Brazilian Journal of Cardiovascular Surgery 30.3

Page 1

30.3 MAY/JUNE 2015

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY | REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

VOL. 30 Nยบ 3 MAY/JUNE 2015


BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

In 2016, the Brazilian Journal of Cardiovascular Surgery will celebrate 30 years of uninterrupted circulation. We will have many new features for our readers and contributors. ournal of lian J Ca azi

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YEARS 1986 - 2016

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Coming soon!!!




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 • Camila Safadi - Postgraduate in Project Management - PMI S. José do Rio Preto (BRA) - camila@sbccv.org.br • Rosangela Monteiro - PhD São Paulo (BRA) - rosangela.monteiro@incor.usp.br

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

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 de Jesus 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) Nova Lima (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 H. Menkis • Alexandre Visconti 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 Biscegli 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

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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

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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

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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: 1,2,3 2015, 30: 2 [supl]

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

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(*) ASSOCIAÇÃO PAULISTA DE BIBLIOTECÁRIOS. Grupo de Bibliotecários Biomédicos. Normas para catalogação de publicações seriadas nas bibliotecas especializadas. São Paulo, Ed. Polígono, 1972

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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.bjcvs.org www.scielo.br/rbccv


BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

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

Impact Factor: 0.550

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR Braz J Cardiovasc Surg/Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brazil) mai/jun - 2015;30(3):295-408

CONTENTS EDITORIALS

Heart lessons Lições do coração Domingo M. Braile.................................................................................................................................................................................. I

Chronotropic incompetence in Chagas disease: usefulness of dual sensor pacemaker based on volume minute and accelerometer A incompetência cronotrópica em doença de Chagas: utilidade do marcapasso com duplo sensor baseado em minuto volume e acelerômetro José Carlos Pachón ................................................................................................................................................................................III

Grown up congenital hearts Cardiopatias congênitas no adulto Jane Sommerville................................................................................................................................................................................. VII

ORIGINAL ARTICLES 1644 Hydrocortisone supresses inflammatory activity of metalloproteinase - 8 in carotid plaque Hidrocortisona suprime a atividade inflamatória da metaloproteinase - 8 presente na placa carotídea Sthefano Atique Gabriel, Leila Antonangelo, Vera Luiza Capelozzi, Camila Baumann Beteli, Otacílio de Camargo Júnior, José Luis Braga de Aquino, Roberto Augusto Caffaro........................................................................................................................................295 1645 Factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of repair of complete atrioventricular septal defect Fatores associados à insuficiência da valva atrioventricular esquerda nos primeiros 30 dias após correção de defeito de septo atrioventricular total Marcelo Felipe Kozak, Ana Carolina Leiroz Ferreira Botelho Maisano Kozak, Carlos Henrique De Marchi, Sirio Hassem Sobrinho Junior, Ulisses Alexandre Croti, Airton Camacho Moscardini............................................................................................................304 1646 Chronotropic incompetence in Chagas disease: effectiveness of blended sensor (volume/minute and accelerometer) Competência cronotrópica em chagásicos: eficácia do duplo sensor (volume/minuto e acelerômetro) Antonio da Silva Menezes Junior, Aline Pereira da Silva, Giovana Gurian Batista Profahl, Catarine Ottobeli, Jutay Fernando Silva Louzeiro...............................................................................................................................................................................................311 1647 Incidence of postoperative atrial fibrillation in patients undergoing on-pump and off-pump coronary artery bypass grafting Incidência de fibrilação atrial no pós-operatório de pacientes submetidos à cirurgia de revascularização do miocárdio com e sem circulação extracorpórea Milton Sérgio Bohatch Júnior, Paula Dayana Matkovski, Frederico José Di Giovanni, Romero Fenili, Everton Luz Varella, Anderson Dietrich.................................................................................................................................................................................................316 1648 Mitral annulus morphologic and functional analysis using real time tridimensional echocardiography in patients submitted to unsupported mitral valve repair Análise morfológica e funcional do anel mitral com o uso da ecocardiografia tridimensional em tempo real em indivíduos submetidos à plástica mitral sem o uso de anéis protéticos Marco Antônio Vieira Guedes, Pablo Maria Alberto Pomerantzeff, Carlos Manuel de Almeida Brandão, Marcelo Luiz Campos Vieira, Flávio Tarasoutchi, Pablo da Cunha Spinola, Fábio Biscegli Jatene...................................................................................................325 1649 Impact of body mass index on outcome in patients undergoing coronary artery bypass grafting and/or valve replacement surgery Impacto do índice de massa corporal no desfecho de pacientes submetidos às cirurgias de revascularização do miocárdio e/ou troca valvar Vinícius Eduardo Araújo Costa, Silvia Marinho Ferolla, Tâmara Oliveira dos Reis, Renato Rocha Rabello, Eduardo Augusto Victor Rocha, Célia Maria Ferreira Couto, José Carlos Ferreira Couto, Alduir Bento...................................................................................335


1650 Surgery of the aortic root: should we go for the valve-sparing root reconstruction or the composite graft-valve replacement is still the first choice of treatment for these patients? Cirurgia da raiz da aorta: deve-se preservar a valva aórtica ou a operação com o tubo valvulado ainda é a primeira opção de tratamento para esses pacientes? Fernando de Azevedo Lamana, Ricardo Ribeiro Dias, Jose Augusto Duncan, Leandro Batisti de Faria, Luiz Marcelo Sa Malbouisson, Luciano de Figueiredo Borges, Charles Mady, Fábio Biscegli Jatene.................................................................................................343 1651 Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion Efeito do pós-condicionamento isquêmico remoto nas alterações inflamatórias do parênquima pulmonar de ratos submetidos à isquemia e reperfusão Rafael Cantero Dorsa, José Carlos Dorsa Vieira Pontes, Andréia Conceição Brochado Antoniolli, Guilherme Viotto Rodrigues da Silva, Ricardo Adala Benfatti, Carlos Henrique Marques dos Santos, Elenir Rose Cury Pontes, José Anderson Souza Goldiano..............353 1652 Impact of respiratory infection in the results of cardiac surgery in a tertiary hospital in Brazil Impacto da infecção respiratória nos resultados da cirurgia cardíaca em hospital terciário no Brasil Isaac Newton Guimarães Andrade, Diego Torres Aladin de Araújo, Fernando Ribeiro de Moraes Neto...........................................360 1653 Risk factors for perioperative ischemic stroke in cardiac surgery Fatores de risco para acidente vascular cerebral isquêmico no perioperatório de cirurgia cardíaca Mário Augusto Cray da Costa, Maria Fernanda Gauer, Ricardo Zaneti Gomes, Marcelo Derbli Schafranski...................................365 SPECIAL ARTICLE 1654 Recommendations for starting a grown up congenital heart disease (GUCH) unit Recomendações para a implantação de uma Unidade de Cardiopatias Congênitas no Adulto Fernando Tadeu Vasconcelos Amaral, Paulo Henrique Manso, André Schmidt, Ricardo Nilson Sgarbieri, Walter Villela de Andrade Vicente, Clovis Carbone Junior, Jane Somerville................................................................................................................................373 REVIEW ARTICLES 1655 MicroRNAs and mesenchymal stem cells: hope for pulmonary hypertension MicroRNAs e células-tronco mesenquimais: esperança para a hipertensão pulmonar Zhaowei Zhu, Zhenfei Fang, Xinqun Hu, Shenghua Zhou..................................................................................................................380 1656 Cardiac myxoma in pregnancy: a comprehensive review Mixoma cardíaco na gravidez: revisão abrangente Shi-Min Yuan.......................................................................................................................................................................................386 MEMORIAL 1657 Dr. Edgard San Juan: a feminine look Prof. Dr. Edgard San Juan: um olhar feminino Vera Lucia Amaral Molari Piccardi......................................................................................................................................................395 Reviewers BJCVS 30.3.......................................................................................................................................................................401 Information for authors.....................................................................................................................................................................402 Meetings Calendar.............................................................................................................................................................................407

Printed in Brazil


Editorial

Heart lessons Lições do coração

Domingo M. Braile1

DOI: 10.5935/1678-9741.20150050

T

he last 12 months have been of deep losses for the Brazilian cardiovascular surgery. Distinguished and competent professionals, fundamental to the consolidation and advancement of the specialty in our country have left us, after serving brilliantly their career in this world. On July 10, 2014, Dr. Geraldo Verginelli died. On November 12, 2014, Dr. Raul Correia Rabelo left our living and just two days later, we had the death of Dr. Adib Domingos Jatene. In 2015, we had three more losses: on February 21, Dr. Edgar San Juan died (see Memorial, written by Dr. Vera Piccardi on page 395), on May 26, Dr. Marcos Vinicius Ferraz Arruda has lost the battle to cancer, the same occurred on the 5th of July with Dr. João Alberto Roso. But we can not just lament these happenings. We must look into the achievements of these cardiac surgeons, draw lessons from their teachings and apply them in our day-to-day, not only in the professional field, but also in personal life. Thanks to the dedication of the pioneers in times when our specialty still crawled, without stopping, let alone giving up in the face of obstacles, making their work and creativity and managing to overcome difficulties, it was possible to put the Brazilian cardiac surgery in the prominent place it occupies today in the world. Their example will be forever and the best way to honor them is with great dedication, whether at work, whether in research, so that the problems we face today with the crisis befalling the country and affects everyone, decreasing financial resources, do not take the courage nor the will to fulfill our role as best as possible. And these teachers gave us real lessons of the heart that we must always have them saved, especially in times where the situation appears adverse. Dr. Adib said: “I am against this story to tell: - I don’t do because they don’t give me conditions. If you are able to do you create the conditions.” We can learn from these true heart lessons! Brazilian Journal of Cardiovascular Surgery (BJCVS) emerged from this dream, and if today is an internationally recognized journal, it owes much to the pioneers. In 2016, we will complete 30 years of uninterrupted movement and we intend to celebrate this important date with a series of events

and activities, held in conjunction with the Brazilian Society of Cardiovascular Surgery (BSCVS), which we’ll disclose in the coming issues. We have been constantly concerned about the BJCVS meet the requirements of databases. An example was the language shift to English and increasing the number of issues of 4 to 6 per year, adoption of standard XML and DOI, among other examples. In July, at the suggestion of Scielo, we will adopt the CC-BY license instead of the CC-BY-NC, previously used. This maximizes the open access and dissemination of science, ensuring that the credit of the authors is properly attributed[1]. If any author who has submitted their study to the BJCVS understands that such change generates conflict, I ask to contact the Editorial Board. ABEC course In order to keep us updated regarding the news of scientific communication, I participated, along with the Executive Editor, Ricardo Brandau, and the Editorial Assistant Camila Safadi of the XIII Scientific Publishing Course, promoted by the Brazilian Association of Scientific Editors (ABEC) of 2527 June in Goiânia-GO. The topics discussed were of interest not only of publishers but also of authors and reviewers. The quality of the studies and the concern with ethics (which involves the issue of plagiarism) were issues largely discussed. The speakers emphasized the increasing concern about the quality, which should be of authors, reviewers and editors, permeating the entire process of execution and submission of a manuscript from the survey data, text writing with accuracy, the properly review and approval, publishing and making available by the journal. The role of all involved in this process is important. I highlight the reviewer’s role, whose observations for the study to be improved are essential so that a quality science is published. At the meeting of ABEC ways to reward the work of revision were discussed. While the CAPES does not accept the suggestion to “reward” those who made a minimum number of evaluations score, each journal has sought alternatives. The BJCVS publishes every edition the list of reviewers who evaluated

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the studies that are part of that issue (in this issue the listing is on page 401). Also, after each review, the system generates a certificate that can be printed or stored electronically.

prevention of misconduct, mechanisms should be created to ensure intellectual property. BJCVS reaffirms its repudiation of political plagiarism which appears in Rules for Authors (http://www.rbccv.org.br/ page/6) - and misconduct and will continue to support actions aiming to combat this nefarious practice in science.

Checking of manuscripts Also in relation to the manuscripts, the importance of the Letter to the Editor was discussed, written in the submission of the study. Without ceasing to be a succinct, it should contain a brief presentation of the study. This will facilitate the Editor’s decision-making with regard to the choice of reviewers accustomed to the topic, streamlining the flow. I would also like to request that the authors, when submitting the manuscript make a prior review not only of the content and form, but also the other information contained in the study, such as author names, name of institution, address, etc. There have been cases of errors in these items, which are only perceived by those who submitted after approval and even publication of the article. In addition to the time spent to send the correction to the site, the biggest problem in the case of wrong names, is the need to request the correction by the Crossref so that the DOI does not bring misinformation and to put an Erratum. I emphasize the need for collaboration for these details either at the time of submission as in checking the PDF before publication, so that these problems are avoided.

CME The articles with CME in this issue are: “Hydrocortisone supresses inflammatory activity of metalloproteinase - 8 in carotid plaque” (page 295), “Chronotropic incompetence in Chagas disease: effectiveness of blended sensor (volume/ minute and accelerometer)” (page 311), “Mitral annulus morphologic and functional analysis using real time tridimensional echocardiography in patients submitted to unsupported mitral valve repair” (page 325), and “Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion” (page 353). I highlight, as always, the importance of CME to update knowledge, noting that the test is worth 0.5 linear points in the SBCCV Proof of Title. My warmest regards,

Globalization x misconduct Another aspect that has been addressed in discussions of scientific publications and was discussed in Goiania is the misconduct issue, which involves several nuances, such as fraud and plagiarism. As much care that publishers take, either through a careful reading of the manuscript or using programs that detect plagiarism, there is always the risk, and if the article is published, it brings many problems to the authors, the editor and the journal. The Internet, which cut distances, facilitated scientific communication and, in recent years, the number of article submissions had a big jump, as well as the requirements of the institutions and development agencies. This creates a true “race to publish” in which ethical principles, which should guide the science, are not always respected. In 2011, the article “Pressure to Publish How Globalization and Technology are Increasing Misconduct in Scholarly Research”[2], a report (“white paper”) available from iThenticated, addressed the issue, showing the problems and concluded that it is necessary that beyond the

Domingo M Braile 1 Editor-in-Chief BJVCS/RBCCV

REFERENCES 1. SciELO adota CC-BY como atribuição principal de Acesso Aberto. SciELO em Perspectiva. [cited 2015 Jul 2]. Available from: http://blog.scielo.org/blog/2015/06/19/scielo-adota-cc-bycomo-atribuicao-principal-de-acesso-aberto/ 2. iThenticate. Pressure to publish: How globalization and technology are increasing misconduct in scholarly research [cited 2015 Jul 3]. Available from: http://cdn2.hubspot.net/hub/92785/ file-5414706-pdf/media/pressure-publish-free-white-paper.pdf

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Editorial

Chronotropic incompetence in Chagas disease: usefulness of dual sensor pacemaker based on volume minute and accelerometer A incompetência cronotrópica em doença de Chagas: utilidade do marcapasso com duplo sensor baseado em minuto volume e acelerômetro

José Carlos Pachón1, MD, PhD, CCDS DOI 10.5935/1678-9741.20150011

Chagas disease or American trypanosomiasis is a chronic parasitosis affecting most Latin American countries where an estimated 8 million people are infected. Current assessments have shown that even in the United States there is a total of 300,000 infected individuals, essentially all of whom are immigrants from the endemic countries. It is a tropical parasitic disease caused by the protozoan Trypanosoma cruzi that is transmitted to humans by blood-sucking triatomine bugs, known as “Kissing Bug”, and via blood transfusion, mother-to-baby or organ transplant. This protozoan causes an acute systemic inflammatory illness that usually progresses to chronic myocarditis and autonomic disease leading to electrical and/or severe dilated cardiomyopathy. Myocardial damage is disseminated throughout the heart. The outcome may present cardiac arrhythmias, life-threatening heart failure, thromboembolism, stroke and sudden death. The latter is sometimes the first manifestation of the disease, even in the structurally normal heart (latent phase). In many patients, a chronic immunologic process may feed the inflammatory phenomenon even without the parasite. As a rule, extensive involvement of the autonomic nervous system and the cardiac conduction system results in a huge variety of supraventricular and ventricular cardiac arrhythmias. As a corollary, in approximately 60% of cases, the sinus node is injured, developing a more or less extensive sick sinus syndrome. Additionally, many patients have to be treated for heart failure and cardiac arrhythmias. Thanks to a coordinated multi-country program in the Southern Cone countries, the transmission of Chagas disease by vectors and via blood transfusion was interrupted in Uruguay in 1997, in Chile in 1999 and Brazil in 2006. For this reason, the incidence of new infections by T. cruzi across the

South American continent has decreased by 70%. The natural course of the disease and the very common pharmacological requirement for treating numerous arrhythmias cause a high sick sinus node syndrome prevalence. One frequent expression of this condition is the “Chronotropic Incompetence” (CI). READ ARTICLE ON PAGE 311

Heart Rate Contribution to Exercise Increasing heart rate during exercise is necessary for Chagas disease patients not only to adjust cardiac output but also to blunt the excessive sympathetic tone increase. The ability to perform physical work is enabled by a growth in oxygen uptake (VO2). During maximal aerobic exercise in a healthy person, VO2 increases approximately 4-fold, that may be composed of 2.2-fold increase in heart rate, 0.3-fold increase in stroke volume and a 1.5-fold increase in the arteriovenous oxygen difference. These data indicate that the heart rate increase is the most important contributor to the ability to perform sustained aerobic exercise. Therefore, it is well known that CI can be one important cause of a symptomatic exercise intolerance. Chronotropic Incompetence Definition CI may be defined as the inability of the heart to increase its rate in proportion to physical activity or metabolic demand. Beyond Chagas disease, it is very common in many other cardiovascular illnesses and pharmacological interventions. It may produce exercise intolerance that causes symptoms and impairs quality of life. In addition, it is an independent predictor of major adverse cardiovascular events and overall mortality[1,2]. Nevertheless, the significance of CI is underappreciated, and it is often disregarded in clinical practice. In part, this may be due to multiple definitions, the confusing effects of aging, cardiopathy and medications, and the need for exercise testing for a conclusive diagnosis. In Chagas disease, CI has an

International Board Heart Rhythm Examiners Certified Cardiac Device Specialist. Director of Pacemaker Service of Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil. E-mail: pachon@usp.br 1

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additional risk as it may prone the patient to present a high and disproportional sympathetic tone during physical effort, as there is a deficient and delayed heart rate response. The association of high sympathetic tone with a marked electrical ventricular instability typical of these patients is one important additional sudden death risk. For this reason, sudden death occurrence during physical effort is well known in these cases. CI must be considered as potentially treatable, and its management can lead to a significant improvement in exercise tolerance, quality of life and complex arrhythmia risk reduction. Technically, CI is considered when the heart rate fails to reach 85%, 80%, or, less commonly, 70% of the age-predicted maximum heart rate (APMHR), usually based on the 220 – age, obtained during a controlled incremental exercise test[3] or failure to attain 80% of heart rate reserve (HR reserve= age-predicted maximal heart rate – resting HR) + resting HR[4]. Nevertheless, the lack of a consistent methodology and standardized criteria to determine CI probably justifies the high range of prevalence described in the literature, 9% to 89%, mainly in pacemaker patients[5]. Despite being an exception as an isolated pacemaker indication, CI must be prevented and treated in all pacemaker’s patients by programming the biosensor. The European Society of Cardiology pacemaker guidelines published in 2013 included CI as one isolated, very specific indication for pacemaker: “CI after heart transplantation: Cardiac pacing should be considered for CI impairing the quality of life late in the post-transplant period” (Class IIa, Level of Evidence C). In addition, they recommend that rate response features should be adopted in pacemaker patients with CI, especially if young and physically active, (Class IIa, Level of Evidence C)[6]. Despite being frequently underdiagnosed in clinical practice, this condition must deserve specific attention in Chagas disease patients with pacemakers, defibrillators[7] or resynchronizators[8], each of one with very peculiar considerations.

response to dobutamine infusion, CI and a biphasic inotropic response (i.e., similar to that seen in ischemic myocardium) to dobutamine despite the normal angiographic appearance of the coronary arteries[11]. Rate Response Pacemaker When the sinus node is normal, it is the best sensor and the DDD pacemaker would not need a biosensor. However, even in this situation the biosensor is necessary to inform the system about physical activity and to manage the heart rate above the upper-track limit. The sleep-rate, for example, must be turned-off in case walking is detected. In addition, this resource may contribute to discriminating pathological and functional tachycardia in defibrillators. When patients with complete AV block exercise, the sinus rate is significantly higher with VVI pacing than during dual chamber or VVIR modes, a response possibly reflecting the increased activity of the sympathetic nervous system when pacing is set to VVI mode[12,13]. This behavior strengthens the need for sensor programming and a good sensor tuning in Chagas disease patients, as the increased sympathetic tone is an additional risk factor for severe ventricular arrhythmias and sudden death in this pathology. Indeed, coronary sinus norepinephrine is higher in patients with VVI pacemaker during exercise. The increase in catecholamine on exercise during VVI pacing is likely to be related to the need for improving contractility and, consequently, cardiac output to compensate for the lack of rate response. This enhanced cardiac sympathetic activity may eventually produce an adverse effect on LV function, with the possible development of congestive heart failure and arrhythmias. On the other hand, an adequate chronotropic response that provides an appropriate increase in cardiac output during physical activity will surely reduce the risk of these arrhythmias. In addition, preliminary data suggest that rate adaptive AAIR and DDDR modes may be more efficacious in preventing atrial arrhythmias than their non-rate adaptive counterparts in Sick Sinus Syndrome[14]. DDDR pacemakers may prevent arrhythmias by eliminating the relative bradycardia noted during exercise in patients with non-adaptive devices, when excessive catecholamine release may increase the likelihood of atrial arrhythmias.

Chronotropic Incompetence in Chagas Disease As the sinus node is usually involved in the pathological process, this condition is very frequent in Chagas disease, even in the latent phase when the heart may be apparently normal. The inflammatory and fibrotic processes reduce the number of “P” cells, destroy the innervation and cause significant barriers to sinus node impulse progression. In addition, sera of patients with Chagas disease contain autoantibodies against both beta1 and beta2 adrenergic receptor subtypes with a theoretical gradual blockade of myocardial neurotransmitter receptors impairing both inotropic and chronotropic effects[9]. More recently, it has been shown that IgG fractions of sera from patients with chronic Chagas disease can decrease the HR of isolated rabbit hearts[10]. Patients in early stages (only serologic evidence of Chagas disease, but without segmental LV dysfunction) as well as those with baseline LV segmental wall motion abnormalities exhibit blunted myocardial contractile

Sensors for Rate Modulation The most common are the sensor based on body mechanical vibration induced by movement and physical activity and the sensor that detects respiratory activity. Additionally, many other types of sensors have been tested and different parameters have been investigated to control the pacemaker rate: central venous temperature, changes of the right ventricular inotropism that may change impedance during the cardiac cycle (CLS, closed loop stimulation), QT interval, venous pH, oxygen saturation, stroke volume, minute ventilation, peak endocardial acceleration, gravitational sensor, etc.

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Dual Sensor Because none of the currently available sensors allow a response equal to the sinus node, there has been an effort of the cardiac pacing industry to associate two complementary sensors to yield a more physiological response. There are systems commercially available with the following associations: activity sensor and respiratory volume minute sensor (Medtronic, Boston and ELA Medical), activity sensor and QT sensor (Vitatron), activity and myocardial contractility sensor (Biotronik) and PEA with activity (Sorin). The combination most commonly used is the activity or accelerometer sensor with the respiratory volume minute sensor that brings the fast response of the first to the proportionality and specificity of the second resulting in a more physiological heart rate modulation. The goal is to harness the advantages and compensate for the shortcomings of each system[15].

There is a great range of advantages and disadvantages in these systems with respect to specificity and response proportionality, energy consumption, effort forecasting, ease of programming, auto-tuning, need for special leads, external interference susceptibility, influence of associated diseases and age limitation. Single sensor technology The most used single sensor is based on a piezoelectric crystal or an accelerometer that senses mechanical activity. The first increases its electrical vibration in response to body mechanical activity, and the second is inertial and responds to the movement direction. Despite a quick response, it is not as specific as responding to vibrations related or not to physical activity and it has an inadequate response to isometric efforts and intellectual activity. In addition, its post-exercise frequency decay is not proportional to the duration of the effort. Nevertheless, its major advantages are simplicity and low power consumption. The QT interval biosensor is based on the fact that this parameter shortens with the increase in metabolic activity, being almost always quite physiological. However, in the case of low T wave amplitude, it may have a reading error, it cannot be used in the atrium and it suffers interference of drugs that prolong or shortens the QT interval, as well as in pathological conditions such as ischemia and infarction, which can lead to an undesirable increase in heart rate. The central venous blood temperature sensor is grounded on the premise that there is a temperature increase during physical effort related to muscle heat production and augmented circulation. However, in the early stages a drop in temperature of the central venous blood may occur, delaying the response. Moreover, it demands a particular lead that reduces their use, especially in cases of generator exchange when the patient has an implanted conventional lead. The respiratory sensor is based on measurements of changes in thoracic bioimpedance as a result of changes in the quantity of air in the chest. It was improved by using the minute ventilation (MV) that takes into account both the respiratory rate and the tidal volume. It holds the advantage of using a conventional bipolar lead that can be implanted in the atrium or the ventricle. It is quite physiological given its high proportionality with the metabolic increase, independent of the quantity of mechanical action. Accordingly, it may change with mental activity and emotions. The post-exercise heart rate decay keeps great proportion to the intensity and duration of the activity performed. A disadvantage is the higher power consumption compared to the piezoelectric crystal sensor and the impossibility of using it in patients with lung diseases and pediatric age. Several other sensors that rely on the need for special leads, such as those based on O2 saturation, pH, PEA (peak endocardial acceleration that means tip movement of the ventricular lead) have been less applied because of the complexity of the lead, the impossibility of using in generator exchange in patients with old leads and the non-applicability in the atrial chambers.

Sensor in Chagas Disease As CI is highly prevalent in this pathology, it is very important to program the pacemaker with this resource. Similar to the long QT syndrome, it would always be desirable that the sensor slightly anticipates the chronotropic needs of the patient by reducing sympathetic stimulation, since in these cases the catecholamines have an unwanted effect on the electrical stability of the myocardium. Especially in this condition, the well-adjusted sensor could have an effect enhancing the beta-blockers action by causing a reflex reduction in sympathetic tone. It can therefore be concluded that the dual sensor, allowing more fine-tuning and more physiologic heart rate, is highly desirable in this pathology. It is also highly recommended that in such cases a detailed program of the sensor be carried out, through exercise testing and/or Holter, in order to obtain the maximum arrhythmia suppression with proper adjustment of the heart rate response, while on the other hand, it is crucial to avoid ventricular dyssynchrony caused by excessive ventricular pacing due to a high biosensor driven heart rate. However, there are very few scientific studies addressing this issue. In addition, there are rare randomized studies comparing different frequency response modes in these patients. In this sense, it is appropriate to consider the results of the DUSISLOG study. DUSISLOG Study The Dual Sensor vs. Single Sensor comparison using patient activity LOGbook (DUSISLOG) study was designed to find if there is any benefit from using dual-sensor for rate response in pacemaker patients. It is a two arms multicenter, prospective, randomized study enrolling 105 patients who received a rate-responsive pacemaker (Insignia, Guidant Corp.). After 1 month of DDD pacing at 60 ppm lower rate, a single sensor (Activity sensor or Minute Ventilation, randomized) was activated for 3 months at the manufacturer’s nominal settings, followed by a 3-month period with dual sensors

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optimized for automatic response. During the last month of each period, the following data concerning patient physical activity were retrieved from pacemaker diagnostics Log: mean percentage of physical activity, mean intensity of activity. Quality of life (QoL) scores and 6-minute walk test (WT) were also recorded. A total of 105 patients achieved the enrollment criteria and completed all the specified follow-up program. WT, QoL, and patient activity significantly improved after activation of a single sensor and there was similar symptomatic benefit by using Activity or Minute Ventilation. However, no additional benefit was found using dual sensor. In spite of this, one important information came from the subgroup analysis. The patients were divided into three subgroups according to the degree of atrial CI, based on their percentage of sensed intrinsic atrial activity, calculated as % of atrial sense (AS) at 1 month follow-up (AS%=0, AS% <10, and AS% >10). A significant increase in the distance covered with the 6-mintue WT, QoL, and percentage of atrial pacing over 70 ppm was observed for single sensor, with an additional advantage of dual sensor, only in patients with major atrial chronotropic disease defined as the absence of intrinsic atrial activity over 60 bpm (0% AS%), which accounted for 17% of the enrolled population. Patients with moderate CI (0–10% AS%) showed only a trend toward symptomatic benefit from rate-responsive pacing, whereas those with mild or no CI (>10% AS%) had less or no benefit. Based on these data, it is worth to conclude that the rate responsive pacemaker with at least one sensor in Chagas disease is highly desirable, being the dual-sensor greatly recommended for the cases presenting severe CI.

5. Gwinn N, Leman R, Kratz J, White JK, Zille MR, Gillette P. Chronotropic incompetence: a common and progressive finding in pacemaker patients. Am Heart J. 1992;123(5):1216-9. 6. European Society of Cardiology (ESC); European Heart Rhythm Association (EHRA), Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace. 2013;15(8):1070-118. 7. Melzer C, Böhm M, Bondke HJ, Combs W, Baumann G, Theres H. Chronotropic incompetence in patients with an implantable cardioverter defibrillator: prevalence and predicting factors. Pacing Clin Electrophysiol. 2005;28(10):1025-31. 8. Sims DB, Mignatti A, Colombo PC, Uriel N, Garcia LI, Ehlert FA, et al. Rate responsive pacing using cardiac resynchronization therapy in patients with chronotropic incompetence and chronic heart failure. Europace. 2011;13(10):1459-63. 9. Rosenbaum MB, Chiale PA, Schejtman D, Levin M, Elizari MV. Antibodies to beta-adrenergic receptors disclosing agonist-like properties in idiopathic dilated cardiomyopathy and Chagas’ heart disease. J Cardiovasc Electrophysiol. 1994;5(4):367-75. 10. de Oliveira SF, Pedrosa RC, Nascimento JH, Campos de Carvalho AC, Masuda MO. Sera from chronic chagasic patients with complex cardiac arrhythmias depress electrogenesis and conduction in isolated rabbit hearts. Circulation. 1997;96(6):2031-7. 11. Acquatella H, Pérez JE, Condado JA, Sánchez I. Limited myocardial contractile reserve and chronotropic incompetence in patients with chronic Chagas’ disease: assessment by dobutamine stress echocardiography. J Am Coll Cardiol. 1999;33(2):522-9.

REFERENCES 1. Dresing TJ, Blackstone EH, Pashkow FJ, Snader CE, Marwick TH, Lauer MS. Usefulness of impaired chronotropic response to exercise as a predictor of mortality, independent of the severity of coronary artery disease. Am J Cardiol. 2000;86(6):602-9.

12. Pehrsson SK, Hjemdhal P, Nordlander R, Aström H. A comparison of sympathoadrenal activity and cardiac performance at rest and during exercise in patients with ventricular demand or atrial synchronous pacing. Br Heart J. 1988;60(3):212-20.

2. Myers J, Tan SY, Abella J, Aleti V, Froelicher VF. Comparison of the chronotropic response to exercise and heart rate recovery in predicting cardiovascular mortality. Eur J Cardiovasc Prev Rehabil. 2007;14(2):215-21.

13. Hedman A, Hjemdahl P, Nordlander R, Aström H. Effects of mental and physical stress on central hemodynamics and cardiac sympathetic nerve activity during QT interval-sensing- rate responsive and fixed-rate ventricular inhibited pacing. Eur Heart J 1990;11(10):903-15.

3. Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment. Cardiol Clin. 1992;10(4):705-17.

14. Marinoni GP, Gundari F, Orlando F. Can the DDDR mode improve the cardiac performance and have an antiarrhrytmic effect in patients with a chronotropic failure. Eur J Cardiac Pacing Electrophysiol. 1992;2:51(Abstract).

4. Azarbal B, Hayes SW, Lewin HC, Hachamovitch R, Cohen I, Berman DS. The incremental prognostic value of percentage of heart rate reserve achieved over myocardial perfusion singlephoton emission computed tomography in the prediction of cardiac death and all-cause mortality: superiority over 85% of maximal age-predicted heart rate. J Am Coll Cardiol. 2004;44(2):423-30.

15. Clémenty J, Barold SS, Garrigue S, Shah DC, Jaïs P, Le Métayer P, et al. Clinical significance of multiple sensor options: rate response optimization, sensor blending, and trending. Am J Cardiol. 1999;83(5B):166D-171D.

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Editorial

Grown up congenital hearts Cardiopatias congênitas no adulto

Jane Sommerville1, MD

DOI: 10.5935/1678-9741.20150041

The exploits and successes of cardiac surgery for congenital heart defects over six decades has created a new population of cardiac patients – the Grown Up Congenital Hearts (GUCHs) which has many names in different countries. From successful cardiac surgery comes the refinement of other specialties – paediatric cardiology, anaesthesia, intensive care, sophisticated imaging, who looks after the GUCHs, and where are the optimal medical services for the adults (adolescents) with congenital heart diseases. At least 90% of children born with such defects can be expected to reach adulthood in regions/ countries or areas where there has been established good paediatric cardiac surgery. Indeed most lesions now can be treated with success and survival. The notion of “total correction” should be dispelled as a dream of surgeons for many years. There are conditions such as closure of the persistent duct, certain ventricular septal defects and a few other simple defects which can be considered as cured of the need for future medical care. Most long-term survivors with congenital heart disease, particularly the complex, need expert medical care for life. Thus their needs must be recognised with provision of funded and staffed specialised units with necessary expertise, taking on the role of education of the problem in the region. Not every region needs a unit but with support services, research and provision of the various levels of needs of the patients. Numbers of units depend on the size and geographical features of the country or area as well as the size of the GUCH population. Too many units lead to loss of expertise and education by diluting numbers. No one in any country knows the true numbers of GUCH patients. Predictions are not true anywhere. John Keith in the late 1950s recognised the need to have a service as his children survived, and so sent John Evans to the Toronto General Hospital to establish such a service, separate from paediatric cardiology in the Children’s

Hospital. So wise. In actual fact not much was established and the concerned doctor left to be a business magnate. Joe Perloff, influenced deeply by Paul Wood in his London training, fascinated by congenital heart disease, recognised GUCH needs in Los Angeles, established with difficult a service as did the National Heart Hospital in London with the opening of an adolescent cardiac unit in 1975 receiving the patients from Dr Richard Bonham-Carter, operated by Dr David Waterston in Hospital for Sick Children (Great Ormond Street). Services grew into Grown Up Congenital Heart unit – called after Paul Wood and rebuilt following the destruction when the Heart Hospital merged into the Brompton Hospital. READ ARTICLE ON PAGE 373

Establishing such a unit has always been difficult for different reasons in different countries and remains so. It was facilitated by having a funded Health Service. It was easy in Malta because the principal doctors wanted it. It remains difficult in the USA where provision is only in a few isolated units. Recognition even that there is this sub specialty of cardiology has been nearly impossible in many countries; even when they have good paediatric cardiac services or because they have, has helped GUCHs since the paediatric cardiologists frequently reserve a parental right to continue looking after their patients into adulthood. It cannot be imagined that paediatricians would consider that an adult trained consultant could have a right to care for an infant. Most would not wish to do so in any specialty, so why should the paediatricians consider their ability (right) to care for adults, because they know the anatomy. In Canada, Japan and a number of European countries including the United Kingdom, it has been recognised that there needs to be a national service controlled and funded for the specialty of Grown Ups with congenital heart abnormalities as part of adult cardiology which is useful as many will acquire the cardiovascular diseases of the population.

Emeritus Professor of Cardiology, Imperial College, London, England.

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

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Gabriel SA, ORIGINAL et al. - Hydrocortisone ARTICLEsupresses inflammatory activity of metalloproteinase - 8 in carotid plaque

Hydrocortisone supresses inflammatory activity of metalloproteinase - 8 in carotid plaque Hidrocortisona suprime a atividade inflamatória da metaloproteinase - 8 presente na placa carotídea

Sthefano Atique Gabriel1, MD, PhD; Leila Antonangelo2, MD, PhD; Vera Luiza Capelozzi3, MD, PhD; Camila Baumann Beteli4, MD, PhD; Otacílio de Camargo Júnior1, MD, PhD; José Luis Braga de Aquino1, MD, PhD; Roberto Augusto Caffaro5, MD, PhD

DOI 10.5935/1678-9741.20150034

RBCCV 44205-1644

Abstract Objective: Matrix metalloproteinases are inflammatory biomarkers involved in carotid plaque instability. Our objective was to analyze the inflammatory activity of plasma and carotid plaque MMP-8 and MMP-9 after intravenous administration of hydrocortisone. Methods: The study included 22 patients with stenosis ≥ 70% in the carotid artery (11 symptomatic and 11 asymptomatic) who underwent carotid endarterectomy. The patients were divided into two groups: Control Group - hydrocortisone was not administered, and Group 1 - 500 mg intravenous hydrocortisone was administered during anesthetic induction. Plasma levels of MMP-8 and MMP-9 were measured preoperatively (24 hours before carotid endarterectomy) and at 1 hour, 6 hours and 24 hours after carotid endarterectomy. In carotid plaque, tissue levels of MMP-8 and MMP-9 were measured. Results: Group 1 showed increased serum levels of MMP8 (994.28 pg/ml and 408.54 pg/ml, respectively; P=0.045) and MMP-9 (106,656.34 and 42,807.69 respectively; P=0.014) at 1 hour after carotid endarterectomy compared to the control

group. Symptomatic patients in Group 1 exhibited lower tissue concentration of MMP-8 in comparison to the control group (143.89 pg/ml and 1317.36 respectively; P=0.003). There was a correlation between preoperative MMP-9 levels and tissue concentrations of MMP-8 (P=0.042) and MMP-9 (P=0.019) between symptomatic patients in the control group. Conclusion: Hydrocortisone reduces the concentration of MMP8 in carotid plaque, especially in symptomatic patients. There was an association between systemic and tissue inflammation.

Faculdade de Medicina da Pontifícia Universidade Católica de Campinas (PUC-Campinas), Campinas, SP, Brazil. 2 Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil and Departamento de Citologia do Laboratório Central do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil. 3 Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil and Departamento de Patologia da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil. 4 Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP, Brazil. 5 Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

This study was carried out at the Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo (FCMSCSP), São Paulo, SP, Brazil.

Descriptores: Hydrocortisone. Carotid Stenosis. Inflammation. Endarterectomy, Carotid. Matrix Metalloproteinases. Resumo Objetivo: As metaloproteinases são biomarcadores inflamatórios envolvidos na instabilidade da placa carotídea. O objetivo deste estudo foi analisar a atividade inflamatória da MMP-8 e MMP-9 plasmática e presente na placa carotídea, após administração intravenosa de hidrocortisona.

1

No financial support. Correspondence address: Sthefano Atique Gabriel R. Dr. Cesário Mota Júnior, 112 - São Paulo, SP, Brazil – Zip Code: 01221-020 E-mail: sthefanogabriel@yahoo.com.br Article received on February 19th, 2015 Article accepted on May 12th, 2015

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Gabriel SA, et al. - Hydrocortisone supresses inflammatory activity of metalloproteinase - 8 in carotid plaque

Resultados: O grupo 1 exibiu elevação dos níveis séricos da MMP-8 (994,28 pg/ml e 408,54 pg/ml, respectivamente; P=0.045) e MMP-9 (106.656,34 e 42.807,69, respectivamente; P=0.014) em 1 hora após a endarterectomia de artéria carótida, em relação ao grupo controle. Os pacientes sintomáticos do grupo 1 exibiram menor concentração tecidual de MMP-8, em relação ao grupo controle (143,89 pg/ml e 1317,36, respectivamente; P=0.003). Houve correlação entre os níveis pré-operatórios de MMP-9 e as concentrações teciduais de MMP-8 (P=0.042) e MMP-9 (P=0.019) entre os pacientes sintomáticos do grupo controle. Conclusão: A hidrocortisona reduz a concentração de MMP-8 na placa carotídea, em especial nos pacientes sintomáticos. Houve associação entre a inflamação sistêmica e a tecidual.

Abbreviations, acronyms & symbols CEA EDTA ICA IL MMPs TIA

Carotid endarterectomy Ethylenediamine tetraacetic acid Internal carotid artery Interleukin Matrix metalloproteinases Transient ischemic attack

Métodos: Participaram do estudo 22 pacientes portadores de estenose ≥ 70% em artéria carótida (11 sintomáticos e 11 assintomáticos), submetidos à endarterectomia de artéria carótida. Os pacientes foram divididos em dois grupos: Grupo Controle - não foi administrado hidrocortisona e Grupo 1 - foi administrado 500 mg intravenoso de hidrocortisona durante a indução anestésica. As dosagens plasmáticas de MMP-8 e MMP-9 foram efetuadas no pré-operatório (24 horas antes da endarterectomia de artéria carótida) e em 1 hora, 6 horas e 24 horas após endarterectomia de artéria carótida. Na placa carotídea foram mensurados os níveis teciduais de MMP-8 e MMP-9.

Descritores: Hidrocortisona. Estenose das Carótidas. Inflamação. Metaloproteinases da Matriz Associadas à Membrana. Endarterectomia das Carótidas.

INTRODUCTION

MMP-8 and MMP-9, after intravenous administration of hydrocortisone.

Inflammation plays an important role in the development of atherosclerotic plaque. In addition, many immunocompetent cells, responsible for the production of inflammatory biomarkers, are identified at all stages of the atherosclerotic phenomenon[1,2]. The imbalance between pro-inflammatory and anti-inflammatory activity of serum and tissue biomarkers contribute to carotid plaque instability and the occurrence of cerebrovascular events such as transient ischemic attack (TIA) and stroke[3,4]. Increased expression of MMP-8 and MMP-9, which are zinc-dependent regulators of the extracellular matrix, has been demonstrated within carotid plaques[5,6]. Overexpression of MMP-8 and MMP-9 stimulates cellular migration, infiltration of T lymphocytes and monocytes in the subendothelium, degradation of the fibrous cap and extracellular matrix, arterial remodeling and intraplaque neoangiogenesis[5,6]. Furthermore, it degenerates collagen fibers type I, II, III, IV, V, VII, X and XII and elastin, contributing to carotid plaque rupture and hemorrhage[5,6]. Recent publications suggest that immunomodulatory therapies directed against the inflammatory process in carotid plaques should be developed and tested in order to reduce disease progression[3,7]. Glucocorticoids are known for its anti-inflammatory and immunosuppressive properties, reducing the secretion of inflammatory cytokines by monocytes, macrophages and lymphocytes[8,9]. Elenkov[10], however, has demonstrated that glucocorticoids are immunomodulatory drugs. The objective of this study was to analyze the inflammatory activity of plasma and carotid plaque

METHODS Population Between October/2012 and September/2013, 22 patients with greater than 70% internal carotid artery (ICA) stenosis were admitted to our center for CEA. The selected patients were 15 (68.18%) men and 7 (31.82%) women, with ages ranging from 50 to 84 years (mean: 69.50±9.09 years). Eleven patients (50%) had experienced a previous neurological event, and 11 (50%) patients had no symptoms. Regarding the contralateral ICA stenosis, 12 (54.54%) patients showed stenosis <50%, 8 (36.36%) exhibited stenosis between 50% to 69% and 2 (9.1%) demonstrated stenosis ≥ 70%. The inclusion criteria were: asymptomatic and symptomatic patients with ≥ 70% ICA stenosis, with indication for CEA. The exclusion criteria comprised: patients who had already undergone CEA; occlusion or < 70% ICA stenosis; patients admitted for carotid artery stenting (post-CEA restenosis, post-irradiation ICA stenosis, high carotid bifurcation); clinical and/or laboratory suspicion of infection; presence of autoimmune or systemic disease; use of anti-inflammatory or glucocorticoid drugs, chemotherapy treatment or immunossupressants; recent (< 1 month) severe infection or recent (< 1 month) stroke and hypersensitivity or contraindication for the use of hydrocortisone. The study was approved by the Ethics Committee of the Faculty of Medical Sciences of Santa Casa de São Paulo (Protocol: 108.870) and was performed according to the

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Guidelines of the World Medical Association’s Declaration of Helsinki. All patients gave their full informed consent prior to participating in the study.

The degree of carotid stenosis was determined by duplex ultrasonography investigation. In patients with greater than 70% ICA stenosis, carotid disease was confirmed by cerebral angiography performed up to one month prior to CEA. All patients were examined by a neurologist for assessment of their preoperative neurological status. As observed in previous publications, we followed the North American Symptomatic Carotid Endarterectomy Trial Criteria for classifying patients as being neurologically symptomatic or asymptomatic[11]. Patients submitted to CEA were divided into two groups: a Control group (11 patients) - patients who did not received intravenous hydrocortisone; and a Hydrocortisone group (11 patients) - patients who received a single 500 mg dose of intravenous hydrocortisone during anesthetic induction. Patients’ randomization was done with aleatory distribution of 22 sequential numbers in envelopes listed from 1 to 22. Even numbers referred to patiens from the control group and odd numbers referred to patients from the hydrocortisone group. The envelopes were opened in numerical order before anesthetic induction.

Preoperative period Baseline data were obtained from clinical records, physical examination, routine laboratory measurement, and from a study protocol filled out by the participating patients, including epidemiological data and cardiovascular risk factors, as summarized in Table 1. Hypertension was defined as a systolic blood pressure ≥ 140 mmHg and/or a diastolic blood pressure ≥ 90 mmHg, or current use of antihypertensive medication at the time of CEA. Diabetes mellitus was diagnosed in patients with fasting blood glucose levels ≥ 126 mg/dL and/or current use of hypoglycemic agents. Smoker was defined as currently smoking or cessation of smoking less than 1 month prior to entering the study. Hypercholesterolemia was defined as a total cholesterol concentration ≥ 200 mg/dL or current use of cholesterol-lowering agents. Abdominal obesity was diagnosed as patient’s body mass index ≥ 30 Kg/m2.

Table 1. Clinical and laboratorial characteristics of the study population. Variables Age (years) Gender Hypertension Diabetes mellitus Smoking Obesity BMI (kg/m2) Total Cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Triglycerides (mg/dL) Glucose (mg/dL) Carotid cross - clamping (minutes) Contralateral Carotid Stenosis Neurologic Symptoms Ischemic heart disease Myocardial Revascularization

Male Female Yes No Yes No Yes No Yes No

< 50% 50% to 69% > 70% Symptomatic Asymptomatic Yes No Yes No

Control Group (11) 69.09±8.30 72.70% 27.30% 90.90% 9.10% 54.50% 45.50% 36.40% 63.60% 9.10% 90.90% 26.64±3.61 189.45±22.39 47.55±11.26 110.64±27.23 156.09±50.08 129.36±53.82 44.18±7.22 54.50% 45.50% 0% 54.50% 45.50% 36.40% 63.60% 36.40% 63.60%

Hydrocortisone Group (11) 69.91±10.20 63.60% 36.40% 100% 0% 81.80% 18.20% 63.60% 36.40% 27.30% 72.70% 26.26±5.14 160.09±33.43 41.18±13.56 92.91±27.53 156.91±112.12 110.27±32.23 48.36±12.44 54.50% 27.30% 18.20% 45.50% 54.50% 63.60% 36.40% 63.60% 36.40%

P 0.718+ 0.647§ 0.306§ 0.170§ 0.201§ 0.269§ 0.669+ 0.023+ 0.200+ 0.212+ 0.511+ 0.869+ 0.430+ 0.287§ 0.670§ 0.201§ 0.201§

Data shown as mean ± standard deviation or percentage. BMI=body mass index; HDL=high-density lipoprotein; LDL=low-density lipoprotein; §Likelihood Ratio Test; + Mann-Whitney Test

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Carotid endarterectomy CEA was performed under general anesthesia. All endarterectomies were performed by an open, non-eversion technique, with careful surgical exposure of the bifurcation into the internal and external carotid arteries. Patients received 5000 IU of heparin intravenously before cross-clamping. The atheromatous plaque was removed and arteriorrhaphy performed. The mean time of carotid cross-clamping was 46.27±10.16 minutes.

for subsequent MMP-8 and MMP-9 measurement (LUMINEX Methodology) at the Laboratory of Medical Investigation at University of São Paulo. Statistical analysis Data were analyzed using the Statistical Package for Social Sciences, version 21.0. Values of continuous variables were expressed as mean ± standard deviation and percentages. Values of P<0.05 were considered statistically significant. For clinical and laboratorial characteristics of the patients, the Likelihood Ratio Test was employed for nonparametric variables and the Mann-Whitney test for parametric variables. The Mann-Whitney test was applied to verify differences between the groups for serum and carotid plaque biomarkers. Correlations between variables were calculated using Spearman rank correlation coefficients.

Hydrocortisone administration Hydrocortisone sodium succinate (Solu - Cortef®) 500 mg, lyophilized in a container, was diluted in 4 ml of distilled water and added to 500 ml of 0.9% saline. The solution was injected intravenously into a peripheral vein at a concentration of 1mg/mL and infusion time of 30 minutes. Measurement of serum MMP-8 and MMP-9 Blood samples were obtained via puncture of peripheral veins with needles at four moments: at preoperative (24 hours before CEA) period and at 1 hour, 6 hours and 24 hours after carotid cross-clamping. The blood collected was distributed in two purple tubes containing ethylenediamine tetraacetic acid (EDTA). The samples were firstly centrifuged at 1.000 rpm for 15 minutes and then at 10.000 rpm for 10 minutes. Plasma was divided into aliquots after sample centrifugation and frozen at -70oC. The analyses of blood samples (LUMINEX Methodology) collected at different points in time were performed at the Laboratory of Medical Investigation at University of São Paulo. The reference values were: MMP-8 between 350 and 4500 pg/mL and MMP-9 between 3858 and 4050 pg/mL.

RESULTS Inflammatory activity of serum MMP-8 and MMP-9 between control group and Hydrocortisone group In the control group, the concentration of plasma MMP-8 and MMP-9 reduced at 1 hour and 24 hours after CEA and exhibited the highest inflammatory activity at 6 hours (1329.75 pg/ml and 248,583.46 pg/ml respectively) after CEA. In the hydrocortisone group, a significant increase in serum levels of MMP-8 (994.28 pg/ml and 408.54 pg/ml, respectively; P=0.045) and MMP-9 (106,656.34 and 42,807.69 respectively; P=0.014) were identified at 1 hour after CEA, while lower concentrations of MMP-8 and MMP-9 were observed at 6 hours after CEA, compared to the control group (Figures 1 and 2). Table 2 demonstrates the inflammatory activity of plasma MMP-8 and MMP-9, between the control group and hydrocortisone group, during the observation period.

Measurement of MMP-8 and MMP-9 in carotid plaque After removal, carotid artery plaque was stored at -70oC

Table 2. Inflammatory activity of plasma MMP-8 and MMP-9 between control group and hydrocortisone group.

MMP-8 (pg/ml)

Preoperative 1h after CEA 6h after CEA 24h after CEA

Control Group (11) 460.58±320.57 408.54±334.77 1329.75±1077.83 794.48±577.92

Hydrocortisone Group (11) 547.56±311.03 994.28±1241.32 1007.40 ± 368.90 900.07±619.11

Total (22) 504.07±311.42 701.41±936.47 1168.57±803.26 847.27±586.93

P 0.412 0.045 0.622 0.533

MMP-9 (pg/ml)

Preoperative 1h after CEA 6h after CEA 24h after CEA

69069.88±57324.15 42807.69±29689.96 248583.46±242990.51 65938.49±36335.00

60720.54±49210.75 106656.34±126215.45 167540.23±140492.18 93193.86±101289.35

64895.21±52309.05 74732.02±95254.03 208061.84±198079.88 79566.18±75556.14

0.922 0,014 0.818 0.922

Data shown as mean ± standard deviation. MMP=matrix metalloproteinase; CEA=carotid endarterectomy; MannWhitney Test

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Fig. 1 - Inflammatory activity of MMP-8 between control group and hydrocortisone group. MMP=metalloproteinase; CEA=carotid endarterectomy

Fig. 2 - Inflammatory activity of MMP-9 between control group and hydrocortisone group. MMP=metalloproteinase; CEA=carotid endarterectomy

Inflammatory activity of plasma MMP-8 and MMP-9 between symptomatic patients in the control group and Hydrocortisone Group Lower concentrations of plasma MMP-8 (890.85 versus 1,625.22, respectively; P=0.086) and MMP-9 (146,464.50 versus 335,931.02, respectively; P=0.153) were observed

in symptomatic patients in the hydrocortisone group at 6 hours after CEA, compared to the control group. On the other hand, higher inflammatory activity of plasma MMP-8 and MMP-9 was identified in the hydrocortisone group at 1 hour and 24 hours after CEA, in comparison to the control group.

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Table 3 exhibits the inflammatory activity of plasma MMP-8 and MMP-9 between symptomatic patients in the control and hydrocortisone groups, during the follow-up period.

Inflammatory activity of tissue MMP-8 and MMP-9 between symptomatic and asymptomatic patients in control group and Hydrocortisone group A significant reduction in tissue levels of MMP-8 was observed in symptomatic patients in the hydrocortisone group, compared to the control group (14.89 pg/ml and 1317.36, respectively; P=0.003). On the other hand, MMP-9 levels were lower in the control group, in comparison to the hydrocortisone group. No significant difference was found in tissue concentrations of MMP-8 and MMP-9 between asymptomatic patients in the control and hydrocortisone groups. Table 5 describes the inflammatory activity of tissue MMP-8 and MMP-9, between asymptomatic and symptomatic patients in the control group and the hydrocortisone group.

Inflammatory activity of plasma MMP-8 and MMP-9 between asymptomatic patients in control group and Hydrocortisone group Higher concentrations of plasma MMP-8 and MMP-9 were measured in asymptomatic patients in hydrocortisone group at 1 hour and 6 hours after CEA, while lower serum levels of MMP-8 and MMP-9 were observed in this group at 24 hours after CEA, compared to the control group. There was a significant difference for MMP-9 values, between the hydrocortisone group and the control group, ​​at 1 hour after CEA (81,650.16 pg/ml and 28,474.82, respectively; P=0.027). Table 4 summarizes the inflammatory activity of plasma MMP-8 and MMP-9, between asymptomatic patients in the control and hydrocortisone groups, during the period analyzed.

Correlation between plasma and tissue MMP-8 and MMP-9 in symptomatic patients in control group An important correlation was observed between preoperative levels of MMP-9 and tissue MMP-8 (Spearman=0.829;

Table 3. Inflammatory activity of plasma MMP-8 and MMP-9 between symptomatic patients in control group and hydrocortisone group.

MMP-8 (pg/ml)

Preoperative 1h after CEA 6h after CEA 24h after CEA

Control Group (6) 621.83±355.76 466.42±376.86 1625.22±1025.44 983.88±663.43

Hydrocortisone Group (7) 516.81±328.99 1134.82±1572.00 890.85±347.30 1093.54±708.74

Total (13) 565.28±331.39 826.33±1189.56 1229.79±802.27 1042.93±661.66

P 0.668 0.317 0.086 0.568

MMP-9 (pg/ml)

Preoperative 1h after CEA 6h after CEA 24h after CEA

97564.42±65483.60 54751.75±32769.94 335931.02±263337.80 79929.31±20569.79

65284.82±61190.30 120945.59±158730.90 146464.50±126781.63 122526.69±119022.91

80183.10±62764.37 90394.59±119268.03 233910.59±215861.11 102866.36±88023.03

0.317 0.153 0.153 0.668

Data shown as mean ± standard deviation. MMP=matrix metalloproteinase; CEA=carotid endarterectomy; MannWhitney Test Table 4. Inflammatory activity of plasma MMP-8 and MMP-9 between asymptomatic patients in control group and hydrocortisone group.

MMP-8 (pg/ml)

Preoperative 1h after CEA 6h after CEA 24h after CEA

Control Group (5) 267.08±113.57 339.09±302.64 975.9±1140.96 567.20±407.95

Hydrocortisone Group (4) 601.38±316.10 748.33±259.06 1211.36±353.88 561.49±181.24

Total (9) 415.66±273.79 520.98±342.76 1080.16±844.60 564.66±309.09

P 0.050 0.086 0.462 0.624

MMP-9 (pg/ml)

Preoperative 1h after CEA 6h after CEA 24h after CEA

34876.43±13252.10 28474.82±19764.07 143766.38±189076.18 49149.51±46105.68

52733.06±21216.62 81650.16±37416.10 204422.76±175488.31 41861.40±18561.66

42812.71±18579.17 52108.30±38803.93 170724.77±174486.26 45910.35±34739.35

0.142 0.027 0.327 0.624

Data shown as mean ± standard deviation; MMP=matrix metalloproteinase; CEA=carotid endarterectomy; MannWhitney Test

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Table 5. Inflammatory activity of tissue MMP-8 and MMP-9 between asymptomatic and symptomatic patients in control group and hydrocortisone group.

MMP-8 (pg/ml)

Symptomatic Asymptomatic

Control Group (11) 1317.36±1889.05 410.78±283.72

MMP-9 (pg/ml)

Symptomatic Asymptomatic

6362.56±5901.41 3584.74±4263.05

Hydrocortisone Group (11) 143.89±62.48 481.59±419.78

TOTAL (22) 685.49±1363.66 442.25±328.21

P 0.003 > 0.999

9810.42±14487.32 2187.64±1858.22

8219.10±11074.88 2963.80±3305.13

0.886 0.806

Data shown as mean ± standard deviation; MMP=matrix metalloproteinase; CEA=carotid endarterectomy; MannWhitney Test

P=0.042) and MMP-9 (Spearman=0.886; P=0.019). Furthermore, a relevant association was identified between tissue MMP-8 and plasma MMP-8 in its highest moment of inflammatory activity (6 hours after EAC) (Spearman=0.886; P=0.019).

hydrocortisone administered during anesthetic induction was chosen since this medication is widely used in the hospital setting. This single dose is known not to cause side effects in our patients and the short half-life of this glucocorticoid (1.5 to 2 hours) may interfere with the inflammatory activity of MMP-8 and MMP-9, which are biomarkers of acute phase response. The inflammatory response after a surgical procedure involves ischemia-reperfusion injury to the end organs, as a result of arterial crossclamping, and the restoration of perfusion after arterial crossclamping[14]. Furthermore, the persistence of any degree of inflammation may be considered potentially harmful to the cardiovascular patient submitted to surgery[14]. Rubens & Messana[15] and Liguori et al.[16] have concluded that the systemic inflammatory response is variable and is influenced by comorbidities exhibited by patients, non-pharmacological intervention during surgery, type of anesthesia, perioperative hemodynamic conditions, surgical aspects (surgical incision, duration, time of arterial crossclamping and need for blood transfusion) and postoperative evolution. In this study, we standardized general anesthesia and classical CEA with longitudinal arteriotomy, in order to keep our patients under the same perioperative conditions. The measurement of serum MMP-8 and MMP-9 were performed after carotid declamping in order to evaluate the highest production of these biomarkers during the time of carotid crossclamping. Hydrocortisone, however, was administered during anesthetic induction rather than in the postoperative period in order to evaluate its immunomodulatory effects also upon biomarkers present in carotid plaque. In our study, symptomatic patients exhibited higher levels of serum MMP-8 and MMP-9 in the preoperative period and in postoperative follow-up, compared to asymptomatic patients. This higher concentration of plasma MMP-8 and MMP-9 in symptomatic patients was also observed by Heider et al.[17]; however, his preoperative levels of MMP8 and MMP-9, both in symptomatic and asymptomatic patients, were higher than those demonstrated in our groups. We believe that this difference has occurred due to the char-

DISCUSSION Although the effect of glucocorticoids on inflammatory activity of metalloproteinases has been explored in the medical literature, to the best of our knowledge, this study demonstrates for the first time that intravenous hydrocortisone may interfere with the inflammatory activity of serum and tissue MMP-8 and MMP-9 in patients with advanced ICA stenosis. Lower concentrations of tissue MMP-8 in symptomatic patients and the tendency to reduce plasma MMP-9 at the moment of its highest activity (6 hours after CEA) demonstrate that the anti-inflammatory property of hydrocortisone reduces the inflammatory activity of MMP-8 and MMP-9 present in peripheral blood and in carotid plaque. Previous publications have exhibited lower concentrations of serum inflammatory biomarkers using methylprednisolone, but they have not shown this effect on MMP-8 and MMP-9, neither demonstrated this inflammatory reduction with hydrocortisone administration nor evaluated this alteration in biomarkers involved in advanced ICA stenosis and in patients submitted to CEA. After administering 30 mg/kg of methylprednisolone, before surgery and before declamping of thoracic aorta, in 16 patients undergoing elective coronary artery bypass graft, Kawamura et al.[12] observed a significant reduction in concentrations of plasma interleukin (IL) - 6 and IL -8 at 1 hour, 2 hours and 3 hours after declamping of thoracic aorta. Komori et al.[13], after administering 1g of methylprednisolone two hours before elective reconstruction of infrarenal abdominal aortic aneurysms, identified lower concentrations of IL-6 after declamping of abdominal aorta and on the first postoperative day, and reduced levels of C-reactive protein on the first postoperative day, in comparison to patients who had not received a preoperative dose of methylprednisolone. In this study, a single dose of 500 mg

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acteristics of the patients analyzed and the methods used for measuring these metalloproteinases. The postoperative concentrations of MMP-8 and MMP9, in this study, demonstrated higher inflammatory activity at 6 hours after CEA and a reduction in their levels at 24 hours after CEA. Taurino et al.[18], after evaluating 15 patients undergoing CEA, identified a significant reduction in serum levels of MMP-9 in 46.7% of them in one week and in 93.4% of them in thirty days after CEA. Intraoperative administration of hydrocortisone, however, has shown a tendency to reduce the concentrations of MMP-8 and MMP-9 at 6 hours after CEA, and this tendency has also been observed in symptomatic patients who received a single dose of hydrocortisone. This behavior of MMP-8 and MMP-9 after administration of hydrocortisone may consist in an immunomodulatory effect of hydrocortisone upon circulating macrophages, which are important secretory cells of MMP-8 and MMP-9. In the group in which intravenous hydrocortisone was administered, the non-significant reduction in these biomarkers at 6 hours after CEA can be explained by the small sample size of this study, the preoperative administration of hydrocortisone, and the short half-life of these corticosteroids. Nevertheless, this result suggests a possible interference of hydrocortisone in the inflammatory activity of MMP-8 and MMP-9. An important result found in this study was the higher concentrations of plasma MMP-8 and MMP-9, at 1 hour after CEA in the hydrocortisone group. We believe that due to the dynamism between the action of inflammatory biomarkers and the activation of systemic defense mechanisms, the presence of hydrocortisone in peripheral blood as an anti-inflammatory agent has stimulated an early compensatory inflammatory activity of MMP-8 and MMP-9 in an attempt to balance the systemic inflammatory and anti-inflammatory response. Therefore, lower inflammatory activity of MMP-8 and MMP-9 at 6 hours after CEA was identified in patients who received a single dose of hydrocortisone, compared to the control group. As observed in plasma measurement, symptomatic patients exhibited higher concentrations of MMP-8 and MMP-9 in carotid plaque in comparison to asymptomatic patients. We found a significant reduction in inflammatory activity of tissue MMP-8 in symptomatic patients in the hydrocortisone group, demonstrating the capacity of these corticosteroids to interfere also with the inflammatory activity present in carotid plaque. Sluijter et al.[19] demonstrated that tissue MMP-8 and MMP-9 are associated with unstable plaques with lower collagen content, lower fibrous layer and higher risk of rupture. Jiang et al.[20], in an experimental study in pigs, demonstrated an association between intraplaque hemorrhage and an overexpression of MMP-9 present in carotid plaque. Peeters et al.[21] , in a follow-up of 3 years after CEA, concluded that higher concentrations of MMP-8 in carotid plaque are associated with higher in-

cidence of coronary events and higher need for peripheral vascular interventions. The correlation between preoperative levels of MMP-9 and the expression of tissue MMP-9 in symptomatic patients was also observed by Taurino et al.[18]. This association suggests the existence of a vicious circle between systemic and tissue inflammation. Alvarez et al.[22] showed a strong association between elevated preoperative levels of MMP-9 and the presence of unstable carotid plaques. In addition, the correlation between tissue MMP-8 and the moment of the highest inflammatory activity of serum MMP-8 at 6 hours after CEA, in symptomatic patients, suggests that inflammation present in carotid plaque may influence systemic inflammation and, as a consequence, maintaining the systemic postoperative inflammatory response even after carotid plaque removal and the restoration of cerebral perfusion. This study has some limitations. Despite hydrocortisone administration having affected the inflammatory activity of MMP-8 and MMP-9 after CEA and due to the small sample size included, our results do not provide prognostic information regarding the progression of contralateral carotid artery disease and carotid restenosis. Our results, however, demonstrate that intravenous hydrocortisone can reduce inflammatory response associated with CEA, providing a relevant basis for future studies evaluating the effect of intravenous hydrocortisone on the prognosis of patients submitted to CEA. CONCLUSION In conclusion, the immunomodulatory effect of hydrocortisone is identified both in plasma and in carotid plaque, with a significant reduction in the concentration of MMP-8 present in carotid plaque, especially in symptomatic patients, and a tendency to reduce the inflammatory activity of plasma MMP-8 and MMP-9, at the highest postoperative inflammatory response of these biomarkers. Authors’ roles & responsibilities SAG

LA VLC CBB OCJ JLBA RAC

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Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; implementation of projects and/or experiments; manuscript writing or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript Analysis and/or interpretation of data; final approval of the manuscript Analysis and/or interpretation of data; final approval of the manuscript; manuscript writing or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript; study design 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; final approval of the manuscript; study design; manuscript writing 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 complete atrioventricular septal defect

Factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of repair of complete atrioventricular septal defect Fatores associados à insuficiência da valva atrioventricular esquerda nos primeiros 30 dias após correção de defeito de septo atrioventricular total

Marcelo Felipe Kozak1, MD; Ana Carolina Leiroz Ferreira Botelho Maisano Kozak1, MD; Carlos Henrique De Marchi1, MD; Sirio Hassem Sobrinho Junior2, MD; Ulisses Alexandre Croti1, MD, PhD; Airton Camacho Moscardini1, MD

DOI 10.5935/1678-9741.20150036

RBCCV 44205-1645

Abstract Introduction: Left atrioventricular valve regurgitation is the most concerning residual lesion after surgical correction of atrioventricular septal defects. Objective: To determine factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of surgical repair of complete atrioventricular septal defect. Methods: We assessed the results of 53 consecutive patients 3 years-old and younger presenting with complete 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 atrioventricular valve regurgitation, abnormalities on the left atrioventricular valve and the use of annuloplasty. Median age was 6.7 months; median weight was 5.3 Kg; 86.8% had Down syndrome. At the time of preoperative evaluation, there were 26 cases with moderate or severe left atrioventricular valve regurgitation (49.1%). Abnormalities on the left atrioventricular valve were found in 11.3%; annuloplasty was performed in 34% of the patients.

Results: At the time of postoperative evaluation, there were 21 cases with moderate or severe left atrioventricular valve regurgitation (39.6%). After performing a multivariate analysis, the only significant factor associated with moderate or severe left atrioventricular valve regurgitation was the absence of Down syndrome (P=0.03). Conclusion: Absence of Down syndrome was associated with moderate or severe postoperative left atrioventricular valve regurgitation after surgical repair of complete atrioventricular septal defect at our practice.

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.

No financial support.

Descriptors: Endocardial Cushion Defects. Mitral Valve Insufficiency. 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. Objetivo: Determinar fatores associados à insuficiência da valva atrioventricular esquerda de grau moderado ou impor-

1

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

This study was 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 December 1st, 2014 Article accepted on May 25th, 2015

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operação, 26 apresentavam insuficiência da valva atrioventricular esquerda pelo menos moderada (49,1%). Anormalidades na valva atroventricular foram encontradas em 11,3% dos casos; anuloplastia foi realizada em 34% dos pacientes. Resultados: Após a correção, houve 21 casos com insuficiência moderada ou grave da valva atrioventricular esquerda (39,6%). Após realização de análise multivariada, o único fator associado com esses graus de insuficiência foi a ausência da síndrome de Down (P=0,03). Conclusão: Ausência de síndrome de Down esteve associada com insuficiência moderada ou grave da valva atrioventricular esquerda após correção cirúrgica de defeito de septo atrioventricular total em nosso serviço.

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

tante nos primeiros 30 dias após correção de defeito de defeito de septo atrioventricular total. Métodos: Avaliamos os resultados em 53 pacientes consecutivos menores de 3 anos com defeito de septo atrioventricular total, 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 6,7 meses e a do peso de 5,3 Kg; 86,8% tinham síndrome de Down. Antes da

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

INTRODUCTION

METHODS

In North America and Europe, between 9% and 17% of patients with complete atrioventricular septal defect (AVSD) are discharged home with significant residual left atrioventricular valve regurgitation (LAVVR) after definitive surgical repair, even with intraoperative monitoring by transesophageal echocardiography[1,2]. Aside from the obvious risk of reoperation that it implies, the presence of LAVVR with hemodynamic compromise in this period may increase length of hospital stay, morbidity and mortality, and it may also increase costs[1-6]. In order to improve outcomes, a clear outline of the predisposing factors leading to residual LAVVR after surgical repair is mandatory. The most common risk factors associated with reoperation are: abnormalities on the atrioventricular (AV) valve, non-closure of the zone of apposition of the AV valve, absence of Down syndrome, low weight, preoperative AVVR, age lower than 3 months at time of repair and a more acute angle of the AV valve[1,4,7-10]. However, there are few studies aimed to detect factors associated with significant immediate postoperative LAVVR[5]. The purpose of our study was to assess whether some of the risk factors for reoperation previously published in the literature would be associated with an at least moderate LAVVR within 30 days of surgical repair of complete AVSD at our practice.

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 complete AVSD at our practice between March 2002 and April 2010 were reviewed. Patients with any right ventricle obstruction, 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. Transesophageal echocardiographic probe was not available at our institution during the period in which the patients were operated on. Pre- and postoperative AVVR were subjectively divided into 4 grades based on the appearance of the color Doppler jets in relation to the surrounding chambers. I: absent or trivial; II: mild; III: moderate; IV: severe[11]. The categorizations

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were based just on official written summaries of the exams. Images stored on tapes or in digital media were not assessed. The mechanisms of AVVR were described in a few cases, therefore these information were not used for analysis. The following risk factors were assessed: age, weight, absence of Down syndrome, grade of preoperative AVVR, abnormalities on the AV valve morphology and the need for the use of annuloplasty. Abnormalities on the AV valve morphology were subjectively described by the surgeon.

Among the 46 patients with Down syndrome, 5 (10.9%) had abnormalities on the AV valve, whereas 1 out of the 7 patients (14.3%) without Down syndrome had these abnormalities (P=0.99). Operative and postoperative management Surgery using a median sternotomy was performed in all patients. Continuous extracorporeal circulation by ascending aortic and bicaval cannulation with deep hypothermia (rectal temperature 22°C) was used in 2 patients, while moderate hypothermia (rectal temperature 25-28°C) was used in 51 patients. Cardiopulmonary bypass time varied between 66 and 200 minutes (median 105 min), and the aortic cross-clamp time varied between 42 and 180 minutes (median 78.5 min). Antegrade cold crystalloid cardioplegia was used at 20-minute intervals for myocardial preservation. The two-patch technique with preserved bovine pericardium was used in 50 patients (94.3%); the single-patch modified technique was used in the other 3 patients, in whom the surgeon considered the ventricular septal defect too small. The zone of apposition or cleft was completely closed in 49 patients (92.4%) and tt was partially closed in 1 patient. It was left open in another 3 patients: in 2 patients the valve annulus was very small, and in another patient the posterior annuloplasty had reduced the diameter of the valve orifice, what made the cleft closure more difficult to be done. Posterior annuloplasty was performed in 18 patients (34%) who presented annular dilation and valve leaking after repair, based on surgical saline testing.

Statistical Analysis Continuous variables were expressed as median, and comparisons were made using the two-sided Mann-Whitney test. Cathegorical variables were expressed using frequency distribution and percentages, and comparisons were made using the Fisher exact test. Univariate odds ratios and their 95% confidence intervals (95% CI) were estimated for variables found to have a statistically significant (P≤0.05) relationship with moderate or severe postoperative LAVVR. These variables were included in the multivariate analysis when they reached a P-value≤0.2. 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). Patient Population We included 53 patients (37 girls and 16 boys): 46 with Down syndrome (86.8%). Age at the time of repair ranged from 2.7 months to 3 years (median 6.7 months); 37.7% of the patients were 6 months-old or younger, and 83% were 1 year-old or younger. Weight varied between 2.9 and 13 Kg (mean 5.3) (Table 1). At the time of preoperative evaluation, there were 4 cases with grade I AVVR (7.5%), 23 with grade II (43.4%), 16 with grade III (30.2%), and 10 with grade IV (18.9%). Patients with Down syndrome had lower grades of preoperative AVVR than those without Down syndrome, but it was not statistically significant (P=0.2). Six cases (11.3%) of abnormalities on the AV valve morphology were found: small left AV valve orifice (3), hypoplastic left mural leaflet (1), accessory cleft (1), and grossly malformed valve (1).

RESULTS The postoperative time on a mechanical ventilator ranged from 4 to 1699.3 hours (median 19.9 hours) and the time of inotropic support varied between 24 and 1146 hours (median 81 hours). The postoperative length of hospital stay ranged from 1 to 149 days (mean 11.5 days). There were 4 deaths (7.1%): one within the first 24 hours due to cardiogenic shock; another due to a complete AV block and cardiogenic shock at the 12nd postoperative day before pacemaker implantation; one due to sepsis at the 24th postoperative day and another at the 25th postoperative day due to multi-systemic organ failure. The postoperative LAVVR grades of these patients who died were II, I, III and IV respectively (their preoperative AVVR grades were respectively III, III, III and II). The echocardiograms considered for analysis were performed between day 1 and day 29 after repair (mean 12.1±8.5 days). At the time of postoperative evaluation, there were 5 cases with grade I LAVVR (9.4%), 27 with grade II (50.9%), 18 with grade III (34%), and 3 with grade IV (5.7%). The difference between pre- and postoperative grades of AVVR was marginally significant (P=0.06). There was a partial or complete improvement of AVVR or maintenance of a trivial

Table 1. Characteristics of the 53 patients enrolled in the study. Characteristic Age at the time of repair in months (median) Female Weight in Kg (median) Down syndrome Grade 1 AVVR Grade 2 AVVR Grade 3 AVVR Grade 4 AVVR AV valve abnormalities

N (%) 6.7 (2.7-35.6) 37 (69.8) 5.3 (2.9-13) 46 (86.8) 4 (7.5) 23 (43.4) 16 (30.2) 10 (18.9) 6 (11.3)

AVVR=atrioventricular valve regurgitation; AV=atrioventricular

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or mild AVVR in 35 patients (66%). A one-grade worsening was found in 12 patients (22.6%). Among the 4 cases in which the cleft was left partially or completely open, there was no difference between pre- and postoperative LAVVR (P>0.99). However, among those in which the cleft was closed, this difference was significant (P=0.05). Regarding those who had undergone annuloplasty, the difference between pre- and postoperative LAVVR was not significant (P=0.4), and among those who had not undergone annuloplasty, this difference was only marginally significant (P=0.08). Other findings on postoperative echocardiograms included the following: 10 cases of right AVVR (18.9%), 7 cases of residual small ventricular septal defects (13.2%), 2 cases of residual small atrial septal defects (3.8%) and 1 case of left AV valve stenosis (1.9%). According to the univariate analysis, absence of Down syndrome was the only factor associated with moderate or severe LAVVR after surgical repair (P=0.01). Presence of mild or more severe preoperative AVVR and presence of AV valve abnormalities were only marginally significant (Table 2). Under multivariate analysis, only absence of Down syndrome continued to be associated with moderate or severe postoperative LAVVR (P=0.03) (Table 3).

DISCUSSION Even in the modern era, with the use of new medical diagnostic tools as routine intraoperative transesophageal echocardiography or 3D-chocardiography, and with the use of different surgical techniques, the risk of late reoperation for LAVVR continues high after repair of AVSD[1,7,9,12-15]. Although rare, early reoperations for LAVVR also happen[16-18]. This is true for both complete and incomplete forms of AVSD, despite different physiology and different ages at repair. What both forms of AVSD 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), as well as a high prevalence of individuals with Down syndrome[19]. Therefore, the clue to understanding this frequent complication may be related more to these two aspects than to another factor such as age at repair, weight at repair, or AV valve malformation. Statements such as “In patients with Down-syndrome valve tissue is more abundant and allows for an easier reconstruction” are often seen[1]. It suggests that patients without Down syndrome would have a higher risk of worse surgical outcomes regarding LAVVR, as found by us and

Table 2. Univariate analysis of preoperative and intraoperative factors related to postoperative left atrioventricular valve regurgitation grade moderate or severe. Factor Age in months (median) Weight in Kg (median) Down syndrome Preoperative AVVR ≥ II Annuloplasty AV valve abnormality

LAVVR ≤ II (n=32) 7.7 5.4 31 (96.9%) 28 (87.5%) 11 (34.4%) 2 (6.2%)

LAVVR ≥ III (n=21) 6.1 5 15 (71.4%) 21 (100%) 7 (33.3%) 4 (19%)

OR

Univariate IC (95%)

0.08

0.002-0.791

P 0.63 0.93 0.01 0.14 > 0.99 0.20

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

Table 3. Multivariate analysis of preoperative and intraoperative factors related to postoperative left atrioventricular valve regurgitation grade moderate or severe. Factor Non-Down syndrome Preoperative AVVR ≥ II AV valve abnormality

PO LAVVR ≤ II n=32 1 (3.1%) 28 (87.5%) 2 (6.2%)

PO LAVVR ≥ III n=21 15 (28.6%) 21 (100%) 4 (19%)

OR 0.08

Multivariate CI 95% 0.009-0.774

AV=atrioventricular; AVVR=atrioventricular valve regurgitation; CI=confidence interval; PO LAVVR=postoperative left atrioventricular valve regurgitation; OR=odds ratio

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P 0.03 0.99 0.21


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some other authors[9,12,13]. In the study by Ferrín et al.[20], it was found that patients with Down syndrome indeed have more tissue in the AV valve, but also a lower prevalence of malformation of the AV valve, what not necessarily meant a better outcome. In the study by Kanani et al.[21], in which the anatomy of the subvalvar apparatus of normal hearts was compared to that of hearts with AVSD, the structural and geometric disarray of the tendinous cords of the hearts with AVSD was clearly visible, along with its possible role on the mechanisms of valve regurgitation. However, there was no mention if patients with Down syndrome were included in the study. In the study by Desai et al.[16], comparing Down and non-Down patients, there were differences neither with respect to grade of preoperative LAVVR, nor with respect to the prevalence of dysplastic AV valves. Studies addressed to explain this very common finding, like histopathological comparisons of the valve and subvalvar apparatus of patients with and without Down syndrome, must be done or, maybe, the surgical approach to patients without Down syndrome should be revisited. Significant preoperative AVVR eventually leads to left ventricular dilation, changing the cordal axis, influencing the mechanism of valve closure, what could be responsible for persistent postoperative LAVVR[21]. In our study, the presence of an at least mild preoperative AVVR was not associated with moderate or severe postoperative LAVVR. It is important to mention that none of the patients enrolled in our study presented left ventricular dysfunction at the moment of postoperative assessment, what could skew the results. Also, in a more recent work by Bharucha et al.[10], the grade of preoperative AVVR didn’t influence the results. With the use of three-dimensional (3D) echocardiography, they 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. Unfortunately, 3D-echo was not available at our institution when the study was performed, therefore this risk factor could not be addressed. The results of our study could not prove any relationship between the presence of AV valve malformation and moderate or severe postoperative LAVVR. Some studies found that AV valve malformation is associated with reoperation or valve replacement[7,9]. However, like in our study some cases of AV valve malformation have been subjectively diagnosed[7]. Ando & Takahashi[22] found a weak correlation between preoperative echocardiographic findings and the surgeon’s judgment in regard to the diagnosis of these malformations. Furthermore, there is little consistency between the findings of two- and three-dimensional (2D and 3D) echocardiography in respect to the analyses of AV valve abnormalities. In the study by Takahashi et al.[23], for instance, the correlation between the findings of both methods was lower than 46% in the examination of the mural leaflet and in the examination

of the commissural abnormalities of the left AV valve leaflets. Three-dimensional echocardiogram was more accurate and more reliable. In another study by Takahashi et al.[24], the overall sensitivity for the assessment of left AV valves using 2D (transthoracic and transesophageal) and 3D-echocardiography was less than 60%, although the specificity and accuracy of 3D-echocardiography were superior, providing complementary information with this relatively new method. With respect to the approach of the zone of apposition, some studies have reported that not closing it would be a risk factor of reoperation, and it has therefore been adopted at our institution[14,25]. However, in 4 cases in this study (7.5%) the cleft was not completely closed due to the risk of stenosis. In these cases, there was no alteration in the functional status of the valve, differently of those who had this procedure performed, who clearly had some benefit from this approach. The rate of annuloplasty in this study (34%) was similar to that reported by Suzuki et al.[7] (30%), and much higher than those reported by Dragulescu et al.[15] (4.7%) and by Stellin et al.[2] (2.5%). These different rates show that there is no common sense on this item. Padala et al.[26] showed, in vitro, the importance of the annular dilation for the AVVR grade: they concluded that performing only the cleft closure is not enough to avoid AVVR, and that there would have a real benefit in shortening the annulus size. Such benefit was not found in the present study. Study Limitations It was a retrospective study, and it was therefore subject to limitations in terms of how correctly the information in the medical records was well filled. The study is limited by the relatively low number of patients and by the lack of immediate postoperative data provided by an intraoperative transesophageal echocardiogram. The postoperative echocardiograms were performed anytime during the first 30 postoperative days, rather than a consistent postoperative interval. It is important since the same patient behaves differently depending on his/her hemodynamical situation, usually more stable the later the evaluation is done. Statements made by the surgeon were merely subjective and the mechanisms of LAVVR were not available for a better understanding of our results, clearly not as good as expected. CONCLUSION Absence of Down syndrome was associated with moderate or severe postoperative LAVVR in patients with complete AVSD operated on at our practice. We suggest that these patients must have a detailed preoperative assessment of their AVV morphology and whenever possible an intraoperative transesophageal echocardiography in order to immediately assess the surgical result and minimize the effect of the genetic background on their surgical outcomes.

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defects in patients weighing less than 5 kg. Ann Thorac Surg. 2004;77(5):1717-26.

Authors’ 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 SHSJ Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript or critical review of its content UAC Analysis and/or interpretation of data; final approval of the manuscript; implementation of projects and/or experiments; 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. 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. 11. 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.

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13. Formigari R, Di Donato RM, Gargiulo G, Di Carlo D, Feltri C, Picchio FM, et al. Better surgical prognosis for patients with complete atrioventricular septal defect and Down’s syndrome. Ann Thorac Surg. 2004;78(2):666-72.

2. Stellin G, Vida VL, Milanesi O, Rizzoli G, Rubino M, Padalino MA, et al. Surgical treatment of complete A-V canal defects in children before 3 months of age. Eur J Cardiothor Surg. 2003;23(2):187-93.

14. 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.

3. Ono M, Goerler H, Boethig D, Bertram H, Westhoff-Bleck M, Haverich A, et al. Improved results after repair of complete atrioventricular septal defect. J Card Surg. 2009;24(6):732-7. 4. Bogers AJ, Akkersdijk GP, de Jong PL, Henrich AH, Takkenberg JJ, van Domburg RT, et al. Results of primary two-patch repair of complete atrioventricular septal defect. Eur J Cardiothorac Surg. 2000;18(4):473-9.

15. 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):1599-604.

5. Boening A, Scheewe J, Heine K, Hedderich J, Regensburger D, Kramer HH, et al. Long-term results after surgical correction of atrioventricular septal defects. Eur J Cardiothorac Surg. 2002; 22(2):167-73.

16. Desai AR, Branco RG, Comitis GA, Maiya S, Vyas DB, Vaz Silva P, et al. Early postoperative outcomes following surgical repair of complete atrioventricular septal defects: is Down syndrome a risk factor? Pediatr Crit Care Med. 2014;15(1):35-43.

6. Prifti E, Bonacchi M, Baboci A, Giunti G, Krakulli K, Vanini V. Surgical outcome of reoperation due to left atrioventricular valve regurgitation after previous correction of complete atrioventricular septal defect. J Card Surg. 2013;28(6):756-63.

17. St Louis JD, Jodhka U, Jacobs JP, He X, Hill KD, Pasquali SK, et al. Contemporary outcomes of complete atrioventricular septal defect repair: analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. 2014;18(6):2526-31.

7. 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.

18. Pontailler M, Kalfa D, Garcia E, Ly M, Le Bret E, Roussin R, et al. Reoperations for left atrioventricular valve dysfunction after repair of atrioventricular septal defect. Eur J Cardiothor Surg. 2014;45(3):557-62.

8. Prifti E, Bonacchi M, Bernabei M, Crucean A, Murzi B, Bartolozzi F, et al. Repair of complete atrioventricular septal

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19. Torfs CP, Christianson RE. Anomalies in Down syndrome individuals in a large population-based registry. Am J Med Genet. 1998;77(5):431-8.

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.

20. Ferrín LM, Atik E, Ikari NM, Martins TC, Barbero-Marcial M, Ebaid M. Defeito total do septo atrioventricular: correlação anátomo-funcional entre pacientes com e sem síndrome de Down. Arq Bras Cardiol. 1997;69(1):19-23.

24. Takahashi K, Mackie AS, Rebeyka IM, Ross DB, Robertson M, Dyck JD, et al. Two-dimensional versus transthoracic real-time threedimensional echocardiography in the evaluation of the mechanisms and sites of atrioventricular valve regurgitation in a congenital heart disease population. J Am Soc Echocardiogr. 2010;23(7):726-34.

21. Kanani M, Elliott M, Cook A, Juraszek A, Devine W, Anderson 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.

25. 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.

22. Ando M, Takahashi Y. Variations of atrioventricular septal defects predisposing to regurgitation and stenosis. Ann Thorac Surg. 2010; 90(2):614-21.

26. Padala M, Vasilyev NV, Owen JW Jr, Jimenez JH, Dasi LP, del Nido PJ, et al. Cleft closure and undersizing annuloplasty improve mitral repair in atrioventricular canal defects. J Thorac Cardiovasc Surg. 2008;136(5):1243-9.

23. Takahashi K, Guerra V, Roman KS, Nii M, Redington A,

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Menezes Junior AS, et al. -ARTICLE Chronotropic incompetence in Chagas disease: ORIGINAL effectiveness of blended sensor (volume/minute and accelerometer)

Chronotropic incompetence in Chagas disease: effectiveness of blended sensor (volume/minute and accelerometer) Competência cronotrópica em chagásicos: eficácia do duplo sensor (volume/minuto e acelerômetro)

Antonio da Silva Menezes Junior1, MD, PhD; Aline Pereira da Silva1, MD; Giovana Gurian Batista Profahl1, MD; Catarine Ottobeli1, MD; Jutay Fernando Silva Louzeiro1, MD

DOI 10.5935/1678-9741.20150035

RBCCV 44205-1646

Abstract Introduction: Technological progress of pacemakers has allowed the association of two or more sensors in one heart rate system response. The accelerometer sensor measures the intensity of the activity; it has a relatively rapid response to the beginning of it, however, it may present insufficient response to less strenuous or of less impact exercise. The minute ventilation sensor changes the pacing rate in response to changes in respiratory frequency in relation to tidal volume, allowing responses to situations of emotional stress and low impact exercises. Objective: To evaluate the cardiorespiratory response of the accelerometer with respect to the blended sensor (BS=accelerometer sensor+minute ventilation sensor) to exercise in chagasic patients undergoing cardiopulmonary exercise test. Methods: This was a prospective, observational, randomized, cross-sectional study. Patients who met the inclusion criteria were selected. The maximum heart rate of the sensor was programmed by age (220-age). The results were analyzed through t test with paired samples (P<0.05). Results: Sample was comprised of 44 patients, with a mean

age of 66±10.4 years, 58% were female, 54% as first implant, in 74% were functional class I and 26% were functional class II, left ventricular ejection fraction was 58±7. As for the cardiopulmonary test, maximum expected heart rate and VO2 were not achieved in both the accelerometer sensor and the blended sensor, however, metabolic equivalent in the blended sensor was higher than the expected, all data with P<0.001. Conclusion: Even though the maximal heart rate was not reached, the blended sensor provided a physiological electrical sequence when compared to the accelerometer sensor, providing better physical fitness test in cardiopulmonary hemodynamics and greater efficiency.

Pontifícia Universidade Católica de Goiás (PUC-GO), Goiânia, GO, Brazil.

Correspondence address: Antonio da Silva Menezes Junior Hospital Santa Helena e Pontifícia Universidade Católica de Goiás Rua 95, nº 99, Setor Sul – Goiânia, GO, Brazil - Zip code: 74083-100 E-mail: a.menezes.junior@uol.com.br

1

Descriptors: Chagas Cardiomyopathy. Cardiac Pacing, Artificial. Heart Rate. Prospective Studies. Resumo Introdução: O progresso tecnológico dos marca passos permitiu a associação de dois ou mais sensores em um único siste-

This study was carried out at Hospital Santa Helena e Pontifícia Universidade Católica de Goiás (PUC-GO), Goiânia, GO, Brazil.

Article received on November 21st, 2014 Article accepted on May 17th, 2015

No financial support.

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Objetivo: Avaliar a resposta cardiorrespiratória do acelerômetro em relação ao duplo sensor ao exercício em pacientes chagásicos submetidos ao teste ergoespirométrico. Métodos: Pesquisa prospectiva, observacional, randomizada e cruzada. Foram selecionados pacientes que preenchiam os critérios de inclusão. A frequência cardíaca máxima do sensor foi programada por idade (220-idade). Os resultados obtidos foram analisados pelo Teste T com amostras pareadas (P<0,05). Resultados: Amostra de 44 pacientes, com idade média de 66±10,4, com 58% do sexo feminino, 54% como primeiro implante, classe funcional I em 74% e II em 26%, fração de ejeção do ventrículo esquerdo de 58±7. Quanto ao ergoespirométrico, a frequência cardíaca máxima prevista e a VO2 máxima prevista não foram atingidas tanto no sensor acelerômetro quanto no sensor volume-minuto, contudo, o equivalente metabólico no sensor volume-minuto foi superior à prevista, todos os dados com P<0,001. Conclusão: Apesar da frequência cardíaca máxima não ter sido atingida, o duplo sensor proporcionou uma sequência elétrica mais fisiológica quando comparado ao sensor acelerômetro.

Abbreviations, acronyms & symbols APMHR BS CI GAPC HR MCA MET MVS PUC REC TV

Age-predicted maximal heart rate Blended sensor Chronotropic incompetence Goiás’ Arrhythmia and Pacemaker Center Heart rate Accelerometer Metabolic equivalent Minute ventilation sensor Pontifical Catholic University Research Ethics Committee Tidal volume

ma de resposta de frequência cardíaca. O sensor acelerômetro afere a intensidade da atividade, possui uma resposta relativamente rápida ao início da mesma, porém pode apresentar respostas insuficientes a exercícios físicos menos intensos ou de menor impacto. O sensor volume-minuto altera a taxa de estimulação cardíaca em resposta à variação da frequência respiratória quanto ao volume corrente, permitindo, assim, respostas a situações de estresse emocional e exercícios de baixo impacto.

Descritores: Cardiomiopatia Chagásica. Estimulação Cardíaca Artificial. Estudos Prospectivos. Frequência Cardíaca.

Chronotropic Incompetence Low tolerance to exercising in patients who have Chagas’ disease may be attributed, among other causes, to chronotropic incompetence (CI), defined as the heart’s inability to elevate the HR to proportionally fulfil the raise in metabolic demand[3,4]. An inappropriate chronotropic response to exercising in Chagas Disease patients lowers the maximal O2 consumption (VO2 max) to between 15% and 20%. It reduces the capacity to exercise. The lack of standardization in the CI diagnostic criteria contributes to the large range of estimated prevalence in medical literature (9% to 89%). CI has been commonly diagnosed when there is failure in reaching an arbitrary percentage (85%, 80% and, less frequently, 70%) of the age-predicted maximal heart rate (APMHR), usually estimated by Astrand’s formula (APMHR=220 – age±10) in the exercise stress test[3]. Another variable used in the CI diagnosis is the HR reserve, which is defined as the difference between resting HR and maximal HR during graded exercise stress. When determined in percentages (adjusted HR reserve), most studies consider values lower than 80% of age-predicted heart rate reserve (APHRR)[5]. Therefore, four different types of CI

INTRODUCTION Recent estimates from the World Health Organization indicate that 18 million people are infected by the Trypanosoma cruzi. In addition, two hundred thousand new cases happen every year. After the acute phase of the Chagas Disease, the infected individuals go through its undetermined stage, which has low morbimortality rates. Half of those will remain stable for the rest of their lives. The other half will develop a chronic form of the illness, followed by cardiac and/ or digestive involvement. The chagasic cardiopathy is the most frequent chronic form of the Chagas Disease and it results in, at least, 21,000 deaths around the world every year[1]. Morphological studies have shown that Chagas patients have parasympathetic denervation due to three mechanisms: T. cruzi direct parasitism, degeneration caused by periganglionar inflammation, and autoimmune reaction against the neurons. Besides, these patients have abnormal autonomic cardiac regulation (dysautonomia). Available studies show that it happens because of a lower sensitivity in the sinus node to the sympathetic stimulation and circulating catecholamines as well as some damage to the vagal mediated mechanism, which responds to transitory pressure changes[2].

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with similar clinical repercussion are recognized: (a) failure to reach maximal HR, (b) delay in reaching maximal HR, (c) post-exercise HR inadequate recovery and (d) HR instability during exercise.

in METS, defined as metabolic equivalent, or the enough amount of energy for an individual to keep resting. When the cost is expressed in METS, we know how many times the resting metabolism was multiplied during an activity[6]. Patients signed a n informed consent, and the project was approved by the Research Ethics Committee (REC) from PUC (Pontifical Catholic University)/Goiás, registered under the number 210.294/2013. Patients also underwent anamnesis, besides physical and ergoespirometry tests. The latter happened according to the Bruce protocol, on a treadmill. First, the patients remained in the biosensor ACCEL programming for 6.2±2 months and in DS for 7.1±2.5 months (r>0.05). The biosensors programming corresponded to Astrand’s formula (220 – age). Thus, they were individually programmed (named predicted rate). The patients were encouraged to exercise up to their maximal age or predicted HR (sensor-programmed). The participants were chosen at random among those who used only one sensor or a double one and, then, they were cross-checked. Quantitative variables were described by the average and measure of dispersion (standard deviation). The obtained results were analyzed in the T Test with paired samples (r<0.05) and IBM SPSS 21 program.

Sensing equipment Sensing equipment was introduced in the cardiac stimulation area as an attempt to mimic the sinus node physiological response by promoting heart rate elevation due to the raise in metabolic demand during physical exercise and emotional stress. When compared to fixed heart rate, its benefits are a result of the improvement in hemodynamic status, which is acchieved through the restoration of the cardiac debt to levels that are closer ideal, and a reduction in the arteriovenous oxygen difference. It results in performance and standard of living improvement. In clinical practice, the most used sensing equipment are the accelerometer (ACCEL), which monitors variations in the individual’s acceleration through piezoresistive or piezoelectric material, and the minute volume (MVS), which detects the thoracic impedance resulting from the raise in respiratory rate and tidal volume (TV). The accelerometer sensor (ACCEL) measures the intensity of the activities. Moreover, it responds relatively fast in the beginning of the movements, yet it might present different insufficient responses to less intense or low impact physical exercises. The minute volume sensor (MVS) changes the cardiac stimulation ratio in response to the variation of the respiratory rate concerning the tidal volume. Hence, it allows responses to emotional stress situations and low impact exercises. The recently obtained technological advance regarding the development of the sensing equipment[4], especially the double sensors, and the poor literature on how to use them, particularly in Chagas Disease patients must be taken into account. Therefore, our study aims at evaluating the cardiorespiratory response of the accelerometer towards the double sensor (ACCEL + MVS) as far as exercising in chagasic patients who underwent the ergoespirometry test is concerned.

RESULTS The 44 patients data were kept in their electronic health records, protected with a password in the Goiás Arrhythmia and Pacemaker Center (GAPC). Gender and age were analyzed as epidemiological characteristics. There was predominance of the female gender (58%) and the average age was 66±10.4 years old. Among these patients, 54% underwent the first implant, and 74% had heart failure class I and 26% had class II. The average ejection fraction from the LV through Simpson’s method was 58±7%. In the ergoespirometry test, the maximal predicted HR average obtained by patients was 153.0±9,4 bpm. In the patients whose pacemakers were programmed with the accelerometer, this rate reached 106.3±2.7 bpm, while the ones with double sensor had a 132.5±6.3 bpm value (r<0.0001, shown in Figure 1). As for oxygen consumption, the predicted value of VO2 max was 48.2±1.7. The accelerometer reached 34.9±9.7 and the double sensor reached 23.6±7.1 (r<0.0001). Eventually, the predicted metabolic equivalent (MET) reached a 6.8±1.6 value, with 5.8±1.7 METs in the accelerometer and 7.8±2.3 METs in the double sensor (r<0.0001) (Figures 2, 3 and 4).

METHODS This is a forward-looking, observational, randomized and cross-sectional study, which evaluated 44 patients. They were selected according to the following criteria: presence Chagas Disease, age between 18 and 70 years old, living in Goiânia’s metropolitan zone, having the sinus node disease associated to chronotropic incompetence, and using an artificial dual chamber pacemaker with two sensors, accelerometer and minute volume. VO2 max represents the maximal oxygen consumption as also being the maximal amount of energy that may be produced by the aerobic metabolism in a given time unit. The energy cost in patients in the exercise stress test is given

Arrhythmia Density Analysis a) Atrial: there was no statistically relevant difference between the two groups (r>0.05) b) Ventricular: there was no statistically relevant difference between the two groups (r>0.05)

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Fig. 1 - Averages obtained in the erogoespirometry test. ACCEL=Accelerometer; MET=Metabolic equivalent; DS=Double Sensor

Fig. 2 - Maximal Heart Rate and standard deviation (in bpm) obtained in the ergoespirometry test.

Fig. 4 - Average and standard deviation of metabolic equivalent in the different groups.

DISCUSSION In cardiac conduction system diseases, the chronotropic pathway gets interrupted. Therefore, for the maintenance of normal physiology, there has to be installation of an artificial stimulation system, enough to supply the heart with electric disability. The great pacemakers evolution is due to their circuits and to how they adapt themselves to the metabolic needs of the patients[6], even with so many types of available devices and sensors. The minute volume sensor receives the respiratory rate and it is well related to physical exercise. However, it is not completely reliable in patients with obstructive pulmonary disease and in cases of hyperventilation. The accelerometer

Fig. 3 - VO2 max: value in the ergoespirometry test in the different groups (average and standard deviation).

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sensor measures the body’s activity or movement associated with physical activity. It is the most used sensor due to its low cost and easy programming. Nevertheless, it might not respond well in very intense exercises that involve less body movements or in emotional stress moments at rest[7- 9]. These data support our results. In fact, the statistically relevant difference in the metabolic equivalent (MET), comparing the ACCEL activity to the DS (ACCEL + MVS), works in a complementary way and shows great advantages and improvements in the chronotropic response. The high cost, need for closer following and reduction in the pacemaker operating life may be considered as disadvantages[7,9]. In our results, none of the groups reached maximal predicted HR. That is why we cannot ascertain whether the chronotropic insufficiency is the one that leads to a lower aerobic capacity or vice-versa. In the Rocha et al.[10] study, similar results were found, as far as HR is concerned. It is important to note that, after the adjustment for maximal estimated oxygen consumption, the chagasic patients went on having less aerobic capacity. It proves that the lower aerobic capacity is not the main cause of the chronotropic insufficiency observed amongst the Chagas Disease patients.

REFERENCES 1. Rassi A Jr, Rassi A, Rassi SG. Predictors of mortality in chronic Chagas disease: a systematic review of observational studies. Circulation. 2007;115(9):1101-8. 2. Marin-Neto JA, Cunha-Neto E, Maciel BC, Simões MV. Pathogenesis of chronic Chagas heart disease. Circulation. 2007;115(9):1109-23. 3. Menezes Junior AS, Comerlatto GC, Lopes LHM. O uso da frequência adaptativa na terapia de ressincronização cardíaca: revisão literária. Relampa. 2012;25(2):134-45. 4. Arce M, VAN Grieken J, Femenía F, Arrieta M, McIntyre WF, Baranchuk A. Permanent pacing in patients with Chagas’ disease. Pacing Clin Electrophysiol. 2012;35(12):1494-7. 5. Okin PM, Lauer MS, Kligfield P. Chronotropic response to exercise. Improved performance of ST-segment depression criteria after adjustment for heart rate reserve. Circulation. 1996; 94(12):3226-31. 6. Coelho-Ravagnani CF, Melo FCL, Ravagnani FCP, Burini FHP, Burini RC. Estimation of metabolic equivalent (MET) of an exercise protocol based on indirect calorimetry. Rev Bras Med Esporte. 2013;19(2):134-8.

CONCLUSION Even though the heart rate was not reached, the double sensor provided a more physiological electric sequence compared to the accelerometer sensor.

7. Gilliam FR 3rd, Giudici M, Benn A, Koplan B, Berg KJ, Kraus SM, et al. Design and rationale of the assessment of proper physiologic response with rate adaptive pacing driven by minute ventilation or accelerometer (APPROPRIATE) trial. J Cardiovasc Transl Res. 2011;4(1):21-6. 8. Occhetta E, Bortnik M, Marino P. Usefulness of hemodynamic sensors for physiologic cardiac pacing in heart failure patients. Cardiol Res Pract. 2011;2011:925653.

Authors’ roles & responsibilities ASMJ Researcher APS Analysis and/or interpretation of data; statistical analysis; implementation of projects and/or experiments GGBP Performing operations and/or experiments; manuscript writing or critical review of its content CO Analysis and/or interpretation of data; statistical analysis; study design JFSL Conception and design; implementation of projects and/or experiments

9. Pilat E, Mlynarski R, Wlodyka A, Kargul W. Influence of DDD rate response pacing with integrated double sensors on physical efficiency and quality of life. Europace. 2008;10(10):1189-94. 10 Rocha ALL, Rocha MOC, Teixeira BOS, Lombardi F, Abreu CDG, Bittencourt RJ, et al. Índice cronotrópico-metabólico na doença de Chagas. Rev Soc Bras Med Trop. 2005;38(5):373-6.

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Bohatch Júnior MS, et al. -ARTICLE Incidence of postoperative atrial fibrillation in ORIGINAL patients undergoing on-pump and off-pump coronary artery bypass grafting

Incidence of postoperative atrial fibrillation in patients undergoing on-pump and off-pump coronary artery bypass grafting Incidência de fibrilação atrial no pós-operatório de pacientes submetidos à cirurgia de revascularização do miocárdio com e sem circulação extracorpórea

Milton Sérgio Bohatch Júnior1; Paula Dayana Matkovski1; Frederico José Di Giovanni2, MD; Romero Fenili1, MD, PhD; Everton Luz Varella2, MD; Anderson Dietrich2, MD

DOI 10.5935/1678-9741.20150040

RBCCV 44205-1647

Abstract Objective: To determine the incidence of postoperative atrial fibrillation in patients undergoing on-pump and off-pump coronary artery bypass grafting. Methods: A retrospective study with analysis of 230 medical records between January 2011 and October 2013 was conducted. Results: Fifty-six (24.3%) out of the 230 patients were female. The average age of patients undergoing on-pump coronary artery bypass grafting was 59.91±8.62 years old, and off-pump was 57.16±9.01 years old (P=0.0213). The average EuroSCORE for the on-pump group was 3.37%±3.08% and for the off-pump group was 3.13%±3% (P=0.5468). Eighteen (13.43%) patients who underwent off-pump coronary artery bypass grafting developed postoperative atrial fibrillation, whereas for the onpump group, 19 (19.79%) developed this arrhythmia, with no significant difference between the groups (P=0.1955). Conclusion: Off-pump coronary artery bypass grafting did not reduce the incidence of atrial fibrillation in the postopera-

tive period. Important predictors of risk for the development of this arrhythmia were identified as: patients older than 70 years old and presence of atrial fibrillation in perioperative period in both groups, and non-use of beta-blockers drugs postoperatively in the on-pump group.

Universidade Regional de Blumenau (FURB), Blumenau, SC, Brazil. Hospital Santa Isabel (HSI), Blumenau, SC, Brazil.

Correspondence address: Milton Sérgio Bohatch Júnior Hospital Santa Isabel/Setor de Cirurgia Cardiovascular Rua Mal. Floriano Peixoto, nº 300 – Centro, Blumenau, SC, Brasil Zip code: 89010-500 E-mail: milton.jr87@hotmail.com

1 2

Descriptors: Atrial Fibrillation. Myocardial Revascularization. Postoperative Complications. Resumo Objetivo: Determinar a incidência de fibrilação atrial no pós -operatório de pacientes submetidos à cirurgia de revascularização do miocárdio com e sem circulação extracorpórea. Métodos: Foi realizado um estudo retrospectivo com análise de 230 prontuários entre janeiro de 2011 e outubro de 2013. Resultados: Do total de 230 pacientes, 56 (24,3%) eram do sexo feminino. A média de idade dos pacientes submetidos à ci-

This study was carried out at Hospital Santa Isabel (HSI), Blumenau, SC, Brazil.

Article received on August 24th, 2014 Article accepted on June 8th, 2015

No financial support.

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para o grupo sem circulação extracorpórea foi de 3,13%±3% (P=0,5468). Entre os pacientes que realizaram a cirurgia de revascularização do miocárdio sem circulação extracorpórea, 18 (13,43%) desenvolveram fibrilação atrial no pós-operatório, enquanto no grupo com circulação extracorpórea, 19 (19,79%) desenvolveram esta arritmia, não havendo diferença significativa entre os grupos (P=0,1955). Conclusão: A cirurgia de revascularização do miocárdio sem circulação extracorpórea não diminuiu a incidência de fibrilação atrial no período pós-operatório. Identificamos como preditores de risco para o desenvolvimento desta arritmia: idade superior a 70 anos e presença de fibrilação atrial no período transoperatório em ambos os grupos estudados, e o não uso de medicamentos betabloqueadores no pós-operatório do grupo com circulação extracorpórea.

Abbreviations, acronyms & symbols AF Atrial fibrillation ARF Acute renal failure CABG Coronary artery bypass grafting CCU Coronary care unit COPD Chronic obstructive pulmonary disease CPB Cardiopulmonary bypass CRF Chronic renal failure DM Diabetes mellitus ECG Electrocardiograms FURB Regional University of Blumenau ICU Intensive care units PTCA Percutaneous transluminal angioplasty PVD Peripheral vascular disease

rurgia de revascularização do miocárdio com circulação extracorpórea foi de 59,91±8,62 anos, e sem circulação extracorpórea, foi de 57,16±9,01 anos (P=0,0213). A média do Euroscore para o grupo com circulação extracorpórea foi de 3,37%±3,08% e

Descritores: Fibrilação Atrial. Revascularização Miocárdica. Complicações Pós-Operatórias.

INTRODUCTION

CPB[4]. Some of the conditions associated with the onset of AF after surgery include: infections, prolonged mechanical ventilation, hemodynamic instability, myocardial ischemia and low cardiac output in the postoperative period[10]. The prevalence of AF, its impact on the health system costs and the patients’ recovery justify the demand for clarification of triggers and therapeutic procedures to reduce AF in the postoperative period. In this context, the off-pump CABG has been explored as an emerging technique that can reduce the adverse effects of the on-pump technique, which predisposes to AF. The number of off-pump procedures performed has increased significantly in recent years. However, definitive conclusions about the incidence of AF in on-pump and in off-pump CABG surgeries have not been well established yet[11,12]. The objective of this study is to determine the incidence of AF in the postoperative period of patients undergoing onpump and off-pump CABG and to identify predictors of risk associated with the development of this arrhythmia.

Atrial fibrillation (AF) is a common complication after cardiac surgery, affecting about 10% to 40% of patients undergoing Coronary Artery Bypass Grafting (CABG)[1-3]. This arrhythmia occurs most frequently in the first five days of the postoperative period, peaking between 24 and 72 hours, being uncommon after the first week[3,4]. The postoperative AF represents a four-fold increased risk of stroke in comparison to the evolution of patients who remain in sinus rhythm[5]. It is meaningfully associated with postoperative complications, such as heart failure, hypoxia, hypovolemia, sepsis and electrolyte disturbances[6], as well as it doubles the overall mortality rate in the postoperative period[7]. Such complications increase significantly the cost of surgical treatment by extending the hospital stay, present higher readmission in Intensive Care Units (ICU), prolong the duration of mechanical ventilation, increase the need for vasoactive drugs, ventricular assist devices and even reintubation[8]. The onset of AF after cardiac surgery is associated with preoperative, intraoperative and postoperative factors[9]. Among the preoperative clinical findings, advanced age is considered an independent predictor of AF[2,3], present in about 50% of patients older than 80 years-old[4]. The intraoperative factors can be consequent to cardiac ischemia and inflammation inherent to the complexity of the surgical technique. In these situations, the time of aortic clamping, handling and atrial cannulation and the use of cardiopulmonary bypass (CPB) are reported as factors that support the installation of AF[8]. The CABG with CPB (on-pump CABG) appears to be associated with a higher incidence of AF in the postoperative compared to off-pump CABG. However, some studies reported no relevant difference in the incidence of this arrhythmia regarding the use or not of

METHODS A retrospective cohort study was conducted with 230 consecutive medical records of patients that underwent onpump and off-pump CABG from January 2011 to October 2013 in the Heart Surgery Service of Santa Isabel Hospital, in Blumenau, Santa Catarina, Brazil. The respective protocol was approved by the Ethics Committee on Human Research of the Regional University of Blumenau (FURB) under number 203/12. Inclusion criteria: - All patients undergoing elective CABG. Exclusion criteria:

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· Chronic AF and/or other cardiac arrhythmias documented. · Heart valve disease. · Emergency surgery. · Cardiac reoperation. They were divided in two groups: patients undergoing onpump CABG (96 patients) and patients undergoing off -pump CABG (134 patients). Data were grouped in preoperative, intraoperative, and postoperative variables. Subsequently, the variables were evaluated in a comparative way. The preoperative variables were: age, sex, smoking, Diabetes Mellitus (DM), hypertension, dyslipidemia, Peripheral Vascular Disease (PVD), use of medications (statins and/ or beta-blockers), Chronic Obstructive Pulmonary Disease (COPD), extra cardiac artery disease, Acute Renal Failure (ARF) or Chronic Renal Failure (CRF), neurological dysfunction, prior and acute Percutaneous Transluminal Angioplasty (PTCA) or chronic coronary insufficiency. The EuroSCORE was calculated for all patients. The perioperative variables were: complications (increased bleeding, hemodynamic instability, arrhythmias, need for pacemaker and/or intra-aortic balloon, acute myocardial infarction), number of grafts, the need for transfusion (packed red blood cells, fresh frozen plasma and platelets), use of vasoactive drugs (noradrenaline, dobutamine, dopamine, nitroglycerin and/or sodium nitroprusside), CPB time (in minutes), aortic clamping time (in minutes) and mortality. It is important to emphasize that each case was individually analyzed for the need of blood transfusion, taking into account the hemodynamic conditions, the volume of bleeding, the patient’s age and history of bleeding disorders. Generically, the bleeding was considered significant when the delivery of chest tubes in the immediate postoperative period was 150 mL/h for more than 3 consecutive hours, or output rate greater than 500 mL in 6 hours, or output rate greater than 1000 mL in 24 hours. The postoperative variables were: Coronary Care Unit (CCU) time, hospital stay, use of vasoactive drugs (noradrenaline, dobutamine, dopamine, nitroglycerin and/or sodium nitroprusside), use of medications (statins and/or beta-blockers) and need for blood products. The complications in the CCU considered were: increased bleeding, need for reoperation, infection (in the surgical wound, pneumonia and/or sepsis), neuropsychiatric (ischemic stroke, delirium and/or altered levels of consciousness), ARF, acute abdomen, pneumothorax, haematological disorders (anemia and/or thrombocytopenia), cardiac disorders (hemodynamic instability, pericarditis, cardiorespiratory arrest, myocardial infarction, circulatory shock and/or use of intra-aortic balloon) and mortality. The analyzed outcome was the incidence of postoperative AF in on-pump and off-pump CABG. The presence of AF in the postoperative period was determined by analysis of electrocardiograms (ECG) present in the medical records. All patients undergoing CABG in this study underwent 12-lead ECG in the immediate postoperative period, every 24 hours

during hospitalization in CCU and in the infirmary, and 24 hours prior to discharge. Data were organized in descriptive tables containing: frequency, mean and standard deviation. The average and proportions estimate were made with a 95% confidence interval. In order to compare the frequencies within the same distribution, it was used the Chi-Squared test of adherence. For the association of categorical variables with the groups, it was used Chi-Squared test of independence in cases of frequencies equal to or greater than 5, and Fisher’s exact test, in cases of frequencies below 5. For the analysis of continuous variables the Student t test was used. In all tests, the significance is considered when P value < 0.05. Data analysis was performed on Microsoft Excel 2010 software and EpiInfo version 7, 2012. The off-pump CABG has become the preferred technique at this service since 2008. It is currently used in approximately 80% of CABG surgery. During the study period, the main criterion used to display on-pump and off-pump CABG was the experience of surgeons. Regarding the surgical data, all patients were submitted to balanced general anesthesia. In the off-pump group, 362 arterial and venous grafts were performed, and about 3 grafts per patient. In this technique, no drug was used for myocardial protection and reperfusion with “bypass” was held only in the proximal right coronary anastomoses. In the on-pump group, 275 arterial and venous grafts were performed, and about 3 grafts per patient. Nipro oxygenator and Saint Thomas Braille cardioplegia for myocardial protection were used. The patients in this group underwent systemic hypothermia 30-32oC. The preoperative variables are shown in Table 1. Fifty-six (24.3%) out of the 230 patients, were female and 174 (75.7%) were male. The average age of patients undergoing on-pump CABG was 59.91±8.62 years-old and off-pump was 57.16±9.01 years-old (P=0.0213). Thirty-five patients were younger than 50 years-old, 26 (19.4%) from the group that underwent off-pump surgery and 9 (9.4%) from the group undergoing on-pump CABG, with significant differences between both groups (P=0.0360). The other preoperative variables are equally distributed between the groups (P>0.05). The average EuroSCORE for the on-pump group was 3.37%±3.08% and for the off-pump group was 3.13%±3% (P=0.5468). RESULTS The intraoperative variables are shown in Table 2. It was observed a higher consumption of blood products in the on-pump when compared to off-pump CABG (64.58% vs. 20.9%; P<0.001), mainly represented by red blood cell units (2.35±0.89 in the on-pump group and 1.71±0.73 in the off-pump group; P=0.0164). Off-pump group showed higher tendency to develop AF, however there was no statistical difference between groups (P=0.0560). The other intraoperative variables are equally distributed between the groups (P>0.05) and there were no deaths in this period.

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Table 1. Preoperative variables of patients undergoing on-pump and off-pump coronary artery bypass grafting. Technical Features Age (years) (mean±SD) Age < 50 50 ≤ i < 60 60 ≤ i < 70 70 ≤ i < 80 Age ≥ 80 Female patients EuroSCORE Statins Beta-blocker Chronic coronary insufficiency Prior percutaneous angioplasty Diabetes Mellitus Hypertension Dyslipidemia Peripheral vascular disease Cerebrovascular disease Arteriopathy extracardiac Acute or chronic renal failure Chronic obstructive pulmonary disease Smokers

On-Pump (n=96) (59.91±8.62) 9 (9.4%) 43 (44.8%) 31 (32.3%) 11 (11.5%) 2 (2.1%) 23 (24.2%) (3.37%±3.08%) 87 (90.6%) 87 (90.6%) 45 (46.9%) 30 (31.25%) 30 (31.25%) 73 (76.04%) 64 (66.67%) 4 (4.17%) 6 (6.25%) 61 (63.54%) 6 (6.25%) 8 (8.3%) 23 (24%)

Off-Pump (n=134) (57.16±9.01) 26 (19.4%) 52 (38.8%) 45 (33.6%) 10 (7.5%) 1 (0.7%) 33 (24.6%) (3.13%±3%) 120 (89.6%) 111 (82.8%) 73 (54.5%) 36 (26.87%) 47 (35.07%) 107 (79.85%) 86 (64.18%) 9 (6.72%) 11 (8.21%) 73 (54.48%) 8 (5.97%) 13 (9.7%) 30 (22.4%)

P Value 0.0213 0.0360 0.3632 0.8374 0.2995 0.9424 0.5468 0.7891 0.0923 0.2553 0.4685 0.5444 0.4898 0.6961 0.4089 0.5755 0.1692 0.9302 0.7224 0.2539

Table 2. Intraoperative variables of patients undergoing on-pump and off-pump coronary artery bypass grafting. Technical Features On-Pump Off-Pump P Value (n=96) (n=134) Number of grafts (Mean±SD) (2.86±0.75) (2.7±0.86) 0.1357 Blood products 62 (64.58%) 28 (20.9%) 0.0000 Packed red blood cells (units) (2.35±0.89) (1.71±0.73) 0.0164 Fresh frozen plasma (units) (2.74±0.89) (2.42±0.51) 0.0957 Platelets (units) (8.6±3.66) (7.33±2.52) 0.5911 Sympathomimetic drugs 41 (42.71%) 58 (43.28%) 0.9308 Dobutamine 26 (27.08%) 40 (30.08%) 0.6218 Noradrenaline 11 (11.46%) 17 (12.78%) 0.7629 Dopamine 10 (10.42%) 10 (7.46%) 0.4330 Vasodilators drugs 22 (22.92%) 29 (21.64%) 0.8185 Nitroglycerine 7 (7.29%) 12 (8.96%) 0.6513 Sodium nitroprusside 18 (18.75%) 18 (13.53%) 0.2846 Complications 27 (28.13%) 46 (34.33%) 0.3189 Increased bleeding 5 (5.21%) 6 (4.48%) 0.7979 Hemodynamic instability 13 (13.54%) 20 (14.93%) 0.7678 Arrhythmias 9 (9.38%) 23 (17.16%) 0.0923 Atrial fibrillation 1 (1.04%) 8 (6.02%) 0.0560 Pacemaker 2 (2.08%) 1 (0.75%) 0.3781 Intra-aortic balloon 3 (2.24%) 0.1400 Acute myocardial infarction 3 (2.24%) 0.1400 Mortality -

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Postoperative variables are shown in Table 3. The group undergoing on-pump CABG showed a higher incidence of anemia, when compared to the off-pump group (27.08% vs. 16.42%, P=0.0497). On-pump group also presented major bleeding when compared to off-pump group (12.5% vs. 2.99%, P=0.0052). For other events there was no statistical difference (P>0.05). In the off-pump group, 18 (13.43%) patients developed AF in the postoperative period, while in the on-pump group, 19 (19.79%) developed this arrhythmia, with no significant difference (P=0.1955). Relations between the main risk factors for the develop-

ment of AF in the postoperative period and the occurrence of this arrhythmia in the groups studied are described in Tables 4 and 5. Among the preoperative risk factors, age over 70 years old is strongly associated with the development of AF in both groups (22.2%; P=0.0047 in the off-pump group and 31.6% in the on-pump group; P=0.0021). There was a tendency in developing this arrhythmia in the on-pump group patients with hypertesion (42.1%; P=0.0545), although this was not statistically significant. Similarly, analyzing the non-use of beta-blocker drugs, the off-pump group had a tendency to develop AF (33.3%; P=0.0505).

Table 3. Postoperative variables of patients undergoing on-pump and off-pump coronary artery bypass grafting. Technical Features Atrial Fibrillation Sympathomimetic drugs Dobutamine Noradrenaline Dopamine Adrenalin Vasodilators drugs Nitroglycerine Sodium nitroprusside Statins Beta-blocker Blood products Complications coronary care unit Increased bleeding Reoperation Infectious complications Wound infection (chest) Bronchopneumonia Sepsis Delirium/altered levels of consciousness Ischemic stroke Acute renal failure Acute abdomen Pneumothorax/Pneumomediastinum Anemia Thrombocytopenia Hemodynamic instability Pericarditis Cardiopulmonary arrest Acute myocardial infarction Circulatory shock Intra-aortic balloon Time of Coronary Care Unit (days) Length of hospital stay (days) Mortality

On-Pump (n=96) 19 (19.79%) 57 (59.38%) 28 (29.17%) 43 (44.79%) 3 (3.13%) 1 (1.04%) 43 (44.79%) 28 (29.17%) 25 (26.04%) 91 (94.79%) 85 (88.54%) 27 (28.13%)

Off-Pump (n=134) 18 (13.43%) 76 (56.72%) 43 (32.09%) 48 (35.82%) 4 (2.99%) 63 (47.01%) 53 (39.55%) 25 (18.66%) 127 (94.78%) 118 (88.06%) 25 (18.66%)

P Value

12 (12.5%) 8 (8.33%) 2 (2.1%) 5 (5.21%) 2 (2.08%) 7 (7.29%) 1 (1.04%) 4 (4.17%) 2 (2.08%) 2 (2.08%) 26 (27.08%) 1 (1.04%) 10 (10.42%) 1 (1.04%) 4 (4.2%) 1 (1.04%) 4 (4.17%) (3.21±2.23) (8.19±7.35) 6 (6.3%)

4 (2.99%) 1 (0.75%) 8 (5.97%) 1 (0.7%) 7 (5.22%) 1 (0.75%) 12 (8.96%) 2 (1.49%) 2 (1.49%) 4 (2.99%) 22 (16.42%) 3 (2.24%) 7 (5.22%) 4 (2.99%) 4 (3%) 2 (1.49%) 3 (2.24%) 1 (0.75%) (3.22±2.7) (7.93±3.99) 3 (2.2%)

0.0052 0.3963 0.4873 0.3781 0.9958 0.3781 0.6513 0.7663 0.2096 0.0933 0.6722 0.0497 0.4934 0.1377 0.3189 0.6296 0.7663 0.4013 0.3963 0.9619 0.7513 0.1218

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0.1955 0.6872 0.6361 0.1701 0.9514 0.2364 0.7387 0.1039 0.1806 0.9958 0.9108 0.0905


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Table 4. Association of the variables with groups that have and have not developed postoperative atrial fibrillation in patients undergoing off-pump CABG. Variables Preoperative Female Age (> 70 years) Hypertension Diabetes Mellitus Chronic obstructive pulmonary disease Non-use of beta-blocker Non-use of statins Intraoperative Blood products Arrhythmias Atrial fibrillation Ventricular fibrillation Ventricular extrasystole Sinus tachycardia Postoperative Time of Coronary Care Unit (days) Length of hospital stay (days) Non-use of beta-blocker Non-use of statins Vasoactive drugs Infectious complications Mortality

Developed atrial fibrillation (n=18)

Not developed atrial fibrillation (n=116)

P Value

6 (33.3%) 4 (22.2%) 5 (27.8%) 9 (50%) 1 (5.6%) 6 (33.3%) 2 (11.1%)

27 (23.3%) 5 (4.3%) 22 (19%) 38 (32.8%) 12 (10.3%) 17 (14.7%) 12 (10.3%)

0.3568 0.0047 0.3858 0.1538 0.5230 0.0505 0.9212

5 (27.8%) 4 (22.2%) 3 (16.7%) 3 (16.7%) 0 (0%) 0 (0%)

23 (19.8%) 19 (16.4%) 5 (4.3%) 7 (6.1%) 2 (1.7%) 2 (1.7%)

0.4402 0.5408 0.0410 0.1135 0.5729 0.5729

(4.72±3.32) (9.89±4.09) 2 (11.1%) 2 (11.1%) 13 (72.2%) 2 (11.1%) 0 (0%)

(2.91±2.25) (7.62±3.91) 14 (12.1%) 5 (4.3%) 63 (54.3%) 6 (5.2%) 3 (2.6%)

0.0374 0.0244 0.9072 0.2276 0.1536 0.3225 0.4902

Table 5. Association of the variables with groups that have and have not developed postoperative atrial fibrillation in patients undergoing on-pump CABG. Variables Preoperative Female Age (> 70 years) Hypertension Diabetes Mellitus Chronic obstructive pulmonary disease Non-use of beta-blocker Non-use of statins Intraoperative Aortic clamping time Cardiopulmonary bypass time Blood products Arrhythmias Atrial fibrillation Ventricular fibrillation Ventricular extrasystole Sinus tachycardia Postoperative Time of Coronary Care Unit (days) Length of hospital stay (days) Increased bleeding Non-use of beta-blocker Non-use of statins Vasoactive drugs Infectious complications Mortality

Developed atrial fibrillation (n=19)

Not developed atrial fibrillation (n=77)

P Value

5 (26.3%) 6 (31.6%) 8 (42.1%) 5 (26.3%) 2 (10.5%) 0 (0%) 1 (5.3%)

18 (23.7%) 5 (6.5%) 16 (20.8%) 25 (32.5%) 6 (7.8%) 9 (11.7%) 8 (10.4%)

0.8107 0.0021 0.0545 0.6044 0.6994 0.1175 0.4923

(67.11±17.18) (100±23.69) 12 (63.2%) 2 (10,5%) 1 (5.3%) 1 (5.3%) 0 (0%) 0 (0%)

(69.41±21.26) (104.41±26.6) 50 (64.9%) 7 (9.1%) 0 (0%) 3 (3.9%) 1 (1.3%) 0 (0%)

0.66299 0.51121 0.8847 0.8476 0.0430 0.7894 0.6175 -

(4.53±3.11) (10.26±11.26) 2 (10.5%) 5 (26.3%) 2 (10.5%) 14 (73.7%) 4 (21.1%) 4 (21.1%)

(2.89±1.69) (7.68±6.01) 3 (3.9%) 6 (7.8%) 3 (3.9%) 43 (55.8%) 4 (5.2%) 2 (2.6%)

0.0652 0.3440 0.2441 0.0232 0.2441 0.1562 0.0251 0.0029

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Amongst the intraoperative risk factors, only the presence of AF during surgery showed relation to the development of this arrhythmia in the postoperative period in both groups, on-pump CABG (5.3%; P=0.0430) and off-pump (16.7%; P=0.0410). Amongst the postoperative risk factors in the off-pump group, CCU time and hospital stay were remarkably higher in patients who developed AF (4.72Âą3.32; P=0.0374 and 9.89Âą4.09; P=0.0244, respectively) when compared to those who did not develop this arrhythmia. Analyzing the non-use of beta-blocker drugs, there was a strong association with the development of AF in the on-pump group (26.3%; P=0.0232). This group showed expressive relationship between the presence of infectious complications and the development of this arrhythmia (21.1%; P=0.0251). The overall mortality of 230 patients undergoing CABG was 3.91%. Six (6.3%) out of the 96 patients in the on-pump group died, compared to 3 (2.2%) out of 134 patients in the off-pump group (P=0.1218). Mortality in the on-pump group was notably higher in patients who developed AF when compared to patients who did not develop the arrhythmia (21.1%; P=0.0029). No deaths were observed in patients undergoing off-pump CABG that developed postoperative AF.

sults in an inflammatory response that may also be involved in the development of AF[4,13,17]. In view of these aspects, it is expected that off-pump CABG be associated with a lower incidence of AF in the postoperative period. Although some studies show such benefit[13], they are still controversial. In a comparative study between on-pump and off-pump CABG, the on-pump group had major complications, such as stroke, reoperation for bleeding, prolonged mechanical ventilation, AF and period of hospitalization[18]. Some well-designed clinical trials comparing the two techniques showed no significant difference in the incidence of arrhythmias, especially of AF[15,19]. In this study, the overall incidence of AF after CABG was 16.1%, similar that found in other studies[14,16]. However, there was no significant difference in the incidence of AF between groups, being 13.43% in the off-pump group and 19.79% in the on-pump group (P=0.1955). These results were similar those found in other studies[14,15]. Lin et al.[14] observed that off-pump CABG also did not reduce the incidence of postoperative AF. The authors believe that the results can be explained by the greater use of beta-blockers in the preoperative period for the on-pump group. It is believed that the use of beta-blockers preoperatively is an effective measure for the prophylaxis of AF[2,12,16]. In our study, the on-pump group also showed greater use of beta-blocker drugs preoperatively, compared to the off-pump group (90.6% and 82.8%, respectively), but these results were not statistically significant (P=0.0923). A notable increase in cases of AF in patients over 70 was identified, regardless of the method used for myocardial revascularization, and it is the preoperative variable statistically relevant among the analyzed. It is estimated that for each decade of life, there is a 75% increase in the odds of developing AF in the postoperative period[20]. Thus, anyone over 70 has a high risk of developing AF[20]. Aging causes degenerative changes in the atrial myocardium, leading to changes in the electrical characteristics of the sinus and AV nodes, which contributes to fragment the impulse propagation[21]. In these patients, the atrium is generally dilated, hypertrophic and/or with fibrosis areas, compromising the structure and function of the sinus node[16]. Often, patients older than 70 years-old are carriers of atherosclerosis, hypertension and/or diabetes mellitus, in addition to having reduced cardiopulmonary reserve as to the younger, contributing greatly to the genesis of AF[16]. In perioperative period, we found in both groups, the occurrence of AF in this period is a predictor for recurrence postoperatively, which is not observed in other analyzed arrhythmias. It is known that prior AF is a risk factor for development of AF in the postoperative period[4,16]. It is speculated that vulnerable individuals with AF, present electrophysiological pro-arrhythmic substrate, which is then exacerbated by surgery[4]. Therefore, the occurrence of AF during surgery could expose susceptible individuals with great potential for

DISCUSSION Atrial fibrillation is the most common arrhythmia in the postoperative period of patients undergoing CABG[13,14]. The presence of this arrhythmia is associated with longer clinical recovery time, besides being able to worsen the hemodynamic state of the patient, to increase the risk of congestive heart failure and trigger thromboembolic events[5,14,15]. The increased morbidity and the consequent prolongation of hospitalization significantly increase the hospital costs[14,15]. Unlike non-surgical cases, the AF in the postoperative period does not have a well-defined cause, but recent studies suggest multifactorial mechanism, involving: oxidative stress, inflammation, atrial fibrosis, changes in autonomic tonus and connexin expression, that increase the dispersion of atrial refractoriness and favor the formation of a proarrhythmic substrate[16]. Some risk factors are related to increased incidence of AF in the postoperative period of cardiac surgery. Among these factors are: paroxysmal AF history, previous myocardial infarction, DM, hypertension, COPD, discontinuation of beta-adrenergic drugs preceding surgery, aortic clamping time, postoperative ischemia and vasoactive amines[16]. Advanced age is one of the most important factors being considered an independent predictor of this arrhythmia after CABG[2,16]. Studies showed the use of CPB as an important risk factor involved in the development of AF, which can be explained by the resulting ischemia of cardioplegia, the CPB time, as well as the cannulation and aortic clamping[4,13,17]. In addition, blood contact with non-physiological surfaces of CPB machine re-

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recurrence postoperatively. Also, the arrhythmia during surgery can result from individuals with paroxysms of AF with spontaneous resolution which were undiagnosed. In the postoperative period, we observed the association of non-use of beta-blocker drugs and the development of postoperative AF in on-pump group. Some studies[3,21,22] showed beta-blockers are effective in preventing postoperative AF. It is believed that the increased sympathetic tonus may predispose patients to the development of AF, and therefore, beta-blockers can prevent this arrhythmia to modulate this pathway[13]. Previous studies have shown that the presence of AF postoperative can increase hospitalization in 2-4 days, thus increasing the cost of treatment[23]. This study showed that the development of postoperative AF in the off-pump CABG is associated with increased length of stay in the CCU and longer total hospitalization compared to patients who did not develop AF. However, there was no statistical difference in mortality to the same group. The on-pump group showed no significant difference in the length of stay, but showed higher mortality in patients who developed AF compared to those who did not develop the arrhythmia. This can be explained by the fact that patients undergoing CABG with CPB had higher rates of infectious complications. The overall mortality in this study was 3.91%, comparable to the study of Sá et al.[24] which showed a mortality of 3.5% for patients classified as moderate risk (EuroSCORE 3-5). As well as the results of the study of Shroyer et al.[25], we found no statistical difference in mortality between onpump and off-pump CABG.

REFERENCES 1. Abbaszadeh M, Khan ZH, Mehrani F, Jahanmehr H. Perioperative intravenous corticosteroids reduce incidence of atrial fibrillation following cardiac surgery: a randomized study. Rev Bras Cir Cardiovasc. 2012;27(1):18-23. 2. Avila Neto V, Costa R, Silva KR, Martins AL, Moreira LF, Santos LB, et al. Effect of temporary right atrial pacing in prevention of atrial fibrillation after coronary artery bypass graft surgery. Rev Bras Cir Cardiovasc. 2007;22(3):332-40. 3. Da Silva RG, de Lima GG, Guerra N, Bigolin AV, Petersen LC. Risk index proposal to predict atrial fibrillation after cardiac surgery. Rev Bras Cir Cardiovasc 2010;25(2):183-9. 4. Ferro CRC, De Oliveira DC, Nunes FP, Piegas LS. Fibrilação atrial no pós-operatório de cirurgia cardíaca. Arq Bras Cardiol. 2009;93(1):59-63. 5. Barbieri LR, Sobral ML, Gerônimo GM, Dos Santos GG, Sbaraíni E, Dorfman FK, Stolf NA. Incidence of stroke and acute renal failure in patients of postoperative atrial fibrillation after myocardial revascularization. Rev Bras Cir Cardiovasc. 2013;28(4):442-8. 6. Auer J, Weber T, Berent R, Ng CK, Lamm G, Eber B. Risk factors of postoperative atrial fibrillation after cardiac surgery. J Card Surg. 2005;20(5):425-31. 7. Fuster V, Rydén LE, Cannom DS, Crijins HJ, Curtis AB, Ellenbogen KA, et al.; American College of Cardiology; American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ ESC Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-354.

CONCLUSION Off-pump CABG did not reduce the incidence of AF in the postoperative period. We identified as predictors of risk for developing this arrhythmia: patients older than 70 yearsold and the presence of AF in the perioperative period in both groups, and non-use of beta-blocker drugs postoperatively in on-pump group.

8. Magee MJ, Herbert MA, Dewey TM, Edgerton JR, Ryan WH, Prince S, et al. Atrial fibrillation after coronary artery bypass grafting surgery: development of a predictive risk algorithm. Ann Thorac Surg. 2007;83(5):1707-12.

Authors’ roles & responsibilities MSBJ PDM FJDG RF ELV AD

Analysis and/or interpretation of data; implementation of projects and/or experiments; manuscript writing or critical review of its content Analysis and/or interpretation of data; implementation of projects and/or experiments; manuscript writing or critical review of its content Final approval of the manuscript; manuscript writing or critical review of its content Study design Final approval of the manuscript Final approval of the manuscript; study design; manuscript writing or critical review of its content

9. Jakubová M, Mitro P, Stančák B, Sabol F, Kolesár A, Cisarik P, et al. The occurrence of postoperative atrial fibrillation according to different surgical settings in cardiac surgery patients. Interact Cardiovasc Thorac Surg. 2012;15(6):1007-12. 10. Sobczyk D, Sadowski J, Sniezek-Maciejewska M. Causes of atrial fibrillation early after coronary bypass grafting. Przegl Lek. 2005;62(3):141-7. 11. Alamanni F, Dainese L, Naliato M, Gregu S, Agrifoglio M,

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Polvani GL, et al. On- and off-pump coronary surgery and perioperative myocardial infarction: an issue between incomplete and extensive revascularization. Eur J Cardiothorac Surg. 2008;34(1):118-26.

19. Athanasiou T, Aziz O, Mangoush O, Weerasinghe A, Al-Ruzzeh S, Purkayasha S, et al. Do off-pump techniques reduce the incidence of postoperative atrial fibrillation in elderly patients undergoing coronary artery bypass grafting? Ann Thorac Surg. 2004;77(5):1567-74.

12. Tineli RA, Rosa e Silva Junior J, Luciano PM, Rodrigues AJ, De Andrade VWV, Evora PRB. Fibrilação atrial e cirurgia cardíaca: uma história sem fim e sempre controversa. Rev Bras Cir Cardiovasc. 2005;20(3):323-31.

20. Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, et al.; Investigators of the Ischemia Research and Education Foundation; Multicenter Study of Perioperative Ischemia Research Group. A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA. 2004;291(14):1720-9.

13. Hashemzadeh K, Dehdilani M, Dehdilani M. Does Off-pump Coronary Artery Bypass Reduce the Prevalence of Atrial Fibrillation? J Cardiovasc Thorac Res. 2013;5(2):45-9.

21. Allessie MA, Boyden PA, Camm AJ, Kléber AG, Lab MJ, Legato MJ, et al. Pathophysiology and prevention of atrial fibrillation. Circulation. 2001;103(5):769-77.

14. Lin WS, Liou JT, Yang SP, Tsai CS, Chung MH, Chu KM. Can off-pump coronary artery bypass graft surgery decrease the incidence of postoperative atrial fibrillation? Acta Cardiol Sin. 2006;22(4):205-11.

22. Koniari I, Apostolakis E, Rogkakou C, Baikoussis NG, Dougenis D. Pharmacologic prophylaxis for atrial fibrillation following cardiac surgery: a systematic review. J Cardiothorac Surg. 2010;5:121.

15. Place DG, Peragallo RA, Carroll J, Cusimano RJ, Cheng DC. Postoperative atrial fibrillation: a comparison of off-pump coronary artery bypass surgery and conventional coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2002;16(2):144-8.

23. Mirhosseini SJ, Forouzannia SK, Ali-Hassan-Sayegh S, HadadZadeh M, Abdollahi MH, Moshtaghiom H, et al. On pump versus off pump coronary artery bypass surgery in patients over seventy years old with triple vessels disease and severe left ventricle dysfunction: focus on early clinical outcomes. Acta Med Iran. 2013;51(5):320-3.

16. Oliveira DC, Ferro CR, Oliveira JB, Prates GJ, Torres A, Egito EST, et al. Fibrilação atrial no pós-operatório de cirurgia de revascularização do miocárdio: características do perfil clínico associadas a óbitos hospitalares. Arq Bras Cardiol. 2007;89(1):16-21. 17. Raja SG, Dreyfus GD. Current status of off-pump coronary artery bypass surgery. Asian Cardiovasc Thorac Ann. 2008;16(2):164-78.

24. Sá MPBO, Soares EF, Santos CA, Figueredo OJ, Lima ROA, Escobar RR, et al. EuroSCORE e mortalidade em cirurgia de revascularização miocárdica no Pronto Socorro Cardiológico de Pernambuco. Rev Bras Cir Cardiovasc. 2010;25(4):474-82.

18. Sá MPB, Lima LP, Rueda FG, Escobar RR, Cavalcanti PEF, Thé ECS, et al. Estudo comparativo entre cirurgia de revascularização miocárdica com e sem circulação extracorpórea em mulheres. Rev Bras Cir Cardiovasc. 2010;25(2):238-44.

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

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Guedes MAV,ORIGINAL et al. - Mitral annulus morphologic and functional analysis ARTICLE using real time tridimensional echocardiography in patients submitted to unsupported mitral valve repair

Mitral annulus morphologic and functional analysis using real time tridimensional echocardiography in patients submitted to unsupported mitral valve repair Análise morfológica e funcional do anel mitral com o uso da ecocardiografia tridimensional em tempo real em indivíduos submetidos à plástica mitral sem o uso de anéis protéticos

Marco Antônio Vieira Guedes1, MD, PhD; Pablo Maria Alberto Pomerantzeff1, MD, PhD; Carlos Manuel de Almeida Brandão1, MD, PhD; Marcelo Luiz Campos Vieira1, MD, PhD; Flávio Tarasoutchi1, MD, PhD; Pablo da Cunha Spinola1, MD, PhD; Fábio Biscegli Jatene1, MD, PhD

DOI 10.5935/1678-9741.20140082

RBCCV 44205-1648

Abstract Introduction: Mitral valve repair is the treatment of choice to correct mitral insufficiency, although the literature related to mitral valve annulus behavior after mitral repair without use of prosthetic rings is scarce. Objective: To analyze mitral annulus morphology and function using real time tridimensional echocardiography in individuals submitted to mitral valve repair with Double Teflon technique. Methods: Fourteen patients with mitral valve insufficiency secondary to mixomatous degeneration that were submitted to mitral valve repair with the Double Teflon technique were included. Thirteen patients were in FC III/IV. Patients were evaluated in preoperative period, immediate postoperative period, 6 months and 1 year after mitral repair. Statistical analysis was made by repeated measures ANOVA test and was considered statistically significant P<0.05. Results: There were no deaths, reoperation due to valve dysfunction, thromboembolism or endocarditis during the study.

Posterior mitral annulus demonstrated a significant reduction in immediate postoperative period (P<0.001), remaining stable during the study, and presents a mean of reduction of 25.8% comparing with preoperative period. There was a significant reduction in anteroposterior and mediolateral diameters in the immediate postoperative period (P<0.001), although there was a significant increase in mediolateral diameter between immediate postoperative period and 1 year. There was no difference in mitral internal area variation over the cardiac cycle during the study. Conclusion: Segmentar annuloplasty reduced the posterior component of mitral annulus, which remained stable in a 1-year-period. The variation in mitral annulus area during cardiac cycle remained stable during the study.

Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP (InCor HC-FMUSP), São Paulo, SP, Brazil. This study was carried out at the Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP (InCor HC-FMUSP), São Paulo, SP, Brazil.

Correspondence address: Marco Antônio Vieira Guedes Instituto do Coração Av. Dr. Enéas de Carvalho Aguiar, 44 Bloco II 2º andar - Sala 13 – Pinheiros, São Paulo, SP, Brazil - Zip code: 05403-900 E-mail: guedesmarco@gmail.com

Financial support Fapesp - Fundação de Amparo à Pesquisa do Estado de São Paulo (Project 06/50454-4).

Article received on March 17th, 2014 Article accepted on June 22nd, 2014

Descriptors: Mitral Valve. Mitral Valve Annuloplasty. Mitral Valve Insufficiency. Echocardiography. Echocardiography, Three-Dimensional.

1

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-operatório imediato, 6 meses e 1 ano. Foi utilizado teste de análise de variância de medidas repetidas para o estudo estatístico, sendo considerado estatisticamente significante P<0,05. Resultados: Não houve óbito, reoperação por disfunção valvar, tromboembolismo ou endocardite durante o estudo. A planimetria posterior do anel mitral demostrou uma redução significativa (P<0,001) no pós-operatório imediato, que se manteve estável durante o estudo, apresentando redução média de 25,8% com 1 ano em relação ao pré-operatório. Houve uma redução significativa dos diâmetros ântero-posterior e médio-lateral no pós-operatório imediato (P<0,001), porém, houve um aumento significativo no diâmetro médio-lateral entre pós-operatório imediato e 1 ano. Não houve diferença na variação da área interna mitral ao longo do estudo. Conclusão: A anuloplastia segmentar reduziu significativamente o componente posterior do anel mitral, permanecendo estável no período de um ano. A variação da área valvar durante o ciclo cardíaco permaneceu estável durante o estudo.

Abbreviations, acronyms & symbols AP Anteroposterior AP Anteroposterior diameter CI Circularity index FC Functional class ML Mediolateral

Resumo Introdução: A plastia valvar mitral é o tratamento de escolha para a insuficiência mitral, porém, a literatura é escassa em relação ao comportamento do anel mitral após a plástica mitral sem utilização de anéis protéticos. Objetivo: Realizar a análise morfofuncional do anel mitral de indivíduos submetidos à plastia valvar mitral pela Técnica de Duplo Teflon, sem utilização de anel protético, por meio da ecocardiografia tridimensional em tempo real. Métodos: Foram incluídos 14 pacientes com insuficiência mitral mixomatosa submetidos à plástica mitral pela técnica de Duplo Teflon. Treze pacientes encontravam-se em classe III/IV. Os pacientes foram avaliados nos períodos pré-operatório, pós-

Descritores: Valva Mitral. Anuloplastia da Valva Mitral. Insuficiência da Valva Mitral. Ecocardiografia Tridimensional. Ecocardiografia.

INTRODUCTION

the cardiac cycle[11] have provided great advances in the techniques for mitral valve conservation. The aim of the present study was to analyze the morphology and functioning of the mitral valve ring in individuals who underwent mitral valvuloplasty by means of the double Teflon technique, using real-time three-dimensional echocardiography.

Epidemiological data have demonstrated that mitral insufficiency secondary to prolapse of the valve, from moderate to severe extent, is the main valve disease in the United States[1] and gives rise to the second most common form of surgically treated heart valve disease in Europe[2]. In Brazil, prolapse of the mitral valve was found to be the etiology of 25.9% of the patients undergoing mitral valvuloplasty, over the course of 12 years of experience at the Heart Institute of Hospital das Clínicas, University of São Paulo Medical School[3]. Previous studies have demonstrated that conserving the mitral valve is better than replacing it[4]. In the technique of quadrangular resection of the posterior cuspid, with plication of the corresponding ring and edge-to-edge suturing of the cuspids, the use of prosthetic rings is still a matter for discussion[5]. In Brazil, Pomerantzeff et al.[6] developed a technical modification in which threads with “pledgets” on a Teflon flap were used for segmental plication of the posterior ring corresponding to the segment removed from the cuspid, without using a prosthetic ring. This technique, named the “double Teflon technique”, has presented excellent long-term results, with low morbidity and mortality rates[7,8]. Three-dimensional is the diagnostic technique that has contributed most to knowledge of the anatomy and functioning of the mitral valve[9]. New discoveries regarding the saddle shape of the mitral valve ring[10] and its dynamics during

METHODS This study was conducted at the Heart Institute, Hospital das Clinicas, Faculty of Medicine, University of São Paulo for Heart Valve Surgery Unit and the Echocardiography Unit, with support from CEPEC (Echocardiography Research Center). After the study was approved by the Ethics Committee of Hospital das Clinicas, Faculty of Medicine, University of São Paulo and obtaining a written post-informed consent, between May/2006 and August/2008 we included 14 consecutive patients with mitral insufficiency secondary to mitral valve prolapse of degenerative etiology, due to elongation or tendon chordal rupture related to the mitral valve posterior cusp, who underwent mitral valve repair with the Double Teflon technique (Figure 1). Patients with associated valvular heart disease or submitted to previous heart surgery were excluded from the study. In this population, the age ranged between 39 and 75 years, with average of 61±11 years. Among all individuals, 10 were male and 4 were female. The average weight and height of patients was 75.6±10.9 kg and 1.69±0.1

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m, respectively. Body surface area ranged between 1.64 and 2.10 m2, with a mean of 1.85±0.17 m2. In the investigation of personal history, 11 patients had hypertension; two patients had diabetes mellitus, two from chronic renal failure requiring dialysis, three had dyslipidemia, and two had coronary artery disease. The additive EuroSCORE ranged between 0 and 6, being that 11 cases presented additive EuroSCORE from 0 to 3 and the other 3 cases showed additive EuroSCORE between 3 and 6. Regarding the functional class (FC) in the preoperative period, one patient was in FC II, 12 in FC III and one in FC IV. Among the 14 patients, eight had atrial fibrillation in the preoperative period. All patients were operated by the same surgical team. In one patient, plication of the free edge of the anterior mitral valve cusp was performed, as a technique associated with the repair. Regarding the location of mitral valve disease, 12 patients had involvement of the P2 segment, one patient had involvement of the P1 segment, and one patient had associated involvement of A2 and P2 segment. Cord rupture were found in 10 patients, it was found string stretching in one patient; stretching and cord snapping found in two patients; calcification of the ring and cord rupture found in one patient. Two patients had coronary heart disease as an associated diagnosis. Of these patients, one patient had distal coronary lesion, not treatable surgically. One patient underwent revascularization of the left marginal branch. Patients were evaluated in the preoperative period (up to 30 days before surgery), in the postoperative period (between 5 and 30 days after surgery), 6 months (between 6 and 7 months after surgery) and 1 year (between the 12th and 15th month after surgery). In order to perform the test, the IE-33 (Philips Medical Systems, Andover, MA, USA) was used. Echocardiographic images were obtained using the matrix transducer positioned in the acoustic parasternal and apical windows. The three-dimensional echocardiographic data were analyzed in a workstation, using specific software QLAB 5.0 and QLAB 6.0 (Philips Medical Systems, Andover, MA, USA). With the acquisition of three-dimensional data, the image was cut and reconstructed to visualize the cardiac structures within the pyramid or the whole heart block. Mitral annulus morphology was evaluated through anteroposterior diameter (AP), mediolateral (ML), annulus circunference, anterior and posterior mitral planimetry measurements (Figure 2). Circularity index was obtained through the relationship of AP and ML diameter. Mitral annulus function was estimated between the difference of mitral valve area during maximum sistole and maximum diastole, in relationship to mitral valve area obtained at maximum sistole, described as valve area reduction during cardiac cycle. In order to analyze the behavior of the group considering the conditions studied, we used the technique of Analysis of

Variance for Repeated Measures. For the study of reproducibility of echocardiographic measurements we used the intraclass coefficient correlation. It was considered statistically significant P<0,05. The software SPSS version 15.0. (Inc, Chicago) was used for this analysis.

Fig. 1 - Intraoperative aspect of the mitral valve after completion of the mitral valve repair technique “Double Teflon”. We can observe the pledgets anchored in Teflon strips and the suture edge to edge of the cusps.

Fig. 2 - Illustration of the echocardiographic variables. Anterior perimeter=red line; posterior perimeter=blue line; anteroposterior diameter=green line; mediolateral diameter=yellow line. Ant=anterior; Post=posterior; CAL=anterolateral commissure, CPM=posteromedial commissure). The white line shows the line of valve coaptation.

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RESULTS

lus perimeter (P=0.17). There was a decrease in 0.2% between IPO and 6 months period (P<0.004). There was no statistical difference when comparing the IPO and 1 year period. The posterior perimeter of the mitral annulus in the preoperative, immediate post-operative, 6 months and 1 year period were 6.97±0.13cm; 5.17±0.10cm, 5.15±0.11 and 5.17±0.11cm, respectively. Significant effect of condition evaluation was observed during the study period (P<0.001). At the end of the study, there was a decrease of 25.8% on the posterior perimeter of the mitral annulus betwwen preoperative and 1 year period. Figure 5 represents the evolution of the posterior mitral annulus perimeter throughout the study. When comparing the preoperative and IPO period, posterior mitral annulus decrease 25.8% (P<0.001), the same decrease value found when comparing the preoperative and 1 year period. There was a decrease in 0.2% between the IPO and 6 months period (P<0.003). There was no statistical difference when comparing the IPO and 1 year period (P=1.0).

During the study period, no death, endocarditis, reoperation for valve dysfunction or thromboembolism were observed. In terms of physical activity in the postoperative period, 12 patients were in functional class I and two in functional class II, one year after surgery. In the immediate postoperative period, 14 patients had mild mitral insufficiency. There was no significant change in the degree of mitral regurgitation after valvuloplasty during the study. The mean circumference of the mitral annulus in the preoperative period, immediate post-operative period, 6 months and 1 year were 11.90±0.16cm; 10.10±0.13cm; 10.06±0.13cm and 10.10±0,13cm, respectively. Significant effect of condition evaluation was observed during the study period (P<0.001). At the end of the study, there was a decrease of 15.1% of the mitral annulus circumference when comparing the averages of the preoperative and 1 year period. Figure 3 represents the evolution of the mitral annulus circumference during the study. There was a decrease of 15.1% in the measurements when comparing the preoperative and IPO period (P<0.001). There was a 0.4% decrease in the circumference of the mitral annulus between the periods IPO and 6 months period (P=0<001). There was no difference between the IPO and 1 year period (P=1.0). The anterior mitral annulus perimeter in the preoperative, immediate postoperative, 6 months and 1 year period were 4.93±0.06cm; 4.92±0.06cm; 4.91±0.06cm and 4.93±0.07cm, respectively. Significant effect of condition evaluation was observed during the study period (P<0.001). There was no difference in the average of the anterior perimeter in the preoperative and 1 year period. Figure 4 represents the evolution of the anterior perimeter of the mitral annulus during the study. When comparing the preoperative and immediate post-operative period there was no significant difference in anterior mitral ann-

Fig. 4 - Evolution of the anterior perimeter of the mitral valve annulus during the study. Values​​=mean±standard deviation. *P<0.05 compared to the immediate postoperative period.

Fig. 3 - Evolution of the circumference of the mitral valve annulus during the study. Values​​=mean±standard deviation. *P<0.05 compared to the immediate postoperative period.

Fig. 5 - Evolution of the posterior perimeter of the mitral valve annulus during the study. Values​​=mean±standard deviation. *P<0.05 compared to the immediate postoperative period.

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The anteroposterior (AP) diameter of the mitral annulus in the preoperative, immediate post-operative, 6 months and 1 year period were 3.47±1.18cm; 3.10±0.90cm; 3.07±0.90cm and 3.18±0.85cm, respectively. Significant effect of condition evaluation was observed during the study period (P<0.001). At the end of the study, there was a decrease in AP diameter of 8.3% compared to the preoperative period. Figure 6 represents the evolution of AP diameter throughout the study. When comparing the preoperative and IPO period, there was evidenced a significant reduction in mean of this variable (P<0.001). When comparing the IPO and 6 months period, it was observed a slight further reduction of 1.0% in the mitral annulus AP diameter, statistically significant (P=0.012). The comparison between the IPO and 1 year period showed an increase in measures of this variable throughout the study, but without statistical significance (P=0.051). Mediolateral (ML) diameter of the mitral annulus in the preoperative, immediate post-operative, 6 months and 1 year period were 3.26±1.22cm, 2.87±1.19cm; 2.84±1.19cm and 2.98±0.17cm, respectively. Significant effect of condition evaluation was observed during the study period (P<0.001). At the end of the study, there was a decrease of 8.6% in the ML diameter of the mitral annulus when comparing the averages of the preoperative period. Figure 7 shows the evolution of the ML diameter the mitral valve annulus during the study. When comparing the preoperative and IPO period, There was evidenced a significant reduction in the average of this variable (P<0.001). When comparing the IPO and 6 months period, a slight further reduction of 1.0% was observed in the ML diameter, statistically significant (P=0.003). The com-

parison between the means of IPO and 1 year period showed an increase in measures of this variable by 3.8%, statistically significant (P=0.004). Mitral annulus circularity index in preoperative, immediate post-operative, 6 months and 1 year period were 0.93±0.07, 0.91±0.13, 0.90±0.14 and 0.91±0.13, respectively. Significant effect of condition evaluation was not observed during the study period (P=0.59). The comparison between the means of POI and 1 year periods showed no difference between the means in these periods (P=0.29). The reduction fraction of mitral internal area during cardiac cycle (variation of the internal area) in the preoperative period, immediate post-operative, 6 months and 1 year were 35.75±9.14%, 33.80±8.59%, and 33.90±8.91% 30.92±8.31%, respectively. Significant effect of condition evaluation was not observed during the study period (P=0.296). The comparison between the means of IPO and 1 year period showed a decrease of this variable by 8.5%, but without statistical significance (P=0.060). The values of the intraclass correlation coefficient of the values obtained in the analysis of the posterior mitral annulus perimeter approached unity (1.0) in all analyzes (0.998 P<0.001). Table 1 describes a subgroup analysis of the mitral valve annulus morphology variables taking into account the presence of atrial fibrillation during the study. There was no statistically significant difference in the behavior of the subgroups studied throughout the study, and the comparison of variable means in different times evaluated: circumference of the mitral annulus, anterior and posterior perimeter, AP and ML diameter, and circularity index.

Fig. 6 - Evolution of antero-posterior diameter of the mitral valve annulus during the study. Values​​=mean±standard deviation. *P<0.05 compared to the immediate postoperative period.

Fig. 7 - Evolution of the medial-lateral diameter of the mitral valve annulus during the study. Values​​=mean±standard deviation. *P<0.05 compared to the immediate postoperative period.

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Table 1. Subgroup analysis regarding the presence of atrial fibrillation. Variable CAM

Ant Annulus

Post Annulus

AP Annulus

ML Annulus

CI

Period Preoperative IPO 6-months 1-year Preoperative IPO 6-months 1-year Preoperative IPO 6-months 1-year Preoperative IPO 6-months 1-year Preoperative IPO 6-months 1-year Preoperative IPO 6-months 1-year

AF (n=8) 11.90±0.18 10.03±0.08 10.00±0.07 10.03±0.08 4.91±0.07 4.90±0.06 4.89±0.06 4.91±0.06 6.99±0.12 5.13±0.06 5.11±0.05 5.13±0.05 3.76±1.25 3.31±1.01 3.27±1.01 3.33±1.01 3.53±1.30 3.22±1.26 3.17±1.26 3.29±1.28 0.93±0.07 0.95±0.10 0.95±0.11 0.97±0.11

No AF (n=6) 11.90±0.16 10.19±0.13 10.15±0.15 10.19±0.15 4.96±0.05 4.95±0.06 4.93 ±0.06 4.95± 0.06 6.94±0.13 5.23±0.13 5.21±0.14 5.23±0.13 3.07±1.05 2.82±0.71 2.79±0.71 2.98±0.62 2.90±1.10 2.41±1.01 2.39±1.02 2.56±0.93 0.94±0.07 0.84±0.16 0.84±0.16 0.84 ± 0.13

PA

P

PB

0.471

0.051

0.845

0.172

0.553

0.086

0.303

0.347

0.166

0.264

0.143

0.155

Values=mean±standard deviation. PA=statistical significance comparing the groups with respect to behavior throughout the study, PB=statistical significance of the comparison of means between groups in different time periods. IPO=immediate postoperative; CAM=circumference of the mitral annulus; Ant Annulus=anterior mitral perimeter; Post Annulus=mitral posterior perimeter; AP Annulus=anteroposterior diameter; ML Annulus=medial-lateral diameter; CI=circularity index

DISCUSSION

these techniques presented low rates of residual mitral insufficiency, between 1 and 2%. In most of the studies reviewed, no early structural failure of the valve repair was observed. Medium-term evaluations showed good results. The actuarial five-year survival rate was approximately 90%. Moreover, the best survival results free from reoperation were found among patients who had undergone segmental plication or semicircular reduction, especially among those with degenerative mitral insufficiency. The actuarial survival curves free from thromboembolism and endocarditis presented excellent results. The authors concluded that the techniques of segmental and semicircular plication may be valid and safe options, especially for patients with prolapse of the posterior cuspid in association with slight dilatation of the mitral ring, thus reviving the doubts in relation to the need to use prosthetic rings[5]. Brandão et al.[8] obtained excellent clinical results from mitral valvuloplasty by means of the double Teflon technique, over a 10-year follow-up period. The actuarial survival rate was 94.1±3.6%, the survival rate free from throm-

The mitral valve system is a complex structure. Clinical use of three-dimensional echocardiography has contributed significantly towards understanding its functioning and anatomy, especially with regard to the mitral valve ring[11]. Fundaró et al.[5] published a review of the most important studies that had analyzed the clinical results from annuloplasty techniques without a prosthetic ring. They classified the techniques as either mural or commissural annuloplasty. Mural annuloplasty techniques were subdivided into semicircular plication, when shortening of the entire posterior segment of the mitral ring is performed; and segmental plication, when plication is performed on the mitral ring corresponding to the segment of the posterior cuspid that is removed through quadrangular resection. They found that the best immediate and late results occurred among patients with degenerative etiologies who had undergone segmental plication or semicircular reduction. In the immediate evaluation, the patients who had undergone

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boembolism was 97.3±1.5% and the survival rate free from reoperation was 99.2±0.8%. A study on cadavers in which 712 valves resected from patients with mitral prolapse were examined showed that the mean ring circumference was 12.3 cm, whereas it was 9.8 cm in patients without annular dilatation[12]. In a study using three-dimensional echocardiography, Sonne et al.[13] found great variation in the measurements of the mitral ring circumference among 123 normal individuals, with a mean of 10.5±1.4 cm and a range from 7.0 to 14.0 cm. In the present study, the mean circumference of the mitral ring before the operation was 11.9±0.16 cm, thus showing that the population studied had slight annular dilatation. This finding is probably related to the fact that most of the patients presented rupture of the tendinous cords as the genesis of their mitral insufficiency. After the surgical intervention, there was a significant reduction of 15.1% in the mitral circumference, attaining a mean value of 10.10±0.13, which then remained stable over the course of the follow-up. The mitral ring was divided into two portions, taking the axis of the mediolateral (ML) diameter into consideration. Anatomically, the anterior portion of the mitral ring is composed of a fibrous portion that is located between the right and left trigones of the mitral ring, and two bilateral muscle portions that line between the ML axis and the corresponding trigone. In a study on cadavers, Hueb et al.[14] found that the anterior intertrigonal distance of the mitral ring was greater in patients with dilated myocardiopathy. Suri et al.[15] compared the anterior intertrigonal distance between patients with degenerative mitral insufficiency and normal individuals, using transesophageal three-dimensional echocardiography, and showed that there were no significant alterations of the anterior intertrigonal distance in these cases. These findings corroborate the idea that the mitral ring has different behavior according to the etiology of the mitral insufficiency. In the present study, planimetry on the anterior portion of the mitral ring showed that there was no significant variation over the study period. The posterior segment of the mitral valve is formed by the muscle portion of the ring. In situations of degenerative etiology, there is annular dilatation corresponding to the posterior ring. Mihalatos et al.[16] demonstrated that the degree of annular dilatation is directly related to the intensity of the mitral regurgitation, especially in patients with mitral prolapse and mitral functional insufficiency. Suri et al.[15] found a mean posterior ring size that was greater than what we found in our study, and this is compatible with the predominance of rupturing of the tendinous cords in the present study. The segmental annuloplasty technique used in the present study significantly reduced the size of the posterior mitral ring, by 25.8%. This reduction remained stable over the course of the study period, and no annular redilatation was observed over this period. The double Teflon technique consists of plication of the anterior portion of the mitral ring alone, without interfering with its

anterior portion. Therefore, the maintenance of the measurements of the anterior mitral ring and the reduction in the posterior ring that was found are compatible with the segmental annuloplasty technique that was applied in these cases. Kwan et al.[17,18] demonstrated that during the cardiac cycle, the variation in valve area is directly related to the increase in anteroposterior (AP) diameter of the mitral valve. This was not observed in relation to the ML diameter. The mitral valve becomes flatter at maximum systole, with increases in AP diameter and in the nonplanar angle, thus acquiring its greatest valve area. We analyzed the diameters at maximum systole and found values similar to those found by Kwan et al.[18] in normal individuals. These findings confirm that the population studied here presented slight annular dilatation. In pathological states, the annular dilatation seems not to be due to distension of the mitral ring fibers but, rather, due to an increase in the nonplanar angle, thereby modifying the shape of the mitral ring. This increase in the nonplanar angle gives the valve a more flattened appearance and seems to interfere more with the AP diameter than with the ML diameter. In our study, we found that there were significant reductions in the measurements of the AP and ML diameters in the immediate postoperative period, compatible with the segmental annuloplasty. In comparing this time with one year after the operation, we found that these measurements had increased slightly: in absolute amounts, a mean of 0.8 mm for the AP diameter and a mean of 1.1 mm for the ML diameter. This change was probably related to the patients’ hemodynamic status. Despite these slight increases from immediately after the operation to one year after the operation, we found that overall, there was a reduction of approximately 8% in the AP and ML diameters, from the preoperative diameters to the diameters at the end of the study period. The circularity index (CI) is the ratio between the AP and ML diameters. The closer that this is to 1.0, the more circular the shape of the mitral valve is. Mahmood et al.[19] compared the nonplanar angle and the CI in patients who had undergone mitral valvuloplasty in which prosthetic rings were used. Out of the 75 patients studied, 40 of them presented degenerative etiologies. In the same study, eight patients were used as controls and their normal mitral valves presented a CI of 0.90. In our study, we found a CI of 0.93 before the operation, which was similar to what Mahmood et al.[19] found in normal valves. Moreover, we did not find any significant changes to this index over the course of the study, thus showing that the proportions between the AP and ML diameters were maintained at the different measurement times of the study. Mahmood et al.[19] also demonstrated that prosthetic ring implants may alter both the nonplanar angle and the CI, thereby changing the saddle shape of the mitral ring, and that prosthetic rings have different behavior in remodeling the mitral ring.

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The measurements of the internal area of the circumference obtained through planimetry can be made both at the end of the systole phase and at the end of the diastole phase, thus enabling comparison of the variation of the internal area during the cardiac cycle. This methodology for measuring the valve area presents the limitation of being a two-dimensional measurement of a three-dimensional structure. It consists of a projection of the three-dimensional mitral ring structure into a transverse plane. Therefore, simple changes to the nonplanar angles would have an impact on the accuracy of the method. In relation to the mitral ring area and the magnitude of the variation of this area during the cardiac cycle, the results described in the literature have been diverse, particularly in clinical studies. We believe that these findings relate mainly to lack of standardization of the times at which measurements were made in different studies, thus causing difficulty in making comparisons between them. Moreover, anatomical evaluations of the mitral ring through echocardiography make use of the insertion site of the mitral cuspid, which does not necessarily reflect the exact intramuscular location of the mitral ring. Nonetheless, the dynamic nature of the mitral ring during the cardiac cycle has been well established, both in experimental studies and in clinical studies. In these studies, the maximum reduction of the mitral ring size in normal individuals during the cardiac cycle has been shown to be between 22-35%[17,18]. Analyses on mitral ring dynamics in relation to valvuloplasty using a prosthetic ring has given rise to divergences in the literature. Okada et al.[20] observed a variation in valve area during the cardiac cycle of 26Âą4%, among patients who underwent implantation of a flexible Duran ring (Duran; Medronic Heart Valve Division, Minneapolis, MN, USA). However, there was no variation in valve area when a rigid Carpentier ring was implanted (Carpentier-Edwards [C-E] Physio; Edwards Lifesciences Corp, Irvine, CA, USA), thus demonstrating behavior that was more physiological than that of the flexible ring. Gillinov et al.[21] evaluated the Cosgrove partial flexible ring (Cosgrove-Edwards annuloplasty band; Edwards Lifesciences Corp, Irvine, CA, USA) and showed that this prosthesis maintained the saddle shape of the mitral ring, and also presented variation in the valve area of 28Âą11%, five years after implantation. Implantation of prosthetic rings interferes with the saddle shape of the ring. Mahmood et al.[19] showed that implantation of a complete ring interfered with the nonplanar angle, both in patients with ischemic and in patients with degenerative mitral insufficiency. Furthermore, different behavior was observed according to the type of partial ring used in the study, thus suggesting that morphological analysis on the mitral valve after implantation might influence the choice of device. Komoda et al.[22] showed that there was a reduction in the contraction of the base of the left ventricle after fixation of the

mitral ring by means of prosthetic rings. Moreover, in a study using magnetic resonance, it was demonstrated that mitral plastic techniques that did not involve using prosthetic rings did not interfere with the contraction of either the mitral valve or the base of the left ventricle, as observed six months after the surgical intervention. In the present study, we observed that after the surgical intervention, there was no significant reduction in mitral ring performance, thus showing that the segmental annuloplasty did not have any significant impact on mitral ring function and that the ring continued to function in a stable manner over the course of the study, such that the mitral ring maintained dynamics that were more physiological. Barlow disease is generally found in young patients and is characterized by myxomatous degeneration affecting the entire valve, thereby resulting in excess of tissue in the cuspids and leading to redundant tissue, with prolapse in different segments of the valve. Surgical intervention is generally required in the fifth or sixth decade of life. Because of the long course of this disease, it is usually associated with significant dilatation of the mitral ring. On the other hand, fibroelastic deficiency is found in patients over the age of 60 years who present a rapid course of mitral valve disease. Fibroelastic deficiency is a disease that essentially affects the tendinous cords and not the cuspids of the mitral valve, and it predisposes towards rupture of the tendinous cords, generally in a single segment of the valve. This condition can be diagnosed by means of preoperative echocardiography findings that suggest that the valve is of normal size, with thin cuspids and little excess tissue, seen in association with rupturing of the tendinous cords, generally in the P2 segment of the mitral valve. Although Barlow disease and fibroelastic deficiency present different characteristics, these conditions cannot be distinguished in approximately 20% of the patients[23]. In our series, we found echocardiographic characteristics that were compatible with fibroelastic deficiency in the majority of our patients. Our patients presented prolapse of a single segment, affecting the P2 segment in 80% of the cases, in association with slight dilatation of the mitral valve. We believe that the decision to use prosthetic rings should be correlated with ventricular function and the size of the mitral ring. It is possible that patients with normal ventricular function and slight annular dilatation (the characteristics observed in cases of fibroelastic deficiency) would benefit from correction of their mitral insufficiency through techniques that do not involve using prosthetic rings. On the other hand, patients with ventricular dysfunction and significant dilatation of the mitral ring might benefit from techniques involving use of prosthetic rings for remodeling and stabilizing the mitral ring, because their disease affects not only the mitral valve but also the left ventricle. Atrial fibrillation is an independent predictor of cardiovascular events[24]. In this series, approximately half of the patients presented this arrhythmia over the course of the

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study. We conducted a subgroup analysis to evaluate whether the presence of atrial fibrillation might have had an impact on the results found from this study. We did not observe any significant alterations to the behavior of the variables evaluated over the course of the study, thus demonstration that the mitral valvuloplasty modified the ring measurements in a stable manner and also enabled reverse atrial and ventricular remodeling, independent of atrial fibrillation[25]. It is possible that the patients who persisted with atrial fibrillation over the course of time presented differences not in relation to behavior but, rather, in relation to the magnitude of the remodeling. However, the results obtained should be viewed with caution because of the small number of patients allocated to each group in this analysis. Although this study had a sample of 14 patients, there is little data in the literature regarding remodeling of the mitral valve ring during the postoperative period. Moreover, the populations studied have been etiologically different from each other and they generally underwent mitral valvuloplasty by means of techniques that involved usie of prosthetic rings. The present study described aspects of the morphology and functioning of the mitral ring over the course of a one-year postoperative period, in a population that was homogenous with regard to the etiology of the mitral insufficiency, which underwent mitral valvuloplasty without involving the use of prosthetic rings.

REFERENCES 1. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet. 2006;368(9540):1005-11. 2. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J. 2003;24(13):1231-43. 3. Pomerantzeff PMA, Brandão CMA, Monteiro ACM, Nersessian AC, Zeratti AE, Stolf NAG, et al. Plástica da valva mitral: resultados tardios de doze anos de experiência e evolução das técnicas. Rev Bras Cir Cardiovasc. 1994;9(1):22-8. 4. Enriquez-Sarano M, Schaff HV, Orszulak TA, Tajik AJ, Bailey KR, Frye RL. Valve repair improves the outcome of surgery for mitral regurgitation. A multivariate analysis. Circulation. 1995;91(4):1022-8. 5. Fundarò P, Tartara PM, Villa E, Fratto P, Campisi S, Vitali EO. Mitral valve repair: is there still a place for suture annuloplasty? Asian Cardiovasc Thorac Ann. 2007;15(4):351-8. 6. Pomerantzeff PMA, Brandão CMA, Rossi EG, Cardoso LF, Tarasoutchi F, Grimberg M, et al. Quadrangular resection without ring annuloplasty in mitral valve repair. Cardiovasc Eng. 1997;2(4):271-3.

CONCLUSION

7. Pomerantzeff PM, Brandão CM, Souza LR, Vieira ML, Grimberg M, Ramires JA, et al. Posterior mitral leaflet repair with a simple segmental annulus support: the ‘double-Teflon technique’. J Heart Valve Dis. 2002;11(2):160-4.

We conclude that the patients who underwent mitral valvuloplasty by means of the double Teflon technique presented reductions in the posterior segment of the mitral ring, and that this remained stable over the one-year period. Moreover, the variation in internal valve area during the cardiac cycle remained stable over the course of the study.

8. Brandão CM, Guedes MA, Silva MF, Vieira ML, Pomerantzeff PM, Stolf NA. Mitral valve repair with “Double Teflon” technique: 10-year results. Rev Bras Cir Cardiovasc. 2007;22(4):448-53. 9. Solis J, Sitges M, Levine RA, Hung J. Three-dimensional echocardiography. New possibilities in mitral valve assessment. Rev Esp Cardiol. 2009;62(2):188-98.

Authors’ roles & responsibilities MAVG PMAP

CMAB

MLCV FT PCS FBJ

Manuscript writing or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript; study design; implementation of projects and/ or experiments; manuscript writing or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript; study design; implementation of projects and/ or experiments; manuscript writing or critical review of its content Analysis and/or interpretation of data; study design; implementation of projects and/or experiments; manuscript writing or critical review of its content Final approval of the manuscript; implementation of projects and/or experiments Performed operations and/or experiments Analysis and/or interpretation of data; final approval of the manuscript; study design; manuscript writing or critical review of its content

10. Pai RG, Tanimoto M, Jintapakorn W, Azevedo J, Pandian NG, Shah PM. Volume-rendered three-dimensional dynamic anatomy of the mitral annulus using a transesophageal echocardiographic technique. J Heart Valve Dis. 1995;4(6):623-7. 11. Kaplan SR, Bashein G, Sheehan FH, Legget ME, Munt B, Li XN, et al. Three-dimensional echocardiographic assessment of annular shape changes in the normal and regurgitant mitral valve. Am Heart J. 2000;139(3):378-87. 12. Olson LJ, Subramanian R, Ackermann DM, Orszulak TA, Edwards WD. Surgical pathology of the mitral valve: a study of 712 cases spanning 21 years. Mayo Clin Proc. 1987;62(1):22-34. 13. Sonne C, Sugeng L, Watanabe N, Weinert L, Saito K, Tsukiji M, et al. Age and body surface area dependency of mitral valve

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and papillary apparatus parameters: assessment by real-time three-dimensional echocardiography. Eur J Echocardiogr. 2009;10(2):287-94.

RC, Maslow A, et al. Three-dimensional echocardiographic assessment of changes in mitral valve geometry after valve repair. Ann Thorac Surg. 2009;88(6):1838-44.

14. Hueb AC, Jatene FB, Moreira LF, Pomerantzeff PM, KallĂĄs E, de Oliveira SA. Ventricular remodeling and mitral valve modifications in dilated cardiomyopathy: new insights from anatomic study. J Thorac Cardiovasc Surg. 2002;124(6):1216-24.

20. Okada Y, Shomura T, Yamaura Y, Yoshikawa J. Comparison of the Carpentier and Duran prosthetic rings used in mitral reconstruction. Ann Thorac Surg. 1995;59(3):658-63. 21. Gillinov AM, Cosgrove DM 3rd, Shiota T, Qin J, Tsujino H, Stewart WJ, et al. Cosgrove-Edwards Annuloplasty System: midterm results. Ann Thorac Surg. 2000;69(3):717-21.

15. Suri RM, Grewal J, Mankad S, Enriquez-Sarano M, Miller FA Jr., Schaff HV. Is the anterior intertrigonal distance increased in patients with mitral regurgitation due to leaflet prolapse? Ann Thorac Surg. 2009;88(4):1202-8.

22. Komoda T, Hetzer R, Siniawski H, Huebler M, Felix R, Maeta H. Mitral annulus after mitral repair: geometry and dynamics. ASAIO J. 2002;48(4):412-8.

16. Mihalatos DG, Joseph S, Gopal A, Bercow N, Toole R, Passick M, et al. Mitral annular remodeling with varying degrees and mechanisms of chronic mitral regurgitation. J Am Soc Echocardiogr. 2007;20(4):397-404.

23. Deloche A, Jebara VA, Relland JY, Chauvaud S, Fabiani JN, Perier P, et al. Valve repair with Carpentier techniques. The second decade. J Thorac Cardiovasc Surg. 1990;99(6):990-1001.

17. Kwan J, Jeon MJ, Kim DH, Park KS, Lee WH. Does the mitral annulus shrink or enlarge during systole? A real-time 3D echocardiography study. J Korean Med Sci. 2009;24(2):203-8.

24. Alexiou C, Doukas G, Oc M, Oc B, Swanevelder J, Samani NJ, et al. The effect of preoperative atrial fibrillation on survival following mitral valve repair for degenerative mitral regurgitation. Eur J Cardiothorac Surg. 2007;31(4):586-91.

18. Kwan J, Kim GC, Jeon MJ, Kim DH, Shiota T, Thomas JD, et al. 3D geometry of a normal tricuspid annulus during systole: a comparison study with the mitral annulus using real-time 3D echocardiography. Eur J Echocardiogr. 2007;8(5):375-83.

25. Guedes MA, Pomerantzeff PM, BrandĂŁo CM, Vieira ML, Leite Filho OA, Silva MF, et al. Mitral valve repair by Double Teflon technique: cardiac remodeling analysis by tridimensional echocardiography. Rev Bras Cir Cardiovasc. 2010;25(4):534-42.

19. Mahmood F, Subramaniam B, Gorman JH 3rd, Levine RM, Gorman

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Costa VEA, ORIGINAL et al. - ImpactARTICLE of body mass index on outcome in patients undergoing coronary artery bypass grafting and/or valve replacement surgery

Impact of body mass index on outcome in patients undergoing coronary artery bypass grafting and/or valve replacement surgery Impacto do índice de massa corporal no desfecho de pacientes submetidos às cirurgias de revascularização do miocárdio e/ou troca valvar

Vinícius Eduardo Araújo Costa1, MD; Silvia Marinho Ferolla1, MD, MSc; Tâmara Oliveira dos Reis1, MD, MSc; Renato Rocha Rabello1, MD; Eduardo Augusto Victor Rocha1, MD, MSc; Célia Maria Ferreira Couto1, MD, MSc; José Carlos Ferreira Couto1, MD; Alduir Bento1, MD

DOI 10.5935/1678-9741.20150027

RBCCV 44205-1649

Abstract Objective: This study aimed to analyze the impact of body mass index on outcomes of 101 patients undergoing coronary artery bypass grafting, valve replacement, or combined valve/ coronary artery bypass grafting surgery in a private hospital in Belo Horizonte, Brazil. Methods: This was a prospective cross-sectional study of patients undergoing cardiac surgery from May 2009 to December 2012. All patients were followed up from the first day of admission until discharge or death. Patients were divided into three groups according to BMI: normal weight, overweight, and obese. The main outcome measure was the association between BMI and postoperative morbidities and mortality. Results: Multivariate analysis identified obesity as an independent predictor of increased risk of surgical reintervention (odds ratio [OR] 13.6; 95%CI 1.1 - 162.9; P=0.046) and reduced risk of bleeding (OR 0.05; 95% CI 0.09 - 0.69; P=0.025). Univariate analysis showed that obesity was associated with increased frequency of wound dehiscence (P=0.021). There

was no association between BMI and other complications or mortality in univariate analysis. There was also no association between body mass index and duration of cardiopulmonary bypass, aortic clamping, mechanical ventilation, and intensive care unit or hospital stay. Conclusion: Obese individuals undergoing coronary artery bypass grafting, valve replacement, or combined surgery have a higher postoperative risk of surgical reintervention and lower chances of bleeding.

Hospital Vera Cruz (HVC), Belo Horizonte, MG, Brazil.

Correspondence address: Vinícius Eduardo Araújo Costa Hospital Vera Cruz Avenida Barbacena, 653 - Barro Preto, Belo Horizonte, MG, Brazil Zip code: 30190-130 E-mail: viniciuseacosta@yahoo.com.br

1

Descriptors: Body mass index. Obesity. Thoracic surgery. Myocardial revascularization. Mitral valve prolapse. Resumo Objetivos: Analisar o impacto do índice de massa corporal no desfecho de 101 pacientes submetidos à cirurgia revascularização do miocárdio, troca valvar ou cirurgia cardíaca combinada em um hospital privado de Belo Horizonte, Minas Gerais.

Work carried out at Hospital Vera Cruz (HVC), Belo Horizonte, MG, Brazil.

Article received on June 30th, 2014 Article accepted on April 23th, 2015

No financial support.

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ção cirúrgica por deiscência de sutura de esterno (OR 13,6; IC95% 1,1-162,9; P=0,046) e redução no risco de sangramento (OR 0,05; IC95% 0,09-0,69; P=0,025). Na análise univariada, obesidade também foi associada a maior frequência de deiscência de sutura (P=0,021). Estado nutricional não foi associado à presença de outras complicações no pós-operatório e nem de mortalidade, ainda na análise univariada. No intraoperatório não houve diferença nos tempos de circulação extracorpórea e de pinçamento aórtico. No pós-operatório, os tempos de ventilação mecânica e de internação na unidade de terapia intensiva ou hospital foram semelhantes entre os pacientes eutróficos, com sobrepeso e obesos. Conclusão: Pacientes obesos apresentam risco aumentado de reintervenção cirúrgica por deiscência de sutura e menor risco sangramento no pós-operatório de cirurgia de revascularização do miocárdio, troca valvar ou cirurgia cardíaca combinada.

Abbreviations, acronyms & symbols BMI CABG CAD CPB ICU MV

Body mass index Coronary artery bypass grafting Coronary artery disease Cardiopulmonary bypass Intensive care unit Mechanical ventilation

Métodos: Trata-se de um estudo transversal com inclusão prospectiva de pacientes submetidos à cirurgia cardíaca no período de maio de 2009 a dezembro de 2012. Todos os pacientes foram acompanhados do primeiro dia de internação até a alta hospitalar ou óbito. Os pacientes foram divididos em três grupos definidos pelo índice de massa corporal aferido no pré-operatório: eutrófico, sobrepeso e obeso. O principal desfecho avaliado neste estudo foi a associação entre índice de massa corporal e morbimortalidade pós-operatória. Resultados: A análise multivariada revelou obesidade como preditor independente de aumento nas chances de reinterven-

Descritores: Índice de Massa Corporal. Obesidade. Cirurgia Torácica. Revascularização Miocárdica. Implante de Prótese de Valva Cardíaca.

INTRODUCTION

disease as independent risk factors of mediastinitis after cardiac surgery[22]. Data on the adverse or protective effects of body weight in Brazilian patients undergoing cardiac surgery remain scarce. The current study was designed to assess the preoperative impact of BMI on morbidity and mortality in the postoperative period in adult and elderly patients undergoing CABG, valve replacement, or combined cardiac surgery.

The prevalence of obesity has been increasing in Brazil and developed countries[1,2]. Research by the Brazilian Institute of Geography and Statistics[1] has shown that almost half of Brazilians (48%) have excess weight. It is well known that obesity increases the risk of coronary artery disease (CAD)[3] and is associated with increased mortality in this population as well as in the general population[4,5]. In 2009, a total of 209,029 Brazilian patients were hospitalized due to CAD, with a mortality rate of 6.04%[5]. Given the endemic nature of obesity in the contemporary world, numerous patients with excess body weight are expected to require cardiac surgery[6-8]. Despite advances in clinical treatment and percutaneous procedures, coronary artery bypass grafting (CABG) is still considered a safe surgical method even in at-risk populations and is widely performed in Brazil and worldwide for treatment of obstructive CAD[9-14]. Conflicting data has been published on the influence of obesity on morbidity and mortality in cardiac surgery. Studies in different countries have documented an “obesity paradox”, suggesting a neutral or beneficial effect of excess weight on the outcome of patients undergoing coronary angioplasty, surgery for valve replacement, and CABG[15-20]. In a retrospective Brazilian study of 290 elderly patients who underwent CABG, obesity had a protective association with pulmonary dysfunction, risk of readmission, and mortality, although it was a risk factor for renal dysfunction during the postoperative period[21]. However, some authors have identified obesity, diabetes, and chronic obstructive pulmonary

METHODS Study Design and Sample This was a prospective cross-sectional study conducted between May 2009 and December 2012 in a private hospital in Belo Horizonte, Minas Gerais, Brazil, with a residency training program in cardiovascular surgery. In all, 101 of 118 patients undergoing elective CABG or valve replacement surgeries were assessed. The same team performed all surgical procedures. Adult and elderly patients (aged 60 years or over) were included. Patients younger than 18 years and those undergoing other surgical modalities such as excision of atrial myxoma and Bentall - De Bono surgery were excluded. All patients were followed up from the first day of hospitalization (pre-operative) until hospital discharge or death (when this occurred during hospitalization). Ethical Aspects The study participants were part of a wide-ranging study, entitled, “The use of nutritional assessment as a predictor of risk of complications in patients undergoing cardiac sur-

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gery”, which was approved by the Research Ethics Committee of Vera Cruz Hospital, Belo Horizonte , Minas Gerais, under number 097/09. All participants voluntarily signed an informed consent form.

sion to the intensive care unit (ICU) during the immediate post-operative period, and the duration of mechanical ventilation (MV), time of stay in the ICU, total length of hospital stay, complications, and postoperative mortality (when this occurred up to 30 days after the surgical procedure) were also recorded. Complications were categorized as: 1) infectious; 2) cardiovascular; 3) requiring surgical reintervention for sternal wound dehiscence; 4) increased bleeding; 5) acute kidney injury; and 6) minor complications. Infectious complications were defined as pneumonia, urinary tract infection, sepsis, septic shock, mediastinitis, infections of the lower limbs, or endocarditis. Cardiovascular complications were defined as acute myocardial infarction, cardiogenic shock, atrial fibrillation, stroke, heart failure, transient ischemic attack, or lower limb ischemia. Increased bleeding was characterized as the need for blood transfusion or surgical reintervention. Acute kidney injury in the postoperative period was defined as serum creatinine levels greater than or equal to 2.0 or requiring hemodialysis. The following were considered minor complications: pericardiotomy syndrome, pleural effusion, pressure ulcers, lowers limb wounds, and sinusitis. The main outcome assessed in this study was the association between BMI and complications during the CABG or valve replacement postoperative period.

Data Collection and Definitions Data were collected prospectively. The clinical variables included in the study were divided into pre-operative, peri-operative, and postoperative variables, as shown in Table 1. Clinical and demographic data including the presence of associated comorbidities and risk factors were obtained from medical history collected during the pre-operative evaluation. Nutritional parameters including body mass index (BMI) and albumin concentration were measured during the pre-operative period. The BMI was calculated using the Quetelet's index[23]. BMI was classified according to criteria from the World Health Organization (WHO)[24]. The study population was divided into three groups: normal weight (BMI between 18.5 and 24.9 kg/m2), overweight (BMI ≥ 25 kg/m2 and < 30 kg/m2), and obese (BMI ≥ 30 kg/m2). All surgical procedures were performed under balanced intravenous general anesthesia. Median sternotomy was performed in all patients. After systemic heparinization, cardiopulmonary bypass was instituted between the ascending aorta and the right atrium using a 2-stage cannula or cannulation of both venae cavae. Cardiac protection was instituted by means of intermittent clamping of the aorta and crystalloid cardioplegia with blood dilution during CABG and valve replacement surgery, respectively. The duration of cardiopulmonary bypass (CPB) and aorta clamping were measured during the perioperative period. The Acute Physiology and Chronic Health Evaluation (APACHE II) score was calculated on patient admis-

Statistical Analysis Descriptive analysis of the data was performed; proportions were calculated for categorical variables and minimum, median, maximum, average and standard deviation were calculated for continuous variables. Chi-square and Kruskal-Wallis tests were used to assess independence between groups and for comparison of medians, respectively[25].

Table 1. Clinical variables in the study. Preoperative variables Perioperative variables Postoperative variables Age Surgical procedure APACHE II Score Gender CPB time (min) Infectious complications BMI (kg/m2) Aorta clamping time (min) Cardiovascular complications Albumin (g/dL; normal ≥3.5g/dL) Surgical reintervention Smoking (current) Acute kidney injury Previous heart surgery Minor complications Heart failure (LVEF < 45%) Mortality (up to 30 DAS) CKD (Cr ≥2.5mg/dL or dialysis) MV duration (days) COPD (drug therapy) ICU stay (days) Glucose intolerance/DM (plasma glucose ≥100mg/dL/ drug therapy) Total lenght of hospital stay (days) HBP (≥130/85 mmHg/ drug therapy) Dyslipidemia (HDL<40mg/dL in men and <50mg/dL in women and/ or TG ≥150mg/dL/ drug therapy) CPB=cardiopulmonary bypass; DM=diabetes mellitus; DAS= days after surgery; COPD=chronic obstructive pulmonary disease; APACHE II score=Acute Physiology and Chronic Health Evalution; HBP=high blood pressure; LVEF=left ventricle ejection fraction; HDL=high density lipoprotein cholesterol; BMI=body mass index CKD=chronic kidney disease; TG=triglycerides; ICU=intensive care unit; MV=mechanical ventilation

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The multivariate analysis used an adjusted multinomial regression model that considered the overweight group as the reference. The model was adjusted for postoperative complications; those without significant P values were retained due to clinical significance[25]. Analyses were performed using STATA version 12.0 (Stata Corporation, College Station, Texas), with a 5% significance level. RESULTS A total of 101 patients were included in this study and most were male (73.3%). Sixty-one percent were elderly, with a mean age of 61.8±10.1 years. The mean BMI was 27.3±4.3 kg/m2 (Figure 1). Approximately 32.0% of patients had a healthy weight, 47.5% were overweight, and 20.8% were obese. The mean serum albumin level in the preoperative period was 4.1±0.6 g/dL. None of the participants was malnourished in the pre-operative period according to BMI classification. A minority (9.0%) had serum albumin less than 3.5 g/dL. When the study population was stratified according to BMI classification, there was no significant difference in the frequency of elderly individuals between the groups (Table 2). Analysis of comorbidities and risk factors identified in the pre-operative period for the entire sample population revealed that the majority of patients were hypertensive (83.2%), dyslipidemic (76.2%), and glucose intolerant or diabetic (68.3%). Approximately 15% had previous history of cardiac surgery and aroundy 17% were smokers. When classified by BMI, the only comorbidities and/or risk factors that showed statistical differences between the groups were diabetes and hypertension that were more prevalent among overweight individuals (Table 2).

Fig. 1 - Body mass index distribution in pre-operative patients for heart surgery.

CABG was the most common surgical procedure in this population (71% of cases), followed by valve replacement (23%) and combined surgery (6%). There was no difference in the frequency of CABG or valve replacement between the normal, overweight, and obese groups (P=0.241). On average, patients remained in CPB for 79.3±24.9 minutes in the peri-operative period, and the average aortic clamping time was 37.6±16.9 minutes. The median CPB times in healthy, overweight, and obese individuals were 73 (interquartile range [IQR]: 58-97 min), 80.5 (IQR: 67-93 min), and 71 min (IQR: 62-81 min), respectively. The median aorta clamping times were 35 (IQR: 28-52 min), 37.5 (IQR: 29-43 min), and 31 min (IQR: 25-35min), respectively,

Table 2. Demographic characteristics, comorbidities, and risk factors during preoperative evaluation of patients undergoing heart surgery. BMI Variable Normal weight Overweight Obesity P value n=32 n=48 n=21 % % % Male gender 31.1% 47.3% 21.6% 0.939 Elderly 32.3% 50.0% 17.7% 0.624 GI/ DM 37.7% 37.7% 24.6% 0.015* HF 55.6% 33.3% 11.1% 0.267 HBP 26.2% 48.8% 25.0% 0.010* COPD 75.0% 25.0% 0.0% 0.151 CKD 0.0% 100.0% 0.0% 0.100 Dyslipidemia 31.2% 45.5% 23.4% 0.507 Smoking 47.1% 29.4% 23.5% 0.222 PHS 40.0% 60% 0.0% 0.099 BMI=body mass index; CKD=chronic kidney disease; COPD=chronic obstructive pulmonary disease; DM=diabetes mellitus; HBP=high blood pressure; GI=glucose intolerance; HF=heart failure; PHS=previous heart surgery

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for the same patient groups. There were no significant differences in median CPB time (P=0.215) and aortic clamping (P=0.064) between groups stratified by BMI. In the immediate postoperative period, 44% of patients had APACHE II scores higher than 8.0. This score was also not different among normal BMI, overweight, and obese patients (P=0.458). The median post-surgical ICU and MV durations were 5 days (min: 3; max: 102) and 1 day (min: 1; max: 35), respectively. The median hospital stay was 16 days (min: 4; max: 117). There was no difference between MV, ICU, and hospitalization duration between patient groups (Table 3). Most patients were discharged from hospital (94.1%), while postoperative mortality occurred in 6 of 101 patients (5.9%). Slightly more than half of the patients (50.5%) had no postoperative complications. The univariate analysis re-

vealed an association between obesity and surgical reintervention due to sternal wound dehiscence (P=0.021). All patients with sternal wound dehiscence were obese (Table 4). Univariate analysis revealed no association between BMI and postoperative mortality (P=0.15). The multivariate analysis was adjusted for classes of complications (cardiovascular, infectious, requirement for surgical reintervention due to sternal wound dehiscence, bleeding, acute kidney injury, and minor complications) using the overweight group as a reference. Obesity was an independent predictor for surgical reintervention due to sternal wound dehiscence (odds ratio [OR]: 13.6; 95% confidence interval [95%CI]: 1.1-162.9; P=0.046) and a protective factor for bleeding (OR: 0.05; 95%CI: 0.09-0.69; P=0.025), as shown in Table 5. Mortality was not entered in the multivariate model due to the low number of deaths.

Table 3. Comparison of MV, ICU, and hospital stay postoperative times from patients undergoing heart surgery. Days

n 32 32 32

MV ICU Hospital stay

Normal weight Median Q1-Q3 1 1-2.5 5 4-9 17 10-23

n 48 48 48

BMI Overweight Median Q1-Q3 1 1-2 5 3-6.5 16 10-26

n 21 21 21

Obesity Median 1 5 13

Q1-Q3 1-2 4-6 9-21

BMI=body mass index; CABG=coronary artery bypass grafting; MV=mechanical ventilation

Table 4. Association between BMI and postoperative complications from CABG and/or valve replacement (univariate analysis). BMI Variable Normal Overweight Obesity P value % % % Cardiovascular complications 32.1 46.2 21.8 0.854 Infectious complications 28.4 48.7 23.0 0.436 Sternal wound dehiscence 0.0 0.0 10.0 0.021* Bleeding 32.4 43.2 24.3 0.249 Acute kidney failure 31.5 47.8 20.7 0.981 Minor complications 32.1 45.2 22.6 0.501 BMI=body mass index; CABG=coronary artery bypass grafting

Table 5. Obesity and postoperative complications risk at CABG and/or valve replacement (multivariate analysis). BMI Normal weight OR 95% IC P value Cardiovascular complications 0.83 0.22-3.13 0.784 Infectious complications 2.27 0.65-7.98 0.200 Sternal wound dehiscence 2.18 0.42-11.43 0.357 Bleeding 0.37 0.08-1.65 0.194 Acute kidney injury 0.74 0.11-5.18 0.761 Minor complications 0.73 0.18-3.01 0.661 BMI=body mass index; CABG=coronary artery bypass grafting Variable

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OR 0.83 2.27 2.18 0.37 0.74 0.73

Obesity 95% IC 0.22-3.13 0.65-7.98 0.42-11.43 0.08-1.65 0.11-5.18 0.18-3.01

P value 0.784 0.200 0.357 0.194 0.761 0.661

P value 0.578 0.741 0.694


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min vs. 74.8±24.2 min, respectively)[19]. In our population, BMI was not associated with changes in CPB duration and aortic clamping, possibly due to little intrathoracic anatomical variation in non-obese and obese patients. In addition, the duration of MV, ICU stay, and total length of hospital stay also did not differ according to BMI in the present study. These findings are consistent with data of other publications[19,31-33]. This study has some methodological limitations, especially with regard to the sample size. It was not possible to evaluate the usefulness of BMI as a predictor of mortality in the multivariate analysis. However, this is perhaps the only prospective study that provides data about the influence of BMI outcomes of adult and elderly patients undergoing myocardial revascularization or prosthetic valve replacement in Brazil. In addition, our results contribute to knowledge about the obesity paradox in cardiovascular surgery.

DISCUSSION To our knowledge, this was the first prospective Brazilian study designed to examine the impact of BMI on the outcome of patients undergoing CABG or valve replacement. The main finding of this study was that obesity in the preoperative period could be considered a predictor of risk for surgical reintervention by wound dehiscence and may reduce the risk of bleeding in the postoperative period of cardiac surgery. Although obesity appears to increase the frequency and risk of sternal wound dehiscence, it was not associated with other complications in the postoperative period or with increased mortality. Univariate and multivariate analyses revealed an association between obesity and increased frequency or risk of reoperation for sternal wound dehiscence in this study. We believe that the increased subcutaneous tissue thickness in individuals with excessive body weight may contribute to this complication. In support of our findings, a cohort study published in 2014 involving 5,815 patients who underwent CABG also noted that obesity was a predictive factor for sternal wound dehiscence, along with diabetes and female sex[26]. In multivariate analysis, obesity was a protective factor for increased bleeding in the CABG or valve replacement postoperative period. The observation that obesity is a protective factor for bleeding in the postoperative period of cardiac surgery was expected, since obese individuals have abundant mediastinal fat and large abdominal pressure, which leads to increased intrathoracic pressure that compresses sites of minor bleeding. In addition, reduced administered volume after CPB and less hemodilution in obese patients may also contribute to lower risk of postoperative bleeding. Thus, obese patients have significantly lower risks of surgical reintervention due to bleeding than non-obese or underweight patients[27,28]. We found no association between obesity and the presence of infectious or cardiovascular complications, acute kidney injury, or minor complications. Gurm et al. analyzed data from 1,526 patients during the CABG postoperative period and also reported no difference in the incidence or risk of major complications (death, myocardial infarction, stroke), cardiopulmonary events (heart failure, cardiogenic shock, reintubation), and wound infection among obese patients[29]. In the present study, there was no association between obesity and increased risk of mortality. However, two recent meta-analyses have noted that obese individuals have reduced risk of mortality after coronary revascularization[18,30]. In other studies, obese patients undergoing valve replacement surgery also showed superior survival time[19,20]. Our results showed lower average durations of CPB and aortic clamping than those described by other authors (79.3±24.9 min vs. 103.4±35.1 min and 37.6±16.8

CONCLUSION Obese patients undergoing CABG or valve replacement may be at increased risk of surgical reintervention by wound dehiscence and seem to be more protected from the risk of increased postoperative bleeding. Obesity does not appear to be related to increased incidence of other complications or postoperative mortality. However, larger studies are needed to establish definitive conclusions about the impact of obesity on mortality in the CABG and valve replacement postoperative period. Authors’ roles & responsibilities VEAC SMF

TOR RRR EAVR CMFC JCFC AB

Manuscript writing. Analysis and/or interpretation of data; Statistical analysis; final approval of the manuscript; study design; implementation of projects and/or experiments; manuscript writing or critical review of its content Conduct of operations and/or experiments Final approval of the manuscript; study design Final approval of the manuscript; manuscript writing or critical review of its content Conception and design; implementation of projects and/or experiments Conception and design; implementation of projects and/ or experiments; manuscript writing or critical review of its content Analysis and/or interpretation of data; statistical analysis; final approval of the manuscript; study design; implementation of projects and/or experiments; manuscript writing or critical review of its content

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19. Smith RL 2nd, Herbert MA, Dewey TM, Brinkman WT, Prince SL, Ryan WH, et al. Does body mass index affect outcomes for aortic valve replacement surgery for aortic stenosis? Ann Thorac Surg. 2012;93(3):742-6.

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20. Vaduganathan M, Lee R, Beckham AJ, Andrei AC, Lapin B, Stone NJ, et al. Relation of body mass index to late survival after valvular heart surgery. Am J Cardiol. 2012;110(11):1667-78.

8. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA. 2012;307(5):491-7. 9. Piegas LP, Bittar OJNV, Haddad N. Myocardial revascularization surgery (MRS): results from National Health System (SUS). Arq Bras Cardiol. 2009;93(5):555-60.

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23. Garrow JS, Webster J. Quetelet’s index (W/H2) as a measure of fatness. Int J Obes. 1985;9(2):147-53.

12. Stevens LM, Carrier M, Perrault LP, Hébert Y, Cartier R, Bouchard D, et al. Influence of diabetes and bilateral internal thoracic artery grafts on long-term outcome for multivessel coronary artery bypass grafting. Eur J Cardiothorac Surg. 2005;27(2):281-8.

24. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser. 2003;916:i-viii, 1-149, backcover. 25. Triola MF. Introdução à estatística. 10ª ed. Rio de Janeiro: LTC; 2008.

13. Kieser TM, Lewin AM, Graham MM, Martin BJ, Galbraith PD, Rabi DM, et al.; APPROACH Investigators. Outcomes associated with bilateral internal thoracic artery grafting: the importance of age. Ann Thorac Surg. 2011;92(4):1269-75.

26. Doherty C, Nickerson D, Southern DA, Kieser T, Appoo J, Dawes J, et al.; Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) Investigators. Trends in postcoronary artery bypass graft sternal wound dehiscence in a provincial population. Can J Plast Surg. 2014;22(3):196-200.

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29. Gurm HS, Whitlow PL, Kip KE. ; BARI Investigators. The impact of body mass index on short- and long-term outcomes in patients undergoing coronary revascularization. Insights from the bypass angioplasty revascularization investigation (BARI). J Am Coll Cardiol. 2002;39(5):834-40.

32. Orhan G, Biçer Y, Aka SA, Sargin M, Simşek S, Senay S, et al. Coronary artery bypass graft operations can be performed safely in obese patients. Eur J Cardiothorac Surg. 2004;25(2):212-7. 33. Pan W, Hindler K, Lee VV, Vaughn WK, Collard CD. Obesity in diabetic patients undergoing coronary artery bypass graft surgery is associated with increased postoperative morbidity. Anesthesiology. 2006;104(3):441-7.

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Lamana FA, et al. - SurgeryARTICLE of the aortic root: should we go for the valveORIGINAL sparing root reconstruction or the composite graft-valve replacement is still the first choice of treatment for these patients?

Surgery of the aortic root: should we go for the valve-sparing root reconstruction or the composite graft-valve replacement is still the first choice of treatment for these patients? Cirurgia da raiz da aorta: deve-se preservar a valva aórtica ou a operação com o tubo valvulado ainda é a primeira opção de tratamento para esses pacientes?

Fernando de Azevedo Lamana1; Ricardo Ribeiro Dias2, MD, PhD; Jose Augusto Duncan2, MD; Leandro Batisti de Faria3, MD; Luiz Marcelo Sa Malbouisson4, MD, PhD; Luciano de Figueiredo Borges5, MD, PhD; Charles Mady2, MD, PhD; Fábio Biscegli Jatene3, MD, PhD

DOI 10.5935/1678-9741.20150028

RBCCV 44205-1650

Abstract Objective: To compare the results of the root reconstruction with the aortic valve-sparing operation versus composite graftvalve replacement. Methods: From January 2002 to October 2013, 324 patients underwent aortic root reconstruction. They were 263 composite graft-valve replacement and 61 aortic valve-sparing operation (43 reimplantation and 18 remodeling). Twenty-six percent of the patients were NYHA functional class III and IV; 9.6% had Marfan syndrome, and 12% had bicuspid aortic valve. There was a predominance of aneurysms over dissections (81% vs.

19%), with 7% being acute dissections. The complete follow-up of 100% of the patients was performed with median follow-up time of 902 days for patients undergoing composite graft-valve replacement and 1492 for those undergoing aortic valve-sparing operation. Results: In-hospital mortality was 6.7% and 4.9%, respectively for composite graft-valve replacement and aortic valve-sparing operation (ns). During the late follow-up period, there was 0% moderate and 15.4% severe aortic regurgitation, and NYHA functional class I and II were 89.4% and 94%, respectively for composite graft-valve replacement and

Medicine student at Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil. 2 Cardiomiopathies and Aorta Diseases Surgical Center at Instituto do Coração of Hospital das Clínicas of Faculdade de Medicina da Universidade de São Paulo (InCor HC-FMUSP), São Paulo, SP, Brazil. 3 Instituto do Coração of Hospital das Clínicas of Faculdade de Medicina da Universidade de São Paulo (InCor HC-FMUSP), São Paulo, SP, Brazil. 4 Anestesiology Department of Hospital das Clínicas of Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, SP, Brazil. 5 Departament of Morfology of Instituto de Ciências Biológicas of Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.

This study was carried out at the Instituto do Coração of Hospital das Clínicas of Faculdade de Medicina da Universidade de São Paulo (InCor HCFMUSP), São Paulo, SP, Brazil.

1

No financial support. Correspondence address: José Augusto Duncan Instituto do Coração Av. Dr. Enéas de Carvalho Aguiar, 44 Bloco II 2º andar - Sala 13 - Pinheiros - São Paulo, SP, Brazil - Zip code: 05403-900 E-mail: duncan@incor.usp.br Article received on September 29th, 2014 Article accepted on April 26th, 2015

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Lamana FA, et al. - Surgery of the aortic root: should we go for the valvesparing root reconstruction or the composite graft-valve replacement is still the first choice of treatment for these patients?

324 pacientes foram submetidos à reconstrução da raiz da aorta. Foram 263 tubos valvulados e 61 preservações da valva aórtica (43 reimplantes e 18 remodelamentos). 26% dos pacientes estavam em classe funcional III e IV; 9,6% com síndrome de Marfan e 12% apresentavam valva aórtica bivalvulada. Houve predomínio dos aneurismas sobre as dissecções (81% contra 19%), sendo 7% de dissecções agudas. O seguimento completo de 100% dos pacientes foi realizado com tempo mediano de seguimento de 902 dias para pacientes submetidos à tubo valvulado e de 1492 para aqueles submetidos à preservação da valva aórtica. Resultados: A mortalidade hospitalar foi de 6,7% contra 4,9% respectivamente para tubo valvulado e preservação da valva aórtica (ns). No seguimento tardio, a insuficiência aórtica importante foi de 0% e 5,8%, e a insuficiência cardíaca crônica, classe funcional I e II de 89,4% e 94%, respectivamente, para tubo valvulado e preservação da valva aórtica (ns). A reconstrução da raiz da aorta com a preservação da valva aórtica apresentou menor mortalidade tardia (P=0,001) e menos complicações hemorrágicas (P=0,006). Não houve diferença para tromboembolismo, endocardite ou necessidade de reoperação. Conclusão: A reconstrução da raiz da aorta com a preservação valvar deve ser a operação a ser realizada por apresentar menor mortalidade e sobrevida livre de eventos hemorrágicos.

Abbreviations, acronyms & symbols ACC AHA AVS CVR NYHA

American College of Cardiology American Heart Association Aortic valve-sparing operation Composite graft-valve replacement New York Heart Association

aortic valve-sparing operation (ns). Root reconstruction with aortic valve-sparing operation showed lower late mortality (P=0.001) and lower bleeding complications (P=0.006). There was no difference for thromboembolism, endocarditis, and need of reoperation. Conclusion: The aortic root reconstruction with preservation of the valve should be the operation being performed for presenting lower late mortality and survival free of bleeding events. Descriptors: Aorta, Thoracic. Aortic Aneurysm. Aortic Aneurysm, Thoracic. Aortic Diseases. Cardiovascular Surgical Procedures. Resumo Objetivo: Analisar comparativamente os resultados da operação de preservação da valva aórtica e do tubo valvulado nas reconstruções da raiz da aorta. Métodos: No período de janeiro de 2002 a outubro de 2013,

Descritores: Aneurisma da Aorta Torácica. Doenças da Aorta. Aorta Torácica. Procedimentos Cirúrgicos Cardiovasculares. Aneurisma Aórtico.

INTRODUCTION

In our midst, we still have little knowledge on the impact of this disease in the general population. It has been observed that its mortality in the state of São Paulo is still very high due to either the shortcomings and inefficiency of our health system in identifying, screening, and treating these patients or the inadequate results obtained with hospitalized patients receiving drug treatment or even those who had undergone a surgical procedure (despite results being substantially better when these patients underwent surgery)[7]. A first step has been taken. In the state of São Paulo, even though a significant increase has been observed in the number of diagnostics, hospitalizations, and procedures during the period of the study[7], there is a lot to be done in order to improve the results of these interventions. In a system where the population still has limited access to healthcare, procedures that allow simpler follow-up should always be pursued as long as their results are similar to those of conventional treatment. To this end, this study sets out to evaluate whether valve-sparing root reconstructions show similar or better results to those obtained with composite graft-valve replacement, especially when comparing similar populations of patients.

The choice of treatment for the correction of diseases affecting the aortic root and aortic valve is its replacement for a valved conduit. However, there is a large amount of discussion about which is the best valved conduit (homograft, xenograft, autograft, mechanical valve and prosthetic conduit or bioprosthetic) and the variety of possibilities according to different age groups[1]. The possibilities for aortic root reconstruction with preservation of the aortic valve, regardless of the degree of aortic regurgitation, has been largely documented albeit with several considerations about its non-applicability to every patient as well as its complexity, making it difficult to be used by all surgeons[2-4]. In an attempt to follow the advances in aortic surgery presented worldwide, we have performed many of the procedures proposed with results similar or very close to the ones presented, especially in reference centers[3-5]. Aortic root operations have low mortality rates and patients who have undergone the procedure show the same life expectancy and quality of life as the healthy population of the same age group[6]. Thus, these patients need to be identified and treated.

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METHODS

Venous drainage was performed preferably through a single two-stage cannula in the right atrium (except when it was necessary to approach the mitral valve) and drainage of the left chambers was done through a catheter placed in the left ventricle via the right superior pulmonary vein. Myocardial protection, initially performed with antegrade intermittent cold cardioplegia (exclusively up to 2009), has been increasingly used in less complex procedures (80.2% CVR) and replaced by histidine-tryptophan-ketoglutarate solution (Custodiol® HTK) in more extensive procedures (19.8% CVR and 24.6% AVS). Systemic perfusion temperature for procedures in which the aortic arch had to be approached (partial approach) was 25°C. When the approach was deemed unnecessary, moderate hypothermia was kept at 32°C. In the aortic root reconstructions performed with CVR, mean CPB and myocardial ischemia time were 136 and 108 minutes, respectively. In AVS procedures, mean times were 158 and 135 minutes, respectively (Table 2).

Between January 2002 and October 2013, 324 patients underwent surgery for aortic root reconstruction. Among them, 263 patients underwent composite graft-valve replacement (CVR) (251 mechanical prosthetic valves and 12 bioprosthetic valves) and 61 patients underwent aortic valve-sparing operation (AVS) (43 reimplantation and 18 remodeling). The indication for surgery was in accordance with the ACC/AHA guidelines[8]. A retrospective data analysis was performed by searching the institution’s database as well as by talking to individual patients on the phone, when needed. The study was approved by the Research Ethics Committee of the institution and informed consent was deemed unnecessary due to the study characteristics. The patients who underwent aortic root reconstruction were predominantly male (73%), with a mean age of 52 years and predominance of aneurysms over dissections (81% vs. 19%), of which 7% were acute dissections. Mean diameter was 5.7cm, mean body mass index was 25, and ventricular function was almost fully preserved. Among the 31 patients who had Marfan syndrome (9.5%), 19 were submitted to CVR and 12 to AVS. The other 39 patients who had bicuspid aortic valve (12%), 38 underwent CVR and 1 AVS. There were 62 reoperations (19%), every single one of them was CVR; 37 were reoperations of previous cardiac surgery (60%) and 25 were reoperations of aortic surgery. In addition, there were 76 associated procedures (23.4%); 54 of them during CVR surgery (71%). Table 1 shows the comparison of demographic characteristics of patients submitted to aortic root reconstruction, before and after the groups were matched according to the propensity score. Patients submitted to aortic root reconstruction in connection with complex thoracic aorta procedures (approach of more than three thoracic aorta segments in a single procedure) were excluded from the study.

Follow-up Information on these patients was continuously gathered from the results of outpatient follow-up and telephone contact with patients from other regions. Patients were evaluated for events related to prolonged use of oral anticoagulants, thromboembolic and hemorrhagic events, infection of prosthetic valve, endocarditis with or without the need for reoperation, and reoperation for any reason. Ecchymosis, conjunctival hemorrhage, epistaxis, hematuria, larger bleedings and those with hemodynamic repercussions (cardiac tamponade, upper gastrointestinal bleeding or enterorrhagia), as well as bleeding to the central nervous system were considered as minor hemorrhagic events. Complete follow-up of 100% of the patients was performed with a median time of 902 days [213 (25th percentile) – 1757 (75th percentile)] for patients who underwent CVR and 1492 days [487 (25th percentile) – 2385 (75th percentile)] for those who underwent AVS. Follow-up period ended in October 2013.

Surgical technique Surgery was performed through median sternotomy when the aortic disease was restricted to the aortic root/ascending aorta and the arterial line was established in the aortic arch (212 patients/65%). In patients where an approach of the aortic arch was necessary, whenever the brachiocephalic trunk was uncompromised it served as the site of the arterial line (91 patients/28%). In cases of acute proximal dissection, there was cannulation of the right subclavian artery (21 patients/6.5%). Cerebral protection was achieved with hypothermia at 25°C and selective cerebral perfusion via a carotid artery associated with topical hypothermia and thiopental sodium.

Statistical Analysis The results were expressed as mean ± SD and percentages. For the analysis, normal distribution was confirmed by the Kolmogorov-Smirnov test and visual analysis of the data. Continuous variables were compared using the Student t-test for pairwise comparisons and the Wilcoxon test for unpaired data. Categorical variables were assessed through either Chisquare or Fischer’s exact test. Kaplan-Meier curves and the log-rank test were used to compare survival rates in the AVS and CVR groups. Values of P<0.05 were considered statistically significant. All analyses were performed using IBM - SPSS (version 21, IBM Corp Armonk, NY).

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Table 1. Preoperative characteristics of patients from the original CVR and AVS groups and propensity score matched groups.

Variables Mean age, years (mean ± SD) Male, n (%) BMI,Kg/m² (mean ± SD) LVEF, % (mean ± SD) LVEDV, mL (mean ± SD) Aortic diameter, mm (mean ± SD) Risk factor Marfan syndrome, n (%) Bicuspid Aortic valve, n (%) Hypertension, n (%) Diabetes mellitus, n(%) Dyslipidemia, n(%) Renal failure, n (%) ARF, n (%) CRF, n (%) Dialytic renal failure, n (%) Smoking n (%) Family history, n (%) COPD, n (%) CVA, n (%) Cancer, n (%) HIV+, n (%) Coronary insufficiency, n (%) AMI, n (%) Chest pain, n (%) Reoperation, n (%)

CVR n=263 55±15 19 (73.8) 25.8±4.5 0.57±0.12 211±85 58±11

Original cohort AVS n=61 48±15 42 (68.9) 24,1±4.6 0.61±0.1 222±108 56±8

0.02 0.43 0.03 0.03 0.48 0.32

Propensity score matched cohort CVR AVS P value n=60 n=61 58±14 48±15 0.001 43 (71.7) 42 (68.9) 0.73 25.3±4 24.1±4.6 0.25 0.59±0.13 0.61±0.1 0.37 233±89 222±108 0.6 57±11 56±8 0.51

P value

19 (7.2) 38 (14.4) 175 (66.5) 18 (6.8) 55 (20.9)

12 (19.7) 1 (1.6) 45 (73.8) 3 (4.9) 10 (16.4)

0.003 0.004 0.27 0.77 0.42

3 (5) 3 (5) 46 (76.7) 3 (5) 11 (18.3)

12 (19.7) 1 (1.6) 45 (73.8) 3 (5) 10 (16.4)

0.02 0.36 0.71 0.99 0.77

6 (2.3) 21 (8) 0 (0) 88 (33.5) 20 (7.6) 19 (7.2) 7 (2.7) 5 (1.9) 6 (2.3) 44 (16.7) 14 (5.3) 91 (34.6) 62 (23.8)

2 (3.3) 2 (3.3) 1 (1.6) 24 (39.3) 7 (11.5) 1 (1.6) 0 (0) 0 (0) 0 (0) 8 (13.1) 1 (1.6) 22 (36.1) 0 (0)

0.65 0.27 0.18 0.38 0,32 0.14 0.35 0.58 0.59 0.48 0.32 0.82 <0.001

1 (1.7) 6 (10) 0 (0) 20 (33.3) 4 (6.7) 6 (10) 2 (3.3) 1 (1.6) 0 (0) 12 (20) 2 (3.3) 12 (20) 11 (18.6)

2 (3.3) 2 (3.3) 1 (1.6) 24 (39.3) 7 (11.5) 1 (1.6) 0 (0) 0 (0) 0 (0) 8 (13.1) 1 (1.7) 22 (36.1) 0 (0)

0.99 0.16 0.31 0.49 0.52 0.06 0.24 0.49 0.3 0.61 0.05 <0.001

Heart failure, n (%) FC I FC II FC III FC IV

132 (50.2) 56 (21.3) 53 (20.2) 22 (8.4)

38 (62.3) 15 (24.6) 6 (9.8) 2 (3.3)

26 (43.3) 18 (30) 14 (23.3) 2 (3.3)

38 (62.3) 15 (24.6) 6 (9.8) 2 (3.3)

Indication for surgery, n (%) Aneurysm Acute type A aortic dissection Chronic type A aortic dissection

204 (77.6) 18 (6.9) 47 (17.9)

58 (95.1) 0 (0) 4 (6.6)

52 (86.7) 1 (1.6) 7 (11.7)

58 (95.1) 0 (0) 4 (6.6)

Function of aortic valve, n (%) Normal Minimal AI Mild AI Moderate AI Severe AI

16 (6.3) 3 (1.2) 47 (17.9) 68 (26.6) 122 (47.7)

5 (8.3) 2 (3.3) 16 (26.7) 18 (30) 19 (31.7)

7 (11.7) 0 (0) 6 (10) 22 (36.7) 25 (41.7)

5 (8.3) 2 (3.3) 16 (26.7) 18 (30) 19 (31.7)

Urgent operation

97 (36.7)

0 (0)

0 (0)

0 (0)

0.02

0.002 0.02 0.03 0.03

<0.001

0.03

0.12 0.49 0.36 0.29

-

CVR=composite graft-valve replacement; AVS=aortic valve-sparing operation; SD=standard deviation; BMI=Body Mass Index; LVEF=left ventricle ejection fraction; LVEDV=left ventricle end diastolic volume; ARF=acute renal failure; CRF=chronic renal failure; COPD=chronic obstructive pulmonary disease; CVA=cerebrovascular accident; HIV+=positive status for human immunodeficiency vírus; AMI=acute myocardial infarction; FC=functional class (NYHA); AI=aortic insufficiency

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Propensity score In order to reduce selection bias resulting from the collection of non-randomized data from distinct periods of time as well as to balance the sample characteristics, patients from the AVS and CVR groups were propensity matched based on the estimated probability of being treated. The procedure consists of matching patients from the intervention group (AVS) with similar characteristics to those of the control group (CVR). First, a logistic regression model was created using the group as the dependent variable. The most relevant confounders (age, left ventricular ejection fraction, degree of aortic regurgitation, and congestive heart failure according to the NYHA classification) were inserted as predictors and the confidence level for corresponding tolerance intervals was 95%. Next, a set for every intervention group patient was selected from the control group based on the propensity score matching obtained from the logistic regression. The model was built based on a sample of patients propensity score matched 01:01, with no replacement or repetition. Sixty-one adequately matching pairs of patients were identified, which was enough to perform all statistical analyses, without compromising the power of the study. The matching process

was done before the analysis of the study results. One of the patients from the CVR group was removed from the analysis due to an inconsistency in the long-term follow-up data. Differences were considered statistically significant for P<0.05. All analyses were performed using IBM - SPSS (version 21, IBM Corp Armonk, NY). RESULTS The group of patients who underwent aortic root reconstruction with AVS was younger. Proportionally, AVS was the most performed procedure in patients with Marfan Syndrome and it was not the technical option for reoperation. After the propensity score matching, there were no differences between groups in frequency of sex, degree of aortic regurgitation, and diagnosis of the underlying disease. Most of the patients were functional class I and II, with moderate and severe aortic insufficiency respectively at 73.3% and 87.9% in the CVR group and 78.4% and 62% in the AVS group. There were no differences in distribution between groups for the remaining variables analyzed (Table 1).

Table 2. Intraoperative data of patients from the original CVR and AVS groups and propensity score matched groups.

Variables CPB time, min (mean±SD) Ischemic time, min (mean±SD)

CVR n=263 136±38 108±30

Original cohort AVS n=61 158±31 135±25

Aortic approach, n (%) Bentall Cabrol Reimplantation Remodeling

225 (85.6) 38 (14.4) 0 (0) 0 (0)

0 (0) 0 (0) 43 (70.5) 18 (29.5)

Arterial line, n (%) CPB CPB + TCA + RCP Femoro-femoral CPB Subclavian + 1 carotid Subclavian + 2 carotids BCT + 1 carotid BCT + 2 carotids BCT + SCP via 2 carotids

161 (61.2) 1 (0.4) 3 (1.1) 19 (7.2) 1(0.4) 68 (25.9) 9 (3.4) 1 (0.4)

51 (83.6) 0 (0) 0 (0) 1 (1.6) 0 (0) 9 (14.8) 0 (0) 0 (0)

Associated procedures, n (%) MR MiVR/plasty Descending Aorta stent gafting Descending Aorta conduit

35 (13.3) 13 (4.9) 3 (1.1) 3 (1.1)

6 (9.8) 16 (16.4) 0 (0) 0 (0)

P value <0.001 <0.001 <0.001

0.13

0.46 0.002 0.4 0.4

Propensity score matched cohort CVR AVS P value n=60 n=61 132±29 158±31 <0.001 100±22 135±25 <0.001 56 (93.3) 4 (6.7) 0 (0) 0 (0)

0 (0) 0 (0) 43 (70.5) 18 (29.5)

35 (58.3) 1 (1.7) 0 (0) 2 (3.3) 0 (0) 21 (35) 1 (1.7) 0 (0)

51 (83.6) 0 (0) 0 (0) 1 (1.6) 0 (0) 9 (14.8) 0 (0) 0 (0)

7 (11.7) 1 (1.7) 3 (5) 0 (0)

6 (9.8) 16 (16.4) 0 (0) 0 (0)

<0.001

0.39

0.74 0.008 0.11 -

CVR=composite graft-valve replacement; AVS=aortic valve-sparing operation; SD=standard deviation; CPB=cardiopulmoray bypass; SCP=selective cerebral perfusion; BCT=brachiocephalic trunk; TCA=total circulatory arrest; RCP=retrogade cerebral perfunsion; MR=myocardial revascularization; MiVR=mitral valve replacement

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Procedure performed (Table 2) There were significant differences in the time needed to perform both aortic root reconstruction procedures (P<0.001); with CPB and myocardial ischemia times in minutes for CVR and AVS groups being 132±29 and 100±22 versus 158±31 and 135±25, respectively. There was no difference between the sites of the arterial line, whose placement was in accordance with the underlying disease. Seventy-six associated procedures were performed (in 23.4% of the patients), with a prevalence of myocardial revascularization (12.6%) followed by mitral valve procedures (9%).

postoperative renal dysfunction at some degree, of which 19.6% needed dialysis; 11.1% surgical wound infection (superficial); 10.5% reoperation resulting from bleeding; and 8.3% neurological complication of any kind. Mortality in 30 days was 8.3% and hospital mortality was 9.9%. Late evaluation of aortic valve function and heart failure The last echocardiographic study performed during late follow-up period was carried out in 247 patients (84.6% of the general sample and 88% of the AVS group) and showed similar intensity of regurgitation between the two groups when the absence of aortic insufficiency, traces, and discrete regurgitation are taken into consideration, reaching 100% and 84.6% in the CVR and AVS groups, respectively. While in the preoperative period, patients of the CVR and AVS groups had moderate to severe aortic regurgitation at 78.4% and 62% of the sample, respectively. The last echocardiography showed 0% and 15.4% (5.7% of which was severe regurgitation), respectively.

Hospital mortality and immediate postoperative complications In terms of incidence of postoperative complications as well as 30-day and hospital mortality, there were no significant differences, regardless of the aortic root reconstruction technique employed, as stated in Table 3. There was 25% respiratory tract infection; 19.4% atrial arrhythmia (all reverted before hospital discharge); 15.7%

Table 3. Intrahospital postoperative complications of patients from the original CVR and AVS groups and propensity score matched groups. CVR n=263

Original cohort AVS n=61

P value

Propensity score matched cohort CVR AVS P value n=60 n=61

Variables Reoperation, n (%) Bleeding Tamponade Gauze removal

19 (97.2) 6 (2.3) 3 (1.1)

4 (6.6) 0 (0) 2 (3.3)

0.85 0.59 0.23

1 (1.7) 1 (1.7) 0 (0)

4 (6.6) 0 (0) 2 (3.3)

0.36 0.49 0.49

Low cardiac output, n (%) Wound infection, n (%) Mediastinitis, n (%) Tracheobronchitis, n (%) Pneumonia, n (%) UTI, n (%) Sepsis, n (%) OTI > 72h, n (%) ARF, n (%) Dialytic ARF, n (%) Psychomotor agitation, n (%) Delirium, n (%) Seizure, n (%) CVA (deficit), n (%) CVA (transiente), n (%) Coma, n (%) AMI, n (%) Atrial arrhythmia, n (%) Ventricular arrhythmia, n (%) Hospital death, n (%)

27 (10.3) 32 (12.2) 2 (0.8) 13 (4.9) 59 (22.4) 9 (3.4) 31 (11.8) 3 (1.1) 34 (12.9) 10 (3.8) 8 (3) 4 (1.5) 5 (1.9) 4 (1.5) 2 (0.8) 2 (0.8) 3 (1.1) 54 (20.5) 7 (2.7) 29 (11)

1 (1.6) 4 (6.6) 0 (0) 2 (3.3) 7 (11.5) 1 (1.6) 4 (6.6) 0 (0) 7 (11.5) 0 (0) 1 (1.6) 0 (0) 0 (0) 1 (1.6) 0 (0) 0 (0) 1 (1.6) 9 (14.8) 0 (0) 3 (4.9)

0.39 0.26 0.99 0.57 0.06 0.69 0.35 0.99 0.75 0.21 0.99 0.99 0.58 0.99 0.99 0.99 0.56 0.37 0.35 0.23

3 (5) 8 (13.3) 0 (0) 1 (1.7) 11 (18.3) 2 (3.3) 3 (5) 0 (0) 3 (5) 1 (1.7) 1 (1.7) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 14 (23.3) 1 (1.7) 4 (6.7)

1 (1.6) 4 (6.6) 0 (0) 2 (3.3) 7 (11.5) 1 (1.6) 4 (6.6) 0 (0) 7 (11.5) 0 (0) 1 (1.6) 0 (0) 0 (0) 1 (1.6) 0 (0) 0 (0) 1 (1.6) 9 (14.8) 0 (0) 3 (4.9)

0.36 0.24 0.99 0.28 0.54 0.99 0.32 0.49 0.99 0.99 0.99 0.22 0.49 0.71

CVR=composite graft-valve replacement; AVS=aortic valve-sparing operation; SD=standard deviation; UTI=urinary tract infection; OTI=orotracheal intubation; ARF=acute renal failure; CVA=cerebrovascular accident; AMI=acute myocardial infarction

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In the last clinical evaluation, 89.4% of the CVR group patients had FC I and II heart failure against 94% of the AVS patients.

thoracoabdominal aorta replacements (one death); two abdominal aortic corrections and one myocardial revascularization. The only reoperation in the AVS group was an aortic valve replacement due to severe regurgitation four years after the initial operation. Mortality during follow-up was higher in the CVR group (P=0.001). Looking at the survival curve, the benefit of aortic root reconstruction with AVS becomes evident (Figures 1A and 1B).

Late mortality and complications associated with the performed operation (Table 4) During the aforementioned follow-up period, a significant difference was observed in the incidence of major hemorrhagic complications (P=0.006) whereas no differences between groups were observed for minor hemorrhagic complications, survival free of thromboembolic events, endocarditis, reoperation, ventricular function, and left ventricular end-diastolic volume. Reoperations in the CVR group had to be performed in 14 patients, five of which died (35.7%). There were four composite graft-valve replacements due to endocarditis (two deaths); five stent grafting of the descending aorta (one death) and one interposition of the polyester conduit (one death), all due to an aneurysm in the descending aorta; two

DISCUSSION The analysis of the results through propensity score matching allows the assessment of similar samples of patients, which would not be possible any other way since the CVR procedure is the choice of treatment for all patients and the AVS procedure is an option for selected patients, thereby making it difficult to perform a comparative analysis of both aortic root reconstruction techniques. However, there is a

Table 4. Data from late postoperative period of patients from the original CVR and AVS groups and propensity score matched groups.

Thromboembolic complications, n (%) Hemorrhagic complications, n (%) no minor major Endocarditis, n (%) Late reoperation, n (%) Days to the last echo, median (25% - 75%) LVEF, % (mean±SD) LVEDV, mL (mean±SD) Late heart failure, n (%) FC I FC II FC III FC IV Function of aortic valve, n (%) Normal Minimal AI Mild AI Moderate AI Severe AI Follow-up time, median (25% - 75%) Death 30 days, n (%) Death during follow-up, n (%)

CVR n=263 8 (3.1)

Original cohort AVS n=61 2 (3.3)

P value 0.99 <0.001

Propensity score matched cohort CVR AVS P value n=60 n=61 4 (6.7) 2 (3.3) 0.43 0.006 48 (80) 61 (100) 2 (3.3) 0 (0) 10 (16.7) 0 (0) 1 (1.7) 1 (1.6) 3 (5) 1 (1.6)

216 (82.1) 11 (4.2) 36 (13.7) 6 (2.3) 14 (5.3)

61 (100) 0 (0) 0 (0) 1 (1.6) 1 (1.6)

933 (342-2049) 64±12 127±48

1545 (611-2555) 61±8 158±80

0.01 0.17 0.03

(n=186) 76 (40.9) 84 (45.2) 20 (10.8) 6 (3.2)

(n=51) 24 (47.1) 24 (47.1) 3 (5.9) 0 (0)

0.134

(n=47) 13 (27.7) 29 (61.7) 4 (8.4) 1 (2.1)

(n=51) 24 (47.1) 24 (47.1) 3 (5.9) 0 (0)

0.43

(n=195) 152 (77.1) 19 (9.7) 20 (10.3) 1 (0.5) 3 (1.5)

(n=52) 12 (23.1) 5 (9.6) 27 (51.9) 5 (9.6) 3 (5.8)

<0.001

(n=28) 22 (81.5) 3 (10.7) 3 (10.7) 0 (0) 0 (0)

(n=52) 12 (23.1) 5 (9.6) 27 (51.9) 5 (9.6) 3 (5.8)

<0.001

902 (213-1757) 24 (9.2) 60 (22.8)

1492 (487-2385) 3 (4.9) 5 (8.2)

0.05 0.44 0.01

0.99 0.32

2050 (529-2841) 1545 (611-2555) 61±8 60±7 140±35 158±80

1637 (578-2617) 1492 (487-2385) 3 (5) 3 (4.9) 20 (33.3) 5 (8.2)

0.76 0.76 0.39

0.51 0.99 0.001

CVR=composite graft-valve replacement; AVS=aortic valve-sparing operation; LVEF=left ventricle ejection fraction; LVEDV=left ventricle end diastolic volume; FC=functional class (NYHA); AI=aortic insufficiency

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Fig. 1A - Survival curve of patients who underwent aortic root reconstruction via aortic valve-sparing operation (AVS) and composite graftvalve replacement (CVR) techniques. 1B - Survival curve of propensity score matched patients who underwent aortic root reconstruction.

bias even with the use of this methodology and study groups usually are not as similar as they would be in randomized studies. Despite good results being shown by the use of aortic valve-sparing procedures, the most appropriate procedure for aortic root reconstruction is still the composite-graft valve replacement[9-12], especially because it can be performed in every single patient and it is widely applied by surgeons. Mortality rates observed for elective patients who underwent aortic root reconstruction was 6.7% and 4.9% for CVR and AVS, respectively, which is slightly higher than the 2.9% observed in a systematic review of patients who had the aortic valve preserved and, at the same time, similar to the number of deaths among patients who underwent associated procedures (24.5%)[9]. The surgical technique adopted is similar to the one used in centers where aortic valve-sparing procedures are performed. Different options adopted for the arterial line were due to the extent of the disease in the ascending aorta/aortic arch, whether the brachiocephalic trunk was compromised (in chronic dissections), and the deliberate use of the right subclavian artery for acute aortic dissections with impairment of proximal segments. In this study, the comparative analysis showed surgical results were entirely similar between the groups, both for 30-day and overall hospital mortality. In spite of the greater complexity of the AVS procedure, clearly reflected on longer CPB and myocardial ischemia times, the immediate result of the procedure was entirely comparable. Why do it, then? Late follow-up of these patients showed evidence of the benefits of preservation of the aortic valve with a direct impact on mortality, especially as a result of the lack of pro-

longed use of oral anticoagulants and the control of adequate levels of anticoagulation. Bleeding had a direct influence on the mortality of these patients (there were two cases of cardiac tamponade, three cerebrovascular accidents, one medullary vascular accident, six upper gastrointestinal bleedings, two cases of enterorrhagia, and one case of epistaxis with hemorrhagic shock). There were other bleeding events, however, without repercussions. In a systematic review of when there was preservation of the aortic valve, the bleeding observed during evolution is not cause worrying[13], differently from what is observed with prolonged use of anticoagulants. There was no significant difference in the incidence of thromboembolic and infectious complications when a valve prosthesis was used or when the native valve was spared, different from some literature citations and even from results previously observed in the present institution for patients treated at different points in time when there was a higher need for reoperation due to endocarditis of the valved conduit compared to the native valve[4,12]. The need for reoperation during evolution of both groups was low. In the case of the CVR group, it was particularly as a result of the incidence of vascular disease in distal segments of those treated initially, followed by prosthetic infection. In this sample, there was no reoperation due to pseudoaneurysm. In the AVS group, average follow-up time was 1492 days and there was only one patient who needed valve replacement (1.7%); two others, despite severe regurgitation (5.1%), were asymptomatic and had neither significant dilation of the left chambers nor worsening of ventricular function and thus continued with clinical follow-up. Therefore, in aortic root reconstructions, one patient needed aortic valve replacement (1.7%) for median follow-up time and for follow-up times of 25% and

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75% of the sample of 4.1 years, 1.3 years, and 6 years, respectively. Two other patients (5.1%) showed severe regurgitation in up to six years of follow-up. Based on the information aforementioned, we suggest a reevaluation of the aortic root reconstruction via composite-graft valve replacement as the gold standard for treatment of aortic root diseases, mainly if these results remain constant in the coming years. This is in accordance with the suggestion of centers of excellence for the treatment of this subgroup of patients[12-16].

3. Dias RR, Mejia OV, Carvalho EV Jr, Lage DO, Dias AR, Pomerantzeff PM, et al. Aortic root reconstruction through valvesparing operation: critical analysis of 11years of follow-up. Rev Bras Cir Cardiovasc. 2010;25(1):66-72. 4. Dias RR, Mejia AO, Fiorelli AI, Pomerantzeff PM, Dias AR, Mady C, et al. Analysis of aortic root surgery with composite mechanical aortic valve conduit and valve-sparing reconstruction. Rev Bras Cir Cardiovasc. 2010;25(4):491-9. 5. da Costa FD, Takkenberg JJ, Formazari D, Balbi Filho EM, Colatusso C, Mokhles MM, et al. Long-term results of the Ross operation: an 18-year single institution experience. Eur J Cardiothoracic Surg. 2014;46(3):415-22.

Limitations of the study It has the limitations of being a retrospective study carried out with infrequent disorders performed in a reduced number of patients by only two surgeons and with limited follow-up time.

6. Zehr KJ, Orszulak TA, Mullany CJ, Matloobi A, Daly RC, Dearani JA, et al. Surgery for aneurysms of the aortic root: a 30-year experience. Circulation. 2004;110(11):1364-71.

CONCLUSION

7. Dias RR, Mejia OA, Fernandes F, Ramires FJ, Mady C, Stolf NA, et al. Mortality impact of thoracic aortic disease in Sao Paulo state from 1998 to 2007. Arq Bras Cardiol. 2013;101(6):528-35.

Aortic root reconstruction with preservation of the aortic valve should be the procedure carried out in patients with diseases in this segment of the aorta since it has lower morbimortality and survival free of hemorrhagic events associated with prolonged anticoagulation.

8. Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, et al. ; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American College of Radiology; American Stroke Association; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of Thoracic Surgeons; Society for Vascular Medicine. 2010 ACCF/AHA/AATS/ACR/ASA/ SCA/SCAI/SIR/STS/SVM. Guidelines for the diagnosis and management of patients with thoracic aortic disease. Circulation. 2010;121(13):e266-e369.

Authors’ roles & responsibilities FAL RRD

JAD LBF LMSM LFB CM FBJ

Analysis and interpretation of the data Analysis and interpretation of data; final approval of the manuscript; study design; implementation of projects and experiments; manuscript writing or critical review of its content Analysis and interpretation of the data Analysis andr interpretation of the data Statistical analysis Manuscript writing and critical review of its content Manuscript writing and critical review of its content Manuscript writing and critical review of its content

9. Skripochnik E, Michler RE, Hentschel V, Neragi-Miandoab S. Repair of aortic root in patients with aneurysm or dissection: comparing the outcomes of valve-sparing root replacement with those from the Bentall procedure. Rev Bras Cir Cardiovasc. 2013;28(4):435-41. 10. David TE, Maganti M, Armstrong S. Aortic root aneurysm: principles of repair and long-term follow-up. J Thorac Cardiovasc Surg. 2010;140(6 Suppl):S14-9.

REFERENCES

11. Svensson LG, Deglurkar I, Ung J, Pettersson G, Gillinov AM, D’Agostino RS, et al. Aortic valve repair and root preservation by remodeling, reimplantation, and tailoring: technical aspects and early outcome. J Card Surg. 2007;22(6):473-9.

1. Etz CD, Girrbach FF, von Aspern KV, Battellini R, Dohmen P, Hoyer A, et al. Longevity after aortic root replacement: is the mechanically valved conduit really the gold standard for quinquagenarians? Circulation. 2013;128(11 Suppl 1):S253-62.

12. Patel ND, Weiss ES, Alejo DE, Nwakanma LU, Williams JA, Dietz HC, et al. Aortic root operation for Marfan syndrome: a comparison of the Bentall and valve-sparing procedures. Ann Thorac Surg. 2008;85(6):2003-11.

2. David TE, Armstrong S, Manlhiot, McCrindle BW, Feindel CM. Long-term results of aortic root repair using the reimplantation technique. J Thorac Cardiovasc Surg. 2013;145(3 Suppl):S22-5.

13. Saczkowski R, Malas T, de Kerchove L, El Khoury G, Boodhwani M. Systematic review of aortic valve preservation and repair. Ann Cardiothorac Surg. 2013;2(1):3-9.

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14. Monsefi N, Zierer A, Risteski P, Primbs P, Miskovic A, KarimianTabrizi A, et al. Long-term results of aortic valve resuspension in patients with aortic valve insufficiency and aortic root aneurysm. Interact Cardiovasc Thorac Surg. 2014;18(4):432-7.

and midterm outcomes in 83 patients. Ann Thorac Surg. 2014;97(4):1267-73. 16. David TE, Feindel CM, Webb GD, Colman JM, Armstrong S, Maganti M. Aortic valve preservation in patients with aortic root aneurysm: results of the reimplantation technique. Ann Thorac Surg. 2007;83(2):S732-5.

15. Coseli JS, Hughes MS, Green SY, Price MD, Zarda S, de la Cruz KI, et al. Valve-sparing aortic root replacement: early

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Dorsa RC, et al. - Effect of remote ischemic postconditioning in inflammatory ORIGINAL ARTICLE changes of the lung parenchyma of rats submitted to ischemia and reperfusion

Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion Efeito do pós-condicionamento isquêmico remoto nas alterações inflamatórias do parênquima pulmonar de ratos submetidos à isquemia e reperfusão

Rafael Cantero Dorsa1, MD, MSc; José Carlos Dorsa Vieira Pontes2, MD, PhD; Andréia Conceição Brochado Antoniolli1, MD, PhD; Guilherme Viotto Rodrigues da Silva1, MD; Ricardo Adala Benfatti3, MD, PhD; Carlos Henrique Marques dos Santos1, MD, PhD; Elenir Rose Cury Pontes1, MD, PhD; José Anderson Souza Goldiano4, MD

DOI 10.5935/1678-9741.20150005

RBCCV 44205-1651

Abstract Objective: To assess the effects of postconditioning remote in ischemia-reperfusion injury in rat lungs. Methods: Wistar rats (n=24) divided into 3 groups: GA (I/R) n=8, GB (R-Po) n=8, CG (control) n=8, underwent ischemia for 30 minutes artery occlusion abdominal aorta, followed by reperfusion for 60 minutes. Resected lungs and performed histological analysis and classification of morphological findings in accordance with the degree of tissue injury. Statistical analysis of the mean rating of the degree of tissue injury. Results: GA (3.6), GB (1.3) and CG (1.0). (GA GB X P<0.05). Conclusion: The remote postconditioning was able to minimize the inflammatory lesion of the lung parenchyma of rats undergoing ischemia and reperfusion process.

Resumo Objetivo: Avaliar os efeitos do pós-condicionamento remoto no fenômeno de isquemia e reperfusão nos pulmões de ratos. Métodos: Ratos Wistar (n=24) divididos em 3 grupos: GA (I/R) n=8, GB pós-condicionamento remoto n=8, GC (controle) n=8, submetidos à isquemia de 30 minutos por oclusão da artéria aorta abdominal, seguida de reperfusão de 60 minutos. Ressecados os pulmões e realizada a análise histológica e classificação dos achados morfológicos de acordo com o grau de lesão tecidual. Análise estatística das médias da classificação do grau de lesão tecidual. Resultados: GA (3,6); GB (1,3) e GC (1,0). (GA X GB P<0,05). Conclusão: O pós-condicionamento remoto foi capaz de minimizar a lesão inflamatória do parênquima pulmonar de ratos submetidos ao processo de isquemia e reperfusão.

Descriptors: Ischemia. Reperfusion. Ischemic Postconditioning. Lung Injury.

Descritores: Isquemia. Reperfusão. Pós-Condicionamento Isquêmico. Lesão Pulmonar.

Federal University of Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil. 2 General Director of the Nucleus of the University Hospital of the Federal University of Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil. 3 Assistant Professor in Cardiovascular Surgery at the Federal University of Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil. 4 Specialist in Cardiopulmonary Bypass of the Federal University of Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil.

No financial support.

1

Correspondence address: Jose Carlos Dorsa Vieira Pontes Hospital Universitário da Universidade Federal de Mato Grosso do Sul Serviço de Cirurgia Cardiovascular Av. Senador Filinto Muller, S/N Jardim Ipiranga - Campo Grande, MS, Brazil Zip code: 79090-900 E-mail: carlosdorsa@uol.com.br Article received on April 28th, 2013 Article accepted on January 26th, 2015

This study was carried out at Federal University of Mato Grosso do Sul (UFMS), MS, Brazil.

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Dorsa RC, et al. - Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion

In the last decade, there have been studies demonstrating the efficacy of ischemic post-conditioning in various organs when subjected to ischemia and reperfusion[4]. Clearly, then came the questions about its protective effect also at a distance, the remote ischemic postconditioning (R-IPo). In 2005, Kerendi et al.[5] were the first to introduce the R-IPo strategy, which consisted of brief period of ischemia and reperfusion, which reduced the size of the infarcted area in the heart of rats. Despite this and other studies[6,7] that assessed the effect of R-IPosC, the literature is still scarce on this topic, especially on the effect in the lung parenchyma, which is considered of great interest, given the importance of the integrity of lungs in patients who undergo ischemia and reperfusion processes for their establishment. The aim of this study is to assess the ability of R-IPo to minimize injury in the process of ischemia and reperfusion in the lungs of rats subjected to ischemia and systemic reperfusion.

Abbreviations, acronyms & symbols AMP ATP COBEA IPoC IPreC R-PosC TROS

Adenosine monophosphate Adenosine triphosphate Brazilian College of Animal Experimentation Ischemic postconditioning Ischemic preconditioning Remote postconditioning Toxic reactive oxygen species

INTRODUCTION Ischemia is a condition of interruption of the supply of oxygen and nutrients for a given area during a period, due to deficiency of arterial blood supply, and is known to be cause of dysfunction and subsequent death of tissues in many clinical situations, e.g., in acute myocardial infarction, pulmonary infarction, mesenteric infarction, ischemic stroke and limb ischemia[1]. Reperfusion of ischemic organ is essential to its viability and functional recovery. However, the arrival of the blood will cause a number of lesions that were called ischemia-reperfusion injury, this term refers to a variety of changes at the time of restoration of blood flow and the impairment of function until the cell death[2]. In addition to the lesions which occur in the tissues which pass through the ischemia and reperfusion process, it is known that distant organs also suffer damage caused by this process[1]. A classic example is the ischemic preconditioning (IPrC), which initially proved to be effective in treating the target organ of the ischemic process, and later studies have also shown its protective effect at a distance, the called remote ischemic preconditioning[3].

METHODS This study was approved by the Research Ethics Committee of the Federal University of Mato Grosso do Sul under No. 296 ratified by the Ethics Committee on the use of animals/CEUA/UFMS on September 12, 2011. 24 Wistar adult male rats (Rattus norvegicus albinos, Rodentia, Mammalia) were used, weighing between 250-350 grams, with an average of 310 grams, raised in the conventional-controlled vivarium of Mato Grosso do Sul Federal University. The animals were kept in controlled conditions of light (light cycle from 7 am to 19 pm), temperature (22ยบC24ยบC) and receiving standardized ration and water ad libitum, attending to the observations advocated by the Brazilian College of Animal Experimentation (COBEA).

Fig. 2 - Clamp in the abdominal aorta.

Fig. 1 - Rat positioned on the operating table with four limbs abducted and antisepsis with iodine performed.

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The animals were divided into three groups: Group A - Ischemia and reperfusion (I/R): Eight rats subjected to ischemia for 30 minutes by occlusion of the abdominal aorta just below the diaphragm, with vascular clamp (Clamp Bulldog De Bakey, gentle, curve, 5cm, EDLO速) followed by reperfusion for 60 minutes for removal of the clamp. Group B - Remote ischemic postconditioning (R-IPo): Eight rats subjected to ischemia and reperfusion procedure as described above. Among ischemia and reperfusion, there was R-IPo reperfusion for three cycles (two minutes each) interleaved with three cycles of ischemia (two minutes each), respectively, by removal and repositioning of the clamp. Group C - Control: Eight rats subjected to aortic dissection and handling in a manner similar to the groups A and B, but without applying vascular clamp. The animals were weighed on an electronic precision balance (Callmex速 - model Q510) and anesthetized with an intramuscular injection in the right posterior limb, of solution of 2:1 of Ketamine hydrochloride (Cetamin速), 50 mg/ml, and Xylazine hydrochloride (Xilazin速), 20 mg/ml, respectively, at a dose of 8 mg/100 g associated with 1 mg/100 g. After verified the anesthesia, the rats underwent abdominal trichotomy, positioned at the operating table with four abducted limbs and performed topical antisepsis (Figure 1). After placement of surgical fields, the rats underwent median laparotomy of four centimeters, dissection and identification of the abdominal aorta. In group A, the abdominal aortic artery was occluded with atraumatic vascular clamp which remained for thirty minutes (ischemic phase) (Figure 2). In all three groups the wound was covered with gauze moistened with saline solution at 0.9%. After the stage of ischemia, vascular clamp was removed, beginning the reperfusion phase, lasting 60 minutes. In all three groups, the surgical wound was closed during the reperfusion sutured by simple running suture using 3-0 mononylon. In group B, ischemia phase (30 minutes) and reperfusion were performed (60 minutes). When preceding the reperfusion the PosC was performed through three cycles of reperfusion (removal of atraumatic vascular clamp from the abdominal aortic artery) lasting two minutes each, interspersed with three

cycles of ischemia (occlusion of the abdominal aorta artery by atraumatic vascular clamp), also lasting two minutes each. In group C, the position at the table of the rats, laparotomy of four centimeters, dissection and identification of the artery abdominal aorta were performed. The atraumatic vascular clamp was positioned for a few seconds in the artery but not applied. Immediately at the end of the reperfusion phase in groups A and B, the abdominal wall was opened again by removing the suture and the lungs were excised (Figure 3), washed with saline 0.9% solution and placed in 10% formaldehyde for later histological analysis. In all three groups, the animals were euthanized by overdose of those same anesthetic intramuscularly into the right hind limb (100 mg/kg). For histological analysis of the lungs we used the hematoxylin-eosin and the reading of the slides was performed by the same pathologist, who was blinded to the study, which considered for description of morphological findings, the classification according to the degree of tissue injury described by Greca et al.[8] (Table 1 and Figure 4). We selected three random locations on each lung for analysis: apex, middle third and base, being observed five fields of each slides, resulting in the predominant lesion.

Fig. 3 - Dried lungs.

Table 1. Classification described by Greca et al.[8]. Grade 1 Normal Normal parenchyma on optical microscopy

Grade 2 Mild Focal edema in few alveolar septa, mild congestion, neutrophils in alveolar septa less than 50 per highpower field

Grade 3 Moderate Moderate edema in the alveolar septa or mild edema in several septa, moderate congestion, neutrophils in alveolar septa between 50 and 100 per high-power field

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Grade 4 Severe Severe edema in the alveolar septa or mild edema in several septa, moderate congestion, neutrophils in alveolar septa more than 100 per high-power field


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Dorsa RC, et al. - Effect of remote ischemic postconditioning in inflammatory changes of the lung parenchyma of rats submitted to ischemia and reperfusion

Fig. 4 - Photograph of histological changes of the lung parenchyma at regular, mild, moderate and intense degrees according Greca et al.[8] classification. (40X optical microscopy - hematoxylin-eosin staining).

The values obtained during the study were compared using the Kruskal Wallis test followed by Student-Newman-Keuls. The significance level was 5%. We used the statistical software BioStat version 5.0.

had grade 1 rating according Greca et al.[8] in the eight mice. In Group A (ischemia and reperfusion - I/R) were observed three rats with classification grade 3 and 5 rats with classification grade 4. In group B (remote ischemic post-conditioning - R-IPosC) were observed six rats with classification grade 1 and two rats with classification grade 2. The mean degree of histological classification of Greca et al.[8] of groups I/R and R-PosC were subjected to statistical analysis by Kruskal Wallis test where it was found a P value of 0.002 showing that the difference between groups was statistically significant (Figure 5).

RESULTS The search program was accomplished using 24 rats. The results of the histological analysis are shown in Table 2. After histological examination of the degree of inflammation of the lung parenchyma, it was observed that the group C (control)

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Table 2 - Number of rats according to the focal edema scores at histological examination in groups: A (ischemia and reperfusion), B (remote post conditioning) and C (control). Focal edema 1 (normal) 2 (slight) 3 (mild) 4 (severe) Total of animals Average scores ± standard deviation Median of scores

A 0 0 3 5 8 A 3.6±0.5 4

B 6 2 0 0 8 B 1.3±0.5 1

C 8 0 0 0 8 B 1.0±0.0 1

Note: Kruskal Wallis test followed by Student-Newman – Keuls test. Equal letters indicate statistically significant difference. Different letters indicate statistically significant difference. A x B x C: P-value=<0.001 A x B: P-value=0.002 A x C: P-value=<0.001 B x C: P-value=0.572

Fig. 5 - Mean and standard deviation scores of the focal edema at histological examination in groups: A (ischemia and reperfusion), B (remote postconditioning) and C (control). Note: Kruskal Wallis followed by Student-Newman – Keuls test. Equal lowercase letters indicate statistically significant difference. Different lowercase letters indicate statistically significant difference. P-value=<0.001; A x B: P-value=0.002; A x C: P-value=<0.001; B x C: P-value=0.572.

DISCUSSION

pend on the time of reperfusion/ischemia and animal species. Therefore, it has been suggested that the duration of ischemia and reperfusion protocol in PosC is species dependent and the number of cycles of ischemia and reperfusion seems to be less important than its duration[9]. Thus, we observed in this study that with three cycles of two minutes interspersed of ischemia and reperfusion in rats we obtained cellular pro-

According to Pinheiro et al.[9] the main mediators and effectors involved in the PosC mechanisms are: adenosine, nitric oxide, the K ATP-dependent channel, the pro-survival kinase and the mitochondrial permeability transition pore. The biological expression of these mediators seems to de-

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tection similar to other literature studies with different cycles and times, but always brief periods, non-lethal, of ischemia and reperfusion applied in an organ or tissue. According Minamino[10] transient limb ischemia is a simple non-invasive stimulation with significant clinical potential and high performance. In addition, the R-PosC procedure can be applied before or during sustained ischemia and/or during reperfusion. The R-PosC could be the most effective way to protect a noble organ such as the heart, brain, lungs and kidneys without applying the method directly on them. It is still uncertain how the R-PosC exerts cardioprotection. However, two main hypotheses are proposed. The neural hypothesis suggests that autocoid released from remote ischemic organ influence the afferent neural pathway, which in turn activates the neural efferent pathways to trigger organ protection. According humoral hypothesis, autacoid released from the remote ischemic tissue are transported to the end-organ, resulting in the activation of kinase signaling pathways in the end body[10]. Loukogeorgakis et al.[11] were the first to assess the effect of R-PosC in humans, demonstrating that it may be induced by limb transient ischemia. The protection offered by the R-PosC was assigned in this research to the activation of KATP channels. This study demonstrated that the R-PosC has the ability to mitigate reperfusion injury distant from the model used. Thus, it opens up numerous possibilities of research to study the lung parenchyma protection in the microcirculation stress situations: shock, cardiopulmonary bypass, organ transplantation, acute organ ischemia, compartment syndrome and sepsis. Considering that the PrC has a protective effect similar to PoC, as demonstrated by Santos et al.[12] in an experimental study of mesenteric ischemia and reperfusion, one would assume that the remote preconditioning (R-PrC) also offers protection similar to R-PosC. However, when confirming this hypothesis, a number of advantages favor the latter, since the most frequent clinical situation is that of establishing the treatment when the process of ischemia has already been occurred and not otherwise. When confirming the effectiveness of the R-PosC in humans in a manner similar to that observed in the present study, it is believed that there will be great importance in clinical practice, like provoking ischemia and reperfusion cycles in a lower limb, in order to protect the heart in the presence of many conditions such as acute myocardial infarction, shock, pulmonary embolism, etc. Thus, this research opens new questions that allow extensive research in order to seek ways to promote cellular protection, using the R-PosC, since it has been shown important protection to the lung parenchyma of rats subjected to ischemia and systemic reperfusion process.

CONCLUSION The remote ischemic postconditioning was able to minimize the inflammatory lesions of the lung parenchyma of rats subjected to ischemia and systemic reperfusion process.

Authors’ roles & responsibilities RCD JCDVP ACBA GVRS RAB CHMS ERCP JASG

Writing; bibliographic survey Review Guidance Bibliographic survey Review Guidance Statistical analysis Experimental Surgery

REFERENCES

1. Santos CHM, Pontes JCVD, Gomes OM. Terapêutica medicamentosa na isquemia e reperfusão mesentérica: revisão da literatura. Rev Bras Coloproctol. 2006;26(1):28-33. 2. Xiong J, Liao X, Xue FS, Yuan YJ, Wang Q, Liu JH. Remote ischemia conditioning-an endogenous cardioprotective strategy from outside the heart. Chin Med J (Engl). 2011;124(14):2209-15. 3. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation. 1993;87(3):893-9. 4. Santos CHM, Pontes JCDV, Gomes OM, Miiji LNO, Bispo MAF. Avaliação do pós-condicionamento isquêmico no tratamento da isquemia mesentérica: estudo experimental em ratos. Rev Bras Cir Cardiovasc. 2009;24(2):150-6. 5. Kerendi F, Kin H, Halkos ME, Jiang R, Zatta AJ, Zhao ZQ, et al. Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res Cardiol. 2005;100(5):404-12. 6. Andreka G, Vertesaljai M, Szantho G, Font G, Piroth Z, Fontos G, et al. Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs. Heart. 2007;93(6):749-52. 7. Gritsopoulos G, Iliodromitis EK, Zoga A, Farmakis D, Demerouti E, Papalois A, et al. Remote postconditioning is more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits. Cardiovasc Drugs Ther. 2009;23(3):193-8. 8. Greca FH, Gonçalves NMFM, Souza Filho ZA, Noronha L, Silva RFKC, Rubin MR. The protective effect of methylene blue in lungs, small bowel and kidney after intestinal ischemia and reperfusion. Acta Cir Bras. 2008;23(2):149-56.

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9. Pinheiro BV, Holanda MA, Araujo FG, Romaldini H. Les達o pulmonar de reperfus達o. J Pneumol. 1999;25(2):124-36.

remote preconditioning and remote postconditioning in humans by ATP channel-dependent mechanism. Circulation. 2007;116(12):1386-95.

10. Minamino T. Cardioprotection from ischemia/reperfusion injury: basic and translational research. Circ J. 2012;76(5):1074-82.

12. Santos CH, Gomes OM, Pontes JC, Miiji LN, Bispo MA. The ischemic preconditioning and postconditioning effect on the intestinal mucosa of rats undergoing mesenteric ischemia/ reperfusion procedure. Acta Cir Bras. 2008;23(1):22-8.

11. Loukogeorgakis SP, Willians R, Panagiotidou AT, Kolvekar SK, Donald A, Cole TJ. Transient limb ischemia induces

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Andrade ING,ORIGINAL et al. - ImpactARTICLE of respiratory infection in the results of cardiac surgery in a tertiary hospital in Brazil

Impact of respiratory infection in the results of cardiac surgery in a tertiary hospital in Brazil Impacto da infecção respiratória nos resultados da cirurgia cardíaca em hospital terciário no Brasil

Isaac Newton Guimarães Andrade1, MD, MSc; Diego Torres Aladin de Araújo2; Fernando Ribeiro de Moraes Neto3, MD, PhD

DOI 10.5935/1678-9741.20150038

RBCCV 44205-1652

Abstract Objective: To assess the impact of respiratory tract infection in the postoperative period of cardiac surgery in relation to mortality and to identify patients at higher risk of developing this complication. Methods: Cross-sectional observational study conducted at the Recovery of Cardiothoracic Surgery, using information from a database consisting of a total of 900 patients operated on in this hospital during the period from 01/07/2008 to 1/07/2009. We included patients whose medical records contained all the information required and undergoing elective surgery, totaling 109 patients with two excluded. Patients were divided into two groups, WITH and WITHOUT respiratory tract infection, as the development or respiratory tract infection in hospital, with patients in the group without respiratory tract infection, the result of randomization, using for the pairing of the groups the type of surgery performed. The outcome variables assessed

were mortality, length of hospital stay and length of stay in intensive care unit. The means of quantitative variables were compared using the Wilcoxon and student t-test. Results: The groups were similar (average age P=0.17; sex P=0.94; surgery performed P=0.85-1.00) Mortality in the WITH respiratory tract infection group was significantly higher (P<0.0001). The times of hospitalization and intensive care unit were significantly higher in respiratory tract infection (P<0.0001). The presence of respiratory tract infection was associated with the development of other complications such as renal failure dialysis and stroke P<0.00001 and P=0.002 respectively. Conclusion: The development of respiratory tract infection postoperative cardiac surgery is related to higher mortality, longer periods of hospitalization and intensive care unit stay.

Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil. Estudante de Medicina da Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil and fellow of the Programa Institucional de Bolsas de Iniciação Científica (Pibic), Recife, PE, Brazil. 3 Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil.

Correspondence address: Isaac Newton Guimarães Andrade Rua Antônio de Sousa Lopes, 100 APT 201-C Catolé, Campina Grande, PB, Brazil Zip code: 58410-180 E-mail: isaacguimaraes@oi.com.br

Descriptors: Bronchopneumonia. Thoracic Surgery. Postoperative Care.

1 2

This study was carried out at Real Hospital Português do Recife, Recife, PE, Brazil.

Article received on March 11th, 2015 Article accepted on May 31st, 2015

No financial support.

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to respiratório, conforme o desenvolvimento ou não infecção do trato respiratório no internamento, sendo os pacientes do grupo sem infecção do trato respiratório, fruto de randomização, utilizando-se para o pareamento dos grupos o tipo de cirurgia realizada. As variáveis de desfecho avaliadas foram mortalidade, tempo de internamento hospitalar e tempo de internamento em unidade de terapia intensiva. As médias das variáveis quantitativas foram comparadas por meio do teste de Wilcoxon e t de student. Resultados: Os grupos mostraram-se semelhantes. A mortalidade no grupo RTI foi significativamente maior (P<0,0001). Os tempos de internamento hospitalar e em unidade de terapia intensiva foram significativamente maiores no grupo infecção do trato respiratório (P<0,0001). A presença de infecção do trato respiratório associou-se ao desenvolvimento de outras complicações como insuficiência renal dialítica e acidente vascular cerebral, P<0,00001 e P=0,002, respectivamente. Conclusão: O desenvolvimento de infecção do trato respiratório no pós-operatório de cirurgia cardíaca relaciona-se a maior mortalidade, maiores tempos de internamento e permanência em unidade de terapia intensiva.

Abbreviations, acronyms & symbols EuroSCORE ICU RFD RHP RTI TSRU

European System for Cardiac Operative Risk Evaluation Intensive care unit Renal failure dialysis Real Hospital Português de Beneficiência Respiratory tract infection Thoracic surgery recuperation unit

Resumo Objetivo: Avaliar o impacto da infecção do trato respiratório no pós-operatório da cirurgia cardíaca no Hospital Português de Pernambuco em relação à mortalidade hospitalar e identificar os pacientes com maior risco de desenvolver essa complicação. Métodos: Estudo do tipo transversal observacional realizado na Unidade de Recuperação de Cirurgia Cardiotorácica, utilizando informações de um banco de dados composto por um total de 900 pacientes operados nesse hospital no período de 01/07/2008 a 31/07/2009. Foram incluídos pacientes cujos prontuários continham todas as informações necessárias, totalizando 109 pacientes, havendo exclusão de dois. Os pacientes foram divididos em dois grupos, com e sem infecção do tra-

Descritores: Pneumonia. Cirurgia Torácica. Cuidados Pós-Operatórios.

Objective The aim of this study is to assess the impact of respiratory tract infection in cardiac surgery postoperative period in RHP, especially regarding the hospital mortality, and to identify patients at higher risk of developing this complication.

INTRODUCTION In Brazil, more than 100,000 heart surgeries are performed each year[1]. In Recife, at Real Hospital Português de Beneficência in Pernambuco (RHP) only, 1,400 surgeries are performed every year, demonstrating the significance of the procedure in our country. Many patients develop complications that affect the results, increasing morbidity and mortality at the individual level, and burdening the health care system. In heart surgery, three major events, when present, increase the chances of death: the development of respiratory infection, perioperative stroke and renal failure dialysis (RFD)[2,3], Besides associated with higher mortality, such occurrences are important causes of readmission to the intensive care unit, increasing hospital costs[4]. An important determinant of bad results in cardiac surgery is the infection[5], especially the respiratory infection, the most frequent in this type of procedure - it exceeds 50% of high mortality infections[6]. It is also known that the early identification of patients at higher risk of developing this complication and the adoption of prophylactic measures can reduce the mortality rate significantly[7-9]. The lack of local studies to determine the prevalence and the impact of renal tract infection (RTI) justifies this study. The understanding of this problem in our region can help implement intervention strategies that change the current situation.

METHODS We used a cross sectional observational study that was made by the Thoracic Surgery Recuperation Unit (TSRU) of RHP. Data were collected from existing database containing information of 900 patients operated and admitted to the TSRU of RHP, from July 1st 2008 to July 31st 2009. The sample was initially composed by 109 patients, being two later excluded because of lack of data. The 107 remaining patients were divided into 02 groups: one defined as RTI Group, composed by 29 patients who developed respiratory tract infection, and Control Group, made up of 78 patients without RTI. The variable used to pair the two groups was the type of performed surgery. Thus the type of surgery proportion performed on the RTI group was determined. Then there was a randomization among patients who did not develop RTI and were part of the database, thus forming the control group, with 78 patients.

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For the RTI diagnosis, we used clinical respiratory infection parameters associated with tracheal aspirate secretion culture, with colony counts equal to or greater than one million units. The sample size calculation was based on the RTI development prevalence in cardiac surgery postoperative, existing in the literature. Demographic variables were assessed, such as gender and age, in addition to the type of surgery performed and the outcome variables, such as mortality, length of hospital stay and ICU length of stay. Categorical variables were expressed by their absolute and relative frequencies and the quantitative variables were expressed by their average and standard deviations. To compare the averages of different groups, we used the t-test when the variables followed a normal distribution. For variables that did not follow this distribution, we used non-parametric tests (Wilcoxon). For association studies, we used the chi-square test or Fisher’s exact when indicated. When the alternative hypothesis was sought, P<0.05 were considered statistically significant. BioStat 5.0 was used. The project was submitted to the Ethics Committee of RHP and to the Ethics Research Committee of UFPE. We requested authorization for the use of the records in this study.

the control group (P<0.0001 and P=0.002 respectively), as Figures 1 and 2 show. In the group with RTI an important association of RTI with the development of other complications, such as renal failure dialysis (RFD) and stroke (P<0.0001 and P=0.002 respectively). This association was not observed in the control group (Table 1). Studying the RTI group specifically and analyzing the risk group by EuroSCORE separately (high, medium and low), we found no statistically significant association between risk group and prevalence of RTI. However, dividing them in low and medium-high, we found a higher prevalence of RTI on medium-high of patients, compared to low risk (P=0.01).

RESULTS The sample was composed by 107 patients, divided into 2 groups: with and without RTI. After pairing the groups, it was observed that they had no difference in age average (P=0.17), gender distribution (P=0.94) and type of performed surgery (P=0.85-1.00), demonstrating the similarity of the population of the two groups. A higher average value of the EuroSCORE was observed in the group WITH RTI, compared to the control group, (WITHOUT RTI), with a tendency to statistical significance (P=0.07). We found a significantly higher mortality in the group with RTI (48% vs.3.8%), as shown in Table 1. The length of hospital stays and ICU length stay was significantly higher in the group WITH RTI compared to

Fig. 1 - Hospitalar stay in the two groups.

Table 1. Respiratory tract infection association with renal failure dialysis and stroke. RFD* Groups % Group with RTI 31 Group without RTI 0

Stroke** Groups % Group with RTI 17 Group without RTI 0

*P<0.00001 Fisher ’s Exact; **P=0.002 Fisher ’s Exact; RTI=respiratory tract infection; RFD=renal failure dialysis

Fig. 2 - Intensive care unit stay in the two groups.

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Table 2. Prevalence of respiratory tract infection in RTI group and chance to develop RTI, according to EuroSCORE risk group. RTI group* Groups N Group low risk 6 Group medium-high risk 23

EuroSCORE group** Risk Group OR Low risk 1.0 High-medium risk 3.83 ( IC 95% =1.36 - 10.79)

*P=0.01; *P=0.016; RTI=respiratory tract infection; OR=odds ratio.

Chance to develop high and medium risk RTI compared to low risk. The chance high and medium risk patients had develop RTI was four times higher than low risk patients (Table 2).

commonly associated with respiratory infection. That is, the RTI is strongly associated with such complications. Failure to observe the presence of RFD and stroke in the group without RTI reinforces this claim.

DISCUSSION

CONCLUSION

Analysis showed the similarity between control groups and disease, the result of proper pairing. No differences were observed between the analyzed groups in relation to gender distribution, age average and performed surgery. Pairing by type of surgery performed eliminated an important bias, since most complex surgeries tend to have higher prevalence of complications[10-12]. A second bias that could sully the results would be the inappropriate use of perioperative antibiotics, or patients who have been operated in the presence of respiratory infection. However all patients enrolled in the study underwent elective surgery and therefore evaluated before discarding infection prior surgery. All patients were subjected to the same antibiotic scheme. The RTI group had higher EuroSCORE[13] average compared to no RTI, with a tendency to statistical significance. That is, higher prevalence of RTIs in high-risk patients, which confirms the results of studies that associate higher risk (such as age, diabetes and kidney disease) to the higher prevalence of complications[14-16]. Mortality in patients with RTI was significantly higher than in the group without RTI, as demonstrated in the literature[17,18]. The length of hospital stay and the time of ICU stay were significantly higher in the group with RTI compared to the control group. This fact implies probably a higher cost, as intensive care units (ICUs) make up about 20% of total hospital costs[19]. Data from this study, in line with published data, show that the existence of complications after heart surgery is directly related to a longer hospital stays and higher mortality rate[20]. Cardiac surgery has as primarily non-cardiac complications the development of infection (most respiratory), IRA and stroke[21]. This was observed in this study, and it is interesting to note the fact that the RFD and stroke are most

The development of RTI in cardiac surgery postoperative is related to higher mortality, as well as to longer hospital and ICU stay. This complication has also been associated with the development of other co-morbidities such as renal failure dialysis and stroke.

Authors’ roles & responsibilities INGA DTAA FRMN

Analysis and/or interpretation of data; Statistical analysis; study design Performed operations and/or experiments Final approval of the manuscript

REFERENCES 1. Braile DM, Gomes WJ. Evolução da cirurgia cardiovascular. A saga brasileira. Uma história de trabalho, pioneirismo e sucesso. Arq Bras Cardiol. 2010;94(2):151-2. 2. Schurr P, Boeken U, Litmathe J, Feindt P, Kurt M, Gams E. Predictors of postoperative complications in octogenarians undergoing cardiac surgery. Thorac Cardiovasc Surg. 2010;58(4):200-3. 3. Riera M, Ibáñez J, Herrero J, Ignacio Sáez De Ibarra J, Enríquez F, Campillo C, et al. Respiratory tract infections after cardiac surgery: impact on hospital morbidity and mortality. J Cardiovasc Surg (Torino). 2010;51(6):907-14. 4. Litmathe J, Kurt M, Feindt P, Gams E, Boeken U. Predictors and outcome of ICU readmission after cardiac surgery. Thorac Cardiovasc Surg. 2009;57(7):391-4. 5. De Santo LS, Bancone C, Santarpino G, Romano G, De Feo M, Scardone M, et al. Microbiologically documented nosocomial

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infections after cardiac surgery: an 18-month prospective tertiary care centre report. Eur J Cardiothorac Surg. 2008;33(4): 666-72.

Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9-13.

6. Bouza E, Hortal J, Muñoz P, Pascau J, Pérez MJ, Hiesmayr M; European Study Group on Nosocomial Infections; European Workgroup of Cardiothoracic Intensivists. Postoperative infections after major heart surgery and prevention of ventilatorassociated pneumonia: a one-day European prevalence study (ESGNI-008). J Hosp Infect. 2006; 64(3):224-30.

14. Just S, Tomasa TM, Marcos P, Bordejé L, Torrabadella P, Moltó HP, et al. Cirugía cardíaca en pacientes de edad avanzada. Med Intensiva. 2008;32(2):59-64. 15. Sampaio MC, Máximo CAG, Montenegro CM, Mota DM, Fernandes TR, Bianco ACM, et al. Comparação de critérios diagnósticos de insuficiência renal aguda em cirurgia cardíaca. Arq Bras Cardiol. 2013;101(1):18-25.

7. El Solh AA, Bhora M, Pineda L, Dhillon R. Nosocomial pneumonia in elderly patients following cardiac surgery. Respir Med. 2006;100(4):729-36.

16. Kalil RAK. Cirurgia de revascularização miocárdica no diabetes mellitus. Arq Bras Endocrinol Metab. 2007;51(2):345-51.

8. Lola I, Levidiotou S, Petrou A, Arnaoutoglou H, Apostolakis E, Papadopoulos GS. Are there independent predisposing factors for postoperative infections following open heart surgery? J Cardiothorac Surg. 2011;14(6):151.

17. Padovani C, Cavenaghi OM. Recrutamento alveolar em pacientes no pós-operatório imediato de cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2011;26(1):116-21.

9. Michalopoulos A, Geroulanos S, Rosmarakis ES, Falagas ME. Frequency, characteristics, and predictors of microbiologically documented nosocomial infections after cardiac surgery. Eur J Cardiothorac Surg. 2006;29(4):456-60.

18. Malviya S, Voepel-Lewis T, Siewert M, Pandit UA, Riegger LQ, Tait AR. Risk factors for adverse postoperative outcomes in children presenting for cardiac surgery with upper respiratory tract infections. Anesthesiology. 2003;98(3):628-32.

10. Ortiz LDN, Schaan CW, Leguisamo CP, Tremarin K, Mattos WLLD, Kalil RAK, et al. Incidência de complicações pulmonares na cirurgia de revascularização do miocárdio. Arq Bras Cardiol. 2010,95(4):441-7.

19. Guimarães RCM, Rabelo ERR, Moraes MA, Azollin K. Severity of postoperative cardiac surgery patients: an evolution analysis according to TISS-28. Rev Lat Am Enfermagem. 2010;18(1):61-6.

11. Vegni R, Almeida GF, Braga F, Freitas M, Drumond LE, Penna G, et al. Complicações após cirurgia de revascularização miocárdica em pacientes idosos. Rev Bras Ter Intensiva. 2008;20(3):226-34.

20. Rahmanian PB, Kröner A, Langebartels G, Özel O, Wippermann J, Wahlers T. Impact of major non-cardiac complications on outcome following cardiac surgery procedures: logistic regression analysis in a very recent patient cohort. Interact Cardiovasc Thorac Surg. 2013;17(2):319-27.

12. Milani R, Brofman P, Varela A, Souza JA, Guimarães M, Pantarolli R, et al. Revascularização do miocárdio sem circulação extracorpórea em pacientes acima de 75 anos: análise dos resultados imediatos. Arq Bras Cardiol. 2005;84(1):34-7.

21. Dorneles CC, Bodanese LC, Guaragna JCVC, Macagnan FE, Coelho JC, Borges AP, et al. O impacto da hemotransfusão na morbimortalidade pós-operatória de cirurgias cardíacas. Rev Bras Cir Cardiovasc. 2011;26(2):222-9.

13. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S,

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Costa MAC, et al. - Risk factors for perioperative ischemic stroke in cardiac ORIGINAL ARTICLE surgery

Risk factors for perioperative ischemic stroke in cardiac surgery Fatores de risco para acidente vascular cerebral isquêmico no perioperatório de cirurgia cardíaca

Mário Augusto Cray da Costa1, MD, PhD; Maria Fernanda Gauer2; Ricardo Zaneti Gomes2, MD, PhD; Marcelo Derbli Schafranski2, MD, PhD

DOI 10.5935/1678-9741.20150032

RBCCV 44205-1653

Abstract Objective: The purpose of this study was to evaluate the risk factors for ischemic stroke in patients undergoing cardiac surgery. Methods: From January 2010 to December 2012, 519 consecutive patients undergoing cardiac surgery were analyzed prospectively. The sample was divided into two groups: patients with stroke per and postoperative were allocated in Group GS (n=22) and the other patients in the group CCONTROL (n=497). The following variables were compared between the groups: gender, age, carotid stenosis ≥ 70%, diabetes on insulin, chronic obstructive pulmonary disease, peripheral arteriopathy, unstable angina, kidney function, left ventricular function, acute myocardial infarction, pulmonary arterial hypertension, use of cardiopulmonary bypass. Ischemic stroke was defined as symptoms lasting over 24 hours associated with changes in brain computed tomography scan. The variables were compared using Fisher’s exact test, Chi square, Student’s t-test and logistic regression. Results: Stroke occurred in 4.2% of patients and the risk factors statistically significant were: carotid stenosis of 70% or more (P=0.03; OR 5.07; IC 95%: 1.35 to 19.02), diabetes on insulin (P=0.04; OR 2.61; IC 95%: 1.10 to 6.21) and peripheral arteriopathy (P=0.03; OR 2.61; 95% CI: 1.08 to 6.28). Conclusion: Risk factors for ischemic stroke were carotid

stenosis of 70% or more, diabetes on insulin and peripheral arteriopathy.

Departamento de Medicina da Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil and cardiovascular surgeon of Santa Casa de Misericórdia de Ponta Grossa, Ponta Grossa, PR, Brazil. 2 Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil.

Correspondence address: Mário Augusto Cray da Costa Santa Casa de Misericórdia de Ponta Grossa Av. Dr. Francisco Búrzio, 774, Centro - Ponta Grossa, PR Brasil – Zip code: 84010-200 E-mail: drmarioaugusto@uol.com.br

Descriptores: Stroke. Cardiac Surgical Procedures. Carotid Artery Diseases. Resumo Objetivo: O objetivo do presente trabalho foi avaliar os fatores de risco para acidente vascular encefálico isquêmico em pacientes submetidos à cirurgia cardíaca. Métodos: Entre janeiro de 2010 e dezembro de 2012, foram analisados prospectivamente 519 pacientes consecutivos submetidos à cirurgia cardíaca. A amostra foi dividida em dois grupos: os pacientes com acidente vascular encefálico isquêmico (AVEi) trans e pós-operatório foram alocados no grupo GAVEi (n=22) e os demais pacientes no grupo CControle (n=497). As seguintes variáveis foram comparadas entre os grupos: sexo, idade, estenose carotídea ≥70%, diabetes em uso de insulina, doença pulmonar obstrutiva crônica, arteriopatia periférica, função renal, angina instável, função do ventrículo esquerdo, infarto agudo do miocárdio recente, hipertensão arterial pulmonar, uso de circulação extracorpórea. Acidente vascular encefálico isquêmico foi definido como presença de sintomas de duração maior que 24 horas associados à alteração em tomografia de crânio. As variáveis foram

1

This study was carried out at Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil, and Cirurgião Cardiovascular da Santa Casa de Misericórdia de Ponta Grossa, Ponta Grossa, PR, Brazil.

Article received on March 19th, 2014 Article accepted on May 12th, 2015

No financial support.

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comparadas, por meio do teste exato de Fisher, Qui quadrado, teste t de Student e regressão logística. Resultados: Verificou-se a ocorrência de acidente vascular encefálico isquêmico em 4,2% dos pacientes e os fatores de risco estatisticamente significativos foram: estenose carotídea de 70% ou mais (P=0,03; OR 5,07; IC 95%: 1,35 a 19,02), diabetes em uso de insulina (P=0,04; OR 2,61; IC 95%: 1,10 a 6,21) e arteriopatia periférica (P=0,03; OR 2,61; IC 95%: 1,08 a 6,28). Conclusão: Foram fatores de risco para acidente vascular encefálico isquêmico: estenose carotídea de 70% ou mais, presença de diabetes em uso de insulina e presença de arteriopatia periférica.

Abbreviations, acronyms & symbols AMI CABG CC COPD CPB CS CT CVA ECST EF EuroSCORE IS MAP NYHA PAH

Acute myocardial infarction Coronary artey bypass surgery Creatinine clearance Chronic obstructive pulmonary disease Cardiopulmonary bypass Carotid stenosis Computed tomography Cerebrovascular accident European Carotid Surgery Trial Ejection fraction European System for Cardiac Operative Risk Evaluation Ischemic stroke Mean arterial pressure New York Heart Association Pulmonary arterial hypertension

Descritores: Acidente Cerebral Vascular. Estenose das Carótidas. Procedimentos Cirúrgicos Cardíacos.

INTRODUCTION

longed cardiopulmonary bypass time, emergency surgery and others[3-5,8,10,11]. Various strategies have been used to reduce the occurrence of perioperative stroke like avoiding low debit, early treatment of arrhythmias, prevent manipulation and aortic cannulation, use of membrane oxygenators and arterial filters, avoid hyperglycemia, maintain good brain oxygenation, off-pump surgery and prophylactic treatment of carotid lesions using stents or carotid endarterectomy in patients with severe stenosis of the carotid[2]. But it is still debated in the literature if the use of stents or carotid endarterectomy in asymptomatic patients actually prevents the perioperative ischemic stroke, because it is believed that most of the ischemic complications is related to embolism of aortic plaques and that the presence of severe carotid atherosclerosis is another ischemic events marker than its etiology, because there is no perfect correlation between ischemic stroke and the plaque side in many cases and more than half of cases of perioperative ischemic stroke has no evidence of carotid disease[2]. Naylor et al.[12] published in 2002 that 50% of cases of IS did not occur during occurrence of severe carotid stenosis, and 60% of cerebral infarctions could not be attributed to carotid disease. Still, in 2011, Naylor & Brown[1] published systematic review and meta-analysis showing that the incidence of ipsilateral stroke in asymptomatic patients with unilateral CS between 50 and 99% was 2% and any stroke was 2.9%. In more severe lesions with 70-99% obstruction or 80-99% there was no increased incidence of ischemic stroke. In bilateral lesions the risk increased to 6.5%, but when endarterectomy was performed concomitant with revascularization the incidence of stroke in the opposite side was still 5.7%. The authors argue that the carotid lesions may be more marker than cause of stroke.

The cerebrovascular accident (CVA) is a major cause of mortality, permanent neurological damage and increased health expenditures[1,2]. American Heart Association data cited by Santos et al.[3] show that in the United States, 18% of the causes of death from cardiovascular cause are due to occurrence of CVA. In the context of heart surgery, ischemic stroke (IS) is one of the largest and most feared perioperative complications, with an incidence is 2% for all cardiac surgeries according Naylor & Brown[1]. When it comes to coronary artey bypass surgery (CABG) the incidence may reach up to 6%, and the risk grows to 12% in patients with severe carotid stenosis (CS)[2-7]. The timing of occurrence of perioperative stroke has a bimodal distribution, approximately 45% of the events are identified on the first day after surgery, in this group are the intraoperative events and those occurring in the first hours after surgery and 55% occur after recovery from anesthesia, the second day onward, thus being postoperative events. Early embolism is due to manipulation of the heart and aorta or particles transported by cardiopulmonary bypass (CPB), the later events may be related to atrial fibrillation, myocardial infarction, low output and hypercoagulability. Patients with carotid stenosis (CS) has increased incidence of ischemic stroke, but contrary to expectations, even in patients with CS, the leading cause of ischemic stroke is the embolism, accounting for 62% of ischemic events[2,8,9]. Are risk factors for ischemic stroke age greater than 70 years, female gender, hypertension, diabetes mellitus, renal failure, smoking, chronic obstructive pulmonary disease (COPD), peripheral artery disease, ejection fraction of 40%, ischemic stroke history or previous transient ischemic attack, carotid stenosis, aortic calcification, surgery with CPB, pro-

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The interest in the use of off-pump surgery in order to reduce stroke has growing, Sรก et al.[13], through a meta-analysis with 13,524 patients, found that off-pump surgery has reduced the incidence of postoperative stroke in 20.7%, similarly to meta-analysis findings with 3,996 patients, developed by Sedrakyan et al.[14]. But since often off-pump surgery can not be ignored, evolution of cannulas and filter devices in the ascending aorta has been used with some advantages. Strategies to prevent aortic clamping with venous grafts anastomosed proximally to the mammary arteries are used in hostile aortas in order to minimize the risk of embolization of aortic plaques[8]. Studies have shown increased mortality in patients suffering stroke in cardiac surgery. According to Mahmoudi et al.[10], the mortality of patients undergoing CABG and those who develop stroke within 24 hours is 25%. Dacey et al.[15] evaluated patients undergoing CABG and observed that the survival rate in patients over 10 years was 26.9% in patients who suffered perioperative stroke and 61.9% in patients without stroke. The literature has several articles addressing stroke and coronary surgery, but few including other types of surgery, especially valve surgery, as well as relating stroke in non-coronary and carotid stenosis surgery. This study aims to show the main risk factors for ischemic CVA during and after surgery in patients undergoing coronary and non-coronary heart surgery in the Santa Casa de Misericรณrdia de Ponta Grossa-PR.

and other variables related to neurological complications, focus of this study. The researchers collected data directly from patients and examinations of electronic medical records evaluated daily during hospitalization of each patient. Preoperative data Age, divided into two groups: under 70 years and 70 or more as other studies[17,18]; the characteristics of the EuroSCORE database were included as determining of that study[16]: gender; renal divided into four groups: (i) considered normal when creatinine clearance (CC) is greater than 85 ml/ min, (ii) moderate dysfunction when CC higher than 50 ml/ min and less than 85 ml/min (iii) severe dysfunction when CC less than 50 ml/min and finally (iv) patient under dialysis; poor mobility caused by neurological or skeletal muscle; poor mobility caused by neurological or muscle disorders; previous heart surgery; chronic lung disease, when the individual is under long-term treatment with steroids or bronchodilators for lung disease; active endocarditis; critical preoperative state including ventricular tachycardia or ventricular fibrillation or aborted sudden death, preoperative cardiac massage, mechanical ventilation before anesthesia, preoperative inotropic or intra-aortic balloon and acute renal failure (anuria or oliguria <10 ml/h); diabetes mellitus under insulin dependence or not; NYHA functional class; presence of class IV angina. Left ventricular function divided into four classes: (i) good, when the ejection fraction (EF) was greater than 50%, (ii) moderate, when EF from 31% to 50%, (iii) poor, when EF from 21% to 30%, and finally (iv) very bad when EF less than 20%; acute myocardial infarction (AMI) in the last three months; pulmonary hypertension, classified as moderate when the systolic blood pressure in the pulmonary artery was between 31 mmHg and 55 mmHg and severe when above this last value; extracardiac arteriopathy: considered positive when the patient presents claudication, amputation for arterial disease and early or planned intervention in the abdominal aorta or arteries of the lower limbs; the presence of carotid lesion was studied separately from other peripheral vascular lesions and is considered as an isolated variable, as described below. All patients with coronary artery disease and all patients were forty years old or more in any surgery routinely performed carotid Doppler at the same institution by a group of six different examiners, except where the urgency of the procedure did not allow enough time for the exam. The carotid examinations were classified from normal up to different degrees of obstruction, according to criteria of ECST (European Carotid Surgery Trial)[19], which measures the residual lumen at the point of maximum degree of stenosis in the internal carotid artery and compared with what would be normal outer limit of the vessel in the same site of obstruction. For the statistical calculation of this sample were considered two groups of patients with or without major CS. Major ca-

METHODS Type of study After approval by the Research Ethics Committee in humans at the Universidade Estadual de Ponta Grossa - Paranรก, Brazil, Opinion No. 172,980, an analytical observational prospective case-control was developed in order to assess the influence of risk factors for the development of perioperative ischemic CVA in coronary and non-coronary heart surgery. Inclusion and exclusion criteria Inclusion: from January 2010 to December 2012 all patients undergoing coronary and non-coronary heart surgery were prospectively evaluated in the Heart Surgery Service of Santa Casa de Ponta Grossa. Exclusion: patients who did not undergo preoperative carotid Doppler or those with incomplete data were excluded. It is routine in the Service performing carotid Doppler in all patients with coronary artery disease and in the other since they are 40 years or more. Prospective database It was created a prospective database with the preoperative, intraoperative and postoperative information below, which allow compose the database of the EuroSCORE[16],

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rotid stenosis was defined as blocking 70% or more in the internal or common carotid on at least one side[9,10]. Patients with important CS had their mean arterial pressure (MAP) maintained above 70 mmHg perioperatively. Left ventricular (LV) function was assessed by echocardiography in most patients, thus being the ejection fraction calculated by Teicholz, when there was no segmental dysfunction and Simpson in segmental dysfunction or significant change in ventricular geometry. In some patients with coronary artery disease was performed only ventriculography to assess LV function, especially in those with normal function and no segmental deficit.

for ischemic stroke. The mortality rate was also evaluated between groups. Statistical Analysis Through statistical analysis, the variables to assess possible risk factors for ischemic stroke were tested. Continuous variables are presented as mean and standard deviation and nominal variables in absolute number and percentage, the distributions were tested for normality. To compare the means we used the Student’ t test and to compare categorical variables the chi-square two-tailed test with Yates correction and logistic regression. For variables with values less than 5 we used for comparison the Fisher exact test. Were considered significant P values <0.05 and odds ratio ≼2.

Trans-operative data Degree of urgency of the surgical procedure divided into four groups: (i) elective, when the patient was admitted for routine operation, (ii) emergency, when the patient was not routinely elected for the operation, but needs intervention or surgery on the same admission for medical reasons, (iii) emergency, when the surgery was performed before the next working day (iv) rescue, when the patient required cardiopulmonary resuscitation on the road to surgery or before the induction of anesthesia; type of surgery performed: CABG, atrial septal defect correction, aortic surgery, left ventricular aneurysm, myxoma resection, or combined procedures and whether CPB was used or not, CPB time, aortic clamping time and use of vasoactive drugs.

Description of the sample The medical records of 626 patients were assessed, of which 73 were excluded for lack of preoperative carotid Doppler for being out of the examination protocol (less than 40 years in non-coronary surgery or urgent surgery with no time to perform Doppler) and 34 were excluded due to missing data. Resulting in a final sample of 519 patients after completion of the aforementioned exclusions. RESULTS In the total sample was observed a prevalence of 4.2% (22) of perioperative ischemic stroke, being 17 in CABG, rate of 4.6% and 5 in non-coronary surgery, prevalence of 3.8%. Through analysis of the sample population, it was found that the mean age was of 61.82 years, with 202 (38.92%) female and 317 (61.08%) males. Carotid stenosis of 70% or more occurred at 3.47% of the patients and 50% or more in 9.63%. For patients with perioperative ischemic stroke the mean age was 64 years, 9 (40.9%) patients were female and 13 (59.1%) were male, 10 (45.6%) had diabetes on insulin, 3 (13.63%) had CS greater than 70%; 9 (40.9%) had peripheral artery disease and 18 (81.8%) patients underwent surgery with CPB. Of the 22 cases of ischemic stroke observed: 3 (13.63%) occurred on the same side of the major carotid lesion, 12 (54.5%) occurred in the absence of any carotid lesion, 5 (22.7%) occurred in the presence of carotid lesion less than 70% and 2 (9%) patients had prior carotid endarterectomy. The average EuroSCORE of patients with ischemic stroke was 13.99 and for the control was 10.2. The other characteristics of the sample are presented in Table 1. The prevalence of risk factors for the event was compared between groups and is shown in Table 2. Of the factors analyzed those statistically significant were as follows: carotid stenosis of 70% or more (P=0.03; OR 5.07; CI 95% 1.35 to 19.02), diabetes mellitus using insulin (P=0.04; OR 2.61; CI 95% 1.10 to 6.21) and peripheral artery disease (P=0.03; OR 2.61; CI 95% 1.08 to 6.28).

Postoperative data Incidence of stroke and mortality. The stroke research was performed by daily review of electronic medical records by researchers and considered as ischemic stroke the presence of clinical changes longer than 24 hours compatible with ischemic injury associated with changes in cranial tomography (CT) as adopted by other authors, wherein the symptoms may have been present already in the recovery from anesthesia indicating an event intraoperatively or during the first postoperative hours, or later when the patient is recovering from anesthesia and subsequently presenting a neurological event after surgery[10,20]. The CT scan was performed immediately after the onset of symptoms, to rule out hemorrhagic event and repeated at 24 and 48 hours or more, when there was a change in the neurological status. Study groups and studied variables Patients with diagnosis of ischemic stroke were allocated to group with IS (GIS) and the other patients in the control group (GControl). The criteria available in the database: gender, age, carotid stenosis, diabetes on insulin, chronic pulmonary disease, peripheral artery disease, renal function, unstable angina, left ventricular (LV) function, recent acute myocardial infarction, pulmonary arterial hypertension (PAH), use of cardiopulmonary bypass (CPB) were tested as risk factors

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Table 1. Basic characteristics of the analyzed sample. Patients n=519 (%) Gender Male 317 (61.08) Female 202 (38.92) IS Present 22 (4.24) Absent 497 (95.76) Age in years Mean 61.82±10.84 ≥70 143 (27.55) <70 376 (72.45) Carotid stenosis ≥70% in at least one side 18 (3.47) No stenosis 501 (96.53) ≥50% in at least one side 50 (9.63) No stenosis 469 (90.37) Diabetes on insulin Yes 130 (25.05) No 389 (74.95) Chronic obstructive pulmonary disease Yes 149 (28.71) No 370 (71.29) Peripheral arterial disease Yes 113 (21.77) No 406 (78.23) Renal function Normal, creatinine clearance (CC)≥85 199 (38.34) Moderate dysfunction (85<CC>50) 256 (49.33) Severe dysfunction (CC<50) 57 (10.98) Dialysis (CC<15) 7 (1.35) Unstable angina Yes 264 (50.87) No 255 (49.13) Left ventricular function Normal ejection fraction (EF)≥ 0% 321 (61.85) Moderate change (EF 30 to 50%) 133 (25.63) Severe change (EF<30%) 65 (12.52) Recent acute myocardial infarction Yes 177 (34.1) No 342 (65.9) Pulmonary arterial hypertension Yes (≥60 mmHg) 38 (7.32) No (<60 mmHg) 481 (92.68) Cardiopulmonary bypass Yes 395 (76.11) No 124 (23.89) CABG Yes 383 (73.8) No 136 (26.2) Mean EuroSCORE ICVA 13.99 Control 10.2 Outcome Discharge 437 (84.2) Death 82 (15.8) CABG n=383 (100) On-pump 260 (67.89) Off-pump 123 (32.11)

Table 2. Risk factors analyzed for the development of postoperative CVA. Gicva n=22

Gender Male 13 Female 9 Age (years)* Mean 64.13±8.1 >or=70 6 <70 16 Carotid stenosis* ≥70% unilateral 3 No stenosis 19 ≥50% 5 No stenosis 17 Diabetes on insulin Yes 10 No 12 Chronic obstructive pulmonary disease Yes 6 No 16 Peripheral arterial disease Yes 9 No 13 Renal function Normal 6 Slight 11 Moderate 5 Severe 0 Renal function Normal 6 Changed 16 Unstable angina Yes 14 No 8 Left ventricular function Normal 13 Moderate change 7 Severe change 2 Recent acute myocardial infarction Yes 8 No 14 Pulmonary hypertension* Yes 1 No 21 Cardiopulmonary bypass* Yes 18 No 4 CABG Yes 17 No 5 Outcome Discharge 16 Death 6 CABG* n=17 On-pump 13 Off-pump 4

GControl n=497 304 193 61.72±10.42 121 376 15 482 45 452

P

0.82 0.28 0.75 0.03 0.05

120 377

0.04

143 354

1.000

104 393

0.03

193 245 52 7

0.26

193 304

0.28

250 247

0.27

308 126 63

0.74

169 328

0.82

37 460

0.92

377 120

0.69

366 131

0.80

421 76 n=366 247 119

0.13 0.61

CABG=coronary artey bypass surgery; CVA=cerebrovascular accident. *Variables analyzed by the Fisher’s exact test.

CABG=coronary artey bypass surgery; IS=ischemich stroke

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DISCUSSION

surgery found rates of 2.7% in patients with carotid stenosis <50%, and 16.7% in patients with carotid stenosis ≥50%. In this series, there was a 10% rate of ischemic stroke in patients with carotid stenosis ≥ 50%, and in carotid stenosis ≥ 70% this index reaches about 16.6%. But it is still debatable the influence of carotid stenosis in the pathophysiology of perioperative ischemic stroke in cardiac surgery, given that patients who have carotid atherosclerosis possibly have severe atherosclerosis of the ascending aorta, which is one of the biggest risk factors for ischemic stroke[2,22]. In this sample, the probability that a patient who had suffered ischemic stroke presenting severe stenosis was 83%, and even though the carotid stenosis greater than 70% has been found as an important risk factor for ischemic stroke, of the 22 events, only 3 (13.63%) showed a correlation between the side of the carotid lesion and the side affected by ischemic injury, which is compatible with data published by Roffi et al.[2] affirming that the prevalence of ipsilateral stroke in patients with asymptomatic lesion and from 50 to 99% was only 2%. This evidence strongly suggests that carotid lesions are more a risk marker than actually the etiology of stroke, this creates great doubt about the benefits of prophylactic treatment of carotid lesions in patients without neurological symptoms. Multicenter randomized studies comparing prophylactic strategies of endarterectomy, carotid angioplasty and no prophylactic treatment, taking into account the degree of stenosis and the presence of unilateral or bilateral disease, could clarify which is the best approach in this group of patients. The CPB is recognized as a potential risk factor for stroke in cardiac surgery especially by increasing the manipulation of the aorta[23], the present study found a risk 1.4 times higher in patients undergoing CPB, but without statistical difference. A larger sample could in the future demonstrate that off-pump surgery is capable of reducing the incidence of stroke, as shown in meta-analyzes[13,14]. Besides plaques in the aorta and extracranial carotid stenosis, other factors interfere with cerebral perfusion, for example intracranial atherosclerosis, arterial pressure and therefore maintain adequate oxygenation is necessary to avoid extended shock or severe hypoxemia that may lead to lesions brain, in the Service it is practice maintaining mean arterial pressure above 70 mmHg in patients with higher risk of stroke, especially in patients with significant carotid disease in patients with surgery with or without cardiopulmonary bypass. It is known that diabetes mellitus, despite being a potentially treatable factor, may be the second largest risk factor for ischemic stroke and its incidence has been increasing in the last decade[24]. In this study, diabetes using insulin was a risk factor for ischemic stroke corroborating findings of other authors[2,15,21]. Diabetes, despite being an important marker of more severe atherosclerosis of large vessels, affects the microcirculation and interferes significantly with endothelial

Most studies address the incidence of stroke in patients undergoing coronary surgery, one of the few reports that addresses different surgical procedures with large case series was developed by Bucerius et al.[21] who analyzed 16,184 patients and found 4.6% of ischemic events, but included in the sample not only stroke patients, but also those with transient ischemic attack; in the present study the incidence of ischemic events was similar to the above study (4.2%), however the samples are different in two aspects, first, here were considered only cases of ischemic stroke confirmed by clinical changes accompanied by change on cranial CT - as criterion adopted by other studies[10,20], and second: we excluded patients without coronary artery disease under 40 years and therefore lower incidence of stroke. It was not found in the widely researched literature a study with identical design to compare the incidence of stroke, and the article by Bucerius et al.[21] was the most closely. The exclusion of patients undergoing coronary surgery and not less than 40 years was performed because these patients do not undergo carotid Doppler, avoiding their inclusion in the statistics, on the other hand, the patients with valvular or congenital diseases with 40 years or more were included since there was lack of publications on the occurrence of stroke in this population, especially correlated with carotid disease. In Brazilian Services living with degenerative valve disease and with a large number of rheumatic diseases, it is worth a look at the causes of neurological ischemic events in this population, given the large number of valve surgeries herein. In this series the prevalence of ischemic stroke in non-coronary surgery was not statistically different in the incidence of ischemic stroke in CABG, showing the relevance of studying also the risk factors for stroke in this population. Although age is mentioned as a risk factor for perioperative stroke in some studies, in this sample, age greater than 70 years was not correlated statistically with higher incidence of stroke. The average age of patients with stroke was three years older than the control average, but without significant differences, showing that other factors such as degree of patient’s atherosclerosis demonstrated by the presence of peripheral artery disease, severe carotid CS and DM on insulin seem to be more relevant than age alone as risk factors for stroke in this sample. Studies with larger samples as Bilfinger et al.[17], who evaluated 2071 patients and Gardner et al.[18], who evaluated 3279 patients, observed a correlation between increased age and increased risk of stroke. An increase of this series, which continues to be expanded, may in future studies to correlate again age and stroke with greater statistical power. According Inzitari et al.[9], asymptomatic carotid stenosis 60-99% are at risk of stroke of 16.2% in five years. Hirotani et al.[20], correlating ischemic stroke with cardiac

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reactivity, damaging tissue perfusion as a whole and predisposing still other possible complications to lead to low output and consequent cerebral ischemia as greater degree of myocardial ischemia, greater inflammatory response and more prone to infection. It was observed in the present series, that the presence of peripheral artery disease was more prevalent in the group with ischemic stroke that comes against the finding of other studies[7,20]. It is clear from the evidence presented herein that the same risk factors for stroke are the markers of most severe systemic atherosclerosis as the presence of diabetes using insulin, severe stenosis of the carotid and peripheral artery disease, and should always serve as a warning to the surgeon in the increased care with this group of patients at high risk for stroke. A patient with the above three features together have 33.8 times more chance of a perioperative ischemic stroke when compared to a patient without these characteristics. Unlike studies by Mahmoudi et al.[10] and Dacey et al.[15], in which the presence of stroke increased mortality, in this study, there was no statistical difference in the mortality rate in patients with and without ischemic stroke, which can be related to the sample size.

3. Santos A, Washington C, Rahbar R, Benckart D, Muluk S. Results of staged carotid endarterectomy and coronary artery bypass graft in patients with severe carotid and coronary disease. Ann Vasc Surg. 2012;26(1):102-6. 4. McDonnell CO, Herron CC, Hurley JP, McCarthy JF, Nolke L, Redmond JM, et al. Importance of strict patient selection criteria for combined carotid endarterectomy and coronary artery bypass grafting. Surgeon. 2012;10(4):206-10. 5. Illuminati G, Ricco JB, Caliò F, Pacilè MA, Miraldi F, Frati G, et al. Short-term results of a randomized trial examining timing of carotid endarterectomy in patients with severe asymptomatic unilateral carotid stenosis undergoing coronary artery bypass grafting. J Vasc Surg. 2011;54(4):993-9. 6. McKhann GM, Grega MA, Borowicz LM Jr, Baumgartner WA, Selnes OA. Stroke and encephalopathy after cardiac surgery: an update. Stroke. 2006;37(2):562-71. 7. Salasidis GC, Latter DA, Steinmetz OK, Blair JF, Graham AM. Carotid artery duplex scanning in preoperative assessment for coronary artery revascularization: the association between peripheral vascular disease, carotid artery stenosis, and stroke. J Vasc Surg. 1995;21(1):154-60. 8. Selim M. Perioperative stroke. N Engl J Med. 2007;356(7):706-13.

CONCLUSION

9. Inzitari D, Eliasziw M, Gates P, Sharpe BL, Chan RK, Meldrum HE, et al. The causes and risk of stroke in patients with symptomatic internal-carotid-artery stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 2000;342(23):1693-700.

In this sample the significant risk factors for perioperative ischemic stroke in cardiac surgery were: carotid stenosis equal to or greater than 70%, presence of diabetes on insulin and presence of peripheral artery disease.

10. Mahmoudi M, Hill PC, Xue Z, Torguson R, Ali G, Boyce SW, et al. Patients with severe asymptomatic carotid artery stenosis do not have a higher risk of stroke and mortality after coronary bypass surgery. Stroke. 2011;42(10):2801-5.

Authors’ roles & responsibilities MACC

MFG RZG MDS

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

11. Souza JM, Berlinck MF, Oliveira PAF, Ferreira RP, Mazzieri R, Oliveira SA. Cirurgia de revascularização do miocárdio associada a endarterectomia de carótida. Rev Bras Cir Cardiovasc. 1995;10(1):43-9. 12. Naylor AR, Mehta Z, Rothwell PM, Bell PR. Carotid artery disease and stroke during coronary artery bypass: a critical review of the literature. Eur J Vasc Endovasc Surg. 2002;23(4):283-94. 13. Sá MP, Ferraz PE, Escobar RR, Martins WN, Lustosa PC, Nunes EO, et al. Off-pump versus on-pump coronary artery bypass surgery: meta-analysis and meta-regression of 13,524 patients from randomized trials. Rev Bras Cir Cardiovasc. 2012;27(4):631-41.

REFERENCES 1. Naylor AR, Brown MJ. Stroke after cardiac surgery and its association with asymptomatic carotid disease: an updated systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2011;41(5):607-24.

14. Sedrakyan A, Wu AW, Parashar A, Bass EB, Treasure T. Off-pump surgery is associated with reduced occurrence of stroke and other morbidity as compared with traditional coronary artery bypass grafting: a meta-analysis of systematically reviewed trials. Stroke. 2006;37(11):2759-69.

2. Roffi M, Ribichini F, Castriota F, Cremonesi A. Management of combined severe carotid and coronary artery disease. Curr Cardiol Rep. 2012;14(2):125-34.

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15. Dacey LJ, Likosky DS, Leavitt BJ, Lahey SJ, Quinn RD, Hernandez F, et al.; Northern New England Cardiovascular Disease Study Group. Perioperative stroke and long-term survival after coronary bypass graft surgery. Ann Thorac Surg. 2005;79(2):532-6.

20. Hirotani T, Kameda T, Kumamoto T, Shirota S, Yamano M. Stroke after coronary artery bypass grafting in patients with cerebrovascular disease. Ann Thorac Surg. 2000;70(5):1571-6. 21. Bucerius J, Gummert JF, Borger MA, Walther T, Doll N, Onnasch JF, et al. Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients. Ann Thorac Surg. 2003;75(2):472-8.

16. Nashef SA, Roques F, Hammill BG, Peterson ED, Michel P, Grover FL, et al.; EuroSCORE Project Group. Validation of European System for Cardiac Operative Risk Evaluation (EuroSCORE) in North American cardiac surgery. Eur J Cardiothorac Surg. 2002;22(1):101-5.

22. Mickleborough LL, Walker PM, Takagi Y, Ohashi M, Ivanow J, Tamariz M. Risk factors for stroke in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1996; 112: 1250-1259.

17. Bilfinger TV, Reda H, Giron F, Seifert FC, Ricotta JJ. Coronary and carotid operations under prospective standardized conditions: incidence and outcome. Ann Thorac Surg. 2000;69(6):1792-8. 18. Gardner TJ, Horneffer PJ, Manolio TA, Pearson TA, Gott VL, Baumgartner WA, et al. Stroke following coronary artery bypass grafting: a ten-year study. Ann Thorac Surg.1985;40(6):574-81.

23. Lobo Filho JG, Leitão MCA, Lobo Filho HG, Soares JPH, Magalhães GA, Leão Filho CSC, et al. Cirurgia de revascularização Coronariana esquerda sem CEC e sem manuseio da aorta em pacientes acima de 75 anos: Análise das mortalidades imediata e a médio prazo e das complicações neurológicas no pós-operatório imediato. Rev Bras Cir Cardiovasc. 2002;17(3):208-14.

19. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351(9113):1379-87.

24. Khoury JC, Kleindorfer D, Alwell K, Moomaw CJ, Woo D, Adeoye O, et al. Diabetes mellitus: a risk factor for ischemic stroke in a large biracial population. Stroke. 2013;44(6):1500-4.

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Amaral FTV, et al. - Recommendations SPECIAL ARTICLE for starting a grown up congenital heart disease (GUCH) unit

Recommendations for starting a grown up congenital heart disease (GUCH) unit Recomendações para a implantação de uma Unidade de Cardiopatias Congênitas no Adulto

Fernando Tadeu Vasconcelos Amaral1, MD, PhD; Paulo Henrique Manso1, MD, PhD; André Schmidt1, MD, PhD; Ricardo Nilson Sgarbieri2, MD, PhD; Walter Villela de Andrade Vicente1, MD, PhD; Clovis Carbone Junior1, MD, PhD; Jane Somerville3, MD

DOI 10.5935/1678-9741.20150037

RBCCV 44205-1654

Abstract During the last decades, advances in diagnosis and treatment of congenital heart disease have allowed many individuals to reach adulthood. Due mainly to the great diagnostic diversity and to the co-morbidities usually present in this age group, these patients demand assistance in a multidisciplinary facility if an adequate attention is aimed. In this paper we reviewed, based in the international literature and also on the authors’ experience, the structural conditions that should be available for these patients. We highlighted aspects like the facility characteristics, the criteria usually adopted for patient transfer from the paediatric setting, the composition of the medical and para-medical staff taking into account the specific problems, and also the model of outpatient and in-hospital assistance. We also emphasized the importance of patient data storage, the fundamental necessity of institutional support and also the compromise to offer professional training. The crucial relevance of clin-

ical research is also approached, particularly the development of multicenter studies as an appropriate methodology for this heterogeneous patient population.

Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil. 2 Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil and Hospital São Francisco, Ribeirão Preto, SP, Brazil. 3 Emeritus Professor of Cardiology, Imperial College, London, England.

No financial support.

Descriptors: Congenital Abnormalities. Heart. Adult. Resumo Durante as últimas décadas, os avanços verificados no diagnóstico e tratamento das cardiopatias congênitas têm permitido que muitos indivíduos cheguem à idade adulta. Devido principalmente à grande diversidade diagnóstica e também às comorbidades habitualmente presentes nesse grupo etário, esses pacientes necessitam ser atendidos numa unidade multidisciplinar, se o objetivo for proporcionar uma assistência adequada. Neste trabalho revisamos, com base na experiência dos autores e na literatura internacional, as condições estruturais

1

Correspondence address: Fernando Tadeu Vasconcelos Amaral Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto USP Av. Bandeirantes, 3900 – Vila Monte Alegre, Ribeirão Preto, SP. Brazil Zip code: 14049-900 E-mail: ftvamaral@bol.com.br

This study was carried out at the Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), Ribeirão Preto, SP, Brazil.

Article received on February 2nd, 2015 Article accepted on May 25th, 2015

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e também o modelo de assistência ambulatorial e hospitalar. Enfatizamos, ainda, a importância do armazenamento dos dados dos pacientes, a necessidade fundamental de apoio institucional e a importância de oferecer treinamento profissional. A relevância da pesquisa clínica é também abordada, particularmente a importância da confecção de estudos multicêntricos, como uma metodologia apropriada para essa heterogênea população de pacientes.

Abbreviations, acronyms & symbols CHD GUCH

Congenital heart disease Grow up congenital heart disease

que devem estar disponíveis para esses pacientes. Procuramos ressaltar aspectos como as características da unidade, o critério usualmente adotado para transferência desses pacientes da unidade pediátrica, a composição das equipes médica e paramédica levando em consideração os problemas específicos dos pacientes

Descritores: Cardiopatias Congênitas. Adulto. Unidades Hospitalares.

INTRODUCTION

the last 20 years. The GUCH outpatient clinic started informally about 12 years ago and since 2006 a data base was developed with almost 1000 patients included by now. Difficulties are many in various aspects. As the development of this area among us is mandatory it is thus appropriate to review the needs and recommendations required to establish GUCH specialized services, a population in many areas of the world continues to be neglected. It may not yet be possible to organize a National Service in Brazil so we must be content to concentrate on the region following the ROCK principle: Recognize need Organise: trying but facing big challenges Centralise facilities and specialists in order not to loose precious resources Knowledge: join specialists and subspecialists – nursing, intensive care, cardiac surgery, complex imaging and anaesthesia altogether.

The remarkable development of paediatric cardiology during the last six decades has been responsible for the fact that up to 90% of children with congenital heart disease (CHD) can now reach adulthood[1]. This notable achievement is due to several factors like, first, the increasing paediatric awareness of these defects and diagnostic imaging improvement. The refinement of the invasive treatment techniques, a better understanding of the cardiorespiratory physiology and its application in the postoperative period, particularly in neonates, as well as the awareness of the crucial importance of following these patients after intervention in specialized outpatient clinics also play an important role. It is well recognized that paediatric cardiac surgery is an important landmark in the history of patients with CHD since before its development less than 20% of these children could survive to adult age[2]. Now we know that the majority of deaths occur at this age range[3] and that the population of adults is greater than that of children with CHD[4]. These patients need special attention in an adequate setting in order that the problems and sequelae intrinsic to the heart defect and also the age related co-morbidities can be well approached. In most developed countries an organized and efficient structure is available to assist these patients. In Brazil, the development of paediatric cardiology and paediatric cardiac surgery has also been responsible for an increasing number of survivors. In the state of São Paulo, where fifteen fully active centers provide assistance for a population of 44 million people, as well as in others where paediatric cardiology and cardiac surgery have been long instituted, there should be GUCH (grown up congenital heart) services as they have contributed so many survivors to the adult population and made such important contributions to the surgical management of CHD. However, adult CHD units well organized in terms of assistance and research are few. In Ribeirão Preto, cardiac surgery has been offered for complex CHD cases in

INITIAL CONSIDERATIONS Organization of a GUCH unit must take into account some basic principles applicable to the majority of grown up congenital heart patients: 1) Any paediatric cardiology unit with cardiac surgery should consider the necessity of having a specialized adult cardiac surgery unit for referral, not necessarily on site but within easy travelling. Referral should be activated as soon as the patients reach a certain age between 16 and 19 years depending on maturity and other factors. This transfer of patients should be well planned as many reach adolescence and adulthood without either the family or patient understanding the problems of their defect[5] and need for advice about special situations which appear in adulthood such as physical exercise[6], bacterial endocarditis prophylaxis[7], sexual behavior and pregnancy[8], employment, other systemic diseases, etc. Most have no idea of the future of their lesion and think they are “totally corrected” as doctors and patients

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have accepted. This requires explanation. Paediatricians and paediatric cardiologists must not lead them into the wilderness of life without explanation or indications of where to go. Loss to follow-up is dangerous for some patients with special conditions. They should be advised, both family and patients. 2) The outpatient demand will increase progressively[9]; discharge is rare except for patients with closed ductus or small shunts like atrial and ventricular septal defects, who can be followed out of the referral center[10]; 3) The number of patients with complex CHD will increase. The type of lesions seems depend on the group expertise dealing with these cases in the paediatric age throughout the developed world. The lesions in GUCH patients needing medical expertise so are the same; 4) Patients admission for electrophysiological studies[11], cardiac catheterization[12] and surgery[13] to treat sequelae and residual lesions secondary to previous interventions will be more frequent as they growth up.

of the CHD that has been treated in childhood and infancy. Examples are certain ventricular and most atrial septal defects, properly closed ventricular septal defects without murmurs, simple pulmonary valve stenosis and closed ductus. Transfer should be based on patient’s age but also taking into consideration his/her psychological and physical maturity[19]. Some centers accept patients as early as above twelve years but in the majority of them the age of transfer from paediatric to adult care is sixteen[20]. Caring of the adolescent is a particularly important matter which could have serious consequences in adulthood. In some aspects of daily life his behavior and also the relationship with the heart problem is different when compared to adults[8]. For this reason we believe that the possible benefit of an outpatient clinic exclusively devoted to this age range should be discussed. Support from adolescent specialists could be helpful preparing theses individuals for adult life. STAFF

LOCAL OF ASSISTANCE

The composition of the group depends on the number of patients and may vary. Two physicians should be in charge of the first contact with patients, as long as they are interested and have knowledge about CHD and its particularities. There have been some discussion about this matter and some reports even suggest a different kind of professional to deal with these cases[3]. In experienced groups there are usually cardiologists and paediatricians[21] who should work in harmony. Specialist imaging must be available to the unit with informed (about GUCH) specialists. At least two surgeons should be available, both with experience in children and adult cases. The anesthetists should also have interest in CHD and have experience in dealing with children and adults. The intensive care physicians in charge of the postoperative care must have an adequate knowledge of CHD in order to understand physiology and its modifications after intervention[22,23]. Due to the high incidence of arrhythmias in this population it is advisable that at least one electrophysiologist be a member of the group and have expertise in ablation techniques[11]. Cooperation with a pneumology group is desirable due to the significant occurrence of pulmonary hypertension in these patients[17]. Despite long-term results are unknown, advanced pharmacologic therapy is available for patients with this complication[24]. Also, a good interdisciplinary relationship with a cardiopulmonary transplantation unit with some experience in CHD is necessary. Obstetricians familiar with high risk pregnancies should be available for consultation and assistance. It is recommended that a pathologist, not necessarily working in the same unit, be contacted when necessary. A specialized nurse, as well as a psychologist, a social assistant and secretaries should be part of the group, depending on patient demand. Dental assistance should be provided.

An adequate population estimative must be available to justify costs and presence of experts. Despite different numbers in the literature, it is accepted that a GUCH unit should serve a population of, at least, 4 million people[3,7]. Extrapolating Wren’s experience in Newcastle, England, based on the number of alive newborns[14], such a number of individuals should generate, in a continuous controlled population, approximately 109 adults with CHD a year. It should be remembered that this population will increase linearly and that demand will naturally increase[9]. Another relevant aspect to be considered is the importance to concentrate these cases, mainly the surgical, in a single center, in order to increase the group experience and achieve better results[15]. Obviously, in such a huge country as Brazil, where travel difficulty is a reality, we believe that all centers offering invasive treatment for children with CHD should gradually incorporate the assistance to adults. Due to the complexity of the cases, mainly verified in more experienced centers, and also due to patients’ age, it is recommended they should be seen in a multidisciplinary unit. Apart from the important occurrence of comorbidities[16], complications and sequelae are frequent, like residual lesions, arrhythmias and pulmonary hypertension[17]. Pregnancy can be particularly problematic[18] and a special attention to the mother should be available at the institution. Patients living far away from the regional center could be seen by an interested professional as long as an easy contact with the referral unit is provided[7]. TRANSFER CRITERIA Certain lesions do not require automatic transfer to specialized GUCH unit care and this probably makes up 35-40%

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OUTPATIENT CLINIC

treated, admission is common due to reoperations[28] and arrhythmias[32]. Also frequent are admissions for interventional catheterization and primary surgery in adults[33,34]. Other less frequent causes of admission are endocarditis and high risk pregnancy, which demands specialized obstetrical care[18]. These patients should stay in an adult cardiology ward where multidisciplinary assistance is available due to the important incidence of non cardiac clinical and surgical problems[7,16]. Centers with high demand should offer a specific ward for these patients[21] which is beneficial for nurse and junior medical experience and training. A crucial aspect is the immediate postoperative care in those with complex CHD particularly when arrhythmias and pulmonary hypertension are present. As well emphasized[22,23] knowledge of pre and post-interventional physiopathological aspects of these defects is essential if proper care is aimed.

It is well known there is a significant difference between the estimated number of adults with CHD and the actual number seen by the referral centers[21]. Most of them are not under routine follow-up[25,26] and were not properly advised after paediatric age[27]. This aspect demands special attention of the unit which should search for the patients lost to follow up. The information provided by the referral center regarding availability of the clinic can increase substantially the workload. However, it is ethically correct and should be instituted in order that patients are cared in a specialized center. The model of assistance should be determined considering the demand of patients and the internal logistic of the center. In most centers the clinic usually occurs in specific week days and the consultation should happen in an adequate and comfortable place including the waiting room. Cyanotic and pulmonary hypertensive patients have a poor tolerance to closed and hot places. These patients need to be educated about CHD and should have a private conversation with the physician in order to discuss aspects like sexual behavior, know to be promiscuous in some age ranges[8], genetic risk, pregnancy, exercise[6], contraception, driving and employment[28]. Apart from the detailed clinical examination, the electrocardiogram, chest X ray, echocardiogram and hematological tests should be available. More sophisticated tests like cardio exercise test, transeshophagical echocardiography and nuclear ventriculography are necessary for a proper assessment. Magnetic resonance, frequently useful for complex cases[29], it is not routinely available in most of our hospitals but its application is necessary, at least in the referral centers. After patient assessment, a decision has to be made regarding where the follow up is going to occur taking into consideration geographical aspects, individual locomotion and social details. Outreach clinics, a strategy adopted in some places for paediatric cardiology patients and not routinely established in our country, can also be employed for adults with CHD[30]. This model of assistance, allowing a specialized consultation, can also be useful to identify those in need of a close follow up[31]. The patients requiring intervention should be referred to centers based on the institutional experience and not necessarily to the original patient district. Electronic or telephone consultation between the cardiologists and paediatricians with the referral center should be easy.

MEDICAL RECORDS This should be considered of great importance in a GUCH unit. Every patient must be included in a database. The availability of detailed follow up information is mandatory for the patient and for the paediatric group, particularly if any intervention has been performed. Knowledge of the interventions long term results is crucial for improving therapeutic methods and strategies. Due to the great variety of diagnostic and clinical features in GUCH patients the relevance of multicentre studies has been emphasized in the international literature[34] and gathering informations from several centers are needed. The construction of a national database, quite possible in an era of great advances regarding information storage should be an accomplishment to be reached. INSTITUTIONAL SUPPORT It is particularly important that the administrators of tertiary hospitals have some knowledge about the main characteristics of adult patients with CHD as well as the natural history of theses defects and survival possibilities. These data will provide a better resource planning to assist well GUCH patients. The costs of this treatment are usually high mainly when dealing with complex CHD like those with Fontan-type surgery. TRAINING

IN HOSPITAL TREATMENT

Cardiologists and paediatricians in training must be exposed to the problems faced by adults with CHD, either to learn about specific diagnostic and therapeutic details of the defects or to experience the complexity of an assistance process that usually starts in infancy and reachs adult life, very often with no possibility of cure. In our institution the first consultation of a patient is made by a cardiology resident in

Due to an increasing number of patients, this is a topic which should be well discussed among each unit aiming to facilitate patient access, which is usually difficult. The number of admissions is directed related to the number of complex cases in follow up. In the more experienced institutions, with an important number of complex CHD cases already

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his final training period together with the paediatric cardiology resident. As long as training is concerned we believe that the organization of a national net of GUCH services will allow identification of those more suitable for this task. It is recommended that cases requiring intervention be discussed before the procedure in order to achieve therapeutic consensus and training for junior staff.

disciplinary institution considering that they will need specific age related attention. Outpatient clinics should be run by interested cardiologists with knowledge of CHD. Percutaneous intervention and heart surgeons with training in complex CHD should be daily available. In hospital treatment should be done in an adult setting with non-invasive and invasive diagnostic resources. Data base storage is essential. Due to the heterogeneous diagnosis verified in this population, research is crucial, including collaborative studies, in order to have good number of patients for data analysis. Junior training is necessary in centers with adequate number of patients and educational facilities. It is necessary that institutions be aware of the peculiar characteristics of these patients, many with complex CHD in need of expensive treatments. We believe that following and adapting theses recommendations to regional care will certainly promote an adequate assistance to the increasing population of GUCH patients. As recently suggested[44] the development of a specific model of assistance is necessary for these patients to minimize risks and offer good treatment.

RESEARCH The international literature, mainly in the last decade, has been contemplated by a substantial number of investigations involving adults with CHD. However, the peculiar characteristics of these patients, expressed by a great diagnostic diversity, different residual lesions after intervention as well as the burning of non cardiac diseases, make it difficult to have homogeneous groups of patients with whom basic and clinical research can appropriately be done. Trying to by pass this problem, cooperations have been made between specialized centers in some countries to develop multicenter studies, with statistically reliable patient data and which could answer questions regarding different aspects of adult CHD. A recent report[35] shows a substantial increase in this type of investigation, mainly in the last decade. It is interesting to mention that, as far as we know, in the last 16 years, only ten papers were published in indexed Brazilian journals regarding CHD in adults[16,34,36-43]. However, a change in this perspective is soon expected. The national awareness of the necessity to provide specialized assistance for this group of patients will generate a substantial number of informations. An adequate analysis of these data, either in a single or multicenter investigation will allow the construction of a national database which will make it possible, in a first moment, to know the characteristics of our patients. The planning of specifics investigations using reliable data will then be possible to be elaborated which could, also in a first moment, disclose the results of the paediatric cardiology assistance in the country. The organizations in charge of financing theses researches should be notified about its relevance if the purpose is to provide a proper assistance to this increasing group of patients. ` CONCLUSION

Authors’ roles & responsibilities FTVA PHM AS RNS WVAV CCJ JS

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; writing of the manuscript or critical review of its contents Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; final approval of the manuscript; writing of the manuscript or critical review of its content Analysis and/or interpretation of data; 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

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Zhu Z, et al. - MicroRNAs and mesenchymal stem cells: hope for pulmonary REVIEW ARTICLE hypertension

MicroRNAs and mesenchymal stem cells: hope for pulmonary hypertension MicroRNAs e células-tronco mesenquimais: esperança para a hipertensão pulmonar

Zhaowei Zhu1, MD, PhD; Zhenfei Fang2, MD, PhD; Xinqun Hu2, MD, PhD; Shenghua Zhou1

DOI 10.5935/1678-9741.20150033

RBCCV 44205-1656

Abstract Pulmonary hypertension is a devastating and refractory disease and there is no cure for this disease. Recently, microRNAs and mesenchymal stem cells emerged as novel methods to treat pulmonary hypertension. More than 20 kinds of microRNAs may participate in the process of pulmonary hypertension. It seems microRNAs or mesenchymal stem cells can ameliorate some symptoms of pulmonary hypertension in animals and even improve heart and lung function during pulmonary hypertension. Nevertheless, the relationship between mesenchymal stem cells, microRNAs and pulmonary hypertension is not clear. And the mechanisms underlying their function still need to be investigated. In this study we review the recent findings in mesenchymal stem cells - and microRNAs-based pulmonary hypertension treatment, focusing on the potential role of microRNAs regulated mesenchymal stem cells in pulmonary hypertension and the role of exosomes between mesenchymal stem cells and pulmonary hypertension.

Resumo A hipertensão pulmonar é uma doença devastadora e refratária, para a qual não existe cura. Recentemente, microRNAs e células-tronco mesenquimais emergiram como novos métodos para tratar a hipertensão pulmonar. Mais de 20 tipos de microRNAs podem participar no processo de hipertensão pulmonar. Ao que parece, microRNAs ou células-tronco mesenquimais podem atenuar alguns sintomas de hipertensão pulmonar em animais de e até mesmo melhorar a função cardíaca e do pulmão durante a hipertensão pulmonar. No entanto, a relação entre células-tronco mesenquimais, microRNAs e hipertensão pulmonar não é clara. E os mecanismos subjacentes a sua função ainda precisam ser investigados. Neste estudo, revisamos as descobertas recentes no tratamento da hipertensão pulmonar baseado em células-tronco mesenquimais e microRNAs, enfocando o papel potencial dos microRNAs para regular as células-tronco mesenquimais na hipertensão pulmonar e o papel dos exossomos entre células-tronco mesenquimais e hipertensão pulmonar.

Descriptors: Hypertension, Pulmonary. MicroRNAs. Mesenchymal Stem Cell Transplantation.

Descritores: Hipertensão Pulmonar. MicroRNAs. Transplante de Células-Tronco Mesenquimais.

The Second Xiangya Hospital, Central South University, Huan Province, P.R. China. 2 Department of Cardiology, Second Xiangya Hospital of Central South University, Huan Province, P.R. China.

Correspondence address: Shenghua Zhou The Second Xiangya Hospital, Central South University Middle Ren-Min road, No.139 - Changsha, Huan Province, P.R. China Zip code: 410011 E-mail: zhoushenghua2011@163.com

1

This study was carried out at the The Second Xiangya Hospital, Central South University, Huan Province, P.R. China.

Article received on December 22th, 2014 Article accepted on May 12th, 2015

No financial support.

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These properties and findings make MSCs treatment a novel and promising approach for protection from and repair of PH. Recently, A number of animal studies taking use of monocrotaline or hypoxia induced animal model in pulmonary medicine have demonstrated that naive or gene-modified mesenchymal stem cells from bone marrow can ameliorate some of the symptoms of pulmonary hypertension. More interesting, both intratracheal and intravenous administration of MSCs can attenuate pulmonary hypertension in the aspects from endothelial dysfunction[7], alveolar loss and lung inflammation[8] even to ventricle remodeling[7,9-11]. Further researches using gene-modified mesenchymal stem cells treatment also seem successful. Recent studies have found that eNOS[12] or prostacyclin synthase[13] or lung-specific HO-1[14] modified MSCs can not only offer ameliorating effects on PH-related RV impairment but also improve the prognosis and even survival time in PH animals. Although haven’t been applied to PH in clinic, all the studies above really provide us a hopeful prospect of MSCs transplantation therapy for PH. However, the mechanisms of MSCs’ therapeutic efficacy are still unclear. Although a robust protection against lung injury on MSCs treatment was observed in most of the above-mentioned animal models, only a small fraction of administered MSCs were detected in the wall of the pulmonary vessels[15]. This observation suggested that engraftment and direct tissue repair were not the sole mechanisms of MSC therapeutic function, and paracrine mechanisms were contemplated. It is known that MSCs can be mobilized from the total pool of bone marrow stromal cells (BMSCs) when influenced by hypoxia or other injury factors[16]. After mobilization, it can localize into the injured tissue, and even few MSCs can fuse with cells from the host[10]. In addition to being mobilized into the circulation, MSCs have been shown to increase production of growth factors, such as VEGF, insulin-like growth factor (IGF), and hepatocyte growth factor (HGF), when under stress by TNF or hypoxia[17,18]. It is possible that transplanted MSCs may repair injured vascular endothelium by an action involving the release of factors that improve endothelial function or stimulate vascular growth in the injured lung[19,20], which can be partly confirmed by the inhibition of lung inflammation after systemic delivery of MSCs-conditioned media[8]. So, mechanisms for this protection may be not limited to tissue repair, such as engraftment and differentiation of MSCs into specific lung cell types, but also include paracrine factors[7,10,21]. Considering the few numbers of MSCs located in injury tissue, MSCs paracrine signaling maybe a primary mechanism accounting for the beneficial effects of MSCs on responses to injury such as PH. Among all the paracrine types of MSCs, exosomes, as mediators of cell-cell communication, provide a novel insight into the efficient role of MSCs in PH[11]. Exosomes

Abbreviations, acronyms & symbols BMPR2 BMSCs CTEPH HGF IGF MSCs PH RV

Bone morphogenetic protein receptor type II Bone marrow stromal cells Chronic thromboembolic pulmonary hypertension Hepatocyte growth factor Insulin-like growth factor Mesenchymal stem cells Pulmonary hypertension Right ventricle

INTRODUCTION Pulmonary hypertension (PH) is a devastating and refractory disease which is defined by a resting mean pulmonary artery pressure at or above 25 mmHg[1]. Untreated chronic PH can cause a hemodynamic and pathophysiological vicious cycle leading to right ventricle (RV) failure and despite modern treatments, the 3-year survival remains less than 60%[2]. Although currently there is no cure for this disease, treatment has been improved during the past decade, offering both relief from symptoms and prolonged survival. Recently, the regenerative method and gene therapy have been introduced to break the vicious cycle of PH. For example, transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is emerging as a regenerative method to treat PH[3,4]. However, current evidence indicates that the efficacy of MSCs transplantation was unsatisfactory, due to the poor viability and massive death of the engrafted MSCs in the injured tissue. MicroRNAs are short endogenous, conserved, non-coding RNAs and important regulators involved in numerous facets of pathophysiologic processes. There is an obvious involvement of microRNAs in cell differentiation, neovascularization, apoptosis, and others. Nevertheless, the relationship between MSCs, microRNAs and PH is not clear. Here we review the recent findings in MSCs- and microRNAs-based PH treatment, focusing on the potential role of microRNAs regulated MSCs in PH. MSCS AND PH MSCs are multipotent progenitor cells that were originally identified in the bone marrow stroma. MSCs have several favorable features for the transplantation therapy of pulmonary hypertension. Besides the ease of isolation and expansion in culture and their capacity to differentiate into multiple lineages, MSCs: have been shown to migrate to sites of injury; they have key interactions with the immune system and generate strong paracrine effects[5]. In addition, Firth et al.[6] identified that a myofibroblast cell phenotype arising from transdifferentiation of differentiation of mesenchymal progenitor cells is predominant within endarterectomized tissues, contributing extensively to the vascular lesion/clot.

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are a kind of better-defined subclass of secreted membrane microvesicles, which are usually 30 to 100 nm in diameter. They have been isolated and characterized from various cell types, including MSCs. Recent study found MSCs-derived exosomes can exert a pleiotropic protective effect on the lung and inhibit pulmonary hypertension through suppression of hyperproliferative pathways, including STAT3-mediated signaling induced by hypoxia[22].

significantly reduced only in monocrotalinetreated rats. miR204 was consistently down regulated in pulmonary artery smooth muscle cells (PASMCs) from patients with PH and in cells from mice with PH[26]. Besides, circulating miR-150 and miR-26a levels are reduced in patients with poor survival in PH[27,28]. All the evidences above indicate a potential role of microRNAs in PH (Table 1). As we all know, hypoxia is an important pathogenesis in PH. Inductions of microRNAs can be observed in SMCs cultured with hypoxia and in whole lungs of mice with chronic hypoxia-induced PH. miR-210 is the predominant miRNA induced by hypoxia, which has also been demonstrated by microarray analysis on human in hypoxic PASMCs and in whole lungs of hypoxic mice[29]. The induction of miR-210 is HIF-1α-dependent and triggers anti-apoptotic effects via directly targeting the transcription factor E2F3[29]. Previously study performed on pulmonary artery endothelial cells (PAECs) found that miR-210 can provide an adaptation to hypoxic conditions by targeting Iron-Sulfur Cluster Assembly Proteins 1/2 (ISCU)[30]. MiR-21 can also be induced by hypoxia and overexpression of miR-21 enhanced the proliferation of human PASMCs in vitro and the expression of cell proliferation associated proteins, such as proliferating cell nuclear antigen, cyclin D1, and Bcl-xL, which indicates that miR-21 plays an important role in the pathogenesis of chronic hypoxia-induced pulmonary vascular remodeling[31,32]. Previous study showed that

MICRORNAS AND PH MicroRNAs (miRs) are small, non-coding RNAs regulating gene expression at the post-transcriptional level by mRNA degradation or translational repression[23]. The human genome has been estimated to contain up to 1000 miRNAs[24]. Many miRNAs exhibit a tissue-specific distribution and they appear to play a key role in cell function both under physiological and pathological conditions. Lots of in vivo and in vitro experiments related with functions of microRNAs in PH have emerged recent years. From animal experiments to clinical trials, microRNA expression profiles in PH have been revealed. A range of miRNAs are dysregulated in the lungs of rats exposed to chronic hypoxic and the monocrotaline model of PAH[25]. MiR-22, miR-30 and let-7f were down regulated, whereas miR-322 and miR-451 were up regulated significantly during the development of PH in both hypoxic and monocrotaline models. miR-21 and let-7a were

Table 1. Summary of microRNAs which may play a potential role in PH. microRNAs MiR-22 miR-30 let-7f miR-21 let-7a miR-150 miR-204 miR-322 miR-451 miR-210 miR-21 miR-759

Expression in PH reduced reduced reduced reduced reduced reduced reduced increased increased increased increased increased

Research object animal animal animal animal and human animal human animal and human animal animal animal animal human

Function in PH unknow unknow unknow unknow unknow protect protect unknow unknow impair impair protect

miR-17/92, 20a miR-145 miR-143

increased incerased increased

animal animal and human animal and human

impair impair impair

miR-17 miR-206 miR-328 miR-26a miR-424 miR-503

increased decreased decreased decreased decreased decreased

animal animal animal and human animal and human animal animal

impair protect protect unknow protect protect

382

Mechanisms References unknow 25 unknow 25 unknow 25 unknow 25 unknow 25 unknow 27 target SHP2, inhibit PASMCs proliferation 26 unknow 25 unknow 25 Antiapoptotic effect in PASMCs 29 Enhanced the proliferation of human PASMCs 31,32 Decrease the amount of total FGA mRNA via 35 affecting the stability of FGA long isoform (aE) mRNA, which can contribute to CTEPH. STAT3-miR-17/92-BMPR2 pathway 37,40 Inhibit the BMPR2 function 38,39 Prevents down-regulation of KLF4 and activation 38 of contractile genes by TGF-β or BMP4 up-regulation of p21 41 down regulating Notch-3 43 Inhibit L-type calcium channel-α1C expression 44 unknow 28 FGF2 pathways 42 FGF2 pathways 42

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BMP-dependent signaling activation of miR-21 represses Rho-kinase activation in pulmonary artery endothelial cells, thus counteracting the Rho signaling in promoting pulmonary vascular pathology[33]. Besides, miR-21-null mice presented overexpression of RhoB and hyperaction of Rho-kinase activity accompanied by exaggerated manifestation of PH[32]. Chronic thromboembolus is another leading cause of severe PH[34]. Chen et al.[35] investigated the involvement of miR-759 in chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH is characterized by persistent pulmonary embolism that increases pulmonary vascular resistance, resulting in pulmonary hypertension and subsequent right ventricular heart failure. The 3′UTR of FGA was found to interact with miR-759, and a 28-bp deletion polymorphism at this site was found to be more frequent in patients with CTEPH. Further studies have been investigated to elucidate the concrete mechanisms of microRNAs participating in PH those years. As we all know, bone morphogenetic protein receptor type II (BMPR2), a receptor for the transforming growth factor (TGF-) b family, plays an important role both in endothelial and vascular smooth muscle cells and vascular remodeling of the pulmonary arterial circulation[36]. Several Studies have been designed to identify miRNAs that could inhibit the translation of BMPR-II, and members of the miRNA cluster 17/92 and miR-143, miR-145, miR-20a were identified as the potential regulators[37-40]. All these microRNAs inhibit the BMPR2 function, which were confirmed by experiments in either the patient vascular cells or the PH animal model. miR-145 and miR-143, two highly expressed miRNAs in SMCs, have been shown to play a pivotal role in the modulation of SMC phenotype. In particular, their expression is transcriptionally activated by both TGF-β and BMP4 and promotes a contractile phenotype in SMC by targeting the Kruppel-like factor-4 (KLF4)[38]. Besides the research in pathogenesis and mechanisms, there are also investigations in therapy efficacy of microRNAs for PH in animal models. Pullamsetti et al.[41] demonstrated that inhibition of miR-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. And recently, Kim et al.[42] found that reconstitution of miR-424 and miR503 can ameliorate pulmonary hypertension in experimental models through FGF2 pathways. Although recent studies found that most PH-related microRNAs usually play a negative role in the pathogenesis process of PH, interestingly, there are still some microRNAs which can play a protective role in PH. miR-204 and miR206 are two well researched microRNAs, both of which are down regulated in PASMCs from patients with PH or in cells from mice with PH. They all paticipate in the SMCs’ proliferation and apoptosis and even differentiation. miR-204 was consistently down regulated in PASMCs from patients with

PAH and in cells from mice with PAH[26]. miR-204 show a direct influence on PASMC function and delivery of miR204 mimics to the lungs of mice with PAH significantly can reduce disease severity. miR-206 can alleviate PAH through down regulating Notch-3 expression, which is key a factor in PAH development[43]. Besides, hypoxia produced a significant inhibition of miR-328 expression, which has been identified as a strong candidate responsible for hypoxic pulmonary vasoconstriction. Overexpressing miR-328 in the transgenic mice remarkably decreased the right ventricular systolic pressure and PA wall thickness under both normoxia and hypoxia. Through inhibiting L-type calcium channel-α1C expression the insulin growth factor 1 receptor, ultimately leading to apoptosis of pulmonary arterial smooth muscle cells[44]. POSSIBLE AND NOVEL LINK BETWEEN MSCS AND MIRNAS IN PH It is well known that miRNAs have been implicated in many processes of stem cell functions, including cell proliferation, differentiation and apoptosis. Recent studies[45] suggest that mesenchymal stem cells have discrete miRNA expression profiles that can account for the intrinsic stem cell properties of self-renewal and pluripotency. Through certain modified microRNAs, up or down regulation, there must be ways to enhance the viability of engrafted MSCs in the injured pulmonary tissue. Exosomes have emerged as a novel media between kinds of cells. And exosomes based therapy has been confirmed by many researches. In consideration of its microRNAs-carried function, it is feasible to treat with PH by the microRNAs-carried exosomes secreted by MSCs. Recently, this hypothesis has been confirmed in a research that demonstrate MSCs can regulate neurite outgrowth by transfer of miR-133b to neural cells via exosomes[46]. In a word, either mimicking or antagonizing microRNA actions, MSCs functions can be regulated by microRNAs to enhance the properties of cell differentiation or anti-apoptosis. Considering that microRNAs can be delivered by exosomes secreted by MSCs, it is likely that overexpression of special microRNAs like miR-204/206/328 in MSCs will hopefully enhance MSCs therapeutic efficacy for PH. So, microRNAs may be used as novel regulators in MSC-based therapy in PH and microRNAs-regulated MSCs transplantation may represent promising therapeutic strategy for PH patients in the future. Authors’ roles & responsibilities ZZ ZF XH SZ

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Study conception and design Study conception and design Analysis and/or interpretation of the data Final approval of the manuscript

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Yuan SM - Cardiac myxoma in pregnancy: a comprehensive review REVIEW ARTICLE

Cardiac myxoma in pregnancy: a comprehensive review Mixoma cardíaco na gravidez: revisão abrangente

Shi-Min Yuan1, MMed, PhD

DOI 10.5935/1678-9741.20150012

RBCCV 44205-1656

Abstract Objective: Cardiac myxoma in pregnancy is rare and the clinical characteristics of this entity have been insufficiently elucidated. This article aims to describe the treatment options and the risk factors responsible for the maternal and feto-neonatal prognoses. Methods: A comprehensive search of the literature of cardiac myxoma in pregnancy was conducted and 44 articles with 51 patients were included in the present review. Results: Transthoracic echocardiography was the most common diagnostic tool for the diagnosis of cardiac myxoma during pregnancy. Cardiac myxoma resection was performed in 95.9% (47/49); while no surgical resection was performed in 4.1% (2/49) patients (P=0.000). More patients had an isolated cardiac myxoma resection in comparison to those with a concurrent or staged additional cardiac operation [87.2% (41/47) vs. 12.8% (6/47), P=0.000]. A voluntary termination of the pregnancy was done in 7 (13.7%) cases. In the remaining 31 (60.8%) pregnant patients, cesarean section was the most common delivery mode representing 61.3% and vaginal delivery was more common accounting for 19.4%. Cardiac surgery was performed in the first, second and third trimester in 5 (13.9%), 14 (38.9%) and 17 (47.2%) patients, respectively. No patients died. In the delivery group, 20 (76.9%) neonates were event-free survivals, 4 (15.4%) were complicated and 2 (7.7%) died. Neonatal prognoses did not differ between the delivery modes, treatment options, tim-

ing of cardiac surgery and sequence of cardiac myxoma resection in relation to delivery. Conclusion: The diagnosis of cardiac myxoma in pregnancy is important. Surgical treatment of cardiac myxoma in the pregnant patients has brought about favorable maternal and feto-neonatal outcomes in the delivery group, which might be attributable to the shorter operation duration and non-emergency nature of the surgical intervention. Proper timing of cardiac surgery and improved cardiopulmonary bypass conditions may result in even better maternal and feto-neonatal survivals.

The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, Fujian Province, People’s Republic of 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: Cesarean Section. Myxoma. Fetal Mortality. Resumo Objetivo: Mixoma cardíaco durante a gravidez é raro e as características clínicas dessa entidade não foram suficientemente esclarecidas. Este artigo tem como objetivo descrever as opções de tratamento e os fatores de risco responsáveis pelo prognóstico materno e fetal-neonatal. Métodos: Foi realizada uma pesquisa abrangente na literatura sobre mixoma cardíaco durante a gravidez e 44 artigos com 51 pacientes foram incluídos na presente revisão. Resultados: Ecocardiografia transtorácica foi a ferramenta de diagnóstico mais comum para o diagnóstico de mixoma

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 September 7th, 2014 Article accepted on February 16th, 2015

No financial support.

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pacientes, respectivamente. Nenhuma paciente morreu. No grupo de parto, 20 (76,9%) recém-nascidos sobreviveram livres de eventos, 4 (15,4%) tiveram complicações e 2 (7,7%) morreram. Os prognósticos neonatais não diferiram entre os modos de parto, opções de tratamento, tempo de cirurgia cardíaca e sequência de ressecção mixoma cardíaco em relação ao parto. Conclusão: O diagnóstico de mixoma cardíaco durante a gravidez é importante. Tratamento cirúrgico de mixoma cardíaco em pacientes grávidas trouxe resultados favoráveis para as mães e os neonatos ​​no grupo de parto, o que pode ser atribuído à duração mais curta da operação e à natureza não emergencial da intervenção cirúrgica. O momento adequado da cirurgia cardíaca e melhoria das condições de circulação extracorpórea podem resultar em sobrevivência materna e do feto-neonato ainda melhor.

Abbreviations, acronyms & symbols CMCI QUOROM

Chinese Medical Citation Index Quality of Reporting of Meta-Analyses

cardíaco durante a gravidez. Ressecção do mixoma cardíaco foi realizada em 95,9% (47/49); enquanto não foi realizada ressecção cirúrgica em 4,1% (2/49) dos pacientes (P=0,000). Mais pacientes tiveram ressecção isolada do mixoma cardíaco em comparação com aqueles com operação cardíaca concomitante ou adicional [87,2% (41/47) vs. 12,8% (6/47), P=0,000]. A interrupção voluntária da gravidez foi feita em 7 (13,7%) casos. Nas restantes 31 (60,8%) pacientes grávidas, a cesariana foi o modo de parto mais comum, representando 61,3% e parto vaginal contabilizou 19,4%. A cirurgia cardíaca foi realizada no primeiro, segundo e terceiro trimestre em 5 (13,9%), 14 (38,9%) e 17 (47,2%)

Descritores: Cesárea. Mixoma. Mortalidade Fetal.

INTRODUCTION

Primary exclusion criteria included articles describing cardiac myxoma diagnosed postpartum, other types of cardiac tumors, undetermined nature of intracardiac mass, or myxoma of the other organs of the pregnant patients, fetal cardiac myxoma, or cardiac myxoma of animals. Papers with no complete data of the pregnant patients were excluded for the statistical analyses. Table 1 shows the results of literature retrieval. Data were carefully extracted for details of the patient population, demographics, diagnosis, clinical features of cardiac myxomas, associated disorders/comorbidities, cardiac surgical procedures, delivery modes, timing of cardiac myxoma and delivery, follow-up length and survival, complication and mortality of both mother and baby, etc. This rare condition was only reported in sporadic single case or small series without larger patient population, comparative, or randomized studies. Accordingly, the qualitative analysis of the collective data from the retrieved articles constituted a systematic review, as suggested in the Quality of Reporting of Meta-Analyses (QUOROM) recommendations[4]. Quantitative data were presented as mean ± standard deviation along with range and median values, and intergroup differences were compared by unpaired t-test. Comparisons of frequencies were made by Fisher’s exact test and P<0.05 was considered statistically significant.

Cardiovascular disorders during pregnancy have become a more and more attracting issue concerning both mother and child in terms of their prognoses[1]. Cardiac surgery during pregnancy remains a tough problem due to the fact that cardiopulmonary bypass jeopardizes fetuses more than mothers[2]. The overall feto-neonatal mortality was 18.6% among the pregnant patients with a cardiac operation[1]. The fetal deaths were apparently associated with cardiac surgery during early pregnancy as well as the use of cardiopulmonary bypass[3]. Cardiac myxoma in pregnancy is one of the cardiovascular disorders that warrant a surgical resection without delay[1]. However, the clinical features of cardiac myxomas in the pregnant patients have not been sufficiently elaborated, and the risk factors influencing the maternal and feto-neonatal outcomes remain uncertain. In order to highlight these aspects, a comprehensive literature review of pregnant cardiac myxoma is conducted. METHODS Publications in all languages reporting on cardiac myxoma during pregnancy until November 2014 were retrieved from MEDLINE, Highwire Press, Google and Yahoo! search engines, Chinese Medical Citation Index (CMCI) and LILACs. The search terms “cardiac myxoma” and “pregnancy” were searched. In addition, “left atrial”, “right atrial”, “left ventricular”, “right ventricular”, “mitral valve”, “tricuspid valve” and “aortic valve” were also used in the search strategy to find articles containing cardiac myxomas.

RESULTS Patient information A total of 47 articles were collected. By excluding 3 duplicate publications[5-7], 44 articles[2,8-50] involving 51 pregnant patients

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Table 1. Literature retrieval. Database

Total

Irrelevant

Relevant

PubMed Google Yahoo! Highwire Press Chinese Medical Citation Index (CMCI) LILACs

58 90 120 662 27 2

34 34 94 659 23 2

24 56 26 3 4 0

were taken for statistical analysis. Their ages were 29.5±5.1 (20-40; median, 29) (n=39). Their pregnant history was not mentioned in 21 (41.2%) patients, while reported in 30 (58.8%) patients with 8 (26.7%) nulliparous, 8 (26.7%) monoparous and 14 (46.7%) multiparous. The timing of the pregnant patients to be symptomatic was available for 15 (29.4%) patients, with a mean duration of diseased course of cardiac myxoma of 4.0±7.2 months (28 hours-24 months; median, 1 month) (n=10) (no quantitative timing was available in 3 patients[11,19,39].

Inclusive (by excluding duplicate indexes) 26 11 3 3 4 0

Clinical features The symptoms of the cardiac myxoma of the pregnant patients were described in 39 (76.5%) patients. Eight (20.5%) patients were asymptomatic[12,16,21,35,41,42,45,48]; while 31 (79.5%) manifested one or two of the Goodwin’s triad, namely circulatory, embolic and constitutional symptoms (Table 2). A cardiac murmur or an abnormal heart sound was audible in 18 (35.3%) patients with a systolic murmur [6 (33.3%)][12,15,26,34,35,43] and a diastolic murmur [4 (30.8%)] [8,14,33,45] being the most common one. Twenty-seven (52.9%) patients had one or more comorbidities or complications of a cardiac myxoma (Table 3).

11 (29.7%)[8-10,26,29,30,40,42,47,48], anterior mitral leaflet in 2 (5.4%) [2,32] , free wall[36] in 1 (2.7%) and unknown in 23 (62.2%) patients[2,13,14,16-18,23,24,26-28,31,33,34,37-39,44-46,50], right atrium in 5 (10.9%)[2,11,15,20,36] (one was multiple[20]), left ventricle in 2 (4.3%)[12,21], right ventricle in 1 (2.2%)[43] and multiple sites (septal tricuspid leaflet, left atrium, intraatrial septum and left atrial appendage) in 1 (2.2%) patient[41]. Three patients had recurrent cardiac myxomas[12,35,41] and one of them were recurrent multiple cardiac myxomas[41]. A total of 12 atrial myxomas including 11 (29.7%, 11/37) left atrial myxomas and 1 (20%, 1/5) right atrial myxoma[20] prolapsed into the ventricle during diastole. The attachment of the myxoma was described in 16 (31.4%) patients, it was pedunculated in 15 (93.8%)[8,9,1215,20,26,29,30,35,36,40,42,48] and sessile in 1 (6.3%) patient[2]. The dimensions of the cardiac myxomas were available in 25 (49.0%) patients. One of them was described as “eggsized”[46] and average dimension of the remaining 24 myxomas was 55.1±24.5 (range, 22-130; median, 55) mm (n=24) [2,8,9,11,12-15,20,21,23,26,27,29,30,32,35,39,42,43,47] . The diagnosis of the cardiac myxoma was delayed in 3 (5.9%) patients in the 1st , 3rd and 3rd week after admission[14,33,49].

Diagnosis The timing of diagnosis of cardiac myxoma was described in 39 (76.5%) individuals. Two (5.1%) patients were diagnosed with a cardiac myxoma in the 1st and 23rd months before the current pregnancy, and their gestational ages were recorded as “-4” and “-92” weeks[2,13]. Among the 37 (94.9%) patients, the cardiac myxoma was diagnosed in the first, second and third trimesters in 7 (18.9%), 19 (51.4%) and 11 (29.7%) patients, respectively (χ2=9.1, P=0.011) with a mean of 21.7±8.4 (range, 6.7-38; median, 22) weeks (n=35). The diagnostic techniques for the cardiac myxoma were described in 34 (66.7%) patients, by transthoracic echocardiography in 26 (70%)[2,8-13,17,20,21,24,27-29,33-35,38,40,42,43,45,47,48,50], transthoracic and transesophageal echocardiography in 4 (13.3%)[15,27,30,32], transesophageal echocardiography in 2 (6.7%)[36,41], cardiac catheterization[14] and a battery of tests[46] in 1 (3.3%) patient. Location of cardiac myxoma was not clearly stated in 5 (9.8%) patients. In the remaining 46 (90.2%) patients, it was located in the left atrium in 37 (80.4%) [intraatrial septum in

Treatment Treatment was not given in 2 (3.9%) patients[22]. Concerning the remaining 49 patients, surgical operation was not performed in 2 (4.1%) patients but with anticoagulant and antibiotic therapy in one[36] and decline of treatment by another[41]. A surgical resection of cardiac myxoma was performed in 47 (95.9%) patients including a sole cardiac myxoma resection in 41 (87.2%)[2,8-21,23-27,29,31-39,43-46,48-50], concurrent mitral valve repair[40,47] and staged mitral valve replacement[28,29] in 2 (4.3%), and staged mitral valve repair[30] and concurrent patent fossa ovalis closure[42] in 1 (2.1%) patient. Cardiac surgery was performed in the first, second and third trimester in 5 (13.9%), 14 (38.9%) and 17 (47.2%) patients (χ2=9.8, P=0.008) at a mean of 25.2±9.4 (range, 9-41; median 27) weeks of gestational age (n=36); while timing of cardiac surgery was not given in 15 (29.4%) patients. A cardiac myxoma resection was delayed in 4 (7.8%) patients for a few[43], 7[21], 15[40] and 690 days[13], respectively. The feto-neonatal fate was not mentioned in 13 (25.5%) cases[15,22,24,27,31,37,38,41,44,47]. Voluntary termination of pregnancy was done in 7 (13.7%) cases with 6 (85.7%) early-

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mid-termed[2,9,12,23,42] and 1 (14.3%) late pregnancy termination[50] with mean gestational age of 17.0±8.3 (range, 11-31; median, 14) weeks (n=5). Delivery modes of remaining 31 (60.8%) pregnant patients were cesarean section in 19 (61.3%) [2,10,11,13,16,20,21,28-30,32,35,36,39,40,43,45,46] , vaginal delivery in 6 (19.4%)

, forceps under epidural analgesia in 1 (3.2%)[33] and unknown in 5 (16.1%) patients[14,17-19,34]. One (3.2%) delivery timing was not given, 2 (6.5%) deliveries were in second trimester and 28 (90.3%) in third trimester with mean gestational age of 35.3±4.6 (range, 22-42; median, 37) weeks (n=30). [8,25,26,48,49]

Table 2. Presenting symptoms of 31 pregnant patients. Symptom Circulatory Dyspnea, palpitation Chest pain, dyspnea/tachypenia Pulmonary edema Dyspnea Palpitation Hemoptysis, dyspnea and cough Dyspnea, pulmonary edema Circulatory + constitutional Palpitations, dyspnea, fatigue Cough, exhaustion Palpitation, fatigue, weight loss Palpitation, dyspnea, night sweat Chest pain, palpitation, cough, fever, chills Embolic Headache, memory loss Transient ischemic attack, weakness Blurred vision Hemiparesis, optalmoplegia Circulatory + embolic Dyspnea, orthopnea, dizziness Chest pain, psychomotor restlessness Chest pain, dyspnea, palpitation, syncope, dizziness Embolic + constitutional Dizziness, fever Circulatory + embolic + constitutional Dyspnea, dizziness, fatigue

n (%) 15 (48.4) 5 (33.3) 4 (26.6) 2 (13.3) 1 (6.7) 1 (6.7) 1 (6.7) 1 (6.7) 7 (22.6) 2 (28.6) 2 (28.6) 1 (14.3) 1 (14.3) 1 (14.3) 4 (12.9) 1 (25) 1 (25) 1 (25) 1 (25) 3 (9.7) 1 (33.3) 1 (33.3) 1 (33.3) 1 (3.2) 1 (100) 1 (3.2) 1 (100)

Table 3. Associated disorders. Associated disorder Stroke/embolic events Recurrent cardiac myxoma Pulmonary edema Mitral stenosis Mitral valve prolapse Ventricular tachycardia/premature Pulmonary hypertension Non-ST-segment elevation myocardial infarction Mitral stenosis, pulmonary hypertension Hodgkin’s disease Diabetic nephropathy, preeclampsia Right adrenalectomy for Cushing’s syndrome Hyperemesis, vascular access Hemodynamic deterioration Congestive heart failure, pulmonary hypertension Brain sarcoma

n (%) 4 (14.8) 3 (11.1) 3 (11.1) 2 (7.4) 2 (7.4) 2 (7.4) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7) 1 (3.7)

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References [20,26,28,47,50] [10,13,32,34] [9,18] [26] [29] [27] [40] [30,39] [19,46] [14] [33] [24] [49] [38] [2] [29] [36] [11] [15] [8] [43]

References [2,15,38,49] [12,35,41] [9,18,40] [26,28] [13,26] [21,42] [10,47] [24] [23] [34] [11] [32] [20] [43] [14] [29]


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All the pregnant patients in the pregnancy termination group received a surgical resection of the cardiac myxoma with an isolated cardiac myxoma resection in 5 (71.4%), myxoma resection with patch repair of the iatrogenic septal defect in 1 (14.3%) and myxoma resection with patent fossa ovalis closure in 1 (14.3%) patient. One (14.3%) patient had pregnancy termination performed before cardiac surgery in 3 (42.9%), after the cardiac surgery in 2 (28.6%) and unknown surgical sequence in 2 (28.6%) patients. The indications for pregnancy termination was maternal pulmonary edema in 1 (14.3%)[9], fetal growth retardation (fetal short femur) in 1 (14.3%)[50] and unknown in 5 (71.4%) patients. In the pregnancy termination group, 6 (85.7%) pregnant patients were event-free and 1 (14.3%) was complicated with postoperative transient acute myocardial infarction[9]. The prognosis of the pregnant patient was not given in 2 patients[22]. In the remaining 42 pregnant patients with a childbirth, 35 (83.3%) were event-free, 6 (14.3%) were complicated, with cerebral involvement (psychomotor agitation and mydriasis anisocoria)[40], heart block[30], pacing dependent rhythm[28], pulmonary edema[32], uterine contractions[26], and premature labor[34]), and 1 (2.4%) was recurrent (requiring reoperation)[29]. No pregnant patients died. Pregnant patients’ event free survival (P=0.680), complication (P=0.686) and recurrence rates (P=0.857) did not differ between pregnancy termination and delivery groups.

Eighteen (42.9%) patients had a delivery before cardiac surgery[8,14,17,19,24,26-30,33,34,38,40,46,47,49], in the first, second, third and unknown trimester in 2 (11.1%), 8 (44.4%), 6 (33.3%) and 2 (11.1%) patients with a mean gestational age of 21.6±6.2 (range, 10-28.1; median, 23) weeks (n=16). Thirteen (31.0%) patients has cardiac myxoma resection performed after delivery in second, third and unknown trimester in 1 (7.7%), 9 (69.2%), and 3 (23.1%) patients at a mean gestational age of 34.2±5.5 (range, 22.2-41; median, 32.7) weeks (n=10)[11,13,16,18,20,21,29,32,35,36,39,41,43]. Two (4.8%) patients received a one-stage delivery and cardiac surgical procedure in the 31st and 32.7th week, respectively. Surgical sequence was unknown in 9 (21.4%) patients. Prognosis In the delivery group, delivery mode was not given in 16 cases. Among the 26 deliveries with either cesarean section or vaginal delivery, 20 (76.9%) were event-free survivals, 4 (15.4%) were complicated and 2 (7.7%) died. Neonatal prognoses did not differ between delivery modes, treatment options, timing of cardiac surgery and sequence of cardiac myxoma in relation to delivery (Tables 4-7). Nomimal regression analysis showed that timing of delivery, delivery mode, surgical resection of the cardiac myxoma, simple or complex cardiac surgery, timing of cardiac surgery, sequence of cardiac surgery in relation to delivery and maternal complications were not predictive risk factors responsible for fetal outcomes.

Table 4. Neonatal prognosis subjected to different delivery modes (Fisher exact test). Total Event-free Complicated Delivery mode 19 (100) 15 (78.9) [2,10,16,20,21,28-30, 2 (10.5) [13,29] Cesarean section, n (%) 35,36,39,40,45,46] 6 (100) 4 (66.7) [5,25] 2 (33.3) [5] Vaginal delivery, n (%) 1 (100) 1 (100) [33] 0 (0) Device delivery, n (%) 29.9 0.7 2.0 χ2 0.000 0.705 0.366 P value Table 5. Neonatal prognosis of different treatment options (Fisher exact test). Treatment Total Event-free Surgical 39 (100) 31 (79.5) Isolated myxoma resection 34 (100) 27 (79.4) [2,8,10,14,16-21,2427,29,31,34,35,37-39,44-46,49] Myxoma resection with 5 (100) 4 (80) [28,30,40,47] concurrent or staged additional cardiac surgery Conservative 2 (100) 2 (100) [36,41] P value (surgical vs. conservative) 0.000 0.475 P value (myxoma resection vs. 0.000 0.976 myxoma resection with concurrent or staged additional cardiac surgery)

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Died 2 (10.5) [11,32] 0 (0) 0 (0) 0.8 0.671

Complicated Died 5 (12.8) 3 (7.7) 4 (11.8) 3 (8.8) [11,12,32] [13,26,33,48] 1 (20) [29]

0 (0)

0 (0) 0.589 0.607

0 (0) 0.684 0.489


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Table 6. Neonatal prognosis according to timing of cardiac surgery (Fisher exact test). Timing of cardiac surgery Total Event-free Complicated 1st trimester 2 (100) 2 (100) [24,38] 0 (0)

Died 0 (0)

8 (66.7) [8,14,17,19,30,39,40,46]

4 (33.3) [26,29,33,48]

0 (0)

16 (100)

13 (81.3) [2,10,16,20,21,26,27, 29,34,35,43,45,49]

1 (6.3) [13]

2 (12.5) [11,32]

χ2

15.6

1.5

4.1

1.9

P value

0.000

0.480

0.132

0.392

2nd trimester

12 (100)

3rd trimester

Table 7. Neonatal prognosis according to sequences of cardiac myxoma resection and delivery (Fisher exact test). Sequence of cardiac myxoma Total Event-free Complicated Died resection 15 (83.3) [8,14,17,19,24, Before delivery 18 (100) 26-28,30,34,38, 3 (16.7) [26,29,33] 0 (0) 40,46,47,49] After delivery

12 (100)

8 (66.7) [16,18,20,21,29, 35,36,39,41]

1 (8.3) [13]

3 (25) [11,12,32]

One-stage

2 (100)

2 (100) [10,45]

0 (0)

0 (0)

χ2

19.5

1.8

0.8

5.5

P value

0.000

0.413

0.683

0.063

DISCUSSION

Nevertheless, surgical indications of both conditions can be somehow different from each other. Congestive heart failure as a consequence of rheumatic mitral stenosis is always a contraindication of pregnancy. But it may be curable to percutaneous inteventional therapy, however, carrying the risk of fetal teratogenicity by manipulation under X-ray. Or else, an urgent valvular operation is warranted in the presence of infective endocarditis, intramural thrombus, paravalvular leakage, stuck prosthetic valve or thrombus formation. Meanwhile, the indications for cardiac myxoma resection are the potential embolic events and sudden death caused by myxoma-obstructed valve orifice[2]. Wang et al.[2] reported three pregnant patients with a cardiac myxoma, two of which were complicated with cerebral infarctions and an urgent cardiac myxoma resection with later curettage was performed. Liu et al.[6] described a pregnant patient with a cardiac myxoma presented with both cerebral infarction and central retinal artery occlusion, and a cardiac surgical resection was performed without delay. As for the potential of cardiogenic embolic events and possible preterm delivery due to hemodynamic changes, a timely surgical resection of cardiac myxoma can be indispensable during pregnancy. The favorable maternal and fetal outcomes suggest that there might be a subset of pregnant patients with intracardiac

Cardiac myxoma is rare in pregnant patients. The diagnosis and management can be challenging in terms of the nature of the intracardiac mass, timing of delivery, necessity of cardiac surgery and risks of subsequent treatment[36]. The clinical manifestations of a cardiac myxoma can be one or more of the Goodwin’s triad[51]. Patients may present with fatigue and dyspnea, which, however, can be misinterpreted as asthma or normal fatigue associated with pregnancy[39]. Echocardiography remains the standard non-invasive diagnostic modality, particularly in the pregnant patient[52]. In some patients, atrial thrombi may have a stalk and may be mistaken for myxomas, leading to unnecessary and potential harmful surgery[53]. A left intraatrial mass can be diagnosed as thrombus if associated with atrial fibrillation, dilated left atrium, mitral or tricuspid stenosis, low ejection fraction, prosthetic mitral or tricuspid valves, or spontaneous atrial contrast echoes[54]. Moreover, in the pregnant patients, cardiovascular magnetic resonance imaging is indicated for visualizing coarctation, aortitis, aortic dissection and atrial myxoma[52]. Surgical management of cardiac myxoma is similar to that of the valvular disorders in the pregnant patients, even with minimally invasive cardiac surgical techniques[55].

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masses who may benefit from non-surgical management[36]. Open heart surgery as well as the use of cardiopulmonary bypass may cause premature labor and endanger the baby[49]. The surgical resection of cardiac myxoma may be associated with a 30% baby loss rate, or postnatal physical or developmental disabilities[39]. It is encouraging that maternal survival rate was 100% in the pregnant patients with a cardiac myxoma, superior to that of the pregnant patients with infective endocarditis[3]. This might be interpreted as the results of the advantaged cardiopulmonary bypass techniques including high flow rate, high perfusion pressure and pulsatile flow applied in cardiac surgery during pregnancy[30]. By comparison, infective endocarditis and acute aortic dissection might be more dangerous to the pregnant patients than cardiac myxoma as for the infective nature of the former and the use of profound hypothermic circulatory arrest for the operation of the latter[3,56]. The present study also revealed that timing of delivery other than the delivery mode (by excluding early termination of pregnancy) and time sequence of cardiac surgery and delivery was closely related to feto-neonatal mortality. Cardiac surgery under cardiopulmonary bypass should be avoided in the first trimester, particularly after six weeks, due to the risk of teratogenesis[50]. The pregnant patients may wait for a few weeks[13], or take weekly thyrotropin-releasing hormone and Ă&#x;-methasone therapies for fetal lung maturation[35]. Precautions during cardiac operation include using blood priming solution, normothermic cardiopulmonary bypass and high perfusion pressure[38]. Possible bias may be generated in present patient setting due to limited data available from the literature for the statistical analysis. Therefore, more abundant information of such patients is necessary for further precise results.

REFERENCES 1. Yuan SM. Indications for cardiopulmonary bypass during pregnancy and impact on fetal outcomes. Geburtshilfe Frauenheilkd. 2014;74(1):55-62. 2. Wang H, Zhang J, Li B, Li Y, Zhang H, Wang Y, et al. Maternal and fetal outcomes in pregnant patients undergoing cardiac surgery with cardiopulmonary bypass. Zhonghua Fu Chan Ke Za Zhi. 2014;49(2):104-8. 3. Yuan SM. Infective endocarditis during pregnancy. J Coll Physicians Surg Pak. 2015;25(2):134-9. 4. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354(9193):1896-900. 5. John AS, Gurley F, Schaff HV, Warnes CA, Phillips SD, Arendt KW, et al. Cardiopulmonary bypass during pregnancy. Ann Thorac Surg. 2011;91(4):1191-6. 6. Liu GF, Wu Y, Sun L, Meng X, Wang J. Left atrial myxoma and obstruction of central retinal artery: a case report. Chin J Ocul Fundus Dis. 2013;29(6):625-6. 7. Stevens N. Word of mom pregnancy: doctors save pregnant woman and unborn baby after performing open-heart surgery [Accessed Aug 8, 2014]. Available at: http://www.whattoexpect. com/wom/pregnancy/0429/doctors-save-pregnant-woman-andunborn-baby-after-performing-open-heart-surgery.aspx 8. Agarwal AK, Venugopalan P. Dizziness during pregnancy due to cardiac myxoma. Saudi Med J. 2004;25(6):795-7. 9. Agosti S, Casalino L, Bertero G, Morelloni S, Barsotti A, Brunelli C. Atrial myxoma presenting during pregnancy. G Ital Cardiol (Rome). 2010;11(6):498-500.

CONCLUSIONS Cardiac myxoma is rare in pregnant patients. In most cases, the cardiac myxoma is diagnosed in the second trimester and is resected in the third. Cesarean section was the most frequent delivery mode. The 100% maternal survival of this patient setting is encouraging. A delivery at early gestation was closely related to an increased feto-neonatal mortality. A delivery postponed to late pregnancy until fetal maturity may improve the feto-neonatal survival. In brief, embolic potential and hemodynamic deterioration are indications for an urgent cardiac myxoma resection. Otherwise, cardiac surgery should be avoided in the first trimester and be postponed until fetal pulmonary maturation or after delivery.

10. Arumugam CG, Raju SV, Varma S, Bhaskaran K. Anaesthetic management of a pregnant patient with left atrial myxoma and myxoma excision of lower segment caesarean. Apollo Med. 2008;5(1):71-3. 11. Berberovic B, Kacila M, Hadzimehmedagic A, Berberovic E. Cardiac myxoma in diabetic pregnancy. Int J Gynaecol Obstet. 2014;125(3):281-2. 12. Bortolotti U, Scioti G, Guglielmi C, Milano A, Nardi C, Tartarini G. Recurrent myxoma of the left ventricle. Case report and review of the literature. J Cardiovasc Surg (Torino). 1999;40(2):233-5. 13. Bryukhina EV, Ishchenko LS, Lomova ES, Ulanova DS. Left atrial myxoma in a pregnant woman: clinical features, tactics. Sci Pract J Obstet Gynecol. 2014;5(9):114-6.

Authors’ roles & responsibilities SMY

Study conception and design; analysis and/or interpretation of data; manuscript writing.

14. Casarotto D, Bortolotti U, Russo R, Betti D, Schivazappa L,

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Thiene G. Surgical removal of a left atrial myxoma during pregnancy. Chest. 1979;75(3):390-2.

Arch Dis Child Fetal Neonatal Ed 2012;97:A52. doi: 10.1136/ fetalneonatal-2012-301809.166

15. Christensen M, Tingleff J, Larsen CT, Kjøller SM. Symptoms debut from a right atrial myxoma during labor. Ugeskr Laeger. 2004;166(47):4267-8.

29. Korbel’ M, Kanáliková K, Fischer V, Niznanská Z, Redecha M, Paulíková Z. Management of intracavitary left atrium tumors during pregnancy: two case reports. Zentralbl Gynakol. 2001;123(10):590-2.

16. Collins N. Woman and baby saved after emergency surgery[Accessed Aug 8, 2014]. Available at: http://www. telegraph.co.uk/health/healthnews/8975647/Woman-and-babysaved-after-emergency-surgery.html

30. Koukis I, Velissaris T, Pandian A. Left atrial myxoma associated with mitral valve pathology in pregnancy. Hellenic J Cardiol. 2013;54(2):138-42.

17. Donahoo JS, Weiss JL, Gardner TJ, Fortuin NJ, Brawley RK. Current management of atrial myxoma with emphasis on a new diagnostic technique. Ann Surg. 1979;189(6):763-8.

31. Mahoori A, Farasatkish R, Aghdaie N, Faritus Z, Mollasadeghi G, Kashfi F. Outcome of anesthesia and open heart surgery in pregnant patients. J Teh Univ Heart Ctr. 2007;2(1):21-4.

18. Elston JH. A case report of a myxoma or rhabdomyosarcoma of the left atrium in the third trimester of pregnancy. Nebr Med J. 1984;69(7):225-6.

32. Manfredini R, Calì G, Foresti A. Acute anterior myocardial infarction in a patient with left atrial myxoma during pregnancy. G Ital Cardiol. 1995;25(11):1419-24.

19. Erikson J. Pregnant woman undergoes rare & risky open-heart surgery to save her baby [Accessed Aug 21, 2014]. Available at: http://thestir.cafemom.com/pregnancy/171380/pregnant_ woman_undergoes_rare_risky

33. Mann MS, Cossham PS, Baker JL, Hurley PA. Left atrial myxoma in the second trimester of pregnancy. Case report. Br J Obstet Gynaecol. 1987;94(6):592-3. 34. Mercer LJ, Aisenbrey G. Atrial myxoma as a complication of tocolytic therapy. A case report. J Reprod Med. 1985;30(7):561-2.

20. Fang YM, Dean R, Figueroa R. Right atrial myxoma mimicking an atrial thrombus in the third trimester of pregnancy. J Matern Fetal Neonatal Med. 2007;20(1):77-8.

35. Nakata S, Nakano S, Mitsuda N, Itou N, Takahashi Y, Matsuda H. Recurrent left atrial myxoma in a patient with a twin fetus pregnancy. Jpn Circ J. 1996;60(2):130-2.

21. Fiorilli R, Tomasco B, Serino W, Tesler UF. Asymptomatic left ventricular myxoma in pregnancy: echocardiographic diagnosis and surgical treatment. G Ital Cardiol. 1996;26(8):887-90.

36. Nelson SC, Coleman L, Zakowski MI. Management and cesarean delivery in a parturient with a right atrial mass. Abstract Number: F-30 [Accessed Aug 21, 2014]. Available at: http://soap.org/ display_2012_abstract.php?id=F-30

22. Gurley FM, Connolly HM, Dearani JA, Warnes CA, Rose CH, Phillips SD, et al. Surgery for valve disease and its sequelae II. Abstract 1806: Cardiac Surgery During Pregnancy: The Mayo Clinic Experience 1976–2005. Circulation. 2006;114:II-356.

37. No authors listed. Interesting cases [Accessed Aug 21, 2014]. Available at: http://www.heartsurgery.in/interesting_cases.htm

23. Han F, Zhao Y, Lu C. Surgery intervention of pregnancy heart disease. J Pract Obstetr Gynecol. 2010;26(3):225-8.

38. Obied HY. SHA 21. Surgical removal of left atrial myxoma in a pregnant lady with recent stroke during 1st trimester. J Saudi Heart Assoc. 2010;22(2):90 [Accessed Aug 21, 2014]. Available at: http://www.journalofthesaudiheart.com/article/S10167315(10)00333-7/fulltext

24. Hasan I, Reddy S, Burns T. Myxoma in the mix [abstract]. J Hosp Med. 2014;9(Suppl 2):443 [Accessed Aug 21, 2014]. Available at: http://www.shmabstracts.com/abstract. asp?MeetingID=800&id=110744 25. Hosseini S, Yaghoubi A, Khamoushi AJ, Raissi K, Kashfi F, Sadeghpour A, et al. Open heart surgery in pregnant women. Iran Heart J. 2004;5(4):34-9.

39. Ogilvie M. ‘I wanted him to have a chance to survive before me’ [Accessed Aug 21, 2014]. Available at: http://www.thestar. com/life/health_wellness/2011/10/22/i_wanted_him_to_have_a_ chance_to_survive_before_me.html

26. John AS, Connolly HM, Schaff HV, Klarich K. Management of cardiac myxoma during pregnancy: a case series and review of the literature. Int J Cardiol. 2012;155(2):177-80.

40. Prieto Macías J, Orea Tejeda A, Santiago Bravo M, Vargas Bustos MA, Castillo Razo R. Left atrial myxoma causing severe mitral valve occlusion. Arch Inst Cardiol Mex. 1989;59(6):611-4.

27. Kanth P, Vu T, Daroowalla F. Hemoptysis in pregnancy as the first sign of left atrial myxoma. Chest. 2014;146(4_ MeetingAbstracts):200A. doi:10.1378/chest.1991271

41. Roldán FJ, Vargas-Barrón J, Espinola-Zavaleta N, Keirns C, Romero-Cárdenas A. Recurrent myxoma implanted in the left atrial appendage. Echocardiography. 2000;17(2):169-71.

28. Kither HJ, Stephen G, Vause S. Atrial myxoma in early pregnancy.

42. Sejhar J, Vambera M. Diagnosis of myxoma of the left heart

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atrium in pregnancy using 2-dimensional sector visualization. Vnitr Lek. 1982;28(12):1186-90.

Available at: http://obgyn.wisc.edu/news/open-heart-surgerypregnancy.aspx

43. Sindjelic R, Vlajkovic G, Djukic P. Management of right ventricular myxoma diagnosed at full-term pregnancy. Med Sci Monit. 2009;15(10):CS158-61.

50. Witters I, Cannie M, Moerman P, Herijgers P, Rademakers F, Coudyzer W, et al. Fetal caudal dysgenesis after maternal cardiopulmonary bypass in Pregnancy. Ultrasound. 2007;15(2):71-2.

44. Siu SC, Sermer M, Harrison DA, Grigoriadis E, Liu G, Sorensen S, et al. Risk and predictors for pregnancy-related complications in women with heart disease. Circulation. 1997;96(9):2789-94.

51. Maruf MF, Akter T, Islam F, Chowdhury AA, Khan JH, Hassan K, et al. Left atrial myxoma in a child: an uncommon presentation of a rare tumour in early age. Cardiovasc J. 2012;4(2):171-3.

45. Smith A. Asymptomatic atrial myxoma during pregnancy. RCOG World Congress 2013 Liverpool UK, 24-26 June 2013 [Accessed Aug 21, 2014]. Available at: http://www.epostersonline.com/ rcog2013/?q=node/409

52. Colletti PM. Guidelines for MRI in the pregnant patient [Accessed Aug 21, 2014]. Available at: cppcongress.com/.../03/Guidelinesfor-MRI-in-the-Pregnant-Patient.pdf

46. Stony Brook University. Open-heart surgery performed on patient 27 weeks’ pregnant [Accessed Aug 21, 2014]. Available at: http:// www.sciencedaily.com/releases/2014/04/140421164150.htm

53. Kim SE, Park DG. Tentatively diagnosed as myxoma: transit thrombus entrapped in patent foramen ovale. J Cardiovasc Ultrasound. 2007;15:19-22.

47. Trimakas AP, Maxwell KD, Berkay S, Gardner TJ, Achuff SC. Fetal Monitoring during cardiopulmonary bypass for removal of a left atrial myxoma during pregnancy. Johns Hopkins Med J. 1979;144(5):156-60.

54. Diaconu CC. Left atrial thrombus: a case report [Accessed Aug 21, 2014]. Available at: http://www.medandlife.ro/ medandlife625.html

48. Tretina M, Hrdlicka M, Ondrásek J, Nĕmec P, Orban M. Cardiac tumor in a pregnant patient. Vnitr Lek. 2010;56(1):79-81.

55. Costa F, Winter G, Ferreira AD, Fernandes TA, Collatusso C, Tremel FT, et al. Initial experience with minimally invasive cardiac operations. Rev Bras Cir Cardiovasc. 2012;27(3):383-91.

49. Wahlberg D. Peaceful Christmas welcome after open heart surgery during pregnancy. Wisconsin State J [Accessed Aug 21, 2014].

56. Yuan SM. Aortic dissection during pregnancy: a difficult clinical scenario. Clin Cardiol. 2013;36(10):576-84.

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Piccardi VLAM - Dr. Edgard San Juan: a feminine look MEMORIAL

Dr. Edgard San Juan: a feminine look Prof. Dr. Edgard San Juan: um olhar feminino

Vera Lucia Amaral Molari Piccardi1 DOI: 10.5935/1678-9741.20150049

RBCCV 44205-1657

The first time I met Professor San Juan and his cardiothoracic surgeons was in 1976, when I started my medical residency in cardiovascular surgery at São Joaquim Hospital of the Real and Benemérita Associação Portuguesa de Beneficência de São Paulo. At that time, I didn’t have the pleasure of knowing him personally; my relationship was limited to his residents and assistants when we sometimes met one another in hospital wards or during shifts in the Intensive Care Unit, where we took care of patients after surgery. Surgical procedures were performed for many years in the old operating theatres on the ninth floor of São Joaquim Hospital, numbers 29 and 31, separated by the washbasin. They were lit by large glazed windows with a beautiful view of the city of São Paulo, a real postcard appreciated during surgery breaks. At this time, only three teams of cardiac surgery worked at Beneficência Portuguesa Hospital, distinguishing themselves by the pioneering of high complexity surgeries and boosting their development, with the use of cardiopulmonary bypass and artificial oxygenators: Professor Euryclides de Jesus Zerbini, Professor Adib Domingos Jatene and Professor Edgard Schroeder San Juan (Figure 1), whose this biography is. Professor San Juan was born in São Paulo, Campos Elísios, neighborhood, on February 23, 1919, descended from European immigrants. His father, Mr. Francisco Severo San Juan, was a civil engineer of Spanish descent from the city of Valencia; a very educated man, worked for Santos City Hall, São Paulo, having participated in the construction of São Vicente Suspension Bridge in the mid-twentieth century. He married Herminia Schroeder, a woman of German descent, who worked as an assistant at a dentist office. The couple had three children: Edgard, Odilon and Ondina.

Fig. 1 - Professor Edgard Schoeder San Juan. The family lived for many years in Santa Cecilia, a neighborhood in São Paulo, on Tatuí Baron Street. The eldest son, Edgard, was dedicated to studies spending hours in the basement of the house reading and doing simple experiments. He was a very dedicated boy who liked to study a lot and soon showed his inclination to practice medicine and care for the sick. Young Edgard attended Saint Adalbert Schule (Escola Santo Adalberto). In 1932, he enrolled in the Ginásio Normal graduating in 1936 and then joined the preparatory course for Medicine (pre-medical program), at Ginásio de São Bento until 1938, when he joined college. He went to the University of São Paulo Medical School and graduated in 1944 (Figure 2). He finished his doctorate degree in Medicine in December 1950 in the same college. Dr. Edgard presented a methodical and systematic study on the topographic distribution of elements and pulmonary pedicle, under the title “Anatomical Observation on Bronchial Distribution in Human’s Middle Lobes of the Lung”.

Specialist Member of the Brazilian Society of Cardiovascular Surgery. Title of specialist in cardiovascular surgery by the Brazilian Medical Association. Specialist Member of the Brazilian Society of Cardiology. Title of specialist in cardiology by the Brazilian Medical Association. Qualified member of the Department of Cardiac Pacing (DECA).Cardiovascular Surgeon of Real e Benemérita Associação Portuguesa de Beneficência, Pulmo Cor Pneumologia e Cardiologia Clínica e Cirúrgica, and Associação Beneficente e Filantrópica da Cruz Azul de São Paulo. São Paulo, SP, Brazil. E-mail: piccardivl@hotmail.com 1

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However, engage in cardiac operations was his dream. In the late forties, Dr. Edgard participated in pioneering surgeries, as treatments for coarctation of the aorta, as well as closure of patent ductus arteriosus, conventionally, which allowed the surgeons of that time overcome the technical difficulties of large blood vessel’s anastomosis. The experience and confidence acquired, encouraged them to carry out more complex cardiac surgeries, getting better results. Shortly after, Professor San Juan performed his first mitral valve surgery: one Digital Mitral Commissurotomy, a technique initiated in the modern era by Bailey of Philadelphia, and Harken from Boston in 1948, with good results in the treatment of rheumatic mitral stenosis. He actively participated in the work carried out by Dr. Zerbini compiling 126 patients with mitral valve disease undergoing digital commissurotomy as from 1951. Being a hardworking doctor, always interested in new techniques developed abroad, Dr. Edgard actively participated in the early days of the use of extracorporeal circulation in Brazil In April 1957, he traveled to London, where attended a graduate program in Thoracic Surgery at the Institute of Diseases of Chest, watching the work of Professor Price Thomas, at Bromptom Hospital (Figure 4). He remained until November at Guy's Hospital, closely watching cardiac interventions with hypothermia aid and extracorporeal circulation performed by Dr. Brock.

Fig. 2 - Graduating from the University of São Paulo Medical School in 1944. He became professor of Clinical Surgery at the University of São Paulo Medical School in 1954, presenting a thesis on “The Surgical Treatment of Congenital Lung Cysts”. During his studies, he expressed great interest in surgical procedures and found true love for surgery, which accompanied him throughout his life. He was a disciple of Professor Zerbini in the early fifties and member of the “Thoracic Group” (Grupo de Tórax) of the first surgical clinic, accompanying him on surgical procedures at Santa Casa de Misericórdia de São Paulo and at the new Clinical Hospital (Hospital das Clínicas), recently opened in São Paulo (Figure 3). He stood out in lung, pleural, mediastinal surgery, and also in the surgical treatment of tuberculosis.

Fig. 4 - Professor San Juan in London, Master’s Degree in Thoracic Surgery-1957. He returned to São Paulo convinced to perform heart surgeries using new techniques in his patients (Figure 5). On August 18, 1958, he participated with Professor Zerbini; in the first heart surgery with extracorporeal circulation at the “Hospital das Clinicas”, it was a case of pulmonary valve stenosis successfully corrected.

Fig. 3 - Thoracic Group - First Surgical Clinic (FMUSP).

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Professor San Juan finished his post doctorate degree in Thoracic Surgery at the Escola Paulista de Medicina in 1970 and in Cardiovascular Surgery at the Escola Nacional de Medicina, in 1972 in Rio de Janeiro, with the thesis entitled “Surgical Treatment of Atrio-Ventricular block performed by pacemaker Implant”. He returned to London in September 1970 to take the Cardiac Surgery Course at the National Heart Hospital (Figure 6). In 1971, Professor San Juan went to the United States to do an internship at Cleveland Clinic in the Department of Cardiovascular Surgery and in 1974 returned to the US for an internship program at the Hospital for Sick Children in Buffalo and St. Luke's and Texas Children’s Hospital, in Houston, under the supervision of Dr. Denton A. Cooley. He returned to Brazil bringing expertise in the treatment of congenital heart diseases, particularly related to Tetralogy of Fallot, his favorite congenital disease. As he had didactic teaching methods, Dr. Edgard was a full Professor of Cardiovascular and Pulmonary Surgery at Bragança Paulista Medical School, from 1975 to 1985. He could combine really well his surgical and educational activities, teaching his classes eloquently in order to pass on medical knowledge to his students. In 1975, he joined other prominent surgeons in São Paulo, such as Dr. Emil Sabino, his assistant and partner for many years, founding the “Pulmo-Cor Edgard San Juan e Médicos Associados” (Figure 7).

Fig. 5 - Professor San Juan in cardiac surgery at the Clinical Hospital – FMUSP. This was the beginning of an embryonic cell, which created a new medical specialty, allowing surgical treatment of the heart with the opening of the cardiac cavities under direct vision. This allowed surgeons to perform: 1- corrections, or replacement of diseased valves, 2- detailed vision of congenital defects to be corrected, and 3- myocardial revascularization through implantation of venous or arterial grafts. He was the first disciple of Professor Zerbini to start his own team, becoming a full member of Cardiovascular and Pulmonary Surgery at Beneficência Portuguesa Hospital in São Paulo since 1958.

Fig. 6 - Professor Edgard San Juan - Post Doctorate Degree in 1970.

Fig. 7 - Pulmo-Cor - Pneumology Course Summary.

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The clinic was aimed at medical care in Cardiology and Pneumology in clinical and surgical areas as well, Medical Residency and Specialization programs. Their Residents were from not only other states of Brazil, but from other countries like Central America and South America, such as Honduras, Dominican Republic, Bolivia and others. Many of these students have become renowned and prestigious international professionals in the medical field. He devoted himself intensely to assistential medicine, having operated a great number of patients, which represented the substrate, to write numerous medical books, and publish many very important articles of high interest mainly in the surgical area. With his great administrative skills, Dr. San Juan was the leader of Cardiac and Pulmonary Surgery at the "Hospital do Servidor Público Estadual de São Paulo”, IAMSPE, between 1963 and 1978. He was the doctor of distinguished people, such as Vinicius de Morais and Marcondes Filho, the Minister of Finance of Getúlio Vargas administration. Years earlier, received Princess Lilian of Belgium, who watched a cardiac surgery with extracorporeal circulation in 1962 at the “Hospital das Clínicas”, University of São Paulo Medical School (Figure 8). He was a distinguished Fellow, of the American College of Surgeons. In Brazil actively participated at various medical societies: founding partner of the “Sociedade Brasileira de Cirurgia Cardiovascular”. Full member at “Academia Paulista de Medicina”, Full Member of “Colégio Brasileiro de Cirurgiões” Chapter São Paulo.

Full member of the “Sociedade Brasileira de Cirurgia Cardiovascular,” where he held several position in the Board of Directors. Full member at Brazilian Society of Cardiology, member of the Department of Pediatrics, and also Brazilian Society of Pulmonology and the Brazilian Society of Thoracic Surgery. Professor San Juan was devoted to gardening, in his leisure time. He was always interested with his plants and flowers, which surround the beautiful house where he lived, in Morumbi. With eclectic tastes, listening to music was his other hobby. His musical taste would go from classical music until Frank Sinatra and Michael Jackson. He was also devoted to his family in his little free time, sometimes as a very understanding father and friend for all times, or as wise and experienced counselor of his five children (Figure 9).

Fig. 8 - Princess Lilian of Belgium visiting the Hospital das Clínicas (Clinical Hospital) – FMUSP.

Fig. 9 - Professor San Juan accompanied by his children.

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I personally met Professor San Juan in 1993 when I was invited to join the team as a surgeon. There was a pressing need for renewal of their surgical staff. In his private clinic, I found a septuagenarian, but with traces of beauty and elegance, with a strong personality, which hid a generous and welcoming heart, an extremely organized and proud administrator admired by all his employees (Figure 10). After a few moments I felt at ease and we began a sincere friendship. He was surprised with no signs of bias, after all that would be a woman operating on his patients in the operating room! He died on February 21, 2015, lucid and convinced that his mission had been accomplished at nearly 96 years old, always loving life and medicine. Professor San Juan leaves a beautiful family with five children: Margarida San Juan Rozzino (Visual Artist); Edgard JosĂŠ San Juan (Economist); JosĂŠ Eduardo San Juan (Business Administrator); Flavia San Juan Laragnoit (Civil Engineer) and Cesar San Juan (Business Administrator), 16 grandchildren and 4 great-grandchildren (Figure 11). Dr. Edgard leaves the Brazilian Cardiac Surgery a priceless legacy. Fig. 10 - Professor San Juan - III Meeting of Professor Zerbini disciples.

Professor Edgard Schroeder San Juan 1919 - 2015

Fig. 11 - The Family of Professor Edgard San Juan.

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Messages from his children:

He was introspective and serious but at the same time liberal and ahead of his time. A smart and loving man. He loved medicine. He was also fond of his glass of red wine, sunbathing and simple life”.

Marguerite San Juan Rozzino “I would say that my father was a very charismatic and handsome man. A great friend and confidant. He taught me the meaning of the words character and responsibility. I'm very proud to be his daughter”.

Cesar San Juan “The memories I’ve had of my father since I was a child is that he was always studying, working in the hospital or business trips and/or medical conference ... At first, I didn't understand this situation because I often missed him. However, I realized over time the importance of the profession that my father had chosen. Besides, he used to do everything with love and dedication, working hard up to the day he could”.

Flavia San Juan Laragnoit “My father was a very intense person and lived his life to the fullest. What to say about a person who lived so much and experienced so many things?

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REVIEWERS

Reviewers BJCVS 30.3 The Brazilian Journal of Cardiovascular Surgery (BJCVS) is grateful for the reviewers, listed below, which collaborate in this edition. Without their work would be impossible to keep the high scientific standard of our journal.

Domingo Braile Editor-in-Chief BJCVS/RBCCV

Alfredo José Rodrigues

Leornardo Augusto Miana Luiz César Guarita Souza

Bruno Botelho Pinheiro Bruno da Costa Rocha

Marcos Aurélio Barboza de Oliveira

Carla Tanamati Charles Simão Filho

Orlando Petrucci Otoni Moreira Gomes

Elaine Soraya Barbosa de Oliveira Severino

Paulo Roberto Barbosa Evora Paulo Roberto Brofman Pedro Paulo Martins de Oliveira

Fábio Papa Taniguchi Fernando Antibas Atik Fernando Platania

Renato Tambellini Arnoni Robison Poffo Rodolfo A. Neirotti

Gibran Roder Feguri Jarbas Jakson Dinkhuysen José Carlos Pachón Mateos

Valquiria Pelisser Campagnucci

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Information for Authors

INFORMATION FOR AUTHORS BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY/ Revista Brasileira de Cirurgia Cardiovascular Editor-in-Chief 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 Step 8: 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.

criteria established by WHO and ICMJE, 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. Ethical Issues 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

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

Experimental Work

ClinicalSurgical Correlation

Multimidia

4

Brief Communication/Previous Note 8

4

6

4

4

100

100

100

-

250

-

-

6.500

1.500

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100 Characters

40 Characters

40 Characters

Original Article

Editorial

Review Article

Case Report

“How to-do-it�

8

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Meetings Calendar

Braz J Cardiovasc Surg 2015;30(3):407-8

MEETINGS CALENDAR - 2015

July

New Castle, United States Informations: Melissa O’Dwyer Phone: +44 (0) 114 225 9036 E-mail: melissa.odwyer@aesculap-academy.com

23 to 25 - Effective Prenatal Screening of Congenital Heart Disease London, United Kingdom Informations: Dr. Julene Carvalho and Professor Yen Ho Phone: 44 207 3518751 Fax: 44 207 351 8230 E-mail: morphology@rbht.nhs.uk Site: www.rbht.nhs.uk/cardiacmorphology

9 and 10 - The 2nd International Surgical Aspects Newcastle, United Kingdom Informations: Melissa O’Dwyer E-mail: melissa.odwyer@aesculap-academy.com Site:https://uk.aesculap-academy.com/ go/?action=AkadEventData&event_id=411797&evdate=411801 14 and 15 - Transcatheter Aortic and Mitral Valve Interventions Windsor, United Kingdom Informations: Sharon Pidgeon Phone: 01753 832166 Fax: 01753 620407 E-mail: sharon.pidgeon@eacts.co.uk

August 15 - ISES Regional Meeting: Southeast Structural Heart Symposium Atlanta, United States Informations: Mariela Murphy Phone: 904-513-1372 E-mail: mariela.murphy@m3meet.com Site: www.isesonline.org

14 and 15 - ‘Elancourt in Strasbourg’ - Maximally and Minimally Invasive Surgery - Tips and Tricks from the experts Strasbourg, France Informations: Yvonne Rice Phone: +44 1392 430671 Fax: +44 1392 430671 E-mail: admin@ests.org.uk Site: http://www.ests.org/education/ests_school/elancourt_school.aspx

21 and 22 - Heart Valve Disease Forum 2015 Muju, South Korea Informations: Kyung-Hwan Kim, MD., PhD. Phone: 821087119327 Fax: 8227657117 E-mail: kkh726@snu.ac.kr Site: www.valveforum.org

18 to 21 - PICS~AICS 2015 Pediatric & Adult Interventional Cardiac Symposium Las Vegas, United States Informations: Kimberly Ray E-mail: kimberly_ray@pics-aics.com Site: http://www.picsymposium.com

September

19 to 22 - 25th WSCTS World Congress Edinburgh, United Kingdom Informations: Phone: 0044 0131 527 1629 E-mail: info@wscts2015.org Site: www.wscts2015.org

3 to 6 - 3rd Heart Care Heart International Heart Symposium – Unite! For Better Heart Care Bangkok, Thailand Informations: Secretariat Phone: +662-591-8943, +6684-134-9898 E-mail: info@cdiheartdisease.org Site: http://www.cdiheartdisease.org

19 to 20 - 14th Annual Symposium on Regional Anesthesia, Pain and Perioperative Medicine New York, United States Informations: Stacy Atkinson E-mail: stacy@nysora.com Site: http://www.nysorasymposium.com

6 to 9 - VALVE 2015 – 7th Training Course for Minimally Invasive Valve Surgery Innsbruck, Austria Informations: Ms. Judith Kutnjak Phone: +43 1 867 49 44-21 Fax: +43 1 867 49 44-9 E-mail: judith.kutnjak@ee-hsec.org Site: http://www.focusvalve.org/index.php

24 to 27 - JCTSE Educate the Educators (EtE) Course Rosemont, United States Informations: Rebecca J. Mark Phone: 312-202-5893 Fax: 312-202-5801 E-mail: rmark@jctse.org Site: http://www.jctse.org/whats-new/ete-2015-announcement/

8 and 9 - The 2nd International Surgical Aspects of Cardiopulmonary Transplantation Course

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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

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