying that they agree with the content of manuscript - Research approved by the Institution Ethics Comitee - Manuscript made out in Word 2007 text processor or superior (format A4); type 12; space 1,5; font Times News Roman; paged

Histogram showing effects of transdermal 17ß-estradiol on left internal mammary artery (LIMA) graft cross-sectional area. It increased by 30% (3.45 ± 1. 2 mm2 versus 4.24 ± 1 mm2; p = 0.039).

- Manuscript within limits adopted by Brazilian Journal of Cardiovascular Surgery for its category

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Maximum number of authors Abstract maximum number of words Maximum number of words Maximum number of references Maximum number of figures and tables Running title

Letters to the Editor

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Meetings Calendar

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MEETINGS CALENDAR - 2015

June

11 to 13 - SVM 26th Annual Scientific Sessions Baltimore, United States Informations: SVM Headquarters Phone: 1 847-480-2961, Ext. 229 E-mail: info@vascularmed.org Site: www.vascularmed.org/AM15

1 and 2 - Anatomy for Electrophysiologists London, United Kingdom Informations: Professor Yen Ho Phone: 44 207 3518751 Fax: 44 207 351 8230 E-mail: morphology@rbht.nhs.uk Site: www.rbht.nhs.uk/cardiacmorphology

17 to 20 - The New Orleans Conference New Orleans, United States Informations: Joseph Basha, CCP Phone: 318-623-0890 E-mail: josephBasha@PerfusionInternational.com Site: http://www.TheNewOrleansConference.com

3 to 6 - ISMICS Annual Scientific Meeting Berlin, Germany Informations: Phone: 978-927-8330 Fax: 978-524-8890 Site: www.ismics.org

18 - Endobronchial Ultrasound Training Course Toronto, Canada Informations: CPD Faculty of Medicine, University of Toronto Phone: 416.978.2719/1.888.512.8173 E-mail: info-SUR1547@cpdtoronto.ca Site: http://www.cpd.utoronto.ca/ebus/

3 to 5 - Hands-on Cardiac Morphology (Summer Edition) London, United Kingdom Informations: Professor Yen Ho Phone: 44 207 3518751 Fax: 44 207 351 8230 E-mail: morphology@rbht.nhs.uk Site: www.rbht.nhs.uk/cardiacmorphology

19 to 21 - Aortic Valve Repair Summit Woluwe-Saint-Lambert, Belgium Informations: Cardiovascular Surgery Thoracic Secretariat Cliniques Universitaires Saint-Luc Phone: 32-2-764 61 07 Fax: 32-2-764 89 60 E-mail: ccv@chir.ucl.ac.be Site: www.valvesymposium.com

03 to 05 - 3rd International Symposium: Perioperative Care for Seniors Prague, Czech Republic Informations: George Silvay, M.D., Ph.D. Phone: 212 241 8346 Fax: 420 284 001 448 E-mail: anesthesiologyforseniors2015@guarant.cz Site: www.anesthesiaforseniors2015.cz

19 to 20 - 41st Annual Toronto Thoracic Surgery Refresher Course Toronto, Canada Informations: CPD Faculty of Medicine, University of Toronto Phone: 416.978.2719 / 1.888.512.8173 E-mail: info-SUR1507@cpdtoronto.ca Site: http://www.torontothoracicrefresher.ca/

8 to 12 - Fundamentals in Cardiac Surgery: Part II Windsor, United Kingdom Informations: EACTS Phone: 212 241 8346 Fax: 420 284 001 448 E-mail: info@eacts.co.uk Site: http://www.eacts.org/academy/2015-programme/

22 and 23 - Perioperative Skills in Cardiac Surgery Windsor, United Kingdom Informations: EACTS Phone: 44 (0)1753 832166 Fax: 44 (0)1753 620407E-mail: info@eacts.co.uk Site: http://www.eacts.org/academy/2015-programme/

10 to 13 - 16th European Congress on Extracorporeal Circulation Technology Krakow, Poland Informations: Judith Moonen Phone: 31104527004 E-mail: office@fecect.org Site: http://www.fecect.org

23 and 24 - Fourth Magna GrĂŚcia AORtic InterventionalÂŽ Symposium: Complex Diseases of Thoracic and ThoracoAbdominal Aorta Catanzaro, Italy Informations: Pasquale Mastroroberto M.D. Program Director MAORI Symposium Phone: 39 0961 3695851 Fax: 3909613647142 E-mail: umgaorta@unicz.it Site: http://maori.unicz.it/

10 to 13 - 11th International Conference on Pediatric Mechanical Circulatory Support Systems & Pediatric Cardiopulmonary Perfusion Verona, Italy Informations: The International Society for Pediatric Mechanical Cardiopulmonary Support Phone: (717) 531-6706 Fax: (717) 531-0355 E-mail: pedsabstracts@hmc.psu.edu Site: http://pennstatehershey.org/web/pedscpb/home

24 to 27 - 11th Global Forum on Humanitarian Medicine in Cardiology & Cardiac Surgery Geneva, Switzerland

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Informations: Mr. Gerhard J. Schneider - GJS Communications Sàrl Phone: +41 79 417 0484 E-mail: info@gjs-swiss.com

Informations: Janie E-mail: info@asaio.com Site: www.asaio.com 26 and 27 - Liverpool Aortic Symposium VI Monarch’s Quay Liverpool, United Kingdom Informations: Lorraine Richardson Phone: 01296 733823 E-mail: lorrainerichardson1@btinternet.com

24 to 26 - EACTA Annual Congress 2015 Gothenburg, Sweden Informations: Ms. Dunja Stauder from vereint Association & Conference Management Ltd. Phone: 43-1-533 35 42 Fax: 43-1-533 35 42 – 59 E-mail: d.stauder@vereint.com Site: http://www.eacta.org/congress-events/future-conference/ eacta-ac-gothenburg-2015/

29 to July 1 - Coronary Surgery Windsor, United Kingdom Informations: Louise McLeod Phone: 01753 832166 Fax: 01753 620407 E-mail: louise.mcleod@eacts.co.uk Site: http://www.eacts.org/academy/courses/coronary-surgery/

24 to 27 - ASAIO 61st Annual Conference Chicago, United States

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The BJCVS/RBCCV made available on Google Play an APP that can be downloaded for free on Smartphones and Tablets (using Android system) and in the APP Store a free device for Iphones and Ipads (IOS system).

Access the full content of BJCVS / RBCCV at any time or place.

Download BJCVS/RBCCV APP using QRCode at the side or at: https://play.google.com/store/apps/details?id=org.bjcvs. journal&hl=pt-BR ANDROID

Download BJCVS/RBCCV APP using QRCode at the side or at: https://itunes.apple.com/us/app/bjcvs/id710774892?mt=8

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