Brazilian Journal of Cardiovascular Surgery 28.1 - 2013 by Revista Brasileira de Cirurgia Cardiovascular

28.1 JANUARY/MARCH 2013

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY | REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

VOL. 28 Nยบ 1 JANUARY/MARCH 2013

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RBCCV REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

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

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY

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

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

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

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

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

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

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Campinas (BRA)

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

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

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ENDEREÇO/ADDRESS

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Publicação trimestral/Quarterly publication Edição Impressa - Tiragem: 250 exemplares (*)

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

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

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

2009, 24: 1,2,3,4 2009, 24: 2 [supl] 2010, 25: 1,2,3,4 2010, 25: 1 [supl] 2011, 26: 1,2,3,4 2011, 26: 1 [supl] 2012, 27: 1,2,3,4 2012, 27: 1 [supl] 2013, 28: 1

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

CDD 617.4105 NLM18 WG 168

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

INDEXADA EM • Thomson Scientific (ISI) http://science.thomsonreuters.com • PubMed/Medline www.ncbi.nlm.nih.gov/sites/entrez • SciELO - Scientific Library Online www.scielo.br • Scopus www.info.scopus.com • LILACS - Literatura Latino-Americana e do Caribe em Ciências da Saúde. www.bireme.org

• ADSAUDE - Sistema Especializado de Informação em Administração de Saúde www.bibcir.fsp.usp.br/html/p/pesquisa_em_ bases_de_dados/programa_rede_adsaude • Index Copernicus www.indexcopernicus.com • Google scholar http://scholar.google.com.br/scholar • EBSCO www2.ebsco.com/pt-br

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

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

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

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

Conselho Deliberativo:

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

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

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

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

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

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

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

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

REVISTA BRASILEIRA DE CIRURGIA CARDIOVASCULAR

ISSN 1678-9741 - Online Issue ISSN 0102-7638 - Printed Issue RBCCV 44205

Impact Factor: 1.239

BRAZILIAN JOURNAL OF CARDIOVASCULAR SURGERY Rev Bras Cir Cardiovasc, (São José do Rio Preto, SP - Brazil) jan/mar - 2013;28(1)1-164

CONTENTS/SUMÁRIO

EDITORIALS/EDITORIAIS

Medicine and Faith Domingo M. Braile...............................................................................................................................................................................I

Fetal cardiac evaluation by 3D/4D ultrasonography (STIC): what is its real applicability in the diagnosis of congenital heart disease? Edward Araujo Júnior, Liliam Cristine Rolo, Luciano Marcondes Machado Nardozza, Antonio Fernandes Moron....................... III

ORIGINAL ARTICLES/ARTIGOS ORIGINAIS 1436 Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery Impacto na mortalidade precoce e tardia após transfusão de hemácias em cirurgia de revascularização miocárdica Antonio Alceu dos Santos, Alexandre Gonçalves Sousa, Hugo Oliveira de Souza Thomé, Roberta Longo Machado, Raquel Ferrari Piotto.................................................................................................................................................................................................... 1 1437 Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery Fatores de risco pré, intra e pós-operatórios para mortalidade hospitalar em pacientes submetidos à cirurgia de aorta Mário Issa, Álvaro Avezum, Daniel Chagas Dantas, Antonio Flávio Sanches de Almeida, Luiz Carlos Bento de Souza, Amanda Guerra de Moraes Rego Sousa........................................................................................................................................................... 10 1438 Impact of coronary artery bypass grafting in elderly patients Impacto da cirurgia de revascularização do miocárdio em pacientes idosos Priscila Aikawa, Angélica Rossi Sartori Cintra, Cleber Aparecido Leite, Ricardo Henrique Marques, Claudio Tafarel Mackmillan da Silva, Max dos Santos Affonso, Felipe da Silva Paulitsch, Evandro Augusto Oss....................................................................... 22 1439 Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center Tratamento cirúrgico para endocardite infecciosa e mortalidade hospitalar em centro único brasileiro Maurício Nassau Machado, Marcelo Arruda Nakazone, Jamil Ali Murad-Júnior, Lilia Nigro Maia................................................ 29 1440 Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium Correção da ruptura de cordas tendíneas na insuficiência mitral degenerativa pelo emprego de cordas padronizadas de pericárdio bovino Francisco Gregori Júnior, Moacir Fernandes de Godoy, Celso Otaviano Cordeiro, Alexandre Noboru Murakami, Rogerio Teruya, Sergio Shigueru Hayashi, Wallace Kohata de Aquino, Luiz Eduardo Gallina................................................................................... 36 1441 Correlation between quality of life, functional class and age in patients with cardiac pacemaker Correlação entre a qualidade de vida, classe funcional e idade em portadores de marca-passo cardíaco Juliana Bassalobre Carvalho Borges, Rubens Tofano de Barros, Sebastião Marcos Ribeiro de Carvalho, Marcos Augusto de Moraes Silva.................................................................................................................................................................................................... 47

1442 Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts Efeitos benéficos da perfusão hiperosmótica no miocárdio após lesão isquemia/reperfusão em corações isolados de ratos Yong Cao, Lie Wang, Hong Chen, Zhiqian Lv.................................................................................................................................. 54 1443 Coping strategies after heart transplantation: psychological implications Estratégias de enfrentamento pós-transplante cardíaco: implicações psicológicas Paula Moraes Pfeifer, Patricia Pereira Ruschel, Solange Bordignon................................................................................................. 61 1444 Analysis of left ventricular function in patients with heart failure undergoing cardiac resynchronization Análise da função ventricular esquerda de pacientes com insuficiência cardíaca submetidos à ressincronização cardíaca Ricardo Adala Benfatti, Felipe Matsushita Manzano, José Carlos Dorsa Vieira Pontes, Amaury Edgardo Mont’Serrat Ávila Souza Dias, João Jackson Duarte, Guilherme Viotto Rodrigues da Silva, Jandir Ferreira Gomes Junior, Neimar Gardenal...................... 69 1445 The use of cell saver system in cardiac surgery with cardiopulmonary bypass O uso de recuperador de sangue em cirurgia cardíaca com circulação extracorpórea Rui M. S. Almeida, Luciano Leitão................................................................................................................................................... 76

REVIEW ARTICLES/ARTIGOS DE REVISÃO 1446 Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients Desfechos de 5 anos do tratamento de lesões de TCE por stents farmacológicos versus CRM: meta-análise e meta-regressão de 2914 pacientes Michel Pompeu Barros de Oliveira Sá, Paulo Ernando Ferraz, Rodrigo Renda Escobar, Eliobas Oliveira Nunes, Alexandre Magno Macário Nunes Soares, Frederico Browne Correia de Araújo e Sá, Frederico Pires Vasconcelos, Ricardo Carvalho Lima............ 83 1447 Criss-cross heart: report of two cases, anatomic and surgical description and literature review Coração entrecruzado (criss-cross heart): relato de dois casos, descrição anatomocirúrgica e revisão de literatura Ítalo Martins de Oliveira, Vera Demarchi Aiello, Marcela Maria Aguiar Mindêllo, Yasmin de Oliveira Martins, Valdester Cavalcante Pinto Jr................................................................................................................................................................................................ 93

SPECIAL ARTICLES/ARTIGOS ESPECIAIS 1448

Religion, spirituality and cardiovascular disease: research, clinical implications, and opportunities in Brazil Religião, espiritualidade e doença cardiovascular: pesquisa, implicações clínicas e oportunidades no Brasil Fernando A. Lucchese, Harold G. Koenig....................................................................................................................................... 103

1449 Cardiac surgery: the infinite quest. Part II Cirurgia cardiaca: a busca infinita. Parte II Rodolfo A. Neirotti........................................................................................................................................................................... 129 1450 Myocardial revascularization in the XXI century Revascularização miocárdica no século XXI Luís Alberto Oliveira Dallan, Fabio Biscegli Jatene........................................................................................................................ 137 SHORT COMMUNICATION/COMUNICAÇÃO BREVE 1451 Endovascular repair of ascending aortic dissection Correção endovascular de dissecção de aorta ascendente José Carlos Dorsa Vieira Pontes, Amaury Mont'Serrat Ávila Souza Dias, João Jackson Duarte, Ricardo Adala Benfatti, Neimar Gardenal........................................................................................................................................................................................... 145

SCIENTIFIC DIFFUSION/DIVULGAÇÃO CIENTÍFICA 1452 Mistakes in Brazilian papers are more from concepts than of expression Erros em artigos científicos brasileiros são mais conceituais do que de expressão Elton Alisson/Agência Fapesp......................................................................................................................................................... 148

LETTERS/CARTAS 1453 Letters to the Editor Cartas ao Editor .............................................................................................................................................................................. 150 1454 Erratum ..........................................................................................................................................................................................155 Reviewers RBCCV 28.1 ................................................................................................................................................................ 156

Impresso no Brasil Printed in Brazil

Projeto Gráfico: Heber Janes Ferreira Impressão e acabamento: Duograf

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

Editorial

Medicine and Faith Domingo M. Braile* DOI: 10.5935/1678-9741.20130001

ontrary to what most people still imagine, science, in its eternal quest to understand and explain the world rationally with facts that need to be proven and demonstrated, and the Faith, whose definition by Paulo (São Paulo for those who practice catholicism), in his epistle to the Hebrews is: “... the substance of things hoped for, the evidence of things not seen” are not incompatible. In lectures and classes for which I have the honor to be invited, I expose to those who give me the pleasure of their audience that, in recent decades, several studies have shown that patients who have some kind of faith, though not necessarily linked to a religious doctrine, often have a better chance of cure than materialists. Among the scientific research performed, a 6-year prospective study with 557 seniors, performed by Lutgendorf et at. [1] in 2004, showed that among those who attended religious services, the relative risk of death was reduced to 78% and the levels of interleukin-6 were 66% lower during the follow-up period. Article of Drs. Fernando Lucchese and Harold Koenig (p. 103) The surgeons, who deal with patients in extreme situations, should also follow with interest researches on this subject. Accordingly, BJCVS (Brazilian Journal of Cardiovascular Surgery) published in this issue, an article by Dr. Fernando Lucchese and Harold Koenig, titled “Religion, spirituality and cardiovascular disease: research, clinical implications, and opportunities in Brazil”. The text reviews the research on the relationship between religion, spirituality and cardiovascular disease, discusses mechanisms that help explain the reported associations, examines the clinical implications of these findings and addresses the need for future research on this topic in Brazil. Even with all the obstacles, such as short-time and working conditions short of ideals, among others, we physicians are committed to seeking the best for the patient. The greater understanding of the needs of the patient, not only physical but also spiritual, is the primary factor in order to treatment is able to be more effective and also fits into

the “humanization” of medicine, a concept so expensive that still endures, despite a world increasingly run and impersonal. Second part of the test by Dr. Rodolfo Neirotti (p. 129) Still, in this issue we publish the second of three parts of the essay by Dr. Rodolfo Neirotti entitled “Cardiac Surgery: the infinite quest”. The topic emphasizes how cardiovascular surgery can learn lessons from other complex systems that identified solutions to intricate obstacles, and that expertise should be always open to innovation. Review article on coronary surgery by Dr. Luis Dallan e Fábio Jatene (p. 137) Nor can I fail to mention the well based retrospective on CABG, written by Drs. Luis Dallan and Fabio Jatene. In a text rich in detail, they recount from the beginning until today the prospects of this today consecrated technique to be known by all who deal with cardiac surgery. 40 th Congress of the Brazilian Society of Cardiovascular Surgery An opportunity we have to talk and delve on these topics will be at the 40th Congress of the Brazilian Society of Cardiovascular Surgery (BSCVS), to be held in the period 18-20 April, at Costão do Santinho, Florianópolis, SC, the same city the event was held in 2007. There will also be the presence of other health professionals, such as Perfusionists, Nurseries and Physiotherapists, beyond academics. Keeping the tradition of recent years, we have the presence of international guests who, with their knowledge and expertise, will showcase innovations and perspectives of international cardiac surgery. There will, as always, several activities of great interest, especially the “Hands On”, which is improved every year and, through practical training of new prostheses and orthoses implant enables surgeons to update their knowledge of what is inside latest in cardiac surgery state of the art, always aiming to provide greater benefits to patients. I

This whole range of attractions was only possible thanks to the commitment of all members of the current Board and the Cardiovascular Surgery Society (BSCVS), chaired by Dr. Walter Gomes, with support from other members. Also, we should mention the incessant work of the Organizing Committee, led by Dr. Lourival Bonatelli Filho, flanked by Dr. Milton de Miranda Santoro, Dr. Renato Bastos Pope and Dr. Ricardo José Choma, so that participants can enjoy the sights and activities in the best way possible. Editorial Board Meeting of BJCVS with the Associate Editors and Editorial Board Members On April 18, from 11am to 12pm, there will be the now traditional meeting of the Editorial Board of BJCVS with the Associate Editors and Editorial Board members also open to all members who wish to participate. We will have the opportunity to discuss the prospects of the Journal, which was indexed in EBSCO database and is finalizing the process for entering the PubMed Central. The presence in new media and distribution through social networks, as well as ways to increase the Impact Factor, 1.239 currently, will also be topics of discussion.

by conquest. Facts like this encourage us to continue our commitment to the BJCVS be consolidated as one of the most important journals of cardiovascular surgery worldwide. The articles available for testing by the Continuing Medical Education (CME) in this issue are as follows: "Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery” (p. 1), “Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center” (p.29), “Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium” (p. 36), “Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and meta-regression of 2914 patients” (p. 83). My warmest regards,

Domingo Braile Editor-in-Chief BJCVS

Article published in BJCVS has 100 citations in Google Scholar (p. 153) We are pleased to inform the study “Basics notions of heart rate variability and its clinical applicability”, published in BJCVS 24.2, reached the milestone of 100 citations. We congratulate the authors Luiz Carlos Marques Vanderlei, Carlos Marcelo Pastre, Rosângela Akemi Hoshi, Tatiana Dias de Carvalho and Moacir Fernandes de Godoy

REFERENCE 1. Lutgendorf SK, Russell D, Ullrich P, Harris TB, Wallace R. Religious participation, interleukin-6, and mortality in older adults. Health Psychol. 2004;23(5):465-75.

Editorial

Fetal cardiac evaluation by 3D/4D ultrasonography (STIC): what is its real applicability in the diagnosis of congenital heart disease? Edward Araujo Júnior1, Liliam Cristine Rolo2, Luciano Marcondes Machado Nardozza3, Antonio Fernandes Moron4 DOI: 10.5935/1678-9741.20130002

The congenital heart diseases (CHD) are the most common major malformations at birth [1], with prevalence ranging from 0.6% to 5% of live births [2]. Despite great efforts and technological advancement of two-dimensional echocardiography (2D) in the past two decades, the accuracy in the detection of CHD at prenatal is between 31% and 96% [3]. In 2003, with the development of Spatio-Temporal Image Correlation (STIC), scientists started the use of third and fourth dimension ultrasonography (3D/4D) in fetal cardiac evaluation [4]. The STIC is a software that enables acquiring volumetric fetal heart with its vascular connections, whose images can be evaluated in either multiplanar or rendering modes, or even surface mode, in a static or moving ways (4D) by means of a sequence of cineloop, which simulates a complete cardiac cycle [4]. This software provides an innovation absent in 2D ultrasound, which is the storage volume of the heart for an offline analysis, in other words, in the absence of the patient. Thus, a detailed assessment of the anatomy and the functioning fetal heart is possible without the need to

cause major discomfort to pregnant women, a relatively frequent situation when more prolonged ultrasound studies are used. Moreover, the storage allows the sending of volumes to specialized centers through an internet link, strengthening the telemedicine and improving the prenatal period tracking [5]. Standardization of volume storage is already a reality, so the investigator responsible for offline analysis has knowledge of the actual position of the heart chambers with respect to the right and left fetal axis to evaluate the presence of possible cardiac isomerisms. Therefore, when the fetus is in cephalic presentation, it should be considered that the heart side corresponds to the fetal side, unlike the pelvic fetuses which stay in opposite sides [6]. The gray scale and color Doppler applications are also present in the STIC, used to improve the evaluation of the ventricular outflow tracts, aortic and ductal arches, besides assisting in the location of septal defects [7]. The 3D technology has allowed the development of new techniques known as inversion mode (analysis technique of liquid structures which reverses voxels of gray scale,

1. Adjunct Professor at the Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil - Main Author. 2. Doctor of Science, Department of Obstetrics, UNIFESP, São Paulo, SP, Brazil - Contribution to the article. 3. Associate Professor, Department of Obstetrics, São Paulo, SP, Brazil - Article Review. 4. Professor, Department of Obstetrics, UNIFESP, São Paulo, SP, Brazil - Article Review.

Correspondence Address: Division of Fetal Cardiology, Department of Obstetrics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil. Edward Araujo Júnior 956 Carlos Weber Street, Apto 113 - Visage - Alto da Lapa - São Paulo, SP, Brazil – Zip code: 05303-000 E-mail: araujojred@terra.com.br Article received on January 22th, 2013 Article accepted on January 28th, 2013

III

Abbreviations, acronyms and symbols 2D 3D 4D CHD STIC TUI

Second Dimension Third Dimension Fourth Dimension Congenital Heart Diseases Spatio-Temporal Image Correlation Tomographic Ultrasound Imaging

so anechoic structures such as the heart chambers, lumen vessels, stomach, bladder and renal pelvis, with inversion mode they become echogenic, whereas normally echogenic structures, such as bone, become anechoic) [8] (Figure 1) and B-flow imaging (technique that improves the weak signal reflected from the blood, and suppresses the strong signals of the surrounding structures) [9]. The inversion mode allows the reconstruction of the cardiac chambers, aortic and ductal arches, and abnormalities of venous connections [8]. The B-flow imaging shows high sensitivity and angle independence, then it is potentially advantageous over color Doppler for the visualization of large vessels and venous return, allowing the identification of small vessel with low-velocity flows, such as pulmonary veins, enhancing the detection of anomalies in pulmonary venous return [9].

Fig. 1 â&#x20AC;&#x201C; Visualization of four heart chambers plane using the inversion mode

Another technique also addressed by STIC Tomographic Ultrasound Imaging's (TUI), which enables the achievement of all the axial planes of the heart from the abdomen to the apex of the chest, increasing the fetal heart tracking and analysis [10] (Figure 2) . STIC also allows the measurement of volumes of cardiac chambers, as well as the calculation of systolic volume, ejection fraction and cardiac output. Thus, to obtain relevant information about IV

Fig. 2 - Use of TUI with simultaneous visualization of sequential axial planes of the fetal chest at heart level (3VT, 5C, 4C). TUI: tomographic ultrasound imaging. 3VT: three vessels and trachea; 5C: five chambers; 4C: four chambers

cardiac function is possible due to the CHD [11]. More recently, a new approach to STIC rendering mode analysis obtained measurements of mitral and tricuspid valves areas, and also and the interventricular septum, determining reference values for these parameters, making it feasible to apply in suspected or pathological cases[12,13]. Recently, some studies have attempted to correlate the technical 3D/4D (STIC) and 2D (echocardiography) with the diagnosis of CHD, however, these studies have shown conflicting results [14,15]. In one of these studies, with the STIC being conducted by the general obstetricians, without specific knowledge of the methodology, the STIC proved itself to be inferior to 2D echocardiography, performed by a specialist in the diagnosis of CHD [14]. In another study, where the STIC was performed by experienced examiners in this methodology, the accuracy in the diagnosis of CHD was similar to that obtained by echocardiography 2D [15]. Based on recent studies, it is still early to say whether the 3D/4D ultrasound (STIC) will surpass 2D echocardiography as a gold standard in prenatal diagnosis of CHD. In our reality, the biggest obstacles are the need for sophisticated and expensive equipment and people with specific training in 3D/4D ultrasound. However, some benefits are already envisioned, as less operator dependence and the possibility of sending volumes to reference centers for fetal and pediatric cardiology, which is of fundamental importance in a country like ours, where these centers are located in major cities. In summary, only in multicenter studies, with examiners experienced in 3D/4D technology, can confirm the real benefits of STIC in prenatal diagnosis of CHD.

REFERENCES 1. Hoffmann JI. Incidence of congenital heart disease: I. Postnatal incidence. Pediatr Cardiol. 1995;16(3):103-13. 2. Grandjean H, Larroque D, Levi S. The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J Obstet Gynecol. 1999;181(2):446-54. 3. Stümpflen I, Stümpflen A, Wimmer M, Bernaschek G. Effect of detailed fetal echocardiography as part of routine prenatal ultrasonographic screening on detection of congenital heart disease. Lancet. 1996;348(9031):854-7. 4. DeVore GR, Falkensammer P, Sklansky MS, Platt LD. Spatio-temporal image correlation (STIC): new technology for evaluation of the fetal heart. Ultrasound Obstet Gynecol. 2003;22(4):380-7. 5. Gonçalves LF, Nien JK, Espinoza J, Kusanovic JP, Lee W, Swope B, et al. What does 2-dimensional imaging add to 3and 4-dimensional obstetrics ultrasonography? J Ultrasound Med. 2006;25(6):691-9. 6. Paladini D. Standardization of on-screen fetal heart orientation prior to storage of spatio-temporal image correlation (STIC) volume datasets. Ultrasound Obstet Gynecol. 2007;29(6):605-11. 7. Gonçalves LF, Lee W, Chaiworapongsa T, Espinoza J, Schoen ML, Falkensammer P. Four-dimensional ultrasonography of the fetal heart with spatiotemporal image correlation. Am J Obstet Gynecol. 2003;189:1792-802. 8. Lee W, Gonçalves LF, Espinoza J, Romero R. Inversion mode: a new volume analysis tool for 3-dimensional ultrasonography. J Ultrasound Med. 2005;24(2):201-7. 9. Pooh PK, Korai A. B-flow and B-flow spatio-temporal image

correlation in visualizing fetal cardiac blood flow. Croat Med J. 2005;46(5):808-11. 10. Yagel S, Cohen SM, Rosenak D, Messing B, Lipschuetz M, Shen O, et al. Added value of three-/four-dimensional ultrasound in offline analysis and diagnosis of congenital heart disease. Ultrasound Obstet Gynecol. 2011;37(4):432-7. 11. Simioni C, Nardozza LM, Araujo Júnior E, Rolo LC, Zamith M, Caetano AC, et al. Heart stroke volume, cardiac output, and ejection fraction in 265 normal fetus in the second half of gestation assessed by 4D ultrasound using spatiotemporal image correlation. J Matern Fetal Neonatal Med. 2011;24(9):1159-67. 12. Rolo LC, Nardozza LM, Araujo Júnior E, Hatanaka AR, Rocha LA, Simioni C, et al. Reference ranges of atrioventricular valve areas by means of four-dimensional ultrasonography using spatiotemporal image correlation in the rendering mode. Prenat Diagn. 2013;33(1):50-5. 13. Nardozza LM, Rolo LC, Araujo Júnior E, Hatanaka AR, Rocha LA, Simioni C, et al. Reference range for fetal interventricular septum area by means of four-dimensional ultrasonography using spatiotemporal image correlation. Fetal Diagn Ther. 2013 [ahead of print]. 14. Wanitpongpan P, Kanagawa T, Kinugasa Y, Kimura T. Spatio-temporal image correlation (STIC) used by general obstetricians is marginally clinically effective compared to 2D fetal echocardiography scanning by experts. Prenat Diagn. 2008;28(10):923-8. 15. Bennasar M, Martínez JM, Gómez O, Bartrons J, Olivella A, Puerto B, et al. Accuracy of four-dimensional spatiotemporal image correlation echocardiography in the prenatal diagnosis of congenital heart defects. Ultrasound Obstet Gynecol. 2010;36(4):458-64.

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

ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2013;28(1):1-9

Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery Impacto na mortalidade precoce e tardia após transfusão de hemácias em cirurgia de revascularização miocárdica

Antonio Alceu dos Santos1, Alexandre Gonçalves Sousa2, Hugo Oliveira de Souza Thomé3, Roberta Longo Machado4, Raquel Ferrari Piotto5 DOI: 10.5935/1678-9741.20130003

RBCCV 44205-1436

Abstract Objective: To assess the 30-day and 1-year mortality associated to the red blood cell transfusion after coronary artery bypass grafting surgery. This procedure has been questioned by the international medical community, but it is still widely used in cardiac surgery. Therefore, it is needed more evidence of this medical practice in our country. Methods: We retrospectively analyzed 3,004 patients who underwent coronary artery bypass grafting surgery between June 2009 and July 2010. Patients were divided into two groups: non-transfused and transfused. Results: The transfused group totaled 1,888 (63%) and non-transfused 1,116 (37%). There were 129 deaths in 30 days, with 108 (84%) in the transfused group and 21 (16%) in the non-transfused (P<0.001). One year mortality totaled 249 distributed in 212 (85%) among transfused patients and 37 (15%) in non-transfused (P<0.001). The adjusted odds ratio for mortality in patients transfused was 2.00 (P=0.007) in 30 days and 2.31 (P=0.003) in 1 year. Even in low risk patients (age < 60 years and EuroSCORE ≤ 2 points), and so with fewer comorbidities, both outcomes, 30 day and 1 year mortality were significantly higher in the transfused patients (7.0% vs. 0.0%, P< 0.001) and (10.0% vs. 0.0%, P< 0.001), respectively.

Conclusion: The perioperative red blood cell transfusions after coronary artery bypass grafting surgery increased significantly the 30-day and 1-year mortality, even after the adjustments for comorbidities and other factors. So, new therapeutic options and autologous blood management and conservation strategies should be encouraged to reduce blood products transfusions.

1. Specialist Cardiologist with the title of AMB and the Brazilian Society of Cardiology Physician Assistant Team Dr. Pedro José da Silva, São Paulo, SP, Brazil. 2. Cardiologist with a specialist title by SBC/AMB, Medical Research Center of the Hospital of Charity of St. Paul Portuguese, São Paulo, SP, Brazil. 3. Cardiology, Charitable Portuguesa de São Paulo / Graduate Diploma in Intensive Care, Hospital Albert Einstein, São Paulo, SP, Brazil. 4. Cardiology, Charitable Portuguesa de São Paulo / Graduate Diploma in Intensive Care - Brazilian Association of Intensive Care Medicine (AMIB), São Paulo, SP, Brazil. 5. Doctorate in cardiology by the Faculty of Medicine of Ribeirão Preto, São Paulo, SP, Brazil.

Work carried out at Portuguese Beneficent Hospital of São Paulo, São Paulo, SP, Brazil.

Descriptors: Blood transfusion. Mortality. Blood cells. Coronary artery bypass. Myocardial revascularization. Postoperative complications. Resumo Objetivo: Avaliar a mortalidade em 30 dias e em 1 ano associada à transfusão de glóbulos vermelhos após cirurgia de revascularização miocárdica. Esse procedimento já vem sendo questionado pela comunidade médica internacional, mas ainda é utilizado em grande escala em cirurgias cardíacas. Portanto, faz-se necessário mais evidência dessa prática médica em nosso meio. Métodos: Analisamos retrospectivamente 3004 pacientes submetidos à cirurgia de revascularização miocárdica entre

Correspondence address: Alceu Antonio dos Santos Rua Maestro Cardim, 769 – Block I – Room 202 – Bela Vista São Paulo, SP, Brazil – Zip code: 01323-001 E-mail: antonioalceu@cardiol.br Article received on June 29th, 2012 Article accepted on July 30th, 2012

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Santos AA, et al. - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery

Abbreviations, Acronyms & Symbols AF CABG CPB EuroSCORE HF ICU KF RBCT

Atrial fibrillation Coronary artery bypass grafting Cardiopulmonary bypass European System for Cardiac Operative Risk Evaluation Heart failure Intensive care unit Kidney failure Red blood cells transfusion

junho de 2009 e julho de 2010. Os pacientes foram divididos em dois grupos: Transfundidos e Não transfundidos. Resultados: O grupo de pacientes transfundidos totalizaram 1888 (63%) e o grupo não transfundidos 1116 (37%). Foi observado 129 óbitos em 30 dias, sendo 108 (84%) no grupo transfundidos e 21 (16%) no grupo não transfundidos (P<0,001). Os óbitos em um ano totalizaram 249 distribuídos

INTRODUCTION Blood transfusions are among the greatest scientific discoveries of medical history. Since the nineteenth century they are used on a large scale worldwide. In Brazil, for example, about four million units of blood and derivatives are transfused annually [1]. The reason for this clinical practice is that the anemic patients have adverse outcomes due to reduced capacity to transport oxygen to the tissues, and hence the replacement of red cells through transfusion could prevent these deleterious outcomes [2]. Other indications, such as getting volemic expansion and blood pressure restoration, have no scientific support [3]. However, as evidenced in the worldwide medical literature, the blood transfusions have been questioned for several reasons. Firstly, we still do not have a specific, safely and effectively hemoglobin level able to set the trigger to indicate a blood transfusion [4], moreover there is a huge discrepancy of its use among physicians and hospitals [5]. Another worrying factor is the increased risk of heart failure (HF) [6], atrial fibrillation (AF), kidney failure (KF), stroke, respiratory infection, severe sepsis, and longer hospital stays [7], in the postoperative cardiac surgery, besides the malignant diseases [8], potential transmission of 68 infectious agents [9], multiple organ failure [10]. But what really has concerned the medical community according to recent studies is the mortality increase in general [11] and cardiac surgery [6,12,13]. Another important factor is the reduction of blood donations, leading to blood bank stocks below than what would be the ideal in Brazil [14] and abroad [15]. 2

em 212 (85%) hemotransfundidos e 37 (15%) sem transfusão (P<0,001). O odds ratio ajustado para mortalidade nos pacientes transfundidos foi de 2,00 (P=0,007) em 30 dias e 2,31 (P=0,003) em 1 ano. Mesmo em pacientes de baixo risco (idade<60 anos e com EuroSCORE ≤ 2%), portanto com menos comorbidades, temos significativamente mais óbitos no grupo transfundidos em 30 dias (7,0% vs. 0,0%; P<0,001) e também em 1 ano (10,0% vs. 0,0%; P<0,001). Conclusão: A transfusão de glóbulos vermelhos após cirurgia de revascularização miocárdica aumenta significativamente a mortalidade em 30 dias e em um ano, mesmo após correção de comorbidades e outros fatores. Novas opções terapêuticas e estratégias de gerenciamento e conservação do sangue autólogo devem ser estimuladas para reduzir as transfusões de hemoderivados. Descritores: Transfusão de sangue. Mortalidade. Células sanguíneas. Ponte de artéria coronária. Revascularização miocárdica. Complicações pós-operatórias.

Based on these findings the use of homologous blood has been proposed more narrowly in cardiovascular surgery [16]. Therefore, it is necessary to have more evidence of this medical practice in our country. Thus, the aim of this study is to assess the 30-day and 1-year mortality associated with the red blood cells transfusion (RBCT) after coronary artery bypass grafting (CABG). METHODS We performed a retrospective cohort study using data from the cardiac surgery service of the Beneficência Portuguesa Hospital of São Paulo. The CABG surgeries database is powered by 14 teams, composed of 3,004 patients who were followed-up during the period of June 8, 2009 to July 26, 2010. For the study, were considered patients undergoing CABG with or without associated procedures, age ≥ 18 years; with no restriction on gender or race. We excluded patients who underwent any other surgery, including cardiac, without CABG. The data collection form presented a total of 243 variables. For this study were assessed nine: age, gender, comorbidities, European System for Cardiac Operative Risk Evaluation (EuroSCORE), type of surgery, packed red blood cells transfusion, length of stay (in hospital and Intensive Care Unit - ICU), acquired comorbidities after surgery, and intraoperative and postoperative complications. We present in Tables 1 and 2 the variables assessed in this study in each group.

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Santos AA, et al. - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery

Table 1. Mean values and standard deviation (for age) and absolute frequencies (%), according to group of death (30 days) Group

30-days mortality (n=129) 66,9 ± 9,6 51 (40)

No death (n=2755) 61,7 ± 9,4 1099 (40)

P < 0,001

59 (46) 19 (5)

1230 (45) 426 (16)

0,961

108 (84)

1676 (61)

< 0,001

55 (43)

981 (36)

0,111

Dyslipidemia

39 (30)

1247 (45)

< 0,001

CKF

22 (17)

126 (5)

< 0,001

SAH

109 (85)

2271 (82)

0,564

Previous Stroke

10 (8)

137 (5)

0,161

COPD

16 (12)

168 (6)

0,004

Peripheral arterial disease

10 (8)

118 (4)

0,062

Cerebrovascular disease

5 (4)

41 (1)

0,052

13 (10)

301 (11)

0,762

Previous CABG

3 (2)

41 (1)

0,446

Previous valvar surgery

1 (1)

7 (0,3)

0,307

Other surgeries

0 (0)

3 (0,1)

1,000

Angioplasty

9 (7)

243 (9)

0,469

Previous AMI

52 (40)

1299 (47)

0,128

CHF

13 (10)

55 (2)

< 0,001

Arrhythmia

15 (12)

134 (5)

< 0,001

2 (2)

22 (1)

0,323

Arterial

13 (10)

484 (18)

Graft type

34 (26)

309 (11)

82 (64)

1961 (71)

8 (6)

337 (12)

89 (69)

2503 (91)

Variable Age

Category Former

Smoker

No Yes

Transfusion

Coronary intervention

Surgical indication-Urgent

Venous

Venous + Arterial CPB use Isolate CABG

With heart surgery

9 (7)

138 (5)

With other surgeries

10 (8)

27 (1)

21 (16)

87 (3)

With valvar

< 0,001

0,039

< 0,001

DM – diabetes mellitus; CKF – chronic kidney failure; SAH – systemic arterial hypertension; COPD - chronic obstructive pulmonary disease; CABG – coronary artery bypass graft; AMI – acute myocardial infarction; CHF – congestive heart failure; CPB – cardiopulmonary bypass

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Santos AA, et al. - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery

Table 2. Mean values and standard deviation (for age) and absolute frequencies (%), according to group of death (1 year) Group

1-Year mortality (n=249) 67,5 ± 9,1 101 (40)

No death (n=2755) 61,7 ± 9,4 1099 (40)

P < 0,001

114 (46) 34 (14)

1230 (45) 426 (16)

0,749

212 (85)

1676 (61)

< 0,001

117 (47)

981 (36)

< 0001

Dyslipidemia

89 (36)

1247 (45)

0,004

CKF

44 (18)

126 (5)

< 0,001

SAH

214 (86)

2271 (82)

0,160

Previous Stroke

30 (12)

137 (5)

< 0,001

COPD

40 (16)

168 (6)

< 0,001

Peripheral arterial disease

28 (11)

118 (4)

< 0,001

Cerebrovascular disease

13 (5)

41 (1)

< 0,001

Coronary intervention

26 (10)

301 (11)

0,814

Previous CABG

6 (2)

41 (1)

0,278

Previous valvar surgery

1 (1)

7 (0,3)

0,500

Other surgeries

1 (1)

3 (0,1)

0,293

Angioplasty

18 (7)

243 (9)

0,393

Previous AMI

109 (44)

1299 (47)

0,307

CHF

28 (11)

55 (2)

< 0,001

Arrhythmia

31 (13)

134 (5)

< 0,001

6 (2)

22 (1)

0,024

Arterial

32 (13)

484 (18)

Graft type

54 (22)

309 (11)

163 (65)

1961 (71)

21 (8)

337 (12)

180 (72)

2503 (91)

Variable Age

Category Former

Smoker

No Yes

Transfusion

Surgical indication-Urgent

Venous

Venous + Arterial CPB use Isolate CABG

With heart surgery

18 (7)

138 (5)

With other surgeries

15 (6)

27 (1)

36 (14)

87 (3)

With valvar

< 0,001

0,076

< 0,001

Santos AA, et al. - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery

Rev Bras Cir Cardiovasc 2013;28(1):1-9

The patients were divided among two groups: 1) transfused, patients who received one or more units of packed red blood cells during and / or after surgery, and 2) non-transfused. We adjusted two models for assessing the mortality in these two groups: a model for 30-day mortality and another for the 1-year mortality. Quantitative variables were described as means and standard deviations or medians, and qualitative variables by absolute and relative frequencies. For the data analysis in both groups we used the t-Student test and Mann-Whitney nonparametric test. For checking homogeneity between ratios we used the chi-square or Fisher's exact test. To obtain mortality prognostic factors the multivariate logistic regression model [17] was used with "stepwise" variable selection process, based on variables that presented P<0.25 in the univariate analysis. The significance level used for the tests was 5%. This study was assessed and approved by the Ethics Committee in Research of the Hospital Beneficência Portuguesa of São Paulo, under No 700-11, according to the Helsinki Declaration.

in the group receiving RBCT, against only 1.9% deaths among non-transfused group (P <0.001). So we have a risk reduction of 3.8%, which is equivalent to state that every 26 RBCT restrictions we avoid one death in 30 days. As shown in the Figure 1, the difference between the two groups became well evident when assessed the adjusted Kaplan-Meier survival curves of 30-day mortality (P <0.001). According to this study, the RBCT also showed to be a predictor of 1-year mortality. After a follow up period of 1 year deaths totaled 249 distributed in 212 (85%) in transfused group against 37 (15%) in non-transfused group (P <0.001) (Table 3). The adjusted odds ratio for 1-year mortality after red blood cell transfusion was 2.31 (95% CI 1.31 to 4.04, P=0.003). So, we also observed differences between groups for RBC transfusion in relation to the presence of death at 1 year, being significantly higher in the transfused group. In terms of percentage, we observed a 1-year mortality rate of 11.2% in the group receiving RBCT against only 3.3% in non-transfused group (P<0.001). Thus, we have a reduced risk of 7.9%, which is equivalent to say that, every 13 RBCT restrictions we avoid a death in one year. Another data analysis in our study allows us to conclude that in both outcomes 30-day and 1-year, the nontransfused group presents significantly greater percentage of alive patients when compared to the transfused group (log-rank test P<0.001), as shown in Figure 2. Even in low risk patients (expected mortality by EuroSCORE ≤ 2%) we have significantly more deaths within 30 days in the transfused group (5% vs. 1%, P=0.007). In one year we also observed survival reduction in patients with low euroSCORE in transfused group (7% vs. 1%, P=0.001) (Table 4). When we separate a specific group of younger patients (<60 years) and EuroSCORE ≤ 2%, and hence less comorbidity, we also have significantly more deaths among transfused, as shown in Table 5. Based on these results, our study objectively shows that the RBCTs are associated with a reduction, adjusted risk, on survival in patients undergoing CABG in both 30day and 1-year outcomes.

RESULTS The group of transfused patients was 1,888 (63%) and non-transfused 1,116 (37%). There was a predominance of male patients (69.9%) and whites (84.6%) with mean age of 62.2 ± 9.5 years. The survival rate was 94.4% at hospital discharge (in four cases to another hospital) and only 0.2% (seven cases) of intraoperative death. Firstly, we found that the RBCT proved to be a predictor of 30-day mortality. The adjusted odds ratio for 30-day mortality in transfused was 2 (95% CI 1.21 to 3.31, P=0.007). The study showed a total of 129 deaths in 30 days, with 108 (84%) in transfused group and 21 (16%) in non-transfused (P<0.001). Thus, the transfusion group showed a significantly greater percentage of deaths in 30 days when compared to non-transfused (Table 3). On the other hand, we observed a mortality rate of 5.7%

Table 3. Association between transfusion and death at 30 days and 1 year Total 30-day Mortality % 1-year Mortality % No Death Non-transfused 1116 21 16 37 15 1079 Transfused 1888 108 84 212 85 1676 Total 3004 129 100 249 100 2755 30-day Mortality vs. No Death: chi-square test, P <0.001; 1-year Mortality vs. No Death: chi-square test, P <0.001

% 39 61 100

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Santos AA, et al. - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery

Fig. 1 – Kaplan-Meier survival curve in the study of death at 30 days (y-axis starts at 60%)

Fig. 2 – Adjusted survival risk after coronary artery bypass grafting (y-axis starts at 60%)

Table 4. Mortality study in patients with low risk (EuroSCORE ≤ 2) Mortality No (n=308) 30-days 1 (1%) 1-year 3 (1%) (*) descriptive level of the chi square probability

Transfused

Yes (n=317) 14 (5%) 22 (7%)

P* 0,007 0,001

Table 5. Mortality study in patients with low risk (EuroSCORE ≤ 2) and age less than 60 years Transfused Mortality No (n=188) Yes (n=154) 30-days 0 (0,0%) 11 (7%) 1-year 0 (0,0%) 15 (10%) * significant difference; † descriptive level of the Fisher's exact test probability. ‡ descriptive level of the chi-square test probability.

DISCUSSION The real purpose of the red blood cell transfusion is to maintain adequate tissue oxygenation. Blood is a living tissue that circulates through the body delivering oxygen and nutrients to all organs. The blood has its classification into groups with the presence or absence of an antigen on the red blood cells surface. Although the ABO and Rh groups (positive and negative) are the most important, there are countless others. A transplant is the transfer of cells, tissues or organs from a living individual (donor) to another (recipient) with the aim at restoring a lost function. Thus, we can say that blood transfusions are the most common type of transplantation [18]. As it occurs with any 6

P* < 0,001† < 0,001‡

transplant, there is an acute immune reaction and it also occurs in long term. We have evidence to support a role of immunomodulatory effect on the transfusion with changes in the blood cells (such as a reduction in the number of circulating lymphocytes, modification in T-cells and activation of immune cells) [19]. The cardiac surgery related traumas together with RBCTs promote a noninfectious inflammatory response reflected by an increase in the inflammatory mediator concentrations. In these circumstances cytokine levels are very high. Other limitations in respect to the blood transfusions is related to the stored blood that have a reduced tissue oxygen delivery and as the storage time increases, the

Santos AA, et al. - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery

Rev Bras Cir Cardiovasc 2013;28(1):1-9

red cells undergo to cellular, biochemical, hormonal and inflammatory structural changes, resulting in the inability of the stored blood to perfuse the microcirculation [20]. Recently, a study reported an association between blood transfusions and the pulmonary coagulation activation, as well as intraoperative thromboembolic complications [11]. These and other still unknown factors, respond largely the negative outcomes associated with blood transfusions, specifically the early mortality of patients undergoing CABG. This study showed that the death risk presented a most influential early impact of the blood transfusion for the first 30 days after surgery, as we can see by comparing the survival curves (Figures 1 and 2). When assessing the graphs it is possible to observe an association between the RBCT and reduced survival, statistically and significantly different, from those who did not receive a RBCT at 30 days (P<0.001). The RBCT effect on the risk of early mortality (first 6 months after surgery) was also found by Koch et al. [13]. Thus, though, an analysis of survival curve in one year it is also possible to observe higher mortality among the transfused group (Figure 2). The long-term mortality related to red blood cell transfusions is still speculative. Some of the mechanisms responsible for this effect would be the systemic inflammatory response and the immunomodulation [19]. But, we also can state that comorbidities (such as: HF, AF, stroke, KF, infectious agents transmission, pulmonary thromboembolism, and other malignancies) [6-11], caused by the transfusions also influence the late mortality. The higher early mortality increase is believed to be related with cardiopulmonary dysfunction, and as well as the infections increase, higher inflammatory response, and the transfusion immunomodulatory effect. With respect to different response we found with a large increase in short term mortality, and then, a sustained increase in long-term mortality in transfused patients, suggesting two distinct processes. One of these processes is the hypothesis that a transfused patient is sicker. However, the increased mortality, also in long term, discards the argument that transfusion is an indicator of hospitalized patients (Figure 2). Other information from our study, contrary to the idea that the higher mortality after a RBCT is due to the patientâ&#x20AC;&#x2122;s more severe condition, was provided by the EuroSCORE calculation, a simple and objective index, but it has been shown as a satisfactory predictor of mortality in patients undergoing CABG [21]. When we have an EuroSCORE â&#x2030;¤ 2%, the mortality is low, but in our study when we provide RBCT the death risk increased significantly in both at 30-day and 1-year mortality (Table 4). Interestingly, when we have patients younger than 60 years and an EuroSCORE â&#x2030;¤ 2%, and so with fewer comorbidities and/or aggravating risk factors for heart

surgery, we had no deaths in the non-transfused group (Table 5), unlike the group that received RBCT, where we had a significant mortality, in both early and late period. It is known that intraoperative allogeneic transfusion, which is usually based on hemoglobin levels and not on the patient's clinical status (symptoms and signs), is also a risk factor for the increased mortality [12]. Thus, we can state that the blood product transfusion is not necessarily an indicator factor of sicker patient, but it is an independent factor of early and late mortality. The potential adverse influence of blood transfusions on early and long term survival is indeed alarming, as was also demonstrated by Kuduvalli et al. [22]. Our findings were also evidenced by Michalopoulos et al. [23], which reported an independent association of blood transfusions with early and late mortality after CABG. Engoren et al. [12] also studying the effects of blood transfusions in patients undergoing CABG alone, also reported that transfused patients had twice the mortality of non-transfused. Even after the adjustment for comorbidities and other factors, the blood transfusion was still independently associated with an increase of 70% in mortality. Other authors also reported an association between RBCT and increased mortality in a series of clinical scenarios, both in cardiac and general surgery [6,11,12]. There is a global real need in making more decisions based on evidence, in relation to the RBCTs. The proposal to maintain certain hemoglobin level via blood transfusions has no strong support in the medical literature. Several randomized and controlled studies have shown that lowering the hemoglobin threshold for recommending a blood transfusion in cardiac surgery [16] and in critically ill patients [4] do not adversely affect patient outcome. In 2010 was published a large study that identified a dramatic variability on RBCT rates (7.8% to 92.8%) in patients undergoing CABG in several hospitals [5], demonstrating thereby that is often the physician and not the patient who does not tolerate low hemoglobin and/or hematocrit levels during or after a surgery [24]. Researchers have found that a hematocrit level between 17% and 21% during CABG together with moderate hypothermia, are well tolerated and have no adverse impact on the outcomes. In our study, even within a single center (hospital) we also recorded a wide variation in blood transfusion rates. Among the fourteen teams that perform CABG, the team who most indicated transfusion had 85.7% of their patients receiving RBCT and that who less indicated transfusion had 54.1%. This demonstrates that blood products are still used on a large scale in our country, hence the relevance of this study that adds itself to several others in highlighting the adverse effects of this medical practice. Various techniques and strategies to reduce the blood 7

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use have been studied; one of these is the blood products during cardiopulmonary bypass (CPB) associated with a reduced hydric balance, proposed by Souza & Braile [25]. Other proposed measures are the use of antifibrinolytic agent, aminocaproic acid [26], minimum use of CPB, especially in relation to its duration [27]. Others relevant care include preoperative patient meticulous assessment, implementation of intraoperative and postoperative measures for reducing blood loss and transfusion, active involvement of the surgeon, physician, anesthesiologist and intensivist, and as well as the use of algorithms for patients assessment and treatment, can significantly reduce transfusion need and prove to be lifesaving in cases of serious bleeding. This was evidenced by previous studies that reported a reduction of up to 50% in transfusion rates with the implementation of the cardiac surgery multidisciplinary protocols [28]. The tolerance of anemia in the perioperative period is one of the three main pillars of the blood conservation, and it does not increase the risk of complications and death in cardiac surgery [29]. Another important pillar is to optimize the erythrocyte mass by stimulating the red blood cell production through specific medication (ferrous sulfate, folic acid, vitamin B12, and erythropoietin). The third pillar, also equally important, involves the blood loss reduction by using all available resources such as electrocautery, argon beam coagulation, heparin-coated circuits, leukocyte filter, anti-fibrinolytic drugs, buffer fibrin glue, hemostatic agents, normothermia, induced hypotension, meticulous hemostasis, phlebotomy, acute normovolemic hemodilution [27], and especially the intraoperative cell salvage (cell saver). The allogeneic blood is expensive, difficult to obtain, transport and store. The local and global shortages are imminence [14,15]. Currently, there are no demonstrated real benefits of blood transfusions, and adverse effects are increasingly described. Thus, alternatives to this procedure provide many advantages, and its use is likely to improve the outcomes, as the safer and more effective agents are developed. Therefore, they should be encouraged worldwide. There are some limitations in our study. The first is that by being a retrospective database study, by its nature, we can only find associations between variables and outcomes, without however showing the causality. A second limitation is the fact that there was not a well-established rule for transfusion in both intra and postoperative period, and the transfusion triggers were dependent on the physician responsible for the patient. Another limitation is that we use all-cause of mortality as a final outcome, not differentiating causes of cardiac and non-cardiac death. A final limitation is that we have no data to differentiate transfusions, both from intraoperative

data to the postoperative period, since intraoperative transfusions, especially in surgery with CPB, are more triggered by levels of hemoglobin or hematocrit rather than patient's clinical status, and having added this parameter in our study probably would reinforce our conclusion.

CONCLUSION The red blood cell transfusion after coronary artery bypass grafting surgery increases significantly the 30day and 1-year mortality, even after the adjustment for comorbidities and other factors. Other therapeutic options and strategies for autologous blood management and conservation should be encouraged to reduce the transfusion need of blood products.

REFERENCES 1. Boletin de Hemovigilância Nº 2-ANVISA-2009; P:7. Accessed in 01/July/2012: http://portal.anvisa.gov.br/wps/wcm/connect /3a17a980474585998f47df3fbc4c6735/boletim_hemo_2009. pdf?MOD=AJPERES. 2. Practice Guidelines for blood component therapy: a report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology. 1996;84(3):73247. 3. American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006;105(1):198-208. 4. Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, et al; American College of Critical Care Medicine of the Society of Critical Care Medicine; Eastern Association for the Surgery of Trauma Practice Management Workgroup. Crit Care Med. 2009;37(12):3124-57. 5. Bennett-Guerrero E, Zhao Y, O’Brien SM, Ferguson TB Jr, Peterson ED, Gammie JS, et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA. 2010;304(14):1568-75. 6. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007;116(22):2544-52. 7. Dorneles CC, Bodanese LC, Guaragna JCVC, Macagnan FE, Coelho JC, Borges AP, et al. O impacto da hemotransfusão na

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morbimortalidade pós-operatória de cirurgias cardíacas. Rev Bras Cir Cardiovasc. 2011;26(2):222-9.

19. Blajchman MA. Immunomodulation and blood transfusion. Am J Ther. 2002;9(5):389-95.

8. Silverman RH, Nguyen C, Weight CJ, Klein EA. The human retrovirus XMRV in prostate cancer and chronic fatigue syndrome. Nat Rev Urol. 2010;7(7):392-402.

20. Spiess BD. Red cell transfusions and guidelines: work in progress. Hematol Oncol Clin North Am. 2007;21(1):185-200.

9. Stramer SL, Hollinger FB, Katz LM, Kleinman S, Metzel PS, Gregory KR, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion. 2009;49(Suppl 2):1S-29S. 10. Moore FA, Moore EE, Sauaia A. Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg. 1997;132(6):620-4. 11. Glance LG, Dick AW, Mukamel DB, Fleming FJ, Zollo RA, Wissler R, et al. Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. Anesthesiology. 2011;114(2):283-92. 12. Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74(4):1180-6. 13. Koch CG, Li L, Duncan AI, Mihaljevic T, Loop FD, Starr NJ, et al. Transfusion in coronary artery bypass grafting is associated with reduced long-term survival. Ann Thorac Surg. 2006;81(5):1650-7. 14. Novaretti MCZ. Importância dos carreadores de oxigênio livre de células. Rev Bras Hematol Hemoter. 2007;29(4):394-405. 15. Sojka BN, Sojka P. The blood donation experience: selfreported motives and obstacles for donating blood. Vox Sang. 2008;94(1):56-63. 16. Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-67. 17. Hosmer Jr. DW, Lemeshow S. Applied logistic regression. New York: John Wiley & Sons;1989. p.307. 18. Berkow R, Fletcher AJ, Bondy PK, Faling LJ, Feinstein AR, Frenkel EP, et al. Transfusão de sangue. Manual Merck. 15ª ed. 1987:p.1246.

21. Moraes Neto F, Duarte C, Cardoso E, Tenório E, Pereira V, Lampreia D, et al. Avaliação do EuroSCORE como preditor de mortalidade em cirurgia de revascularização miocárdica no Instituto do Coração de Pernambuco. Rev Bras Cir Cardiovasc. 2006;21(1):29-34. 22. Kuduvalli M, Oo AY, Newall N, Grayson AD, Jackson M, Desmond MJ, et al. Effect of peri-operative red blood cell transfusion on 30-day and 1-year mortality following coronary artery bypass surgery. Eur J Cardiothorac Surg. 2005;27(4):592-8. 23. Michalopoulos A, Tzelepis G, Dafni U, Geroulanos S. Determinants of hospital mortality after coronary artery bypass grafting. Chest. 1999;115(6):1598-603. 24. Senay S, Toraman F, Karabulut H, Alhan C. Is it the patient or the physician who cannot tolerate anemia? A prospective analysis in 1854 non-transfused coronary artery surgery patients. Perfusion. 2009;24(6):373-80. 25. Souza DD, Braile DM. Avaliação de nova técnica de hemoconcentração e da necessidade de transfusão de hemoderivados em pacientes submetidos à cirurgia cardíaca com circulação extracorpórea. Rev Bras Cir Cardiovasc. 2004;19(3):287-94. 26. Benfatti RA, Carli AF, Silva GVR, Dias AEMAS, Goldiano JA, Pontes JCDV. Influência do ácido épsilon aminocapróico no sangramento e na hemotransfusão pós-operatória em cirurgia valvar mitral. Rev Bras Cir Cardiovasc. 2010;25(4):510-5. 27. Souza HJB, Moitinho RF. Estratégias para redução do uso de hemoderivados em cirurgia cardiovascular. Rev Bras Cir Cardiovasc. 2008;23(1):53-9. 28. Van der Linden P, Dierick A. Blood conservation strategies in cardiac surgery. Vox Sang. 2007;92(2):103-12. 29. Moskowitz DM, McCullough JN, Shander A, Klein JJ, Bodian CA, Goldweit RS, et al. The impact of blood conservation on outcomes in cardiac surgery: is it safe and effective? Ann Thorac Surg. 2010;90(2):451-8.

ORIGINAL ARTICLE

Rev Bras Cir Cardiovasc 2013;28(1):10-21

Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery Fatores de risco pré, intra e pós-operatórios para mortalidade hospitalar em pacientes submetidos à cirurgia de aorta

Mário Issa1, Álvaro Avezum2, Daniel Chagas Dantas3, Antonio Flávio Sanches de Almeida4, Luiz Carlos Bento de Souza5, Amanda Guerra de Moraes Rego Sousa6 DOI: 10.5935/1678-9741.20130004

RBCCV 44205-1437

Abstract Objectives: The primary objective was to identify predictors of hospital mortality in patients undergoing aortic surgery. The secondary objective was to identify factors associated with clinical outcome composed hospital (death, bleeding, neurologic complications or ventricular dysfunction). Methods: A cross-sectional design with longitudinal component. Through chart review, 257 patients were included. Inclusion criteria were: aortic dissection Stanford type A and ascending aortic aneurysm. Exclusion criteria were acute aortic dissection, of any kind, and no aortic aneurysm involving the ascending segment. Variables assessed: demographics, preoperative factors, intraoperative and postoperative. Results: Variables with increased risk of hospital mortality (OR, 95% CI, P value): black ethnicity (6.8, 1.54-30.2; 0.04), cerebrovascular disease (10.5, 1.12-98.7; 0.04), hemopericardium (35.1, 3.73-330.2; 0.002), Cabrol operation (9.9, 1.47-66.36; 0.019), CABG simultaneous (4.4;

1.31 to 15.06; 0.017), bleeding (5.72, 1.29-25.29; 0.021) and cardiopulmonary bypass (CPB) time [min] (1.016; 1.0071.026; 0.001). Thoracic pain was associated with reduced risk of hospital death (0.27, 0.08-0.94, 0.04). Variables with increased risk of hospital clinical outcome compound were: use of antifibrinolytic (3.2, 1.65-6.27; 0.0006), renal complications (7.4, 1.52-36.0; 0.013), pulmonary complications (3.7, 1.58.8, 0.004), EuroScore (1.23; 1.08-1.41; 0.003) and CPB time [min] (1.01; 1.00 to 1.02; 0.027). Conclusion: Ethnicity black, cerebrovascular disease, hemopericardium, Cabrol operation, CABG simultaneous, hemostasis review and CPB time was associated with increased risk of hospital death. Chest pain was associated with reduced risk of hospital death. Use of antifibrinolytic, renal complications, pulmonary complications, EuroScore and CPB time were associated with clinical outcome hospital compound.

1 - Surgeon at Dante Pazzanese Institute of Cardiology (IDPC), PhD in Cardiology at University of São Paulo (USP)/IDPC São Paulo, SP, Brazil. 2 - PhD in Cardiology at USP. Director of the Teaching and Research Division at IDPC, São Paulo, SP, Brazil. Advisor of PhD Thesis, article starting point. 3 - Resident in Cardiovascular Surgery at IDPC, São Paulo, SP, Brazil. Record data survey. 4 - PhD in Sciences at USP, cardiovascular surgeon at IDPC, São Paulo, SP, Brazil. Data survey. 5 - PhD in Medicine at Federal University of São Paulo (UNIFESP), Director of the Surgery Division at IDPC, São Paulo, SP, Brazil. Article advisor. 6 - Full Professor at USP, Technical Director of the Health Department at IDPC, Article advisor.

This study was carried out at Dante Pazzanese Institute of Cardiology São Paulo, SP, Brazil.

Descriptors: Aortic Aneurysm. Thoracic. Aortic Aneurysm, surgery.

Aortic

Aneurysm,

Correspondence address: Mário Issa Av. Dante Pazzanese 500 – Vila Mariana – São Paulo, SP. Brazil Zip code: 04012-909. E-mail: drmarioissa@yahoo.com.br

Article received on November 27th, 2012 Article accepted on December 28th, 2012

Rev Bras Cir Cardiovasc 2013;28(1):10-21

Issa M, et al. - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery

Abbreviations, Acronyms & Symbols Stroke CPB Cm SD LVEF CI Min OR

Stroke Cardiopulmonary bypass Centimeters Standard deviation Left ventricular ejection fraction Confidence interval Minutes Oddis ratio

Resumo Objetivos: O objetivo primário deste estudo é identificar preditores de óbito hospitalar em pacientes submetidos à cirurgia de aorta. O objetivo secundário é identificar fatores associados ao desfecho clínico composto hospitalar (óbito, sangramento, disfunção ventricular ou complicações neurológicas). Métodos: Delineamento transversal com componente longitudinal; por meio de revisão de prontuários, foram incluídos 257 pacientes. Os critérios de inclusão foram: dissecção crônica de aorta tipo A de Stanford e aneurisma de aorta ascendente. Foram excluídos casos de dissecção aguda de aorta, qualquer tipo, e aneurisma de aorta não envolvendo segmento ascendente. As variáveis avaliadas foram demografia, fatores pré, intra e pós-operatórios.

INTRODUCTION In the United States, approximately 15 000 people a year are diagnosed with thoracic aortic aneurysm. Additionally, more than 47 thousand people per year die from aortic diseases, more than breast cancer, AIDS, homicides or car crashes, making aortic disease a silent epidemic [1]. Aneurysms and dissection constitute the main aortic diseases, which can be subjected to common principles and surgical treatment techniques. Surgical management remains a challenge in elective procedures as well as in emergencies. The decision on surgery is based on the balance between the risk and the chance of surgical aortic rupture, which can be particularly difficult in elective cases. Furthermore, among patients with thoracic aortic rupture, mortality is extremely high, reaching above 94% [2]. The primary aim of this study was to identify predictors independently associated with hospital mortality in patients undergoing surgical repair of aortic diseases. The secondary

Resultados: Variáveis com risco aumentado de óbito hospitalar (RC; IC95%; P valor): etnia negra (6,8; 1,5430,2; 0,04), doença cerebrovascular (10,5; 1,12-98,7; 0,04), hemopericárdio (35,1; 3,73-330,2; 0,002), operação de Cabrol (9,9; 1,47-66,36; 0,019), cirurgia de revascularização miocárdica simultânea (4,4; 1,31-15,06; 0,017), revisão de hemostasia (5,72; 1,29-25,29; 0,021) e circulação extracorpórea (CEC) [min] (1,016; 1,007-1,026; 0,001). Dor torácica associou-se com risco reduzido de óbito hospitalar (0,27; 0,08-0,94; 0,04). Variáveis com risco aumentado do desfecho clínico composto hospitalar foram: uso de antifibrinolítico (3,2; 1,65-6,27; 0,0006), complicação renal (7,4; 1,52-36,0; 0,013), complicação pulmonar (3,7; 1,5-8,8; 0,004), EuroScore (1,23; 1,08-1,41; 0,003) e tempo de CEC [min] (1,01; 1,00-1,02; 0,027). Conclusão: Etnia negra, doença cerebrovascular, hemopericárcio, operação de Cabrol, revascularização miocárdica simultânea, revisão de hemostasia e tempo de CEC associaram-se com risco aumentado de óbito hospitalar. Dor torácica associou-se com risco reduzido de óbito hospitalar. Uso de antifibrinolítico, complicação renal, complicação pulmonar, EuroScore e tempo de CEC associaram-se ao desfecho clínico composto hospitalar. Descritores: Aneurisma aórtico/cirurgia. Aneurisma da aorta torácica. Aneurisma aórtico.

aim was to identify variables independently associated to compound clinical outcome during hospitalization (death, bleeding, neurologic complications or ventricular dysfunction). METHODS This research involves a cross-sectional design, with data collection and retrospective and prospective longitudinal component. Consecutive patients with a confirmed diagnosis of ascending aortic aneurysm or type A Stanford chronic dissection were included from the record review, through retrospective data collection, beginning in January 2004. From January 2009, consecutive patients were enrolled through prospective data collection, until December 2010. The observed sample included 257 patients whose events hospital mortality and compound clinical outcome were assessed in terms of quantitative and qualitative measures. 11

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Inclusion criteria were patients who had undergone surgery for type A Stanford chronic dissection and ascending aortic aneurysm, involvement of the ascending aorta in all patients, commitment present or not of other aortic segments, both genders and no age limit. Exclusion criteria were patients with acute aortic dissection (of any kind), patients with aneurysms involving other aortic segments that were not ascending aorta and type B Stanford chronic dissection. The composite clinical outcome refers to the presence of hospital mortality or neurologic complications (stroke or coma > 24 hours) or ventricular dysfunction (symptomatic heart failure and/or cardiogenic shock) or clinically relevant bleeding (presence of hemostasis review and/or need for transfusion of packed red blood cells â&#x2030;Ľ 3U), or that is, patients who had at least one of these events was characterized as having composite clinical outcome. For statistical analysis, the sample of patients studied was described by absolute (n) and relative (%) frequencies of qualitative measures (factors) and summary statistics of mean, median, standard deviation (SD) and 25 and 75 percentiles of quantitative measurements (covariates). The association between the qualitative measures and groups (mortality and composite clinical outcomes) was assessed by chi-square test or Fisher exact test. To compare quantitative measures between the two groups the nonparametric Mann-Whitney test was applied. For death after surgery were observed the Kaplan-Meier survival curves or average survival and, initially, the effects of factors assessed by the Log-Rank test and the covariates by Cox regression. The effects of factors and covariates considered statistically significant (P<0.10) or clinically relevant, were also observed, all present in a logistic regression model for multiple variables on hospital mortality and compound clinical outcome. For late death, in the long-term after surgery, multivariate were assessed by Cox regression model The level of significance was set at 5%, or that is, differences were considered significant when P value of the tests was less than 5%. The cases in which the P value remained between 5% and < 10% suggested trends of significant effect. This study was approved by the Research Ethics Committee of the Dante Pazzanese Institute of Cardiology in October 2010, under protocol number 3994.

diabetes mellitus in 13.2% and hypertension in 78, 6%. Chest pain was present in 41.6% of patients, the diagnosis of Marfan syndrome in 2.7%, and mean left ventricular ejection fraction (LVEF) assessed in 57.8%, mean EuroScore of 6.12. In this sample, 55 (21.4%) patients underwent reoperation, and in 29 (50.9%) of them only aortic valve replacement was performed in the first procedure, in nine (16.4%), surgery for myocardial revascularization, in five (9.1%), correction of acute aortic dissection, in four (7.3%), repair of aortic coarctation, in three (5.4%), aortic aneurysm, and only one case in each of the following situations: mitral valve replacement, tricuspid valvuloplasty, correction of patent ductus arteriosus, a ventricular septal defect, tetralogy of Fallot and interrupted aortic arch. The simultaneous surgery for myocardial revascularization was required in 49 (19.1%) patients. Demographic data for all patients enrolled in this study are described in Table 1. Quantitative measures are summarized in amplitude, mean and standard deviation; qualitative measures in absolute frequency and percentage. The Tables 2 and 7 summarize the assessments performed in this study.

RESULTS We included 257 patients, from January 2004 to December 2010, being 33.9% female, 7% of black ethnicity, with a mean age of 57.7 years. Of this population, 75% had a diagnosis of ascending aortic aneurysm and 25% of type A Stanford chronic dissection, with smoking present in 40.5%, 12

DISCUSSION In this analysis including 257 consecutive patients who had undergone surgery during the period from January 2004 to December 2010, the overall hospital mortality rate was 8.17%. By multivariate analysis, the logistic model identified the following factors independently associated with death during hospital stay: patients of black ethnicity, associated CABG, Cabrol operation, presence of cerebrovascular disease, need for revision of hemostasis, prolonged cardiopulmonary bypass (CPB) and the presence of hemopericardium. The presence of chest pain was identified as a protective factor. Factors such as axillary cannulation site, use of antifibrinolytic, neurological complications, presence of severe arrhythmia, EuroSCORE, anoxia (min) and bleeding in the first 24 hours, by multivariate analysis, were independently associated with the occurrence of the composite clinical outcome. Contemporary surgical series involving patients with ascending aortic disease with the use of modern techniques of grafting and methods of cerebral and myocardial protection present hospital mortality rates ranging from 1.7% to 17.1%, probably due to the heterogeneity of patient population assessed. The causes of mortality include haemorrhage, stroke and respiratory failure, and heart failure is considered the most common cause of premature death in this population [3-5]. Gazoni et al. [5] compared immediate results of elective thoracic aortic aneurysm surgery, among low-volume centers (< 40 surgeries/year) and high volume (> 80

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surgeries/year). Operative mortality was 8.3% and 3.7%, respectively (P=0.02). In logistic regression analysis, lowvolume centers were significantly associated with increased rates of complications and mortality (P<0.05). In this study, 66.1% of patients were male and among hospital deaths, 57.1% were male. Gender and age had no statistically significant impact on hospital and late mortality rates, after adjustment among the different variables in the multivariate model. It should be mentioned that the age is presented as an independent risk factor for mortality in other areas of cardiovascular disease, such as acute coronary syndrome, atrial fibrillation or heart failure, but also female patients have

higher mortality rates when subjected to myocardial revascularization surgery, when compared with male patients. The results of this research can be explained by two considerations: age and gender do not represent predictors independently associated with mortality in patients with aortic disease assessed in this study or due to lack of statistical power, we could not demonstrate the effect of these two variables on clinically relevant outcomes. The inclusion of additional number of patients could clarify the above considerations. Despite these differences, when all variables are entered into the logistic model, in the present study, these variables did not emerge as independent predictors of mortality.

Table 1. Demographics and preoperative factors. Age (years) Weight (kg) Gender Ethnicity Functional class (NYHA) Diagnosis Diagnostic methods Smoking Diabetes mellitus PAD SAH (mmHg) SAP DBP CRF Dialytic CRF Prior stroke COPD Cerebrovascular disease Marfan Syndrome Syncope Pericardial effusion Chest pain Neurological symptoms Prior cardiac surgery Coronary disease Associated CABG EF (%) EF Creatinine EuroScore Elective

18 to 81 41 to 115 Male 170 (66.1%) Black 18 (7%) I 70 (27.2%) Aneurysm 193 (75%) Ecocardiogram 242 (94.2%) 104 (40,5%) 34 (13.2%) 11 (4.3%) 202 (78.6%) 110 to 220 40 to 130 21 (8.2%) 1 (0.4%) 15 (5.8%) 7 (2.7%) 4 (1.6%) 7 (2.7%) 7 (2.7%) 3 (1.2%) 107 (41.6%) 4 (1.6%) 55 (21.4%) 53 (20.6%) 49 (19.1%) 20 to 80 Ecocardiogram 256 (99.6%) 0.5 to 2.4 3 to 17 247 (96.1%)

Mean 57.7 Mean 72.8 Female 87 (33.9%) Not black 239 (93%) II 119 (46.3%) Dissection 64 (24.9%) CT 162 (63%)

SD 13 SD 13.27 III 65 (25.3%)

IV 3 (1.2%)

Catheterization 181 (70.4%) MNR 2 (0.8%)

Mean 151.5 Mean 85.5

SD 20.1 SD 14.9

Mean 57.8 NMR 1 (0.4%) Mean 1.13 Mean 6.12

SD 11.6 SD 0.32 SD 2.52

Stroke:; PAD: Peripheral Arterial Disease, SD: standard deviation; COPD: Chronic obstructive pulmonary disease, EF: ejection fraction; SAH: Systemic Arterial Hypertension; CRF: Chronic Renal Failure; kg: kilogram; mmHg: millimeters of mercury; NYHA: New York Heart Association; DBP: diastolic blood pressure, SBP: Systolic blood pressure; CABG: Coronary artery bypass surgery, MRI: Magnetic resonance imaging, CT: computed tomography

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Issa M, et al. - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery

Table 2. Demographics and preoperative factors and operative death.

n (%) Female Black Dissection ECHO Smoking Diabetes COPD SAH CRF Prior stroke COPD Cerebrovascular disease Marfan syndrome Syncope Pericardial effusion Thoracic pain Neurological symptoms Prior cardiac surgery Coronary disease Elective Aortic cannulation Bicuspid aortic valve Aortic insufficiency Hemopericardium Mean (SD) Median (Per25;Per75) Age (years) Last Creatinine

Variables Hospital death No (N=236) Yes (N=21) 78 (33.05%) 9 (42.86%) 14 (5.93%) 4 (19.05%) 54 (22.88%) 10 (47.62%) 226 (95.76%) 16 (76.19%) 96 (40.68%) 8 (38.1%) 29 (12.29%) 5 (23.81%) 8 (3.39%) 3 (14.29%) 183 (77.54%) 19 (90.48%) 17 (7.2%) 4 (19.05%) 13 (5.51%) 2 (9.52%) 6 (2.54%) 1 (4.76%) 2 (0.85%) 2 (9.52%) 7 (2.97%) 0 (0%) 6 (2.54%) 1 (4.76%) 2 (0.85%) 1 (4.76%) 102 (43.22%) 5 (23.81%) 3 (1.27%) 1 (4.76%) 46 (19.49%) 9 (42.86%) 45 (19.07%) 8 (38.1%) 226 (95,76%) 21 (100%) 170 (72.34%) 14 (66.67%) 37 (15.68%) 2 (9.52%) 147 (62.29%) 13 (61.9%) 3 (1.27%) 2 (9.52%)

Total (N=257) 87 (33.85%) 18 (7%) 64 (24.9%) 242 (94.16%) 104 (40.47%) 34 (13.23%) 11 (4.28%) 202 (78.6%) 21 (8.17%) 15 (5.84%) 7 (2.72%) 4 (1.56%) 7 (2.72%) 7 (2.72%) 3 (1.17%) 107 (41.63%) 4 (1.56%) 55 (21.4%) 53 (20.62%) 247 (96,11%) 184 (71.88%) 39 (15.18%) 160 (62.26%) 5 (1.95%)

P value 0.360 (P) 0.085 (F) 0.012 (P) 0.004 (F) 0.810 (P) 0.170 (F) 0.018 (P) 0.160 (P) 0.058 (P) 0.450 (P) 0.540 (P) 0.002 (P) 0.420 (P) 0.540 (P) 0.220 (F) 0.084 (P) 0.290 (F) 0.012 (P) 0.039 (P) 0,330 (P) 0.580 (P) 0.450 (P) 0.970 (P) 0.055 (F)

57.5 (13.13) 59 (48.25;68) 1.11 (0.33) 1 (0.9;1.3)

57.56 (12.95) 59 (48;67.25) 1.13 (0.32) 1 (0.9;1.3)

0.471

59.9 (11.62) 60 (53.5;67.5) 1.26 (0.29) 1.2 (1.05;1.45)

0.019

F: Fisher test, P: Pearson test. Stroke; PAD: Peripheral Arterial Disease, SD: standard deviation; COPD: Chronic obstructive pulmonary disease, SAH: Systemic Arterial Hypertension; CRF: Chronic renal failure

In a study on the quality of life of patients undergoing aortic aneurysm, Lohse et al. [6] demonstrated a highly significant connection between cardiac surgeries and postoperative death (P=0.001). There was also a significant association between death and myocardial infarction (P<0.001), stroke (P=0.001), prolonged ventilation time (P<0.001), increased use of transfusion products (P=0.016) and prolonged surgical time ( P<0.001). The high incidence of myocardial infarction perioperatively was associated with a high percentage of patients with coronary artery disease. With regard to quality of life, functional class improved according to the classification of the Canadian Cardiovascular Society. One of the major impacts in reducing the quality of life of these patients was the presence of stroke, as well as prolonged hospitalization. 14

In a study published by Czerny et al. [7], age was not associated with increased risk of mortality and neurological injury in patients undergoing surgical repair of acute or chronic diseases of the thoracic aorta with hypothermic circulatory arrest, a finding consistent with the results of this study. In our series, 55 (21.4%) patients underwent reoperation, and in 29 (51%) only aortic valve replacement was performed in the first procedure, in nine (16.4%), surgery for myocardial revascularization, in five (9.1%), correction of acute aortic dissection, in four (7.3%), repair of aortic coarctation, in three (5.5%), aortic aneurysm repair. Each of the following events: mitral valve replacement, tricuspid valvuloplasty, correction of patent ductus arteriosus, a ventricular septal defect, tetralogy of Fallot and aortic arch interruption occurred in only 1 case.

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Issa M, et al. - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery

Table 3. Intra- and postoperative factors and hospital death. Variables Hospital death n (%) Coronary surgeries Hemiarch Bentall Cabrol Supracoronary tube Tirone David Yacoub Descending aorta stent Reimplantation of block base vessels Separated reimplantation Aortoplasty Hemostasis review Blood products Antifibrinolytic Neurological complication Renal complication Infectious complication Pulmonary complication Vascular complication Gastrointestinal complication Arrhythmia Multiple organ failure Heart Failure Cardiogenic shock Malperfusion syndrome ASA Clopidogrel ACEI/ARB Betablocker Statin Antiarrhythmic Diuretic Spironolactone Mean (SD) Median (Per25;Per75) Bleeding in the first 24 hours (ml) CPB time (min) Anoxia time (min) EuroScore

No (N=236) 42 (17.8%) 18 (7.63%) 85 (36.02%) 7 (2.97%) 125 (52.97%) 4 (1.69%) 4 (1.69%) 19 (8.05%) 11 (4.66%)

Yes (N=21) 7 (33.33%) 2 (9.52%) 6 (28.57%) 2 (9.52%) 12 (57.14%) 1 (4.76%) 0 (0%) 3 (14.29%) 3 (14.29%)

Total (N=257) 49 (19.07%) 20 (7.78%) 91 (35.41%) 9 (3.5%) 137 (53.31%) 5 (1.95%) 4 (1.56%) 22 (8.56%) 14 (5.45%)

P value 0.082 (P) 0.750 (P) 0.490 (P) 0.110 (P) 0.710 (P) 0.340 (F) 1.000 (F) 0.320 (P) 0.060 (P)

2 (0.85%) 3 (1.27%) 15 (6.36%) 178 (75.42%) 84 (35.59%) 13 (5.51%) 13 (5.51%) 31 (13.14%) 33 (13.98%) 1 (0.42%) 4 (1.69%) 66 (27.97%) 0 (0%) 12 (5.08%) 2 (0.85%) 0 (0%) 165 (69.92%) 1 (0.42%) 193 (81.78%) 169 (71.61%) 58 (24.58%) 44 (18.64%) 92 (38.98%) 13 (5.51%)

0 (0%) 0 (0%) 4 (19.05%) 20 (95.24%) 11 (52.38%) 4 (19.05%) 9 (42.86%) 10 (47.62%) 14 (66.67%) 6 (28.57%) 0 (0%) 14 (66.67%) 14 (66.67%) 13 (61.9%) 15 (71.43%) 16 (76.19%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

2 (0.78%) 3 (1.17%) 19 (7.39%) 198 (77.04%) 95 (36.96%) 17 (6.61%) 22 (8.56%) 41 (15.95%) 47 (18.29%) 7 (2.72%) 4 (1.56%) 80 (31.13%) 14 (5.45%) 25 (9.73%) 17 (6.61%) 16 (6.23%) 165 (64.2%) 1 (0.39%) 193 (75.1%) 169 (65.76%) 58 (22.57%) 44 (17.12%) 92 (35.8%) 13 (5.06%)

1.000 (F) 1.000 (F) 0.033 (P) 0.039 (P) 0.120 (P) 0.017 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) 1.000 (F) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) 1.000 (F) < 0.001 (P) < 0.001 (P) 0.010 (P) 0.030 (P) < 0.001 (P) 0.270 (P)

509.39 (303.3) 434 (320;640) 138.83 (45.25) 137.5 (105;162.25) 101.44 (32.87) 101 (79;123) 5.98 (2.5) 6 (4;7)

594.62 (465.31) 450 (275;999) 185.95 (90.31) 180 (122.5;195) 115.95 (57) 99 (86.5;138.5) 7.62 (2.18) 7 (6;9)

516.35 (319.23) 438 (320;650) 142.67 (50.24) 140 (110;170) 103.6 (35.29) 103 (80;125) 6.05 (2.47) 6 (4;7.25)

0.756 0.006 0.464 0.002

F: Fisher test, P: Pearson test. ASA: acetylsalicylic acid; ARB: angiotensin receptor blockers; CPB: cardiopulmonary bypass, SD: standard deviation; ACEI: Inhibitors of angiotensin-converting enzyme, min = minutes; ml: milliliters.

Rev Bras Cir Cardiovasc 2013;28(1):10-21

Issa M, et al. - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery

Table 4. Logistic model for hospital death. Black ethnicity Cerebrovascular disease Chest pain Hemopericardium Type of surgery: Cabrol Coronary surgery Hemostasis review CPB time (min) Constant

Effect 1.92 2.35 -1.32 3.56 2.29 1.49 1.74 0.02 -5.8

SE 0.76 1.14 0.64 1.14 0.97 0.62 0.76 0 1.01

OR 6.82 10.51 0.27 35.08 9.86 4.43 5.72 1.016 0

1.54 1.12 0.08 3.73 1.47 1.31 1.29 1.007

CI95%

30.2 98.7 0.94 330.2 66.36 15.06 25.29 1.026

P value 0.011 0.04 0.04 0.002 0.019 0.017 0.021 0.001 < 0.001

P value (Hosmer and Lemeshow) = 0.553. CPB: cardiopulmonary bypass; SE: Standard Error, CI: Confidence interval; OR: Odds Ratio

Table 5. Preoperative factors and compound clinical outcome.

n (%) Female Black ethnicity Dissection Smoking Diabetes PAD SAH CRF Prior stroke COPD Cerebrovascular disease Marfan Syndrome Syncope Pericardial effusion Chest pain Neurological symptoms Prior heart surgery Coronary disease Elective Aortic cannulation Bicuspid aortic valve Aortic failure Hemopericardium Mean (SD) Median (Per25;Per75) Age (years) Last Creatinine

Variables Combined event No (N=159) Yes (N=98) 103 (64.78%) 67 (68.37%) 11 (6.92%) 7 (7.14%) 33 (20.75%) 31 (31.63%) 69 (43.4%) 35 (35.71%) 18 (11.32%) 16 (16.33%) 3 (1.89%) 8 (8.16%) 125 (78.62%) 77 (78.57%) 11 (6.92%) 10 (10.2%) 8 (5.03%) 7 (7.14%) 5 (3.14%) 2 (2.04%) 2 (1.26%) 2 (2.04%) 4 (2.52%) 3 (3.06%) 3 (1.89%) 4 (4.08%) 1 (0.63%) 2 (2.04%) 68 (42.77%) 39 (39.8%) 2 (1.26%) 2 (2.04%) 23 (14.47%) 32 (32.65%) 27 (16.98%) 26 (26.53%) 155 (97.48%) 92 (93.88%) 121 (76.58%) 63 (64.29%) 28 (17.61%) 11 (11.22%) 103 (64.78%) 57 (58.16%) 1 (0.63%) 4 (4.08%)

57.35 (12.38) 59 (49;67) 1.08 (0.31) 1 (0.9;1.2)

58.26 (14.01) 60.5 (48.75;69) 1.19 (0.34) 1.2 (1;1.4)

Total (N=257) 170 (66.15%) 18 (7%) 64 (24.9%) 104 (40.47%) 34 (13.23%) 11 (4.28%) 202 (78.6%) 21 (8.17%) 15 (5.84%) 7 (2.72%) 4 (1.56%) 7 (2.72%) 7 (2.72%) 3 (1.17%) 107 (41.63%) 4 (1.56%) 55 (21.4%) 53 (20.62%) 247 (96.11%) 184 (71.88%) 39 (15.18%) 160 (62.26%) 5 (1.95%)

P value 0.550 (P) 0.560 (F) 0.500 (P) 0.220 (P) 0.250 (P) 0.016 (P) 0.990 (P) 0.350 (P) 0.480 (P) 0.710 (F) 0.630 (F) 1.000 (F) 0.430 (F) 0.560 (F) 0.630 (P) 0.630 (F) 0.001 (P) 0.066 (P) 0.140 (P) 0.033 (P) 0.160 (P) 0.280 (P) 0.071 (F)

57.7 (13.01) 59 (49;68) 1.13 (0.32) 1 (0.9;1.3)

0.393 0.004

Mann-Whitney F: Fisher test, P: Pearson test. Stroke; PAD: Peripheral Arterial Disease, SD: standard deviation; COPD: Chronic obstructive pulmonary disease, hypertension: Hypertension; CRF: Chronic renal failure

Rev Bras Cir Cardiovasc 2013;28(1):10-21

Issa M, et al. - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery

Table 6. Intra- and postoperative factors and compound clinical outcome.

n(%) Coronary surgeries Hemiarch Bentall Cabrol Supracoronary tube Tirone David Yacoub Descending aortic stent Reimplantation of block base vessels Separeted reimplantation Aortoplasty Hemostasis review Blood products Antifibrinolytic Neurological complication Renal failure Infectious complication Pulmonary complication Vascular complication Gastrointestinal complication Arrhythmia Multiple organ failure Heart failure Cardiogenic shock Malperfusion syndrome ASA Clopidogrel ACEI/ARB Betablocker Statin Antiarrhythmic Diuretic Spironolactone Mean (SD) Median (Per25;Per75) CPB time (min) Bleeding in the first 24 hours (ml) Anoxia time (min) EuroScore

Variables Combined event No (N=159) Yes (N=98) 24 (15.09%) 25 (25.51%) 10 (6.29%) 10 (10.2%) 52 (32.7%) 39 (39.8%) 3 (1.89%) 6 (6.12%) 89 (55.97%) 48 (48.98%) 4 (2.52%) 1 (1.02%) 4 (2.52%) 0 (0%) 12 (7.55%) 10 (10.2%) 9 (5.66%) 5 (5.1%)

Total (N=257) 49 (19.07%) 20 (7.78%) 91 (35.41%) 9 (3.5%) 137 (53.31%) 5 (1.95%) 4 (1.56%) 22 (8.56%) 14 (5.45%)

P value 0.039 (P) 0.250 (P) 0.240 (P) 0.073 (P) 0.270 (P) 0.650 (F) 0.300 (F) 0.460 (P) 0.840 (P)

0 (0%) 1 (0.63%) 0 (0%) 101 (63.52%) 37 (23.27%) 1 (0.63%) 2 (1.26%) 10 (6.29%) 11 (6.92%) 1 (0.63%) 1 (0.63%) 44 (27.67%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 110 (69.18%) 1 (0.63%) 132 (83.02%) 114 (71.7%) 40 (25.16%) 33 (20.75%) 51 (32.08%) 7 (4.4%)

2 (2.04%) 2 (2.04%) 19 (19.39%) 97 (98.98%) 58 (59.18%) 16 (16.33%) 20 (20.41%) 31 (31.63%) 36 (36.73%) 6 (6.12%) 3 (3.06%) 36 (36.73%) 14 (14.29%) 25 (25.51%) 17 (17.35%) 16 (16.33%) 55 (56.12%) 0 (0%) 61 (62.24%) 55 (56.12%) 18 (18.37%) 11 (11.22%) 41 (41.84%) 6 (6.12%)

0.140 (F) 0.560 (F) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) 0.013 (F) 0.150 (F) 0.120 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) < 0.001 (P) 0.034 (P) 1.000 (F) < 0.001 (P) 0.011 (P) 0.200 (P) 0.049 (P) 0.110 (P) -

130.72 (39.96) 130 (100;155) 430.84 (187.27) 380 (290;520) 96.72 (31.05) 98 (75;116) 5.55 (2.2) 6 (4;7)

162.09 (62.19) 152.5 (123.75;185) 655.1 (424.72) 540 (350;873.75) 112.19 (40.12) 111 (83;137.5) 7.04 (2.73) 7 (5.75;8)

142.68 (51.81) 140 (110;170) 516.35 (319.23) 438 (320;650) 102.62 (35.52) 101 (80;123) 6.12 (2.52) 6 (4;8)

< 0.001 < 0.001 0.002 < 0.001

Mann-Whitney F: Fisher test, P: Pearson test. ASA: acetylsalicylic acid; ARB: angiotensin receptor blockers; CPB: cardiopulmonary bypass, SD: standard deviation; ACEI: Inhibitors of angiotensin-converting enzyme, min = minutes; ml: milliliters

Rev Bras Cir Cardiovasc 2013;28(1):10-21

Issa M, et al. - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery

Table 7. Logistic model for compound clinical outcome. Cannulation site: axillary Antifibrinolytic Type of surgery: Cabrol Renal failure** Pulmonary complication*** Severe arrhythmia**** EuroESCORE CPB time (min)

Effect 1.011 1.169 1.662 2.001 1.295 1.196 0.209 0.009

SE 0.54 0.34 0.857 0.81 0.45 0.64 0.07 0.004

OR 2.75 3.22 5.27 7.40 3.65 3.31 1.23 1.01

Constant

-4.183

0.768

0.02

0.95 1.65 0.98 1.52 1.51 0.95 1.08 1

CI95%

7.96 6.27 28.25 36.01 8.84 11.51 1.41 1.02

P value 0.062 0.0006 0.0524 0.0132 0.0041 0.0602 0.0026 0.0265 < 0.0001

P value (Hosmer and Lemeshow) = 0.432; Renal Complication**: creatinine > 2 mg/dl or 2x > preoperatively; Pulmonary Complications*** : need for invasive ventilation > 48 hours; Severe arrhythmia **** : VT, VF and AVB. CPB: cardiopulmonary bypass; SE: Standard Error, CI: Confidence interval, min = minutes, OR: odds ratio

Although in univariate analysis for hospital mortality the prior heart surgery variable had demonstrated statistical significance (P=0.012) in multivariate analysis there was persistence of the level of significance of this variable, showing not being an independent predictor. As shown by Estrera et al. [8], patients with type A acute dissection after previous cardiac surgery showed similar risks of poor perfusion, hypotension and cardiac tamponade. This finding suggests that adhesions formed after the operation does not eliminate the risk of cardiac tamponade due to aortic rupture. Although the results are plausible, hospital mortality was higher (31% vs. 13.8%, P <0.007) than among patients without a history of cardiac surgery. It is recommended prophylactic replacement of the ascending aorta, although apparently normal, where there is any swelling in cases of bicuspid aortic valve. Even in the absence of significant aortic valve disease, there is often association with dilatation of the aortic root, annuloaortic ectasia and aortic dissection. After replacement of the bicuspid aortic valve, this finding is reported as a risk factor for late acute dissection and ascending aorta aneurysm [9-11]. For patients with bicuspid aortic valve normofunctioning and dilatation of the ascending aorta, the surgery is recommended for those with a diameter > 5 cm and differentiated approach for patients under surveillance in the absence of significant increase (> 0.5 cm/year). Overall survival is considered equivalent to that of a normal population considered the same age and gender. The surgery was required in approximately 10% of patients treated each year [12]. 18

Regarding risk factors for hospital mortality, Ogengâ&#x20AC;&#x2122;o et al. [13] studied the pattern of aneurysms among young black Kenyan. The patients were divided into two groups: â&#x2030;¤ 40 years (group I) and > 40 years (group II). Located in the aorta, 49.6% were in group I and 68.6% in group II. Most in the abdominal aorta (64.9%), especially in the infrarenal segment. In the aortic ascending segment, below 5%, and equivalent for both groups. The gender ratio is 2.7: 1, with predominance in males. In aortic and intracranial segments, the highest incidence occurred between 31 and 40 years and between 21 and 30 at the periphery. The comorbidities in both groups were: hypertension, smoking, AIDS, alcoholism, obesity and Marfan syndrome. However, only in patients aged over 40 years, atherosclerosis and dyslipidemia were present, and diabetes mellitus was associated with peripheral and intracranial aneurysms, but not in the aorta. The prevalence of atherothrombotic traditional risk factors varied significantly among ethnic groups. The use of medical therapy to reduce the risk was comparable among all groups. In less than 2 years of follow-up, the rate of cardiovascular mortality was significantly higher in blacks (6.1%) compared to all other ethnic groups (3.9%, P=0.01), according to Meadows et al. [14]. In previous studies, we observed that the procedure for simultaneous correction of ascending aorta and coronary artery bypass grafting can be performed safely and with good results. Ueda et al. [15] demonstrated that the incomplete coronary revascularization was identified as a risk factor for cardiovascular events (P=0.016). In an analysis for the surgical treatment of aortic root, comparing the valved tube with preservation of the aortic

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valve, Dias et al. [16] demonstrated, in a consistent manner with the findings of this research, that the Cabrolâ&#x20AC;&#x2122;s operation is one of the independent predictors of hospital and late mortality. Murphy et al. [17], in a recent publication, found that blood transfusion in patients undergoing cardiac surgery was strongly associated with infection and ischemic postoperative morbidity, prolonged hospital stay, increased early and late mortality and increased hospital costs. Costs were substantially higher in patients who required re-exploration for bleeding, as demonstrated by Alstrom et al. [18]. As reported by Svensson et al. [19], patients undergoing surgical procedures on the ascending aorta and aortic arch, and those participating in blood conservation techniques had significantly (P<0.05) lower incidence of homologous transfusions, were extubated earlier, had lower hospitalization and were discharged in improved functional class. The multivariate analysis of 60 patients showed that the predictors of in-hospital homologous transfusion, with P values â&#x20AC;&#x2039;â&#x20AC;&#x2039;<0.05 were: age, duration of CPB and increased drainage postoperatively. Pericardial effusion is more common in acute aortic dissection or during exacerbation of a chronic dissection. Mehta et al. [20] reported that the rate of hospital mortality for type A Stanford acute aortic dissection is high and can be predicted with the use of a clinical model incorporated into a simple risk prediction. The pericardial effusion in the clinical presentation of these patients has been identified as an independent predictor (P=0.07), as well as the cardiac tamponade complication (P<0.0001). In the model proposed predictor, the composite outcome arterial hypotension, shock and cardiac tamponade was associated with higher mortality (OR = 2.97, 95% CI 1.83 to 4.81, P<0.001). Ranucci et al. [21] suggest that a multifactorial approach seems better suited to meet the complex reactions that lead to inflammatory lesions and activation of the coagulation cascade during cardiac surgeries. Probably, the key issue is the thrombin formation which, simultaneously, is a marker of activation of the clotting cascade and a trigger for the reactions of endothelial base, including consumption of antithrombin and protein C, activation, platelet adhesion and aggregation, expression of molecules adhesion and leukocyte adhesion and activation. The onset of chest pain with a protective effect, reducing the risk of hospital mortality by 73% (P=0.04), can be interpreted and substantiated by epidemiological and clinical plausibility, because the waiting time for the transaction be shortened regardless of the aortic diameter, thus preventing rupture, dissection or cardiac tamponade. With regard to compound clinical outcome in the series published by Souza & Moitinho [22], measures adopted with the use of antifibrinolytic agents, hemodilution and

total replacement of the perfusate allowed to reduce the need for blood transfusion in the postoperative of cardiac surgery. Patients with CPB time greater than 120 minutes tended to need blood transfusion. The combination of surgery in elderly patients and CPB time greater than 120 minutes resulted in increased use of blood and blood products in the postoperative period. Brown et al. [23] performed a metaanalysis to compare aprotinin, epsilon-aminocaproic acid and tranexamic acid. The results included a loss of whole blood, packed red blood cell transfusion, reexploration, mortality, stroke, myocardial infarction, renal dialysis and renal dysfunction. All antifibrinolytic agents were effective in reducing blood loss and transfusion. There was no significant risks or benefits for mortality, stroke, myocardial infarction or renal failure. However, the high dose of aprotinin is associated with increased risk of statistically significant renal dysfunction. The EuroSCORE showed clear association with the occurrence of compound clinical outcomes in this study population and should be considered an important tool in determining the risk of these patients, even being prepared in other countries, with different people and medical services. Chertow et al. [24] assessed 42,773 patients undergoing cardiac valve surgery or CABG to determine the association between acute renal failure and need for dialysis and operative mortality. Acute renal failure occurred in 1.1% of patients. The operative mortality was 63.7% in these patients, compared to 4.3% in patients without this complication. After adjusting for factors related to comorbidities, the OR was 27, 95% CI 22-34. It was concluded that acute renal failure was independently associated with early mortality after cardiac surgery and that interventions to prevent or improve the treatment of this condition are necessary and should be implemented as soon as within this clinicalsurgical scenario. Wynne & Botti [25] described the frequency of pulmonary complications after cardiac surgery: pleural effusion (25-95%), atelectasis (17-88%), phrenic nerve palsy (30-75%), prolonged mechanical ventilation (6-58%), diaphragmatic dysfunction (2-54%), pneumonia (4-20%), diaphragmatic paralysis (9%), pulmonary embolism (0.4 to 3.2%), acute respiratory distress syndrome (0.4-2%), aspiration (1.9%) and pneumothorax (1.4%). CONCLUSION 1. Black ethnicity, cerebrovascular disease, hemopericardium, Cabrol operation, associated CABG, hemostasis review and CPB time were independently associated with increased risk of hospital death. The presence of chest pain was independently associated with reduced risk of hospital death. 2. Use of antifibrinolytic, renal complications, 19

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Rev Bras Cir Cardiovasc 2013;28(1):10-21

pulmonary complications, EuroSCORE and prolonged cardiopulmonary bypass time were independently associated with increased risk of hospital composite clinical outcome (death, bleeding, neurologic complications or ventricular dysfunction).

and transverse aortic arch. Factors influencing survival in 717 patients. J Thorac Cardiovasc Surg. 1989;98(5 Pt 1):659-73.

ACKNOWLEDGEMENTS The authors thank Roberta de Souza, statistics, Simone Batista da Cruz, secretary of the Division of Translational Epidemiology and Wellington Cícero de Carvalho, systems analyst.

5. Gazoni LM, Speir AM, Kron IL, Fonner E, Crosby IK. Elective thoracic aortic aneurysm surgery: better outcomes from highvolume centers. J Am Coll Surg. 2010;210(5):855-9. 6. Lohse F, Lang N, Schiller W, Roell W, Dewald O, Preusse CJ, et al. Quality of life after replacement of the ascending aorta in patients with true aneurysms. Tex Heart Inst J. 2009;36(2):104-10. 7. Czerny M, Krähenbühl E, Reineke D, Sodeck G, Englberger L, Weber A, et al. Mortality and neurologic injury after surgical repair with hypothermic circulatory arrest in acute and chronic proximal thoracic aortic pathology: effect of age on outcome. Circulation. 2011;124(13):1407-13. 8. Estrera AL, Miller CC, Kaneko T, Lee TY, Walkes JC, Kaiser LR, et al. Outcomes of acute type a aortic dissection after previous cardiac surgery. Ann Thorac Surg. 2010;89(5):1467-74.

REFERENCES 1. 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: a report of the 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, and Society for Vascular Medicine. Circulation. 2010;121(13):e266-369. 2. Johansson G, Markström U, Swedenborg J. Ruptured thoracic aortic aneurysms: a study of incidence and mortality rates. J Vasc Surg. 1995;21(6):985-8. 3. Kouchoukos NT, Wareing TH, Murphy SF, Perrillo JB. Sixteen-year experience with aortic root replacement. Results of 172 operations. Ann Surg. 1991;214(3):308-18. 4. Crawford ES, Svensson LG, Coselli JS, Safi HJ, Hess KR. Surgical treatment of aneurysm and/or dissection of the ascending aorta, transverse aortic arch, and ascending aorta

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da aorta com tubo valvulado e com a preservação da valva aórtica. Rev Bras Cir Cardiovasc. 2010;25(4):491-9.

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17. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation. 2007;116(22):2544-52. 18. Alström U, Levin LA, Stahle E, Svedjeholm R, Friberg Ö. Cost analysis of re-exploration for bleeding after coronary artery bypass graft surgery. Br J Anaesth. 2011;108(2):216-22. 19. Svensson LG, Sun J, Nadolny E, Kimmel WA. Prospective evaluation of minimal blood use for ascending aorta and aortic arch operations Ann Thorac Surg. 1995;59(6):1501-8. 20. Mehta RH, Suzuki T, Hagan PG, Bossone E, Gilon D, Llovet A, et al; International Registry of Acute Aortic Dissection (IRAD) Investigators. Predicting death in patients with acute type A aortic dissection. Circulation. 2002;105(2):200-6. 21. Ranucci M, Balduini A, Ditta A, Boncilli A, Brozzi S.

22. Souza HJ, Moitinho RF. Estratégias para redução do uso de hemoderivados em cirurgia cardiovascular. Rev Bras Cir Cardiovasc. 2008;23(1):53-9. 23. Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation. 2007;115(22):2801-13. 24. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med. 1998;104(4):343-8. 25. Wynne R, Botti M. Postoperative pulmonary dysfunction in adults after cardiac surgery with cardiopulmonary bypass: clinical significance and implications for practice. AM J Crit Care. 2004;13(5):384-93.

Aikawa P, et al. - Impact of coronary artery bypass grafting in elderly ORIGINAL ARTICLE patients

Rev Bras Cir Cardiovasc 2013;28(1):22-8

Impact of coronary artery bypass grafting in elderly patients Impacto da cirurgia de revascularização do miocárdio em pacientes idosos

Priscila Aikawa1, Angélica Rossi Sartori Cintra2, Cleber Aparecido Leite3, Ricardo Henrique Marques4, Claudio Tafarel Mackmillan da Silva5, Max dos Santos Afonso5, Felipe da Silva Paulitsch6, Evandro Augusto Oss7 DOI: 10.5935/1678-9741.20130005

RBCCV 44205-1438

Abstract Objective: To assess the results of isolated on-pump coronary artery bypass graft surgery (CABG) in comparison to patients ≥ 65 years-old. Methods: We assessed 253 patients undergoing isolated on-pump CABG from December 1st 2010 to July 31th 2012 were divided in two groups: GE (elderly ≥ 65 years-old, n=103) and GA (adults < 65 years-old, n=150). Preoperative data, intraoperative (as cardiopulmonar bypass time, aortic clamping time, time length of stay in mechanical ventilation - MV - and number of grafts), and postoperative variable (as morbidity, mortality and time length of stay in hospital) were analyzed during hospitalization. Results: In GE, the morbidity rate was greater than in GA (30% vs. 14%, P=0.004), but there was no difference in the mortality rate (5.8% vs. 2.0%, P=0.165). In GA, there was higher prevalence DM (39.6% vs. 27%, P=0.043) and smoking (32.2% versus 19.8%, P=0.042); and in GE, higher prevalence of stroke (17% vs. 6.7%, P=0.013). There was no difference between the groups regarding intraoperative variables. After multivariate analysis, age ≥ 65-year-old was associated with greater morbidity, but it was not independent

predictive factor for in-hospital mortality. Considering in-hospital mortality, stay in ward time length (P=0.006), cardiac (P=0.011) and respiratory complications (P=0.026) were independent predictive factors. Conclusion: This study suggests that patients ≥ 65-yearold were at increased risk of postoperative complications when submitted to isolated on-pump CABG in comparison to patients < 65-year-old, but not under increased risk of death.

1. PhD - Faculty of Medicine of University of Sao Paulo, Faculty Anhanguera of Rio Grande, Associação de Caridade da Santa Casa do Rio Grande, Rio Grande do Sul, Brazil. 2. PhD - Faculty of Medicine of University of Campinas, Faculty Anhanguera of Campinas, São Paulo, Brazil. 3. PhD – Federal University of Sao Paulo, Faculty Anhanguera of Santo Andre I, São Paulo, Brazil. 4. PhD - Faculty Anhanguera of Santo Andre III, University of Mogi das Cruzes, São Paulo, Brazil. 5. Student of Physicaltherapist of Faculty Anhanguera of Rio Grande, Rio Grande do Sul, Brazil. 6. PhD in Cardiology (Faculty of Medicine of University of Sao Paulo), Faculty of Medicine of Federal University of Rio Grande, Rio Grande do Sul, Brazil. 7. Cardiovascular surgeon of Associação de Caridade da Santa Casa do Rio Grande, Rio Grande do Sul, Brazil.

This study was carried out at Hospital de Cardiologia Doutor Pedro Bertoni da Associação de Caridade da Santa Casa do Rio Grande, Rio Grande, RS, Brasil.

Descriptors: Myocardial revascularization. Hospital mortality. Postoperative complications.

Elderly.

Resumo Objetivo: Analisar os desfechos da cirurgia de revascularização do miocárdio (CRM) isolada com circulação extracorpórea em pacientes com idade ≥ 65 anos em comparação àqueles com < 65 anos. Métodos: Foram analisados 253 pacientes submetidos consecutivamente à CRM isolada entre 1º de dezembro de 2010 a 31 de julho de 2012. Os pacientes foram separados em dois grupos: GI (idosos ≥ 65 anos) e GA (adultos < 65 anos).

Correspondence address Priscila Aikawa Rua General Câmara, 432 – Centro – Rio Grande, RS, Brasil – Zip code: 96200-320 E-mail: priaikawa@hotmail.com Supported by FUNADESP, Sao Paulo/Brazil, protocol number 5500255.

Article received on October 30th, 2012 Article accepted on December 18th, 2012

Rev Bras Cir Cardiovasc 2013;28(1):22-8

Aikawa P, et al. - Impact of coronary artery bypass grafting in elderly patients

Abbreviations, Acronyms & Symbols AMI CABG CAD CAT CHF CPB CRF DM GA GE ICU MV PVD SD SPSS

Acute myocardial infarction Coronary artery bypass grafting Coronary artery disease Coronary arteriography Chronic heart failure Cardiopulmonary bypass Chronic renal failure Diabetes mellitus Group of adult (patients < 65years-old) Group of elderly (patients ≥ 65years-old) Intensive care unit Mechanical ventilation Peripheral vascular disease Standard deviation Statistical Package for the Social Science

Foram analisadas variáveis pré-operatórias, intraoperatórias (tempo de CEC, tempo de pinçamento aórtico, tempo de submissão à VM e número de enxertos) e pós-operatórias (morbidade, mortalidade e tempo de internação). Resultados: Dos 253 pacientes, 103 pertenciam ao GI

INTRODUCTION The growth of the elderly population, in absolute and relative numbers, is a worldwide phenomenon and is occurring at an unprecedented level. Currently, one in ten people aged 60 or older, and for 2050, it is estimated that the ratio will be one to five in the world, and one to three in developed countries. In Brazil, life expectancy has increased more than ten years (62.57 years to 73.17 years) and it is estimated that in 2050, the Brazilian population over 15% of people have 70 years or older [1]. Advanced age is a risk factor for development of coronary artery disease (CAD), and diabetes mellitus, hypertension, dyslipidemia, smoking, obesity and family history of CAD. With the increasing elderly population, the prevalence of CAD is increasing and increasingly these individuals are being subjected to major surgery, for example, coronary artery bypass graft (CABG). Additionally, cardiovascular disease is the major factor contributing to death, especially in elderly [2-4]. CABG is a safe procedure often performed around the world with low rates of mortality and morbidity in the general population. The number of octogenarians undergoing CABG increased from 0.13%, in 1986, to 3.5%, in 2001, at the Heart Institute of the Clinical

(40,7%) e 150 ao GA (59,3%). A taxa de morbidade foi significativamente maior no GI quando comparada ao GA (30% vs. 14%, P=0,004), porém não houve diferença na taxa de mortalidade (5,8% vs. 2,0%, P=0,165). No GA havia maior prevalência DM (39,6% vs. 27%, P=0,043) e tabagismo (32,2% vs. 19,8%, P=0,042); e no GI, maior prevalência de acidente vascular encefálico prévio (17% vs. 6,7%, P=0,013). Não houve diferença entre os grupos quanto às variáveis intraoperatórias. Na análise multivariada: tempo de internação na enfermaria (P=0,006), complicações cardíacas (P=0,011) e complicações respiratórias (P=0,026) foram variáveis preditoras de risco para maior mortalidade intrahospitalar. No entanto, a idade ≥ 65 anos não foi um fator preditor de risco associada a variável óbito. Conclusão: Este estudo sugere que pacientes com idade igual ou superior a 65 anos possuem um maior risco de complicações intra-hospitalares no pós-operatório de CRM isolada com CEC em comparação com pacientes mais jovens. Descritores: Revascularização miocárdica. Idoso. Mortalidade hospitalar. Complicações pós-operatórias.

Hospital of the Faculty of Medicine, University of São Paulo, the last 16 years (1986-2001) [5]. Thus, recent studies demonstrate the concern of evaluating the outcomes of CABG in elderly patients and comparison with younger individuals to verify the risks to which the elderly are more vulnerable because they are considered high risk patients for this surgery [6,7]. Another important fact is that in the last decade, there have been many changes in surgical techniques, such as the advent of minimally invasive surgery, withoit the use of cardiopulmonary bypass (CPB), and new devices. Thus, the indication of CABG for elderly patients is increasing because it provides better survival and quality of life [8-12]. The aim of this study was to assess the outcomes of CABG in patients aged 65 years or older compared with younger patients (<65 years) at a regional reference hospital in Southern Brazil. METHODS The project was approved by the Research Ethics Committee of the Hospital Associação de Caridade Santa Casa Rio Grande (RS, Brazil) under protocol number 001/2011. 23

Aikawa P, et al. - Impact of coronary artery bypass grafting in elderly patients

Rev Bras Cir Cardiovasc 2013;28(1):22-8

This is a prospective study in which all patients who consecutively underwent CABG alone between 1st December 2010 to 31th July 2012 were assessed at the Cardiology Hospital Doutor Pedro Bertoni of the Associação de Caridade Santa Casa Rio Grande (RS / Brazil). Patients undergoing CABG alone or associated with other cardiac surgery were excluded from the study. We included patients who needed surgery elective and urgent or emergency according to the criteria of the American Heart Association and the American College of Cardiology. Patients were divided into two groups, the group of elderly (GE) consisted of patients aged greater than 65 years and the adult group (GA) with patients under the age of 65. Data were collected daily directly from medical records and interviews with patients since its admission to discharge through a pre-structured form. All patients were elucidated on the research and signed an informed consent form. The variables collected from the medical records and through interviews with patients were: gender, age, weight, height, race, comorbidities, prior CABG, prior coronary angiography, angioplasty surgery, sedentary lifestyle, smoking, alcohol consumption, number of grafts, time CPB, aortic clamping time, time of submission to mechanical ventilation (MV), length of stay in the Intensive Care Unit (ICU) and in the ward, postoperative complications and progression to hospital discharge or death. The data were analyzed with the Statistical Package for Social Science (SPSS, version 13.0, Inc., Chicago, IL, USA). Continuous variables were expressed as means and standard deviations (SD), while categorical variables by proportions. Normality was checked using the Kolmogorov-Smirnov test. In the statistical analysis we used the Student t test to compare the means, and the chi-square or Fisher exact test to compare proportions. To determine which factors independently influence the development outcomes of the study was analyzed using multivariate logistic regression "stepwise forward". To verify the correlation between risk factors preoperative, intraoperative, postoperative variables and mortality Spearman test was used. In all assessments were considered significant when P <0.05.

lifestyle, acute myocardial infarction (AMI), coronary angiography (CAT), previous angina pectoris, previous peripheral vascular disease (PVD), previous CABG, chronic renal failure (CRF) and failure chronic heart failure (CHF) and dyslipidemia among two groups of patients. However, patients in the GA had a higher prevalence of diabetes mellitus (DM) (39.6% vs. 27%, P=0.043) and smoking (32.2% vs. 19.8%, P=0.042), whereas the GE patients had a higher prevalence of stroke prior (17% vs. 6.7%, P=0.013). Table 2 shows the results of the surgery. There was no significant difference in mortality between the groups (P=0.165), but the rate of hospital morbidity was significantly higher in GE (30% vs. 14%, P=0.004).

RESULTS During the study period, 253 consecutive patients underwent isolated CABG, of whom 103 (41%) patients belonged to Elderly Group (GE) and 150 (59%), the Adult Group (GA). The clinical and demographic characteristics of the patients are summarized in Table 1, which demonstrates a higher prevalence of males in both groups: GE = 61% and GA =70%; no difference regarding gender, history of CAD in the family, hypertension, alcohol consumption, sedentary 24

Table 1. Clinical and demographic preoperative characteristics. Male (%) Age (mean ± SD years) Hypertension (%) DM (%) CAD family history (%) Smoking (%) Alcoholism (%) Sedentary Lifestyle (%) Previous AMI (%) Previous CAT (%) Previous stroke (%) Angina pectoris (%) PVD (%) Previous CABG (%) CRF (%) CHF (%) Dyslipidemia (%)

GA (150) 70 57 ± 6 81.2 39.6 68 32.2 23.6 68.2 49.7 27.7 6.7 72.3 12.2 3.4 5.4 13.5 42.9

GE (103) 61 72 ± 5 79 27 61.6 19.8 20 67 45 24 17 75 10 3 9 8 50

P 0.175 0.000 0.745 0.043 0.339 0.042 0.536 0.890 0.518 0.558 0.013 0.663 0.685 1.000 0.310 0.221 0.299

GA= adult group; GE= elderly group; DM= diabetes mellitus; CAD= coronary artery disease; AMI= acute myocardial infarction; CAT= coronary arteriography; PVD= peripheral vascular disease; CABG= coronary artery bypass grafting; CRF= chronic renal failure; CHF= chronic heart failure

Table 2. Surgical outcomes. Mortality (%) Morbidity (%) Complications categories: Respiratory (%) Cardiac (%) Gastrintestinal (%) Neurological (%) Other (%)

GA (150) 2.0 14

GE (103) 5,8 30

P 0.165 0.004

2 8 0 0 4

5 13 3 2 7

0.277 0.191 0.066 0.165 0.389

GA= adult group; GE= elderly group

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As a facilitating factors for analysis, complications were divided into five categories: (1) pulmonary complications: respiratory infection, (2) cardiac complications: arrhythmia, cardiac arrest, reinfarction, precordial pain and atrial fibrillation, (3) gastrointestinal complications: abdominal distension, (4) neurological complications: stroke, and (5) other complications: increased postoperative bleeding, mediastinitis, septic shock and sternal instability. There was no significant difference between the categories of complications comparing the groups. Intraoperative data, MV and length of stay for both groups are shown in Table 3. There was no significant difference between groups in the time length of stay on MV <24 hours (P=0.096), MV between 24 and 48 hours (P=0.071) and MV> 48 hours (P=1.000); time of CPB (P=0.334) and aortic clamping (P=0.214), number of grafts (P=0.412), length of stay in ICU (P=0.140) and total time in hospital (P=0.144). However, the GE patients had more days hospitalized than patients in GA (P=0.036). In Table 4, assessed the length of stay in ICU and total hospitalization time in the two groups with respect to the criterion of length of stay ≥ 5 days in ICU and overall

length of stay ≥ 11 days, and the permanence of GE in the ICU was higher than in the GA (P=0.010), but in total time length stay in hospital there was no difference between groups according to the criterion imposed (P=0.141). In univariate analysis, the risk factors associated with hospital mortality were chronic renal failure, dyslipidemia, length of stay for 5 or more days in the ICU, length of ICU stay, length of stay in hospital, MV for more than 24 hours, CPB time, cardiac and respiratory complications. However, the age ≥ 65 years was not a risk factor (Table 5). In multivariate logistic regression analysis, we found that length of stay in the ward (P=0.006), cardiac complications (P=0.011) and respiratory complications (P=0.026) were predictors of risk (P≤0.05) for hospital mortality (Table 6). In GE, we found that hospital mortality was positively correlated with length of stay in ICU ≥ 5 days (P=0.008), MV ≥ 48 hours (P<0.001), postoperative complications (P<0.001) and cardiac complications (P=0.004). Already in GA, hospital mortality showed positive correlation with DM (P=0.031), chronic renal failure (P=0.030), dyslipidemia (P=0.044), MV ≥ 48 hours (P=0.029), postoperative complications (P<0.001) and respiratory complications (P<0.001).

Table 3. Intraoperative data, mechanical ventilation and length of stay. MV 24 hours (%) MV > 24and ≤ 48 hours (%) MV > 48hours (%) CPB (mean ± SD, minutes) Aortic clamping time (mean ± SD, minutes) Grafts (%)

Lenght of stay in ICU (mean ± SD, days) Lenght of stay in ward (mean ± SD, days) Total time in-hospital (mean ± SD, days)

1 2 3 4

GA (150) 80 15 5.3 63 ± 19 40 ± 14 12.7 40.7 34 12.7 3.74 ± 3,91 5.71 ± 2.57 10.28 ± 5.79

GE (103) 70 25 5 60 ±16 37 ± 12 7.8 36.9 42.7 12.6 4.60 ± 5.27 6.48 ± 3.23 11.48 ± 7.09

P 0.096 0.071 1.000 0.334 0.214 0.412 0.140 0.036 0.144

GA= adult group; GE= elderly group; MV= mechanical ventilation; CPB= cardiopulmonary bypass; ICU= intensive care unit

Table 4. Results of the length of stay in the ICU and total time in-hospital. Lenght of stay in ICU ≥ 5 days (%)

GA (150) 14.8

GE (103) 28.7

P 0,010

Total time in-hospital ≥ 11 days (%)

22.1

30.7

0.141

GA= adult group; GE= elderly group; ICU= intensive care unit

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Aikawa P, et al. - Impact of coronary artery bypass grafting in elderly patients

Table 5. Univariate analysis. Variable Age ≥ 65 anos BMI Gender CAD Grafts DM Smoking Alcoholism Sedentary lifestyle Previous AMI Previous CAT Previous stroke Angina pectoris PVD Hypertension Previous CABG CRF CHF Dyslipidemia Lenght of stay in ICU ≥ 5 dias Lenght of stay in ICU Lenght of stay in ward Total time in-hospital Total time in-hospital ≥ 11 days MV > 24 hours Time in CPB Aortic clamping time Cardiac complications Respiratory complications Other complications Gastrintestinal complications Neurological complications

OR 3.031 0.941 1.610 1.064

IC 0.740 – 12.407 0.789 – 1.124 0.421 – 6.157 0.191 – 5.931

3.927 2.797 1.783 0.951 1.095 1.421 1.662

0.705 – 21.887 0.550 – 14.212 0.318 – 10.002 0.171 – 5.305 0.217 – 5.532 0.254 – 7.945 0.187 – 14.776

4.154 1.231

0.725 – 23.795 0.141 – 10.781

5.675 4.154

1.020 – 31.578 0.725 – 23.795

7.174 1.091 0.499 1.030 1.800 4.101 1.047 1.036 8.960 11.333 2.417

1.655 – 31.103 1.018 – 1.170 0.337 – 0.737 0.944 – 1.123 0.418 – 7.754 1.065 – 15.784 1.014 – 1.081 0.993 – 1.081 2.227 – 36.048 1.934 – 66.405 0.279 – 20.920

P 0.123 0.503 0.487 0.943 0.038* 0.119 0.215 0.511 0.955 0.913 0.689 0.649 0.346* 0.110 0.851 0.999* 0.047 0.110 0.009* 0.008 0.014 < 0.001 0.509 0.430 0.040 0.005 0.104 0.002 0.007 0.423 0.999* 0.999*

BMI= body mass index; CAD= coronary artery disease; DM= diabetes mellitus; AMI= acute myocardial infarction; CAT= coronary arteriography; PVD= peripheral vascular disease; CABG= coronary artery bypass grafting; CRF= chronic renal failure; CHF= chronic heart failure; ICU= intensive care unit; MV= mechanical ventilation; CPB= cardiopulmonary bypass; * Fisher exact test

Table 6. Predictive factors of hospital mortality by logistic regression analysis. Lenght of stay in ward Cardiac complications Respiratory complications

DISCUSSION This study in patients undergoing CABG alone suggests that patients aged ≥ 65 years are subject to greater risk of postoperative complications than patients under 65, but there was no difference between the mortality rate between the groups. 26

OR 0.542 10.580 12.819

IC95% 0.350 – 0.840 1.722 – 64.999 1.352 – 121.586

P 0.006 0.011 0.026

Regarding to mortality rate, a study examining predictors of hospital mortality in patients undergoing CABG in acute myocardial analyzed that advanced age is a risk factor related to mortality [13]. Rocha et al. [14] also reported on a study conducted at the National Institute of Cardiology of Rio de Janeiro that the variables: age ≥ 70 years, need for reoperation for revision of homeostasis,

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sepsis and respiratory complications postoperatively were associated with hospital mortality. As well, in another study in Santa Catarina/Brazil, the authors found the same relationship [15]. But in our study, we found that age ≥ 65 years was not a predictor of mortality, similar to other reported by Ng et al. [16] in a retrospective study with 1594 patients undergoing CABG alone, where no significant difference in hospital mortality between patients aged ≥ 70 years (5.4%) compared to those with less than 70 years (3.8%). Even after 30 days of surgery, the mortality of patients aged ≥ 70 years was 3.8% compared with 3.3% of patients aged <70 years (P<0.740). The morbidity rate in hospital was higher in the GE compared to the GA. This data is in according to other study, which were also investigated the outcomes of CABG in elderly patients [14,17,18]. Pivatto et al. [19] observed that the morbidity rate was 34.4% in octogenarian patients undergoing CABG alone. In our study we observed a morbidity rate of 30% in GE that was significantly higher compared to patients in the GA (14%). These data support the hypothesis that elderly patients have more postoperative complications. In the GE, we founded that the prevalence of respiratory, cardiac, gastrointestinal, neurological, and other complications were higher compared to the GA, but there was no significant difference. Rocha et al. [14] observed that these complications were more developed for patients aged ≥ 70 years, which had more respiratory complications (21.4% vs. 9.1%, P<0.001), mediastinitis (5.1% vs. 1.9%, P=0.013), stroke (3.9% vs. 1.3%, P=0.016), acute renal failure (7.8% vs. 1.3%, P<0.001), sepsis (3.9% vs. 1.9%, P=0.003), atrial fibrillation (15.6% vs. 9.8%, P=0.016) and complete atrioventricular block (3.5% vs. 1.2%, P=0.023) in the postoperative period compared to patients < 70 years-old. In a retrospective study, Machado et al. [5] reported 10% mortality rate in octogenarian patients undergoing CABG, and observed the occurrence of cardiac arrhythmias (especially atrial fibrillation), cerebrovascular, and respiratory complications in the postoperative period. In our study, the cardiac complications were also major postoperative complications (12.6%). However, it was followed by respiratory complications (4.9%), and a lower incidence of neurological complications (1.9%). Anderson et al. [20] observed predictors of mortality in patients undergoing cardiac surgery comparing septuagenarians and octogenarians, there was no significant difference in mortality rate between the groups. As observed in our study, preoperative variables did not increase the risk to death, but researchers have shown that cardiopulmonary bypass time > 75 minutes has 3.2 times (CI: 1.3 - 7.9) greater chance of to death than patients with cardiopulmonary bypass time < 75 minutes, and

postoperative variables such as prolonged mechanical ventilation above 12 hours, length of stay in ICU, reoperation, inotropic support more than 48 hours, and the need for blood products are associated with increased mortality. In this study, we found that postoperative variables such as length of stay in hospital, and cardiac and respiratory postoperative complications are associated with higher mortality, suggesting that patients who had postoperative complications remained more time hospitalized, increasing the risk of mortality hospital. Recently, in a retrospective study [14] with 655 patients undergoing CABG, the authors observed that length of stay in ICU ≥ 3 days had positive correlation with death, but this study did not examine this relationship by age, and yes, total population sample. Our results show that length of stay ≥ 5 days had positive correlation with death in GE, emphasizing the importance of studies that evaluate the outcomes of CABG in elderly patients. Assessing the most recent data in the literature, there is disagreement about what age, in elderly patients, the morbimortality appears to be significantly higher compared to adult patients. We found studies that described their groups of elderly with age ≥ 65 years-old [12], ≥ 70 yearsold [13-17], ≥ 75 years-old [6,21], ≥ 80 years-old [22] and ≥ 85 years-old [23]. Therefore we will suggest that more studies to be made in order to can to conclude in which age the risks factors of this surgery appear enlarged, whether preoperative, intraoperative or postoperative outcomes. CONCLUSION This study suggests that patients with 65 years old or more undergoing isolated coronary artery bypass grafting using cardiopulmonary bypass have a higher risk of postoperative complications in comparison with younger patients. The highest prevalence was heart complications, followed by respiratory complications; and lower prevalence of gastrointestinal and neurological complications.

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Machado MN, et al. - Surgical treatment for infective endocarditis and ORIGINAL ARTICLE hospital mortality in a Brazilian single-center

Rev Bras Cir Cardiovasc 2013;28(1):29-35

Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center Tratamento cirúrgico para endocardite infecciosa e mortalidade hospitalar em centro único brasileiro

Maurício Nassau Machado1,2, Marcelo Arruda Nakazone1-3, Jamil Ali Murad-Júnior1, Lilia Nigro Maia4 DOI: 10.5935/1678-9741.20130006

RBCCV 44205-1437

Abstract Objective: We evaluated patients underwent cardiac valve surgery in the presence of infective endocarditis in an attempt to identify independent predictors of 30-day mortality. Methods: We evaluated 837 consecutive patients underwent cardiac valve surgery from January 2003 to May 2010 in a tertiary hospital in São José do Rio Preto, São Paulo (SP), Brazil. The study group comprised patients who underwent intervention in the presence of infective endocarditis and was compared to the control group (without infective endocarditis), evaluating perioperative clinical outcomes and 30-day all cause mortality. Results: In our series, 64 patients (8%) underwent cardiac valve surgery in the presence of infective endocarditis, and 37.5% of them had surgical intervention in multiple valves. The study group had prolonged ICU length of stay (16%), greater need for dialysis (9%) and higher 30-day mortality (17%) compared to the control group (7%, P=0.020; 2%, P=0.002 and 9%, P=0.038; respectively). In a Cox regression analysis, age (P = 0.007), acute kidney injury (P = 0.004), dialysis (P = 0.026), redo surgery (P = 0.026), re-exploration for bleeding (P = 0.013), tracheal reintubation (P <0.001) and type I neurological injury (P <0.001) were identified as independent predictors for death. Although the manifestation of infective endocarditis influenced on mortality in univariate

analysis, multivariate Cox regression analysis did not confirm such variable as an independent predictor of death. Conclusion: Age and perioperative complications stand out as predictors of hospital mortality in Brazilian population. Cardiac valve surgery in the presence of active infective endocarditis was not confirmed itself as an independent predictor of 30-day mortality.

1. Cardiologist Assistant at the Postoperative Cardio Surgery Care Unit and Coronary Care Unit from Hospital de Base, São José do Rio Preto Medical School (FAMERP). Specialist in Cardiology by SBC/AMB, São José do Rio Preto, SP, Brazil. 2. Post-graduation program in Health Sciences, FAMERP, São José do Rio Preto, SP, Brazil. 3. Technical Scientific Coordinator at Centro Integrado de Pesquisas – Hospital de Base /FAMERP, São José do Rio Preto, SP, Brazil. 4. Professor from São José do Rio Preto Medical School. Chief of the Coronary Care Unit and Medical Clinical Research Coordinator at Centro Integrado de Pesquisas – Hospital de Base /FAMERP, São José do Rio Preto, SP, Brazil.

Some results were presented in XXXII Congress from Sociedade de Cardiologia do Estado de São Paulo, SP, Brazil.

This studied was carried out at Postoperative Cardiac Surgery Care Unit - Hospital de Base, São José do Rio Preto Medical School, São José do Rio Preto, SP, Brazil.

Descriptors: Bacterial endocarditis. Cardiac surgical procedures. Hospital mortality. Resumo Objetivo: Avaliamos pacientes submetidos à cirurgia valvar em vigência de endocardite infecciosa na tentativa de identificar preditores independentes de mortalidade intrahospitalar em 30 dias. Métodos: Foram avaliados 837 pacientes consecutivamente submetidos à cirurgia valvar, no período de janeiro de 2003 a maio de 2010, em um hospital terciário de São José do Rio Preto, SP, Brasil. O Grupo de Estudo compreendeu indivíduos submetidos à intervenção em vigência de endocardite infecciosa e foi comparado ao Grupo Controle, considerando complicações clínicas perioperatórias e óbito por todas as causas em 30 dias.

Correspondence address: Maurício Nassau Machado Hospital de Base de São José do Rio Preto Av. Brigadeiro Faria Lima, 5544 – 5° floor – Unidade Coronária (UCor) – São José do Rio Preto, SP, Brazil – Zip code: 15090-000 E-mail: maunmac@gmail.com

Article received on July15th, 2012 Article accepted on September 25th, 2012

Rev Bras Cir Cardiovasc 2013;28(1):29-35

Machado MN, et al. - Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center

Abbreviations, Acronyms & Symbols CG CI CVS SG EuroSCORE HR ICU IE SD

Control group Confidence interval Cardiac valve surgery Study group European System for Cardiac Operative Risk Evaluation Hazard ratio Intensive care unit Infective endocarditis Standard deviation

Resultados: Em nossa casuística, 64 (8%) pacientes foram submetidos à cirurgia valvar em vigência de endocardite infecciosa, sendo 37,5% deles com indicação de intervenção cirúrgica em múltiplas valvas. O Grupo de Estudo apresentou maior permanência em Unidade de Terapia Intensiva (16%),

INTRODUCTION Surgical mortality for infective endocarditis (IE), while declining in the last decades, stands out as an important cause of death in native or prosthetic valve interventions [1-3], justifying early diagnosis and appropriate antibiotic therapy as key points to the success of the treatment [4]. Clinical complications and treatment failure may suggest surgical valve replacement for IE by up to 60% of cases [5-7]. However, due to possible association between increased incidence of postoperative complications and mortality, the real benefit of early surgical intervention on IE remains doubtful [8]. In the absence of adequate treatment, IE can be fatal. Despite the medical and surgical treatment being able to modify the course of disease, mortality remains high, ranging from 17% to 36% of cases according to the population studied [9,10]. In this context, this study evaluated the mortality of patients undergoing cardiac valve surgery (CVS) in the presence of IE in an attempt to identify independent predictors of 30-day mortality in a regional referral center. METHODS This study evaluated 837 patients admitted to the São José do Rio Preto Medical School Cardiac Surgery Postoperative Intensive Care Unit after CVS from January 2003 to May 2010. This Brazilian Hospital is a regional tertiary referral service with 540 beds for a population demand of 1.5 million inhabitants. In this research, patients were divided into two groups: (SG) study group, subjects undergoing CVS in the presence of 30

necessidade de diálise (9%) e maior mortalidade em 30 dias (17%) comparado ao Grupo Controle (7%, P=0,020; 2%, P=0,002 e 9%, P=0,038; respectivamente). A análise de regressão de Cox confirmou idade (P=0,007), lesão renal aguda (P=0,004), diálise (P=0,026), reoperação (P=0,026), reintervenção por sangramento (P=0,013), reintubação orotraqueal (P<0,001) e lesão neurológica tipo I (P<0,001) como preditores independentes para óbito. Embora a manifestação de endocardite infecciosa influencie na mortalidade na análise univariada, a regressão de Cox não confirmou tal variável como preditor independente de óbito em nossa casuística. Conclusão: Idade e complicações perioperatórias destacam-se como preditores de mortalidade hospitalar em população brasileira. Cirurgia valvar em vigência de infecção ativa não se confirma como preditor independente de óbito nesta casuística. Descritores: Endocardite bacteriana. Procedimentos cirúrgicos cardíacos. Mortalidade hospitalar.

IE; and (CG) control group, consisting of patients with CVS performed in the absence of IE. The analysis was conducted as a prospectively historical type, including gathering information on the local computer database. The constitution of SG considered the recent recommendations of the American College of Cardiology / American Heart Association for IE surgical approach [11]. This study was approved by the São José do Rio Preto Medical School Ethics Committee (6079/2010) and, because of its observational nature, the informed consent was waived. We evaluated demographic data, clinical outcomes and complications occurred in the postoperative period, and 30-day all cause mortality. Categorical data are presented as absolute numbers and percentages, and continuous variables as mean ± standard deviation (SD) or median and interquartile, when applicable. Categorical data were compared by chi-square test or Fisher's exact test and continuous variables were compared using the nonparametric Mann-Whitney test. Survival curve was constructed to demonstrate the outcome of 30-day mortality for both groups. The Cox regression analysis was used to determine independent predictors of 30-day mortality. Hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated for predictors of mortality. The analysis was performed with the SPSS software (version 20) and P value <0.05 (two-tailed) was considered statistically significant. RESULTS In our series, 64 (8%) patients underwent CVS in the presence of IE, and 37.5% had surgical intervention in multiple valves. In the SG there was predominance of males (67%) lower body mass index (23 kg/m2), greater value for

Machado MN, et al. - Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center

Rev Bras Cir Cardiovasc 2013;28(1):29-35

European System for Cardiac Operative Risk Evaluation (EuroSCORE) (9 points), and greater cardiopulmonary bypass time (100.5 min) compared to CG (47%, P = 0.002, 24 kg/m2, P = 0.028, 90 min, P = 0.020 and 4 points, P <0.001, respectively). Table 1 shows the demographic and baseline characteristics of all groups. The analysis of clinical outcomes demonstrated that the EG had a higher percentage of subjects with prior cardiac valve surgery (47%), higher prolonged intensive care unit (ICU) length of stay (over 14 days) (16%) and need for dialysis (9%) compared to CG (28%, P = 0.001; 7%, P = 0.020 and 2%, P = 0.002, respectively, Table 2). Consequently, patients undergoing CVS in the presence of IE had higher 30-day mortality (17%) compared to those without active infection (9%, P = 0.038). The following variables were included in the univariate Cox analysis: age (years), male gender, body mass index

(kg/m2), readmission to intensive care, diabetes mellitus, CVS in the presence of IE, multiple valve surgery, acute kidney injury, dialysis, left ventricular systolic dysfunction moderate or severe, redo surgery, reoperation for bleeding, tracheal reintubation and type I neurological injury. Table 3 shows the variables associated with 30day mortality, highlighting age (P = 0.007), acute kidney injury (P = 0.004), dialysis (P = 0.026), redo surgery (P = 0.026), reoperation for bleeding (P = 0.013), tracheal reintubation (P <0.001) and type I neurological injury (P <0.001) as independent predictors of death determined by multivariate Cox regression model. Cardiac valve surgery in the presence of infective endocarditis was a predictor of death in the non adjusted analysis (HR = 1.96, 95% CI = 1.04 - 3.70, P = 0.038, Figure 1). However, after adjustment for predictors in the multivariate model, this variable was not independent (P = 0.06).

Table 1. Demographic data and baseline characteristics of patients. Baseline Characteristics Age (median, Q1 e Q3) Men [n (%)] BMI (median, Q1 e Q3) Diabetes Mellitus [n (%)] Mitral Valve Surgery [n (%)] Aortic Valve Surgery [n (%)] Tricuspid Valve Surgery [n (%)] Multiple Valve Surgery [n (%)] LV Dysfunction moderate/severe [n (%)] ECC Time (median, Q1 e Q3) Additive EuroScore (median, Q1 e Q3)

All Patients n 837 52 (40 – 61) 405 (48%) 24 (22 – 28) 46 (5%) 602 (72%) 374 (45%) 213 (25%) 300 (36%) 121 (14%) 91 (76 – 113) 5 (3 – 6)

Endocarditis ( + ) n 64 52,5 (40 – 61) 43 (67%) 23 (20 – 26) 4 (6%) 43 (67%) 33 (52%) 17 (27%) 24 (37,5%) 10 (16%) 100,5 (80 – 125) 9 (6 – 11)

Endocarditis ( - ) n 773 52 (40 – 61) 362 (47%) 24 (22 – 28) 42 (5%) 559 (72%) 341 (44%) 196 (25%) 276 (36%) 111 (14%) 90 (75 – 111,5) 4 (3 – 6)

P 0.902 0.002 0.028 0.773 0.380 0.249 0.831 0.854 0.782 0.020 <0.001

n= number of individuals; Q1 and Q3 in reference to Quartis 25% and 75%; BMI= body mass index; LV= left ventricle; ECC= extracorporeal circulation

Table 2. Perioperative clinical complications. Clinical complication Length of ICU stay (median, Q1 e Q3) ICU Readmission [n (%)] Length of ICU stay > 14 days [n (%)] Reoperation [n (%)] Reintervention for bleeding [n (%)] AF [n (%)] Reintubation for lung complications [n (%)] Acute Renal Failure [n (%)] Dialysis [n (%)] Mediastinitis [n (%)] Neurological disorder type I [n (%)] Death in 30 days [n (%)]

All Patients n 837 2 (2 – 4) 47 (6%) 61 (7%) 246 (29%) 33 (4%) 78 (9%) 106 (13%) 222 (27%) 19 (2%) 23 (3%) 39 (5%) 82 (10%)

Endocarditis ( + ) n 64 4 (2 – 11) 2 (3%) 10 (16%) 30 (47%) 0 (0%) 1 (2%) 9 (14%) 20 (31%) 6 (9%) 0 (0%) 2 (3%) 11 (17%)

Endocarditis ( - ) n 773 2 (2 – 4) 45 (6%) 51 (7%) 216 (28%) 33 (4%) 77 (10%) 97 (13%) 202 (26%) 13 (2%) 23 (3%) 37 (5%) 71 (9%)

P 0.006 0.571 0.020 0.001 0.168 0.026 0.726 0.373 0.002 0.248 0.761 0.038

n= number of individuals; ICU= Intensive Care Unit; Q1 and Q3 in reference to Quartis 25% and 75%; AF= atrial fibrillation

Rev Bras Cir Cardiovasc 2013;28(1):29-35

Machado MN, et al. - Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center

Table 3. Independent predictors for hospital mortality in 30 days. Independent predictors for hospital mortality Univariate analysis Infective endocarditis Age (years) Men BMI (kg/m2) Readmission in ICU Diabetes Mellitus Multiple valve surgery Acute renal failure Dialysis LV Dysfunction Moderate/Severe Reoperation Reintervention for bleeding Reintubation Neurological dysfunction type I

Wald

CI 95%

P Value

0.673 0.035 -0.135 -0.018 0.954 0.641 0.493 1.767 2.419 0.197 0.927 1.943 2.162 1.885

4.318 18.339 0.372 0.554 8.668 2.969 9.644 57.483 63.101 0.452 17.597 46.110 95.180 49.689

1.96 1.04 0.87 0.98 2.60 1.90 1.64 5.85 11.24 1.22 2.53 6.98 8.69 6.59

1.04 – 3.70 1.02 – 1.05 0.57 – 1.35 0.94 – 1.03 1.38 – 4.90 0.92 – 3.94 1.20 – 2.23 3.71 – 9.24 6.19 – 20.41 0.69 – 2.17 1.64 – 3.89 3.98 – 12.23 5.63 – 13.41 3.90 – 11.12

0.038 <0.001 0.542 0.457 0.003 0.085 0.002 <0.001 <0.001 0.501 <0.001 <0.001 <0.001 <0.001

Multivariate analysis Age Acute renal failure Dialysis Reoperation Reintervention for bleeding Reintubation Neurological dysfunction type I

0.024 0.806 0.771 0.528 0.769 1.076 1.093

7.214 8.389 4.946 4.937 6.217 16.580 14.531

1.03 2.24 2.16 1.70 2.16 2.93 2.98

1.01 – 1.04 1.30 – 3.86 1.10 – 4.27 1.06 – 2.70 1.18 – 3.95 1.75 – 4.92 1.70 – 5.24

0.007 0.004 0.026 0.026 0.013 <0.001 <0.001

HR=Hazard Ratio; CI= Confidence Interval; BMI= body mass index; k=kilogram; m=meter; ICU= intensive care unit

Fig. 1 – In-hospital survival curve following 30 days

DISCUSSION Despite the current knowledge including prevention, diagnosis and treatment, IE remains a not rare cause of hospitalization with high morbidity and mortality [12,13]. 32

In our analysis, we found 8% of valve-related surgery approaching to IE, percentage similar to that observed in national, North American and European casuistic [14-16]. Moreover, we confirmed high 30-day mortality (17%) for patients undergoing CVS in the presence of active infection, as recently reported by Prendergast & Tornos (ranging from 6% to 25%) [17]. However, the surgical approach in the presence of IE wasn’t confirmed as an independent predictor of death in our series. Our series of patients considered subjects with high severity disease transferred from other hospitals for surgery treatment with established diagnosis of IE, justified by the infection refractory to medical treatment. In this context, factors such as age, comorbidities, clinical presentation and surgical technique used in valve approach can influence the postoperative results [18,19]. Although there is no statistical difference between the groups in age, this variable was found as an independent predictor of 30-day mortality in patients with IE, reinforcing results of Murdoch et al. [20]. Furthermore, in contrast to data of Chirillo et al. [21], the prevalence of diabetes mellitus was similar between the groups do not representing a risk factor for poor clinical outcome in patients with active IE

Machado MN, et al. - Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center

Rev Bras Cir Cardiovasc 2013;28(1):29-35

undergoing CVS. Although evidenced greater proportion of male gender and lower body mass index in EG, these parameters were not associated with worse postoperative prognosis. The higher cardiopulmonary bypass duration in this group may reflect the greater surgical difficulty for a complete removal of the cardiac valve in patients with IE [17]. The International Collaboration on EndocarditisProspective Cohort Study [20] reported 17.7% of overall in-hospital mortality for patients with IE, while Wallace et al. [22] reported 15% mortality in the group undergoing medical treatment and 22% for those who underwent additional surgery. Still, the hospital mortality in patients with valvular abscess due to complications of IE has been reported as 19.2% in Brazilian patients [23]. Similarly, the present study found a hospital mortality rate of 17% at 30 days for patients undergoing CVS due to IE and prolonged ICU length of stay, probably reflecting the severity of sepsis in these individuals [24-26]. However, the anatomical location of the valve infection was similar among the groups, confirming the absence of its association with clinical complications, including mortality, reflecting results previously presented by Rostagno et al. [13]. In this context, the presence of signs of heart failure, persistent infection, acute kidney injury, thrombocytopenia, paravalvular abscess at echocardiography and need for urgent surgery are indicated as predictors of hospital mortality [27-29]. Several studies have associated renal dysfunction with worse prognosis in the evolution and treatment of IE, reporting sepsis, lesions in glomerular architecture and antibiotic toxicity as etiologic factors [22,30,31]. Results of this analysis confirmed the acute kidney injury requiring dialysis as independent predictors of hospital mortality. This study demonstrated that reoperation, including re-exploration due to postoperative bleeding, was also a predictor of 30-day mortality. Attempting to decrease perioperative mortality for valve replacement surgery in the presence of IE, Musci et al. [32] recently proposed valvuloplasty as an effective alternative in previously selected cases, with consequent reduction in the need for reoperation and recurrent infections, but this surgical modality was not evaluated in this analysis. Besides these factors, the type I neurological injury and tracheal reintubation stood out as predictors of mortality in patients undergoing CVS in the presence of IE, in agreement with previous studies [33,34]. In this case, the manifestation of encephalopathy due to cardiovascular surgical procedure or severe sepsis, characterized by altered mental status or focal neurological deficit without evidence of impairment in anatomical imaging methods may have contributed definitely to returning to invasive mechanical ventilation and consequent high risk of in-hospital deaths.

Study limitations Studies related to IE approach are limited by its low relative frequency, the huge variability of the population affected and their underlying risk factors, represented mostly by series of case reports or single centers experience. In our sample, due to the small number of valve involvement by IE, there was limitation in demonstrating the relationship between prognosis, native or prosthetic valve involvement and etiologic agent identified in blood cultures, a fact worsen by the wide range of pathogens involved in its manifestation, affecting the scope and statistical power to draw definitive conclusions. Further investigations are needed to evaluate whether more sensitive prognostic markers may improve the detection of high-risk patients for whom aggressive surgical valve treatment during an IE can really contribute to the reduction of in-hospital mortality. CONCLUSION Although hospital mortality rate for patients undergoing cardiac valve surgery due to refractory infective endocarditis remains high in the Brazilian population, the surgical approach during an active infection is not confirmed as an independent predictor of death in our series. In this case, age, acute kidney injury, dialysis, redo surgery, re-exploration for bleeding, tracheal reintubation and type I neurological injury stand out as predictors of inhospital mortality (30 days) in this population.

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Gregori JuniorORIGINAL F, et al. - Surgical repair of chordae tendineae rupture after ARTICLE degenerative valvular regurgitation using standardized bovine pericardium

Rev Bras Cir Cardiovasc 2013;28(1):36-46

Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium Correção da ruptura de cordas tendíneas na insuficiência mitral degenerativa pelo emprego de cordas padronizadas de pericárdio bovino

Francisco Gregori Júnior1, Moacir Fernandes de Godoy2, Celso Otaviano Cordeiro3, Alexandre Noboru Murakami3, Rogerio Teruya3, Sergio Shigueru Hayashi4, Wallace Kohata de Aquino5, Luiz Eduardo Gallina6

DOI: 10.5935/1678-9741.20130007

RBCCV 44205-1440

Abstract Objective: To evaluate clinically and by Doppler Echocardiography 22 patients submitted to mitral valve repair after valvular regurgitation using standardized bovine pericardium chordae. Methods: The patients had degenerative mitral regurgitation. Fourteen (63.6%) patients were male and the age ranged from 19 to 76 years (mean 56.8 ± 13.8 years). The strings of bovine pericardium treated with glutaraldehyde were reinforced in its transverse ends forming a trapezoid. Results: One patient (4.5%) died in the immediate postoperative period with in low cardiac output syndrome and three (13.6%) in the late postoperative period. One patient (4.5%) was reoperated. The actuarial curves for survival free of death from cardiovascular causes and free

from reoperation for patients who left the hospital (21), showed rates of 82.0 ± 9.8% and 83.9 ± 10.4% at 70 months postoperatively, respectively. Seventeen patients (77.3%) are alive with native valves. Of the 17 patients alive with native valves 16 (94.1%) were in functional class I. The Doppler Echocardiography postoperatively (mean 41 months, 4-70 months), showed no mitral regurgitation in 11 (64.7%) patients and mild regurgitation in five (29.4%). Conclusion: The technique of standard cords of bovine pericardium implantation to replace chordae tendineae of the mitral valve in patients with degenerative mitral regurgitation showed satisfactory results.

1. Associate professor, Head of the Cardiac Surgery Discipline of the Londrina State University, Londrina, PR, Brazil – Idealizer of the study; Data collection; discussion, writing. 2. Adjunct professor and Full Professor at Cardiology and Cardiovascular Surgery Department at São José do Rio Preto Medical School (Famerp), Teaching Adjunct professor at Famerp, São José do Rio Preto, SP, Brazil – Statistical Analysis/Discussion. 3. Surgeon at Hospital Evangélico de Londrina and Hospital João de Freitas de Arapongas, Londrina, PR, Brazil –Data collection; discussion. 4. Cardiologist at Hospital Evangélico de Londrina, Londrina, PR, Brazil – Data collection; discussion. 5. Cardiologist at Hospital Evangélico de Londrina, Londrina, PR, Brazil – Discussion. 6. Cardiologist at Hospital João de Freitas de Arapongas, Arapongas, PR, Brazil – Discussion.

This study was carried out at Surgical Clinics at Londrina State University (UEL), Hospital Evangélico de Londrina and Hospital Regional João de Freitas de Arapongas, Paraná, Brazil. Cardiology and Cardiovascular Surgery Department at São José do Rio Preto Medical School (Famerp), São José do Rio Preto, SP, Brazil.

Descriptors: Mitral valve insufficiency. Papillary muscles. Chordae Tendineae. Pericardium.

Correspondence address Moacir F. Godoy Rua Garabed Karabashian, 570 – São José do Rio Preto, SP, Brazil – Zip code: 15070-600 E-mail: mf60204@gmail.com Article received on January 27th, 2013 Article accepted on January 29th, 2013

Rev Bras Cir Cardiovasc 2013;28(1):36-46

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Abbreviations, acronyms & symbols LA MVA FE MMTG NYHA PD2VE PTFE VDFVE

Left atrium diameter Mitral valve area Ejection fraction Mean Mitral Trasvalvar Gradient New York Heart Association Left ventricular end-diastolic pressure Polytetrafluoroethylene Left ventricular end-diastolic pressure

Resumo Objetivo:Avaliar, clinicamente e pelo ecodopplercardiograma, o funcionamento da valva mitral em 22 pacientes submetidos à correção do refluxo valvar com substituição das cordas tendíneas nativas por cordas padronizadas de pericárdio bovino. Métodos: Os pacientes apresentavam insuficiência mitral degenerativa. Quatorze (63,6%) pacientes eram do gênero masculino e a idade variou de 19 a 76 anos (média 56,8±13,8 anos). As cordas de pericárdio bovino foram tratadas com

INTRODUCTION If not the most frequent, surely one of the most important causes of mitral regurgitation has been ruptured chordae, present in all etiologies, especially in degenerative. The chordae rupture, leading to prolapse of the corresponding leaflet, were surgically treated at the beginning of surgery with cardiopulmonary bypass by McGoon [1], by plication of the prolapsed portion of the leaflet. Initial results were good, but in the long-term led to the decreased mobility of the leaflet, especially the anterior. Merendino et al. [2] proposed the resection of the posterior leaflet of the mitral valve, thus eliminating the prolapse and suturing edge to edge this leflet, preceded by plication of the mitral ring. This technique has been used to the present day, with excellent results; limited, however, to rupture of the posterior leaflet [3]. Poor results with resection of the anterior leaflet of the mitral valve led Carpentier et al. [4] to introduce the technique of transferring strings of the posterior leaflet to the anterior leaflet of the mitral valve in cases of ruptured chordae. The creation of new chordae from tissue flap of the anterior leaflet was proposed by Gregori et al. [5], for correction of prolapse in cases of rupture of the anterior leaflet chordae. However, this technique has been reserved for those cases where there is exuberant tissue, which is common in the degenerative disease. Since January 1991,

glutaraldeído, com reforço de suas extremidades transversais formando um trapézio. Resultados: Um (4,5%) paciente faleceu no pós-operatório imediato em síndrome de baixo débito cardíaco e três (13,6%) no pós-operatório tardio. Uma (4,5%) paciente foi reoperada. As curvas atuariais de sobrevivência livre de óbitos por causa cardiovascular e livres de reoperações para os pacientes que deixaram o hospital (21) demonstraram taxas de 82,0±9,8% e 83,9±10,4%, aos 70 meses de pós-operatório, respectivamente. Dezessete (77,3%) pacientes estão vivos com a própria valva. Dos 17 pacientes vivos com a própria valva 16 (94,1%) estão em classe funcional I. O ecodoppler pós-operatório (média de 41 meses; 4 a 70 meses) demonstrou ausência de regurgitação mitral em 11 (64,7%) pacientes e regurgitação discreta em cinco (29,4%). Conclusão: A técnica de implante de cordas padronizadas de pericárdio bovino para substituição de cordas tendíneas da valva mitral em pacientes com insuficiência mitral degenerativa demonstrou resultados bastante satisfatórios. Descritores: Insuficiência da valva mitral. Músculos papilares. Cordas tendinosas. Pericárdio.

we employed a technique for correction of prolapse of the anterior leaflet of the mitral valve secondary to ruptured chordae, with good results. It consists in providing chordae from the partial transfer of the tricuspid valve to the mitral valve [6]. The valve prolapse has been treated by other techniques that try to avoid any kind of restriction on the mobility of the anterior leaflet of the mitral valve, such as the making of bovine pericardium [7] or polytetrafluoroethylene (PTFE) [8] artificial chordae. Since 2006, we have used a prosthesis for replacement of ruptured tendineae chordae [9,10]. It deals with bovine pericardium premolded chordae preserved in glutaraldehyde. The technique is similar to the partial transfer of the tricuspid valve to the mitral valve for the supply of new chordae [6]. The aim of this study is to present the postoperative outcome of a consecutive series of patients with degenerative mitral regurgitation secondary to ruptured chordae, who had undergone reconstructive surgery with implantation of bovine pericardium premolded chordae treated in glutaraldehyde and anti-calcifying agents. METHODS We prospectively studied 22 patients undergoing mitral valve failure repair surgery of degenerative cause, from May 1996 to May 2012. These patients had mitral valve prolapse by chordal rupture leading to regurgitation. The patients 37

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Rev Bras Cir Cardiovasc 2013;28(1):36-46

underwent consecutively surgery by the same surgeon, at Hospital Evangélico de Londrina (Londrina, PR, Brazil) and Hospital João de Freitas de Arapongas (Arapongas, PR, Brazil), by the technique of replacing the ruptured chordae tendineae by implantation of bovine pericardium premolded chordae treated in glutaraldehyde and anti-calcifying agents (Braile Biomédica, São José do Rio Preto, SP, Brazil). The clinical preoperative data of patients are shown in Table 1. Fourteen (63.6%) patients were male and eight (36.4%) were female. The age of patients ranged from 19 to 76 years, mean 56.8 ± 13.8 years. All patients had mitral regurgitation of degenerative etiology, and fibroelastic degeneration in 16 (72.7%) patients and Barlow syndrome in six (27.3%). Fifteen (68.2%) patients were in functional class III and seven (31.8%) in class IV according the New York Heart Association (NYHA).

Auscultation of the mitral regurgitation has shown murmur in all patients, being severe in 13 (59.1%) and very severe in nine (40.9%). Atrial fibrillation was present in four (18.2%) patients. The clinical diagnosis was confirmed by echocardiography and hemodynamic Doppler then when surgery was indicated. Five (22.7%) patients had tricuspid regurgitation, one (4.5%), atrial septal defect and one (4.5%), chronic coronary failure. The preoperative hemodynamic data are shown in Table 2. On hemodynamic examination, performed in 21 patients, mitral regurgitation was moderate in five (23.8%) and severe in 16 (76.2%) patients. As the left ventricle contractility observed by ventriculography we found: normal in eight (38.1%) patients, mild hypokinesia of the left ventricle in five (23.8%), moderate in six (28.6%) and severe hypokinesia in two (9.5%). The average left ventricular end-diastolic pressure (DP2LV) was 19.8 mmHg (range 12-31 mmHg).

Table 1. Preoperative clinical data. N o.

Patients

Gender

Age (years)

Diag

Assoc Diag

Etiol

SMM

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean ± SD

VG CLSF JR AM AMB SFN ATF GMG JAO PSM AC SM NAN GAL JC MAT MLPS AR HJA JAL RF ABR

M F M M M F F F M M M M F M M F F M M F M M

61 51 59 58 53 23 68 69 61 19 72 76 45 55 66 53 62 53 55 70 62 58 56.8 ± 13.8

IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM IM

TI IC TI CoF TI TI TI -

FD FD FD FD FD FD FD FD FD FD FD BARLOW FD FD BARLOW FD FD BARLOW FD BARLOW BARLOW BARLOW

IV III III III III III III III IV IV III IV III III IV III III IV IV III III III

++++ +++ +++ +++ +++ +++ +++ +++ ++++ ++++ +++ ++++ +++ +++ ++++ +++ +++ ++++ +++ ++++ ++++ ++++

M = Male, F = Female, FC = Functional Class (NYHA) = Diag = diagnosis, Assoc Diag = Associate diagnosis, Etiol = Etiology, SMM = Systolic mitral murmur, MF = Mitral failure, TI =Tricuspid Insufficiency, IC = Interatrial communication, CoF = Coronary Failure, FD = Fibroelastic degeneration, Barlow = Barlow syndrome, SD = Standard deviation.

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Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Table 2. Preoperative hemodynamic data. No.

Patients

Gender

Cat date

Surg Date

LV Cont

ED2LVP

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean

VG CLSF JR AM AMB SFN ATF GMG JAO PSM AC SM NAN GAL JC MAT MLPS AR HJA JAL RF ABR

M F M M M F F F M M M M F M M F F M M F M M

15/05/06 04/08/06 06/06/06 26/09/06 17/04/06 08/11/06 03/05/06 22/12/06 12/01/07 14/02/07 21/05/07 02/08/08 28/11/08 13/07/09 10/09/09 08/10/09 12/03/10 28/09/10 20/10/10 05/01/11 28/02/12

31/05/06 29/08/06 20/09/06 09/10/06 16/10/06 14/11/06 04/12/06 06/12/06 29/01/07 12/02/07 27/02/07 30/05/08 19/08/08 15/12/08 19/08/09 17/09/09 31/03/10 20/05/10 06/10/10 03/11/10 16/03/11 05/03/12

Sev Hipo Normal Normal Normal Disc Hypo Normal Normal Mod Hypo Mod Hypo Disc Hypo Disc Hypo Disc Hypo Mod Hypo Normal Disc Hypo Normal Mod Hypo Mod Hypo Mod Hypo Sev Hipo Normal

Import Import Import Mod Mod Import Import Import Import Import Import Mod Import Import Import Import Mod Import Import Import Mod

30 18 31 15 16 25 20 16 28 20 15 14 24 15 12 24 12 15 22 23 21 19.8 [12 to 31]

Disc Hypo = Discrete Hypokinesia, Mod Hypo = Moderate Hypokinesia, Sev Hypo = Severe Hypokinesia, Cat date = Date of catheterization, Surg Date = Date of Surgery, LV Cont = Left ventricular contractility, MR = Mitral regurgitation, ED2LVP = End-diastolic left ventricular pressure

In all patients, two changes were always present, ruptured chordae and dilatation of the mitral valve annulus. In 13 (59.1%) patients, chord rupture was on the anterior leaflet of the mitral valve, in eight (36.4%), in the posterior leaflet and in one (4.5%) in both leaflets. Prosthesis The bovine pericardium premolded chordae were performed in monoblock (Braile Biomédica, São José do Rio Preto, SP, Brazil), trapezoid-shaped, with enhanced bovine pericardium or Dacron in their upper and lower beams. The chordae are premolded in number from five to seven, with lengths ranging from 20 to 35 mm. Its width is 2 mm and are distant from each other by 3 mm. The standardization of the chordae was confirmed by the use of steel meters corresponding to the size of the prostheses. The pericardium was treated with 0.5% glutaraldehyde, subjected to anti-calcification treatment with glutamic acid and preserved in 4% formaldehyde solution. Strength and durabil-

ity tests showed levels of rupture of about 15 kg/cm2 [11]. The prostheses implanted were in numbers 35, 30, 25 and 20 in one (4.5%), 12 (54.5%), seven (31.8%) and two (9.1%) patients, respectively. The size of the graft was determined based on the distance from the top of the papillary muscle to the free edge of the leaflet in its original position, not prolapsed. Thirteen (59.1%) patients received prostheses to the anterior leaflet, eight (36.4%) to the posterior leaflet and one (4.5%) for both. The implant prosthesis begins with setting the lower part of the trapezoid at the top of the papillary muscle associated with the chordae using a U-section 5-0 polypropylene, anchored in a Dacron pad. In sequence, the larger beam of the trapezoid will be sutured on the free edge of the compromised mitral leaflet with interrupted sutures using 5-0 polypropylene. The prosthesis with five to seven chordae in their original form can be reduced up to two chordae if necessary. It can also have its upper stem (larger) divided, and thus can be both tops sutured to the anterior and posterior leaflets while correcting occasional prolapse of two leaflets. 39

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Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Associated repair techniques (Table 3)

Annuloplasty - The dilatation of the mitral annulus, present in all cases, was corrected with the use of GregoriBraile® prosthetic ring [12]. In association, in two (91%) cases, was performed plicature of the mitral annulus near the posteromedial commissure using technique by Wooler et al. [13]. This is a hemi-ellipse prosthesis industrialized and commercially available (Braile Biomédica, São José do Rio Preto, SP, Brazil). Its shape resembles the Carpentier ring without the anterior segment, and presents a modification in its right half. This is a correction of the ring curve. Thus, the prosthesis is hemi-ellipse-shaped, and the right curvature is rectified. The material used is 316 stainless steel, medical grade coated with a layer of silicone rubber, and finally by Dacron. It presents in various sizes, according to various dimensions of the mitral annulus. Choosing the ideal

ring was based solely on the distance between the fibrous trigones, which generally correspond to the projections of the commissures in mitral annulus of the patient, regardless of the anteroposterior diameter. The fixation of the prosthesis in the mitral annulus was performed usingh U-section 2-0 polyester thread in the mitral annulus 1-2 mm apart and then on the outside of the prosthetic ring. The two thresholds which correspond to the ends of the prosthesis are applied to the mitral annulus, at the height of the commissures of the projection, so that after the fixation of the prosthesis, the posterior leaflets moves to the anterior, and what is important, the posteromedial portion moves more sharply in the anterior-lateral directon, thus correcting existing dilation. In two (9.1%) patients, annuloplasty was performed according Wooler et al. [13] to correct the excessive dilation of the posterior annulus of the mitral valve near the posteromedial commissure.

Table 3. Surgical data. No.

Patients

Surg Date

Annulus

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Mean

VG CLSF JR AM AMB SFN ATF GMG JAO PSM AC SM NAN GAL JC MAT MLPS AR HJA JAL RF ABR

05/31/06 08/29/06 09/20/06 10/09/06 10/26/06 11/14/06 12/04/06 12/06/06 01/29/07 02/12/07 02/27/07 05/30/08 08/19/08 12/15/08 08/19/09 09/17/09 03/31/10 05/20/10 10/06/10 11/03/10 0316/11 03/05/12

Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring+ WOOLER Ring Ring + WOOLER

Techniques

Chordae No.

DeVega A 30 SHORT GREGORI CHORDAE A 20 RES. CALCIF SHORT. CHORDAE FRATER/CARP A 30 SHORT. CHORDAE CARP/ IAC CLOS P 30 MERENDINO + RES. ANT LEAF P 30 SHORT. CHORDAE FRATER P 20 MERENDINO + MMDA P 30 SHORT. CHORDAE CARP+DeVega P 30 MERENDINO + SHORT GREGORI CHORDAE A 30 MERENDINO P 35 ENL POST LEAF A 25 A+P 30 SHORT. CHORDAE FRATER A 25 A 30 P 25 A 25 A 25 MERENDINO P 30 A 25 DeVega A 30 MERENDINO SHORT. CHORDAE CARP + DeVega A 25 MERENDINO A 30

CBT

TMA

94 98 98 92 117 90 87 75 100 81 182 120 71 99 97 67 82 100 85 86 121 151 100

41 63 66 52 62 27 48 26 58 44 123 61 37 52 57 22 42 41 34 51 59 79 52

Surg Date = Date of surgery, Annulus = Type of annuloplasty, CBT = Cardiopulmonary bypass time, TMA = Time of myocardial anoxia, Short = Shortenings, RES = Resection, Calcif = Calcification, Carp = Carpentier, AntLeaf = Anterior leaflet, Post leaf = Posterior leaflet, MMDA = Mammary/anterior descending coronary artery, Enl post leaf = Enlargement of posterior leaflet, A = Anterior, P = Posterior, IAC Clos = Interatrial communication closure.

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Rev Bras Cir Cardiovasc 2013;28(1):36-46

Chordal shortening - The chordal shortening was performed in eight (36.4%) patients. In two (9.1%) of these patients, chordal shortening was performed according to Carpentier et al. [14] with longitudinal incision of the papillary muscle and burial intrapapillar stretched chord. In two (9.1%) patients was used the method described by shortening according Gregori Jr. et al. [15]. We performed a small incision in the anterior leaflet near the elongated cords beam being pulled through the incision and then fixed to the surface of the anterior leaflet. In four (18.2%) patients, we used the technique by Frater et al. [7], or that is, fixing the elongated chordae on the inner face of the anterior leaflet. Minor shortenings are achieved with this technique. Eventually, we use the three methods described for the shortening of elongated chordae in the same patient. Leaflet resection - In eight (36.4%) patients, we performed resections of leaflets, being quadrangular in the posterior leaflet [2] in seven patients and triangular in anterior leaflet in one [1]. We avoid this last procedure in the anterior leaflet because it could lead to mitral stenosis by decreasing leaflet mobility. After quadrangular resection of the posterior leaflet and posterior leaflet prolapse correction, the two edges of the leaflet were approximated and sutured using 5-0 polypropylene sutures. Leaflet enlargement - In one (4.5%) patient, we expanded the posterior leaflet of the mitral valve using a bovine pericardial patch to thereby facilitate better coaptation of the posterior leaflet to the anterior.

EchoDopplercardiographic assessment Seventeen patients underwent Doppler echocardiography to assess left ventricular function, left atrial diameter, mitral valve area, mean gradient, end-diastolic left ventricular volume and the degree of valvular regurgitation. The classification of Doppler echocardiographic mitral regurgitation was based on the extent and magnitude of the regurgitant jet in the left ventricular systole. We assessed the following indices: ejection fraction (EF) of the left ventricle, left atrium diameter (LA), mitral valve area (MVA), mitral mean gradient (GTVM) and left ventricular end-diastolic volume (LVEDV). The mean postoperative assessment of the 17 surviving patients was 47 months (range 4-70 months).

Other Associated Surgical Techniques Four (18.2%) patients with functional tricuspid insufficiency underwent annuloplasty according to the technique described by DeVega [16], which consists in encircling the tricuspid annulus to flee the area corresponding to the passage of the conduction beam near the atrioventricular node. One (4.5%) patient had their interatrial communication closed and another (4.5%) underwent myocardial revascularization with internal thoracic artery to the anterior interventricular branch of the left coronary artery. Postoperative Clinical Evaluation Hospital and late mortality, the rate of reoperation due to failure of reconstructive surgery, and the postoperative morbidity were observed. The surviving patients (17) were clinically assessed at a median time after surgery of 47 months (range 4-70 months). As preoperatively, patients were classified according to the clinical status according to the NYHA classification of symptoms. On physical examination, during this same period, the auscultation of the mitral valve was assessed for the presence of murmurs.

Statistical Analysis Actuarial survival curve free of death and actuarial survival free of reoperation were obtained for total (22) of patients and for the 21 patients who were discharged from hospital and outpatients [17]. RESULTS The postoperative clinical data are presented in Table 4. There was one death in the immediate postoperative period (4.5%) in low cardiac output syndrome in 70-yearold patients, diagnosed with mitral and associated tricuspid insufficiency and carrier of Barlow syndrome. The mitral annuloplasty ring consisted of using Gregori-Braile ring and tricuspid annuloplasty was performed using DeVega technique [6]. There were no thromboembolic events or hemolysis postoperatively. Four patients who had atrial fibrillation preoperatively continued with arrhythmia in the postoperative period. Two (9.1%) patients required reoperation at 35 and 46 months for mitral valve replacement, the latter died in low cardiac output syndrome in the first hours after arriving at the Intensive Care Unit. In both patients, the chordae shortening technique was associated and in none of them the bovine pericardium chordae were compromised implanted in the posterior leaflet. There was evolution of fibroelastic degeneration, especially involving the anterior leaflet of the mitral valve that received no artificial chordae. Two patients died, one month and 12 months postoperatively, suddenly, being previously in functional class I, one without mitral regurgitation and one with slight reflux at Doppler echocardiography. In the first patient, ventricular fibrillation on mobile ICUâ&#x20AC;&#x2122;s electrocardiogram was recorded. These patients had severe left ventricular dyskinesia on preoperative cineventriculography, and high left ventricular end-diastolic pressure. The total number of later deaths was 3 (13.6%) patients, if added these two deaths to those of reoperation after valve replacement. Eighteen (81.8%) patients are alive and 17 (77.3%) are alive 41

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Rev Bras Cir Cardiovasc 2013;28(1):36-46

with native valves. Sixteen (94.1%) of 17 surviving patients are in functional class I and one (5.9%) in functional class II (NYHA). Fifteen (88.2%) patients had no murmurs in the mitral valve, and two (11.8%), there was presence of

slight systolic murmur, one (5.9%) of them associated with a diastolic murmur at the apex. Actuarial survival free of death of 22 patients from cardiovascular causes demonstrated survival probability at 70 months of 78.3 ± 10.1% (Figure 1).

Table 4. Postoperative clinical data. No.

Patients

Gender

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

VG CLSF JR AM AMB SFN ATF GMG JAO PSM AC SM NAN GAL JC MAT MLPS AR HJA JAL RF ABR

M F M M M F F F M M M M F M M F F M M F M M

Age (years) Surg Date 61 51 59 58 53 23 68 69 61 19 72 76 45 55 66 53 62 53 55 70 62 58

05/31/06 08/29/06 09/20/06 10/09/06 10/16/06 11/14/06 12/04/06 12/06/06 01/29/07 02/12/07 02/27/07 05/30/08 08/19/08 12/15/08 08/19/09 09/17/09 03/31/10 05/20/10 10/06/10 11/03/10 03/16/11 03/05/12

Evol Date

Evol

SMM

DMM

12 M 06/16/12 05/15/12 07/18/12 06/19/12 10/22/09 04/20/12 08/05/10 06/11/12 06/11/12 07/20/12 07/20/12 06/12/12 03/13/12 07/05/12 01/03/12 06/04/12 06/15/12 07/11/12 1M 07/04/12

LAT SUDDEN DEATH GOOD GOOD GOOD GOOD MVR REOP GOOD LAT DEAT TVM REOP GOOD GOOD GOOD GOOD GOOD GOOD GOOD GOOD GOOD GOOD GOOD IMMED DEATH LOS LAT DEAT VF GOOD

I I I I I I II I I I I I I I I I I

0 0 0 0 0 0 0 + + 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 + 0 0 0 0 0 0 0 0 0 0

Evol = Evolution, Evol Date = Date of Evolution, FC = Functional Class, = SMM = Systolic mitral murmur, DMM = Diastolic mitral murmur, M = Male, F = Female, Lat Death = Late Deat, Immed Deat = Immediate Death, Reop = Reoperation, MVR = Mitral Valve Replacement, VF = Ventricular Fibrillation, LOS = Low output syndrome.

Fig. 1 - Actuarial survival curve of the patients (22). It is observed that 78.3 ± 10.1% of the patients are still alive after 70 months of follow-up

Fig. 2 - Actuarial survival curve of patients who were discharged from hospital and were followed-up as outpatients (21). It is observed that 82.0 ± 9.8% are alive at 70 months postoperatively

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Rev Bras Cir Cardiovasc 2013;28(1):36-46

The actuarial survival of patients who left the hospital and remain under outpatient treatment (21) demonstrated survival probability at 70 months of 82.0 ± 9.8% (Figure 2). The Doppler echocardiographic assessment was performed in the 17 surviving patients, between the months of January and July 2012, with a mean postoperative followup of 47 months (range 4-70 months). Left ventricular function measured by EF showed a mean of 0.59 (range 0.27 to 0.76). The average diameter of the left atrium was 4.5 cm (ranging from 3.0 to 6.9 cm). The mean MVS assessed was 2.9 cm2 (range 1.6 to 4.5 cm2), and satisfactory in all except

one (1.6 cm2) patient. The mean GTVM was 3.3 mmHg (range 1-9 mmHg), with negligible values in all patients except one. The average LVFDV was 141 ml (range 83-247 ml), which is normal in 12 (70.5%). The analysis of valve competence showed no mitral regurgitation in 11 (64.7%) of the 17 surviving patients assessed, slight regurgitation in five (29.4%) and mild/ moderate in one (5.9%). Therefore, satisfactory competence of the mitral valve was observed in 94.1% of cases. Mild tricuspid regurgitation was observed in four (23.5%) patients and mild regurgitation of the aortic valve in four (23.5%). The actuarial reoperation-free after implantation of standardized bovine pericardium chordae treated with glutaraldehyde and non-calcifying agent for replacement of ruptured chordae tendineae of the mitral valve was at 70 months postoperatively, 83.9 ± 10.4% (Figure 3). The actuarial reoperation-free for the 21 patients who were discharged and followed as outpatients at 70 months postoperatively showed rate of 83.9 ± 10.4% (Figure 4). DISCUSSION

Fig. 3 - Actuarial survival curve of the surgical method, or that is, the implanted prosthesis in the mitral valve (22 patients). It is observed that 83.9 ± 10.4% of the prostheses are free from dysfunction at 70 months postoperatively

Fig. 4 - Actuarial curve free of reoperation for 21 patients who were discharged and were followed-up as outpatients at 70 months postoperatively (83.9 ± 10.4%)

Several techniques have been described over the years aiming at mitral valve reconstruction. Therefore, a thorough knowledge of anatomical pathology is necessary. The mitral valve is composed by an incomplete fibrous ring that goes from the right fibrous trigone to the left fibrous trigone - its anterior portion is occupied by the ring of the aortic valve and it was previously thought that it did not dilate until Hueb et al. [18] showed pathological changes of this portion of the mitral valve in hearts with ischemic and degenerative disease. Anyway, changing that part or not, the annular dilatation should be corrected - and this is the last step of the reconstruction, restoring the original shape of the ring which is of a vat, culminating with a perfect approximation of the anterior and posterior leaflets and commissures. There are six valves composing the mitral valve, one anterior and three posterior (posterolateral, posteromedial and posterior itself), besides the two commissures containing leaflets and chordae attached to the papillary muscles and/or the free wall the left ventricle. During left ventricular systole, the mitral valve contracts, similarly to a sphincter - takes the form of a kidney while relieving the outflow of the left ventricle. In the dilated left ventricle (either in volume overload or cardiomyopathy), the ring expands subsequently acquiring the ovoid form, but more intensely at right next to the posteromedial commissure. Hence the reason we have used the ring developed by us [12] that with the shape of a hemi-ellipse approximates the posterior leaflets to the anterior leaflet, and because it has correction on its right side, approximates this part of the mitral annulus, more often dilated. Even being open, in its anterior portion, the upper ends of the prosthesis, fixed 43

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

Rev Bras Cir Cardiovasc 2013;28(1):36-46

along the trigone, prevent annular dilatation on that site, occupied by the fibrous ring of the aortic valve. Stretching and rupture of chordae are the most common complications in degenerative mitral valve. Changes in the leaflets also occurs, with sagging and proliferation of connective tissue and may be exaggerated, as in Barlow syndrome (six patients in this study), much harder to be treated than in fibroelastic degeneration, when there is plenty of tissue. Faced with cases of chordae rupture, surgeons commonly have different behavior if it is located in the anterior leaflet of the mitral valve. The chordae rupture of the anterior leaflet is a major challenge, since in these cases the valve failure is usually significant. The anterior leaflet has basically function of excursion and the posterior leaflets have function of containing and support to the anterior leaflet. Valve prolapse by chordae rupture are easier to be treated when present in the posterior leaflet. The repair by Merendino et al. [2], have been used successfully for a long time, often solving the problem often in such cases. Contrary to what the literature shows, in our cases, correction of chordae rupture of the anterior leaflet was more frequent than in the posterior leaflet. The surgical technique to be used depends on the level of commitment and the location of the damaged chordae. There are several procedures that can be adopted in chordal rupture. Transfering chordae from the posterior leaflet to the anterior leaflet of the mitral valve proposed by Carpentier et al. [4] has been used, including in our department. Constructing a neocord through the removal of a flap of the anterior leaflet of the mitral valve when lowered on top of the papillary muscle, replacing ruptured chordae tendineae is an alternative technique [5], but its use is restricted to patients with the anterior leaflet well developed, which does not occur in rheumatic, ischemic or even in endocarditis diseases. It is therefore almost exclusively of degenerative disease. Partial transfer of the tricuspid valve (posterior leaflet in most cases) to the mitral valve, providing chordae to the anterior leaflet, was proposed by Gregori et al. in 1992 [6], with very satisfactory results. These techniques require handling of leaflets and chordae with normal anatomy and, in general, are feared by surgeons that initiate in reconstructive surgery of the mitral valve. Synthetic and biological materials have been used for the replacement of chordae. The PTFE threads, proposed by David et al. [8] have been shown to be more frequently used in the world. A recent study using PTFE showed excellent results at five and 10 years postoperatively, with no reoperation in 93.3% and 81.7%, respectively [19]. However, the use of these techniques requires enormous degree of subjectivity, requiring a high degree of individual skill. Dang et al. [20] described a simplified method for using PTFE, slightly easing its implementation. With biological materials, Frater et al. [7] were the first

to employ the bovine pericardium for chordal replacement with satisfactory initial results. Their study was interrupted due to fear of calcification over the years. However, in their original study, two groups of patients undergoing implant of PTFE and bovine pericardium chordae were compared. It should be emphasized that a pericardial measured 4 mm wide, with not being premolded chordae, nor standardized by instruments (meters). In addition, follow-up time was longer in the group which used bovine pericardium than in the group that used PTFE. Even so, there was no significant difference in long-term evolution of the two groups, nor calcification of bovine pericardium implanted. Calcification is really a problem and should be matter of concern. Many efforts have been made to improve the durability of the bovine pericardium with the introduction of new chemical reagents as used in our case, the glutamic acid. It has been very frequent the use of bovine pericardium in cardiovascular surgery. Its use is common in the manufacture of prostheses, in orifice occlusions in congenital heart defects, reconstructions of the ventricular outflow tract, in ventricular repair after repair of left ventricular aneurysms, among other procedures. In mitral valve surgery, the pericardium has been used as a rope to maintain the tension between the top of the papillary muscles and the mitral valve in valve replacement, with significant improvement in ventricular function [21]. The use of standardized bovine pericardium prosthesis makes the procedure easier and therefore fast, objective and reproducible. Laboratory tests of the artificial chordae showed a rupture level in 15 kg/cm2. It must be remembered that in a patient with high blood pressure of 140 mmHg in systole of his left ventricle, the tension to which the chordae are subjected is approximately 0.5 kg/cm2, therefore thirty times smaller. The chordae implantation technique is similar to that described by us in case of partial transfer of the tricuspid valve (posterior leaflet, usually) to the mitral valve [6]. In this study, in all patients was performed annuloplasty using rigid open Gregori-Braile ring [12], preceeded in both cases, of Wooler annuloplasty [13], along the posteromedial commissure. Clinical improvement was observed in surviving patients, both with respect to functional class (16 of them in functional class I and one in functional class II) and the excellent auscultation of mitral valve (15 with no murmurs and two with discrete systolic murmur in the mitral focus, one of them associated with a diastolic murmur at the apex). Aiming standardization of laboratory data, we assessed hemodynamically patients preoperatively, since echocardiograms were performed by different clinicians, which has not happened postoperatively. It is noted that, in the two patients with sudden death in the late postoperative period, the preoperative ventriculography showed severe left

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Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

ventricular hypokinesis, in addition to high left ventricular end diastolic pressure. The Doppler echocardiography has been the best method for postoperative assessment of mitral valve and, in the patients of this study, implantation of standard bovine pericardial chordae associated with open rigid annuloplasty and other techniques presented postoperative quite satisfactory. We attribute these results to a significantly greater coaptation line between the leaflets, since extensive resections are avoided. The postoperative data of this prospective study confirmed the clinical findings observed. Except in one case, the mean transvalvular gradients were normal, in over 70% of cases, left ventricular end-diastolic volume was normal and the mitral valve area was satisfactory. Satisfactory results were also observed in the analysis of mitral valve competence in view of the absence of regurgitation or only mild mitral regurgitation in 16 of 17 patients. The benefit of the artificial chordae implantation is more evident in cases of ruptured chordae of the anterior leaflet, in which resection should be avoided because it may damage its main function, which is excursion. However, it is still interesting its application in the posterior leaflet. Falk et al. [22] corroborated this statement in a prospective randomized study comparing the use of PTFE chordae with resection of the posterior leaflet prolapse. Thus, the good late results are technique-dependent. A prospective analysis of our cases is valid because the series is consecutive, the patients had mitral valve lesions of the same etiology (degenerative) and underwent surgery by the same surgeon. The actuarial survival curves free of death and reoperation showed probability of survival at 70 months postoperatively for more than 80%, confirming our previous publications [9,10]. Over 90% of the 17 surviving patients showed competent mitral valve postoperatively, and none showed signs of calcification of the implanted prosthesis. Furthermore, in no patient with events of death or reoperation was confirmed dysfunction of the bovine pericardium prosthesis preserved in glutaraldehyde for the replacement of ruptured chordae tendineae. The early death in the first surgery and early death in a patient who had undergone surgery for mitral valve replacement were due to low cardiac output syndrome, with prostheses functioning normally. In the two patients who died suddenly in the late postoperative period, the most likely cause would have been ventricular fibrillation - documented in a mobile ICU. In the rupture of mitral valve chordae, patients have usually in severe cases, acute pulmonary edema. With good postoperative follow-up, with respect to the patient who had undergone surgery for mitral valve replacement, during surgery was observed that the mitral valve showed severe degeneration of the anterior leaflet, being with good aspect the implant of bovine pericardium chordae in the posterior leaflet.

CONCLUSION Despite a follow-up not extensive, the outcomes obtained, both clinical and Doppler echocardiographic, allow us to affirm that clinical outcome after use of the technique of chordae replacement by premolded chordae of bovine pericardium preserved in glutaraldehyde are satisfactory in patients with impaired mitral degenerative etiology.

REFERENCES 1. McGoon DC. Repair of mitral insufficiency due to ruptured chordae tendineae. J Thorac Cardiovasc Surg. 1960;39:357-62. 2. Merendino KA, Thomas GI, Jesseph JE, Herron PW, Winterscheid LC, Vetto RR. The open correction of rheumatic mitral regurgitation and/or stenosis; with special reference to regurgitation treated by posterormedial annuloplasty utilizing a pump-oxygenator. Ann Surg. 1959;150(1):5-22. 3. Pomerantzeff PAM, Brandão CMA, Rossi EG, Cardoso LF, Tarasoutchi F, Grimberg M, et al. Quadrangular resection without ring annuloplasty in mitral valve repair. Eur Cardiovasc Surg. 1997;2:271-3. 4. Carpentier A, Relland J, Deloche A, Fabiani JN, D'Allaines C, Blondeau P, et al. Conservative management of the prolapsed mitral valve. Ann Thorac Surg, 1978;26(4):294-302. 5. Gregori F Jr, Takeda R, Silva S, Façanha L, Meier MA. A new technique for mitral insufficiency caused by ruptured chordae of the anterior leaflet. J Thorac Cardiovasc Surg, 1988;96(5):765-8. 6. Gregori F Jr, Cordeiro C, Croti UA, Hayashi SS, Silva SS, Gregori TE. Partial tricuspid valve transfer for repair of mitral insufficiency due to ruptured chordae tendineae. Ann Thorac Surg, 1999;68(5):1686-91. 7. Frater RW, Gabbay S, Shore D, Factor S, Strom J. Reproducible replacement of elongated or ruptured mitral valve chordae. Ann Thorac Surg. 1983;35(1):14-28. 8. David TE, Bos J, Rakowski H. Mitral valve repair by replacement of chordae tendineae with polytetrafluorethylene sutures. J Thorac Cardiovasc Surg. 1991;101(3):495-501. 9. Leal JCF, Gregori Jr. F, Galina LE, Thevenard RS, Braile DM. Avaliação ecocardiográfica em pacientes submetidos à substituição de cordas tendíneas rotas. Rev Bras Cir Cardiovasc. 2007;22(2):184-91.

Gregori Junior F, et al. - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium

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10. Gregori F Jr, Leal JC, Braile DM. Premolded bovine pericardial chords for replacement of ruptured or elongated chordae tendineae. Heart Surg Forum. 2010;13(1):E17-20.

17. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Statist Assoc. 1958;53:457-8.

11. Braile DM, Ardito RV, Pinto GH, Santos JLV, Zaiantchik M, Souza DRS, et al.. Plástica mitral. Rev Bras Cir Cardiovasc. 1990;5(2):86-98.

18. Hueb AC, Jatene FB, Moreira LF, Pomerantzeff PM, Kallás E, 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.

12. Gregori F, Silva SS, Hayashi SS, Aquino W, Cordeiro C, Silva LR. Mitral valvuloplasty with a new prosthetic ring. Analysis of the first 105 cases. Eur J Cardiothorac Surg. 1994;8(4):168-72.

19. Kobayashi J, Sasako Y, Bando K, Minatoya K, Niwaya K, Kitamura S. Ten-year experience of chordal replacement with expanded polytetrafluoroethylene in mitral valve repair. Circulation. 2000;102(19 Suppl 3):III30-4.

13. Wooler GH, Nixon PG, Grimshaw VA, Watson DA. Experience with the repair of the mitral valve in mitral in competence. Thorax. 1962;17:49-57.

20. Dang NC, Stewart AS, Kay J, Mercando ML, Kruger KH, Topkara VK, et al. Simplified placement of multiple artificial mitral valve chords. Heart Surg Forum. 2005;8(3):E129-31.

14. Carpentier A, Deloche A, Dauptain J, Soyer R, Blondeau PH, Piwinica A, et al. A new reconstructive operation for correction of mitral and tricuspid insufficiency. J Thorac Cardiovasc Surg. 1971;61(1):1-13.

21. Gomes OM, Pitchon M, Barros MVL. Utilização de cordas tendíneas de pericárdio bovino em cirurgia da valva mitral. Coração. 1990;2:20-2.

15. Gregori Júnior F, Silva S, Façanha L, Cordeiro C, Aquino W, Moure O. Preliminary results with a new technique for repairing elongated chordae tendineae of the anterior mitral valve leaflet. J Thorac Cardiovasc Surg. 1994;107(1):321-3. 16. DeVega NF. La anuloplastia selectiva, regulable y permanente. Rev Esp Cardiol. 1972;25:555-6.

22. Falk V, Seeburger J, Czesla M, Borger MA, Willige J, Kuntze T, et al. How does the use of polytetrafluoroethylene neochordae for posterior mitral valve prolapse (loop technique) compare with leaflet resection? A prospective randomized trial. J Thorac Cardiovasc Surg. 2008;136(5):1205. 23. Gregori Junior F. Conservative surgical management of mitral insufficiency: an alternative approach. Rev Bras Cir Cardiovasc. 2012;27(2):312-7.

Borges JBC, et al. - Correlation between quality of life, functional class ORIGINAL ARTICLE and age in patients with cardiac pacemaker

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Correlation between quality of life, functional class and age in patients with cardiac pacemaker Correlação entre a qualidade de vida, classe funcional e idade em portadores de marca-passo cardíaco

Juliana Bassalobre Carvalho Borges1, Rubens Tofano de Barros2, Sebastião Marcos Ribeiro de Carvalho3, Marcos Augusto de Moraes Silva4

DOI: 10.5935/1678-9741.20130008

RBCCV 44205-1441

Abstract Objective: To evaluate whether there is a correlation between quality of life and functional class in early heart pacemaker in patients, and its relationship with age. Methods: 107 patients of both sexes (49.5% female /50.5% male) were investigated, average implant time of 6.36 months (±2.99), and average age of 69.3 years (±12.6). To assess the FC, a scale suggested by Goldman was used; for QoL the AQUAREL questionnaire was used, associated with SF-36. Statistical analysis was conducted using Spearman's correlation with 5% significance. Results: Negative correlations were observed between QoL and FC: AQUAREL in the three domains, chest discomfort (r=-0.197, P=0.042), dyspnea (r=-0.508, P=0.000), arrhythmia (r=-0.271, P=0.005), and the SF-36 in the eight domains. Regarding age, there was a negative correlation with the SF36 Functional Capacity (r=-0.338, P=0.000) and no correlation was found with AQUAREL. Positive correlation (r=0.237, P=0.014) was observed between age and FC.

Conclusion: In this study we found a significant negative correlation between QoL and FC, indicating that patients in this sample who belong to a better FC demonstrated better QoL. The older the patient, QoL is worse in functional capacity and FC. It is suggested that age and FC influence QoL, and the functional classification scales may be established as one of the assessment tools and reflect QoL in patients with pacemakers.

1. Doctor of Medicine / Universidade Estadual Paulista, Botucatu Medical School, UNESP (FMB-UNESP); University Professor at FFC-UNESP, Botucatu, São Paulo, Brazil. Responsible Researcher. 2. Master`s degree, Santa Casa de Misericordia de Marília, Marília, São Paulo, Brazil. Researcher. 3. Doctor of Medicine at FFC-UNESP, Marilia Campus, Marilia, São Paulo, Brazil. Researcher. 4. Assistant Professor at FMB-UNESP, Botucatu, São Paulo, Brazil. Researcher.

Correspondence address: Juliana Bassalobre Carvalho Borges Rua Venancio de Souza, 422 - Aeroporto - Marília, São Paulo, SP, Brazil – Zip code: 17514-072 E-mail: salobre@ig.com.br

Work performed at Botucatu Medical School - UNESP, Botucatu, São Paulo, Brazil.

Article received on October 15th, 2012 Article accepted on December 19th, 2012

Descriptors: Quality of life. Pacemaker, artificial. Indicators of quality of life. Resumo Objetivo: Avaliar se existe correlação entre qualidade de vida e classe funcional em pacientes no pós-implante de marca-passo cardíaco, e sua relação com idade. Métodos: Investigados 107 pacientes de ambos os sexos (49,5% do sexo feminino e 50,5% do sexo masculino), tempo

Borges JBC, et al. - Correlation between quality of life, functional class and age in patients with cardiac pacemaker

Abbreviations, Acronyms & Symbols FC QOL ICD

functional class quality of life implantable cardioverter defibrillator

médio de implante 6,36 ±2,99 meses e média de idade 69,3 ±12,6 anos. Para avaliação da classe funcional, foi utilizada escala proposta por Goldman e para qualidade de vida, questionário AQUAREL associado ao SF-36. Realizada análise estatística pela correlação de Spearman, com significância de 5%. Resultados: Foram observadas correlações negativas entre qualidade de vida e classe funcional: AQUAREL nos três domínios, desconforto no peito (r=-0,197, P=0,042), dispneia (r=-0,508, P=0,000), arritmia (r=-0,271, P=0,005) e, no SF-36

INTRODUCTION The complex cardiac stimulant is released by a process of cell specialization and reflects the effort of millions of years in the phylogeny for the maintenance of life. Naturally, the replacement of components of the conduction system, with the maintenance of their properties, has always been a major challenge in the field of cardiac electrotherapy [1]. The normal process of conducting the heart is damaged when one of the coronary vessels is obstructed, making the conduction blocked. When this type of abnormality is detected, it can indicate pacemakers implantation, which consists of mechanisms of cardiac pacing, in order to correct or lessen the changes [2]. These electrical devices are responsible for providing cardiac electrical activity as physiological as possible, contributing primarily to correct heart rate and resynchronization of cardiac chambers [1,3]. Currently, artificial electrical cardiac pacing is no longer just a way to save patients’ lives with atrioventricular blocks, becoming a way to correct heart rhythm disturbances and atrioventricular synchrony [4]. The concern went beyond prolonging life, but also enabling those patients achieve quality of life consistent with the average population. In this regard, several studies have been developed focusing on the quality of life of patients with pacemakers [3,5 - 11]. The term quality of life has many definitions. According to the World Health Organization, quality of life is the "individual's perception of their position in life within the 48

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nos oito domínios. Em relação à idade, correlação negativa com Capacidade Funcional do SF-36 (r=-0,338, P=0,000) e não se observou correlação com AQUAREL. Entre idade e classe funcional observou-se correlação positiva (r=0,237, P=0,014). Conclusão: Neste estudo, encontrou-se correlação negativa entre qualidade de vida e classe funcional, evidenciando nesta amostra que os pacientes pertencentes a melhor classe funcional apresentaram melhor qualidade de vida. Conforme maior idade, pior a qualidade de vida em Capacidade Funcional e em classe funcional. Sugere-se, que idade e classe funcional influenciam qualidade de vida e as escalas de classificação funcional podem constituir um dos instrumentos que integram a avaliação e refletem a qualidade de vida em portadores de marca-passo. Descritores: Qualidade de vida. Marca-passo artificial. Indicadores de qualidade de vida.

cultural context and values t hat he lives as well as in relation to their goals, expectations, standards and concerns" [12]. The evaluation of quality of life and its measurement, initially aimed to complement the survival analyzes, adding to other clinical parameters. However, this evaluation has broadened its scope when it became part of the costeffectiveness analyses [13]. The concern with the concept of "quality of life" comes to rescue broader aspects than symptom control, reduced mortality or increased life expectancy. The quality of life related to health refers to a subjective view of the patient about their health status, and may be contrasted with physiological assessments with clinical interpretations relating to the patient welfare and their functional capacity [13,14]. Several tools have been proposed to assess the quality of life in health, the most used questionnaires are the the generic and specific ones [3,14-16]. For patients with pacemakers, the literature recommends using a specific questionnaire related to general health issues contained in a generic questionnaire [5-8]. According to Cunha et al. [9], the quick development in recent decades of sophisticated devices and the increasing number of indications for implantation of pacemaker, draw attention to the use of new methods that assess the quality of life and daily activity level of these patients. They observed in their studies important aspects of correlation between two forms of evaluation: quality of life and functional classification.

Borges JBC, et al. - Correlation between quality of life, functional class and age in patients with cardiac pacemaker

Rev Bras Cir Cardiovasc 2013;28(1):47-53

Functional rating scales are often used during evaluations of patients with pacemakers in order to categorize the degree of cardiovascular dysfunction. Among them, the Goldman scale is the most important one [3,5,17]. The instruments to assess quality of life and functional classification are a complementary way to assess the patients’physical, emotional and functional aspects. However, it is still debatable the correlation between functional class and quality of life of definitive cardiac pacemaker users. This question is the basis of this study, therefore, it is necessary to deeply discuss the theme "functional capacity and quality of life in patients with pacemaker", as suggested in studies by Stofmeel et al. [18] Oliveira et al. [8] and Cunha et al. [9]. The aim of this study was to evaluate the correlation between quality of life and functional class in patients after implantation of cardiac pacemakers, and their relationship with age.

and have been divided into functional classes: I (able to perform all the activities questioned equivalent to metabolic consumption ≥ 7 mets) II (perform activities with metabolic consumption ≥ 5 mets), III (able to perform activities with metabolic consumption ≥ 2mets) and IV (unable to perform activities that require consumption above 2 mets) [3,8,9,17]. While evaluating the quality of life, we used two questionnaires that should be applied together in patients with pacemakers: quality of life questionnaire specific for patients with pacemakers, the Assessment of Quality of Life and Reletad events - AQUAREL and generic questionnaire The Medical Study 36-item Short-Form Health Survey - SF36, [3,8,9]. Both instruments were translated and adapted to Portuguese and are valid, reliable and reproducible in the Brazilian population [8,15]. The questionnaire AQUAREL consists of twenty questions divided into three domains: chest discomfort, arrhythmia and dyspnea during physical activities. [3,6-8]. Chest discomfort involves the questions: 1 to 6 (regarding chest pain) and questions 11 and 12 (relating to dyspnea at rest). Arrhythmia is mentioned in questions 13 to 17. Dyspnoea during exercise includes questions 7 to 10 (relating dyspnea during exercise) and 18 to 20, (referring to fatigue) [3]. Each part consists of particular items which have five categories of response, with values from 1 to 5. The individual scores obtained for each part of the questionnaire were added up and computed by the formula shown in the data analysis. The final scores can range from zero (all complaints) to 100 (no complaints), when the latter represents perfect quality of life [8]. The SF-36 is a multidimensional questionnaire consisting of 36 items grouped into eight domains: functional capacity, physical aspects, pain, health status, vitality, social aspects, emotional conditions and mental health. It presents a final score from 0 to 100, where 0 corresponds to the worst and 100 to the best health status [15]. Regarding the sum of the scores, each questionnaire could vary their final score of 0 to 100, thus, a cut-off value of 50 was set (average) to determine the good and the bad areas. The areas that scored less than 50 would be with the worst quality of life and those that scored 50 or more would be with good quality of life [20]. AQUAREL and SF-36 questionnaires were applied in the form of an interview by a single examiner trained and unaware of the results of functional class. The sum of the points was performed according to literature descriptions for each questionnaire [3,15].

METHODS We conducted a cross-sectional study, a type of descriptive and quantitative observational study in patients with pacemakers, at the Department of Cardiac Surgery and Pacemaker at Santa Casa de Misericórdia, Marília, SãoPaulo. Data collection occurred from August 2009 to June 2010. The minimum sample size was estimated at n=85, taking into account a 5% significance level (a=0.05), a 20% type II error (b=0.20) and magnitude of effect | r | = 0.30 [19]. The study was approved by FAMEMA Research Ethics Committee, protocol: #nº 442/08, in accordance with the Declaration of Helsinki. Volunteers signed an informed consent form. The study included individuals of both genders, between three and 12 months after pacemaker implantation for conduction system disease, with no coronary artery disease and also clinically stable over the age of 18. We excluded individuals under the age of 18, patients that did not understand the sequence of tests, and also those that showed restraint of speech, hearing and understanding and individuals who did not want to participate. The volunteers were evaluated using a protocol that included personal data, questions regarding the cardiac pacemaker (time, reason, pacing mode), comorbidities, functional class and quality of life questionnaires. The functional classes was assessed by specific activity scale functional classification proposed by Goldman et al. [17], applied as an interview by a single trained individual. This scale consists of simple questions about specific activities, and each one relates to metabolic expenditure. Patients answered questions with “YES” or “NO” according to the statement of functional classification for that scale

Statistical Analysis Data were summarized using tables, absolute frequency, percentage, mean, standard deviation, maximum and minimum value. 49

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Borges JBC, et al. - Correlation between quality of life, functional class and age in patients with cardiac pacemaker

In order to calculate the scores of the three domains of the questionnaire to measure AQUAREL quality of life (chest discomfort: questions 1 to 6, 11 and 12; dyspnoea: questions 7-10, 18-20; arrhythmia: questions 13 to 17) (1) de Oliveira [3] (203, p.46) equation was used with the following letters equivalence for the responses of each question of AQUAREL questionnaire and a 5-point Likert scale: a) = 5 b) 4 = c) = 3, d) = 2) and e) = 1. Equation = 100 - {[(ΣN - nº N) / (number NX 5) - nº N]} X 100. Where: ΣN = summation of scores of questions that compose the score and nº N = number of questions that compose the score. In the study of correlations among quantitative variables, the non-parametric Spearman test (r s) was used. The significance level adopted was 5% of probability to reject the null hypothesis. RESULTS We evaluated 107 individuals of both genders (49.5% female and 50.5% male) with a mean implant pacemaker period of 6.36 months (± 2.99 months), mean age of 69.3 years (± 12.6 years). We observed 12.1% of Chagas disease, 64.5% of hypertension, 24.3% of diabetes mellitus and 48.6% were non-smokers. In relation to functional class, the majority with 70% class I. Table 1 presents the sample characterization. The study results showed significant negative correlations between quality of life and functional class. In the AQUAREL analysis, we observed a negative correlation between overall quality of life and in all three areas: chest discomfort, dyspnea and arrhythmia with functional class. On the other hand, we did not observe a correlation with quality of life regarding age by AQUAREL (Table 2). There were also significant negative correlations between the SF-36 in all its domains and functional class. Regarding age, there was a significant negative correlation with physical functioning (Table 3). In studying the association between age and functional class, there was a significant positive correlation (r=0.237, P=0.014).

DISCUSSION Quality of life x functional classification According to a recent publication of the Brazilian Pacemakers, Resynchronizers and Defibrillators Registry (RBM) in 2012, while analyzing the implants of cataloged pacemakers, the current profile of indications is: 11.4% of patients in class I , 15.9% in class II, 41.3% in class III and 31.3% in class IV [21]. These numbers represent the universe of cardiac pacing in Brazil, the indications are prevalent in patients in classes III and IV.

Table 1. General characteristics and clinical study in 107 patients. Variables Gender Female Male Education Iliterate Incomplete Elementary School education Incomplete High School education High School Higher Education Chagas Disease Yes No Implant indication Atrioventricular block Sinus node disease Others Types of stimulation Bicameral Unicameral Implantation time (months) Mean (SD) Minimum – Maximum Functional Classification Class I Class II Class III Class IV

Table 2. Mean values of quality of life (AQUAREL), and correlations between the domains of the questionnaire with functional class and age. Mean (SD) Correlation coeficient Functional class

Chest pain 90.8 ± 14.9

r=-0.197 P=0.042* Age r=0.188 P=0.052 * Significant (P<0.05). Spearman correlation test

Dyspnea 75.0 ± 21.3

Arrhythmia 89.0 ± 14.1

Total AQUAREL 84.9 ± 13.9

r=-0.508 P=0.000* r=-0.041 P=0.678

r=-0.271 P=0.005* r=0.051 P=0.600

r=-0.441 P=0.000* r=0.028 P=0.774

% 49.5 50.5 30.8 55.1 1.9 7.5 3.7 12.1 87.8 57.9 28.0 14.1 86.9 13.1 6.36 ± 2.99 1 - 13 70 7 21 2

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Borges JBC, et al. - Correlation between quality of life, functional class and age in patients with cardiac pacemaker

Table 3. Mean values of quality of life (SF-36), and correlations between the domains of the questionnaire with functional class and age.

Mean (dp) Correlation coeficient Class Functional Age

Functional Capacity 69.2 ± 24.9

Physical Aspects 58.4 ±37.6

r=-0.686 P=0.000* r=-0.383 P=0.000*

r=-0.359 P =0.000* r= 0.063 P=0.520

Pain 63.5 ±27.0

Health Conditions 72.4 ±23.6

Vitality Social Aspects Emotional Aspects 74.2 ±20.6 89.1 ±21.8 62.6 ±43.1

Mental Health 74.0 ±23.0

r=-0.356 P=0.000* r=-0.089 P=0.360

r=-0.465 P=0.000* r=-0.089 P=0.360

r=-0.462 P=0.000* r=-0.044 P=0.651

r=-0.194 P=0.045* r=-0.070 P=0.476

r=-0.358 P=0.000* r=0.093 P=0.340

r=-0.336 P=0.000* r=-0.003 P=0.973

* Significant (P <0.05). Spearman correlation test

Regarding the assessment of quality of life with AQUAREL and SF-36 questionnaires, it was observed that no domain resulted in values below 50, showing that the patient quality of life after implantation is above average, therefore, the quality of life for these patients was good. Analyzing the highest and the lowest scores in AQUAREL, the lowest quality of life according to patients’ opinion was in the dyspnea domain with 75 and, the best quality in discomfort with 90.8, the factor which was less affected in the life of these patients. In the SF-36 questionnaire, the domain with the highest quality of life was the social aspects with 89.1, it was also observed that the physical domain (impact of physical health on performance of daily activities and / or professional) had the lowest average in the both questionnaires with 58.4, but the most affected in patients’ opinion. These findings corroborate with the study by Oliveira [3], which evaluated the quality of life (AQUAREL and SF-36) in 139 patients with pacemakers and, observed impairment in quality of life by AQUAREL in dyspnea (75.3) and better quality in discomfort (85.3). In the SF-36, the worst quality of life was emotional (46.7), followed by physical (51.4) and best quality of life in social aspects (74.3). Cesarino et al. [22] studied the quality of life in 50 patients with implantable cardioverter defibrillators (ICDs) by the SF-36. The social domain had the highest score (80.5) and the worst was the physical one (40.5), in agreement with this study. We observed a negative correlation between all domains of quality of life and functional class in patients with pacemakers, suggesting that those individuals belonging to the best functional class had higher QOL scores, and those belonging to the worst levels of functional class (in this study, class III and IV) had the lowest scores. In accordance with the findings of Cunha et al. [9] who studied functional class in their research (Goldman) and

quality of life (AQUAREL and SF-36) in 14 patients with pacemakers, also observed a significant correlation among the instruments: in the three domains of AQUAREL with functional class; and the SF-36 questionnaire, vitality, pain and functional capacity with functional class. In the study of Stofmeel et al. [6,7], with 74 patients with pacemaker, a negative correlation of scores of quality of life (AQUAREL and SF-36) was observed with the functional classification of New York Heart Association (NYHA). According to Oliveira et al. [8], the observed correlations among AQUAREL scores and instruments already recognized, such as the SF-36 scale and functional classification of Goldman, suggest that AQUAREL is an instrument for assessing quality of life capable of registering through its variation of their specific scores, changes in subjective points of view of patients with pacemakers. In accordance with this study, we also observed correlations between functional class and quality of life. Oliveira et al. [23] studied quality of life in 139 patients with pacemakers, identified relationship between poorer quality of life related to health in patients with pacemakers with Chagas disease, female gender, unmarried status and the worst functional class. In multivariate analysis, the worst functional class stood out as an independent predictor of poor quality of life related to health in the physical component of the SF-36 and in all domains of AQUAREL. Therefore, this study also showed a direct relationship of functional class, which reflects the degree of heart failure, quality of life in patients with pacemakers, confirming reports by other authors, such as Stofmeel et al. [18] Oliveira et al. [8,23]; Cunha et al. [9]. Age x quality of life x functional classification According to Cunha et al. [9], the literature contains conflicting results regarding the correlation between age and quality of life in different populations [14,24,25]. It is believed that age has a relationship mainly with variables 51

Borges JBC, et al. - Correlation between quality of life, functional class and age in patients with cardiac pacemaker

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relating to patients’ physical condition [9,24,26]. In this study, we observed a negative correlation between age and the physical functioning domain of SF36, one of which represents the physical condition. This domain indicates how much health conditions interfere with everyday activities, suggesting that patients with advancing age have greater impairment in physical and functional activities, thus with worse quality of life in functional capacity. Similar to these findings, Cunha et al. [9] observed a negative correlation between age and the SF36 in the physical functioning domain, on the other hand, we also found a correlation between age and emotional aspect, supporting the controversial issue of the relationship between quality of life and age. Van Eck et al. [27] studied quality of life in patients awaiting pacemaker implantation with a control population (without pacemakers). They emphasized that the most important predictors of a good quality of life were age, presence of cardiac comorbidities and atrial fibrillation. They also reported that age is inversely related to the quality of life, in accordance with the findings of this study. In agreement with the results of Cunha et al. [9] the present study did not find any correlation between quality of life by AQUAREL and age. The authors explained in their paper that possibly this difference of association between age and the two instruments of quality of life is due to the fact that SF-36 is a generic questionnaire and has broader domains, which may cover different aspects susceptible to interference of age. However, Cesarino et al. [22], research on perception of quality of life (SF-36) in patients with IDC, observed that the quality of life in relation to age showed no statistically significant difference. Two studies developed in the state of Goiás also observed no significant association between the scores of quality of life and age: Gomes et al. [25] evaluated the quality of life (SF-36 and AQUAREL) after pacemaker implantation in 23 patients and Anthony et al. [11] evaluated the quality of life (SF-36) of 25 cardiac patients eligible for implantation of pacemaker in a hospital. The age reflects the aging, which is a non-modifiable risk factor, with greater frequency and greater severity in cardiovascular disease. Even though the pacemaker implantation may provide a benefit in terms of quality of life, this is not often measured in older populations due to other coexisting diseases and lower life expectancy [25]. In the present study we observed significant positive correlation between age and functional class, suggesting that older patients had worse functional class. We believe that this fact can be explained by the physiology of aging, because the scale of Goldman is sensitive to detect reduction of activities that relate to the ability to perform tasks that require a certain metabolic expenditure, disagreeing with the results of Cunha et al. [9] since no correlation was found.

It is suggested that the functional classification scales may constitute one of the tools that integrated the assessment and reflect the quality of life in patients with pacemakers, may help health staff in clinical practice.

CONCLUSION In this study, negative correlation was found between all domains of quality of life with functional class. Age was negatively correlated with quality of life and functional class. The age and functional class have influence on quality of life, so these variables must be considered in strategies to improve quality of life in individuals with pacemakers.

REFERENCES 1. Silva Jr O, Melo CS, Marra M, Correia D. Sítios endocárdicos alternativos na estimulação cardíaca artificial. Arq Bras Cardiol. 2011;96(1):76-85. 2. Ramos G, Ramos Filho J, Rassi Jr A, Pereira E, Gabriel Neto S, Chaves E. Marcapasso cardíaco artificial: considerações pré e per-operatórias. Rev Bras Anestesiol. 2003;53(6):854-62. 3. Oliveira BG. Medida da qualidade de vida em portadores de marcapasso: tradução e validação de instrumento específico [Dissertação de Mestrado]. Belo Horizonte: Escola de Enfermagem, Universidade Federal de Minas Gerais;2003. 116p. 4. Aredes AF, Lucianeli JG, Dias MF, Bragada VCA, Dumbra APP, Pompeo DA. Conhecimento dos pacientes a serem submetidos ao implante de marcapasso cardíaco definitivo sobre os principais cuidados domiciliares. Relampa. 2010;23(1):28-35. 5. Stofmeel MA, Post MW, Kelder JC, Grobbee DE, van Hemel NM. Quality-of-life of pacemaker patients: a reappraisal of current instruments. Pacing Clin Electrophysiol. 2000;23(6):946-52. 6. Stofmeel MA, Post MW, Kelder JC, Grobbee DE, van Hemel NM. Changes in quality-of-life after pacemaker implantation: responsiveness of the Aquarel questionnaire. Pacing Clin Electrophysiol. 2001;24(3):288-95. 7. Stofmeel MA, Post MW, Kelder JC, Grobbee DE, van Hemel NM. Psychometric properties of Aquarel: a disease-specific quality of life questionnaire for pacemaker patients. J Clin Epidemiol. 2001;54(2):157-65.

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8. Oliveira BG, Melendez JG, Ciconelli RM, Rincón LG, Torres AA, de Sousa LA, Et al. The Portuguese version, crosscultural adaptation and validation of specific quality-of-life questionnaire - AQUAREL - for pacemaker patients. Arq Bras Cardiol. 2006;87(2):75-83.

18. Stofmeel MA, van Stel HF, van Hemel NM, Grobbee DE. The relevance of health related quality of life in paced patients. Int J Cardiol. 2005;102(3):377-82.

9. Cunha TMB, Cota RMA, Souza BK, Oliveira BG, Ribeiro ALP, Sousa LAP. Correlação entre classe funcional e qualidade de vida em usuários de marca-passo cardíaco. Rev Bras Fisioter. 2007;11(5):341-5. 10. van Hemel NM, Holwerda KJ, Slegers PC, Spierenburg HA, Timmermans AA, Meeder JG, et al. The contribution of rate adaptive pacing with single or dual sensors to health-related quality of life. Europace. 2007;9(4):233-8.

19. Hulley SB, Cummings SR, Browner WS, Grady DG, Newman TB. Delineando a pesquisa clínica: uma abordagem epidemiológica. Porto Alegre: Artmed;2003. 20. Servelhere KR, Fernandes YB, Ramina R, Borges G. Aplicação da escala SF-36 em pacientes operados de tumores da base do crânio. Arq Bras Neurocir. 2011;30(2):69-75. 21. Pachón Mateos JC. RBM – Registro Brasileiro de Marcapassos, Ressincronizadores e Desfibriladores. DECA - SBCCV. [s.l.:s.n.] 2012. 35p.

11. Antônio IHF, Barroso TL, Cavalcante AMRZ, Lima LR. Qualidade de vida dos cardiopatas elegíveis à implantação de marcapasso cardíaco. Rev Enferm UFPE. 2010;4(2):200-10.

22. Cesarino CB, Beccaria LM, Aroni MM, Rodrigues LCC, Pacheco SS. Qualidade de vida em pacientes com cardioversor desfibrilador implantável: utilização do questionário SF-36. Rev Bras Cir Cardiovasc. 2011;26(2):238-4.

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

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

13. Monteiro R, Braile DM, Brandau R, Jatene FB. Qualidade de vida em foco. Rev Bras Cir Cardiovasc. 2010;25(4):568-74. 14. Favarato MECS, Favarato D, Hueb WA, Aldrighi JM. Qualidade de vida em portadores de doença arterial coronária: comparação entre gêneros. Rev Assoc Med Bras. 2006;52(4):236-4. 15. Ciconelli RM, Ferraz MB, Santos W, Meinao I, Quaresma MR. Tradução para a língua portuguesa e validação do questionário genérico de avaliação de qualidade de vida SF-36 (Brasil SF36). Rev Bras Reumatol. 1999;39:143-50.

24. Santos PR. Relação do sexo e da idade com nível de qualidade de vida em renais crônicos hemodialisados. Rev Assoc Med Bras. 2006;52(5):356-9. 25. Gomes TB, Gomes LS, Antônio IHF, Barroso TL, Cavalcante AMRZ, Stiva MM, et al. Avaliação da qualidade de vida pósimplante de marcapasso cardíaco artificial. Rev Eletr Enf [internet]. 2011;13(4):735-42. Disponível em: www.fen.ufg. br/revista/v13/n4/v13n4a19.htm.

16. Alleyne GAO. Health and the quality of life. Rev Panam Salud Publica. 2001;9(1):1-6.

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

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

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

Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the ORIGINAL ARTICLE myocardium after ischemia/reperfusion injury in isolated rat hearts

Rev Bras Cir Cardiovasc 2013;28(1):54-60

Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts Efeitos benéficos da perfusão hiperosmótica no miocárdio após lesão isquemia/reperfusão em corações isolados de ratos

Yong Cao1, Lie Wang2, Hong Chen3, Zhiqian Lv4

DOI: 10.5935/1678-9741.20130009

RBCCV 44205-1442

Abstract Objective: A simple method to reduce the ischemia/ reperfusion injury that can accompany cardiac surgery would have great clinical value. This study was to investigate the effect of hyperosmotic perfusion on ischemia/reperfusion injury in isolated perfused rat hearts. Method: Forty male Sprague-Dawley rats were randomly divided either to have their isolated hearts perfused with normal osmotic buffer or buffer made hyperosmotic by addition of glucose. Hearts were then subjected to 30 min ischemia followed by 30 min reperfusion. Coronary flow, time to ischemic arrest, reperfusion arrhythmia, and ventricular function were recorded. Creatine phosphokinase leakage into the coronary artery, and myocardial content and activity of superoxide dismutase and catalase were also examined. Results: Rat hearts with hyperosmotic perfusion showed

higher coronary flow, a prolonged time to ischemic arrest (10.60 vs. 5.63 min, P<0.005), a lower reperfusion arrthythmia score (3.2 vs. 5.3, P<0.001), better ventricular function, and less creatine phosphokinase leakage (340.1 vs. 861.9, P<0.001) than normal osmotic controls. Myocardial catalase content and activity were increased significantly (1435 vs. 917 U/g wet weight, P<0.001) in hearts perfused with hyperosmotic solution in comparison to the normal osmotic controls. Conclusion: Pretreatment with hyperosmotic perfusion in normal rat hearts, which is attributed partly to the increased antioxidative activity, could provide beneficial effects from ischemia and reperfusion-induced injury by increasing coronary flow, and decreasing reperfusion arrhythmia.

1. Doctor at Shangai 6th People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Participated the experiment and drafted the manuscript. 2. Doctor - Research Institute of General Surgery, General Hospital, Fuzhou Military Area Command of PLA, Shanghai, China. Participated in the experiment and drafted the paper. 3. Doctor - Department of Pharmacology, Shanghai Jiaotong University School of Medicine, Shanghai, China. Designed the experiment and participated in the experiment. 4. Doctor at Shangai 6th People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Provided the research grant and research plan.

The work was carried out at Shangai 6th People's Hospital and at the Department of Pharmacology, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Descriptors: Ischemia. Reperfusion injury. Myocardial infarction.

Correspondence address Zhiqian Lv and Hong Chen Department of Cardiosurgery, Shangai 6th People's Hospital, Shanghai Jiaotong University School of Medicine, 200233, Shanghai, P R. China E-mail: luzhiqian@gmail.com and hchen100@hotmail.com Article received on September 18th, 2012 Article accepted on October 1st, 2012

Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts

Abbreviations, acronyms & symbols CPK HR LVEDP LVP NO ROS SDS-PAGE SOD VF-VT

Creatine phosphokinase Heart rate Left ventricular end diastolic pressure Left ventricular pressure Nitric oxide Reactive oxygen species Sodium dodecyl sulfate–polyacrylamide gel electrophoresis Superoxide dismutase Ventricular fibrillation-ventricular tachycardia

Resumo Objetivo: Um método simples para reduzir a lesão de isquemia/reperfusão que pode acompanhar a cirurgia cardíaca teria grande valor clínico. O objetivo deste estudo foi investigar o efeito da perfusão hiperosmótica na isquemia/ reperfusão em corações isolados de ratos perfundidos. Métodos: Quarenta ratos machos Sprague-Dawley foram divididos aleatoriamente e tiveram os seus corações isolados perfundidos com tampão osmótico normal ou tampão hiperosmótico com a adição de glucose. Os corações foram então submetidos a 30 minutos de isquemia, seguida de 30

INTRODUCTION Each year in the United States, approximately 1 million myocardial infarctions occur, and 700,000 patients undergo cardioplegic arrest for various cardiac surgeries. Minimizing ischemic time in these clinical scenarios has appropriately received a great deal of attention because of the long-established relationship between duration of ischemia and extent of myocardial injury. However after coronary flow is restored, the myocardium is susceptible to another form of insult stemming from reperfusion of the previously ischemic tissue. Given that cardiac ischemia is either unpredictable (myocardial infarction) or inevitable (in the operating room), there is great interest in developing strategies to minimize reperfusion-mediated injury. Hyperosmotic saline has been used successfully in haemorrhagic and other types of shock to protect different tissues and organs [1,2]. Hyperosmotic saline perfusion has also been shown to decrease ischemia/reperfusion injury in rat hearts [3]. Elevated blood glucose also

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min de reperfusão. O fluxo coronariano, tempo de parada isquêmica, arritmia de reperfusão e da função ventricular foram registrados. Vazamento creatinofosfoquinase na artéria coronária, o miocárdio e atividade de superóxidodismutase e catalase foram também examinados. Resultados: Crações de ratos com perfusão hiperosmótica apresentaram maior fluxo coronariano, tempo prolongado de parada isquêmica (10,60 vs. 5,63 min, P<0,005), menor pontuação de reperfusão arritmica (3,2 vs. 5,3, P<0,001), melhor função ventricular e menos vazamento de creatina fosfoquinase (340,1 vs. 861,9, P<0,001) do que controles normais osmóticos. Teor de catalase e atividade do miocárdio também tiveram aumento significativo (1435 vs. 917 peso U/g de peso fresco, P<0,001) em corações perfundidos com solução hiperosmótica em comparação com os controles normais osmóticos. Conclusão: O pré-tratamento com perfusão hiperosmótica em corações de ratos normais, o que é atribuído, em parte, ao aumento da atividade antioxidante, pode oferecer efeitos benéficos de isquemia e reperfusão induzida por lesão, aumentando o fluxo coronário e diminuindo a arritmia de reperfusão. Descritores: Isquemia. Traumatismo por reperfusão. Infarto do miocárdio.

increases plasma osmolarity, and resistance to ischemia/ reperfusion injury is increased in hearts from type 1 diabetic rats that have severe hyperglycaemia [4]. Because both hypertonic saline and, in diabetic rats, hyperglycemia are cardioprotective, we sought to determine whether addition of glucose instead of sodium chloride (NaCl) to produce hyperosmolarity would, in hearts of normal rats, provide protection from ischemia/reperfusion injury. If hyperosmotic glucose perfusion were found to be protective, it might, in the future, be able to be used clinically to attenuate ischemia/reperfusion injury during cardiac bypass surgery. The present study investigates the effect of hyperosmotic perfusion pretreatment with glucose on ischemia/reperfusion arrhythmia and ventricular function damage in isolated rat hearts in vitro. Coronary creatine phosphokinase leakage (leakage of this cardiac enzyme from damaged myocardial cells into the perfusate from the coronary artery), and myocardial content and activity of two antioxidant enzymes, superoxide dismutase and 55

Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts

Rev Bras Cir Cardiovasc 2013;28(1):54-60

catalase, were also measured in order to assess the effect of hyperosmotic perfusion with glucose in myocardial cell damage and anti-oxidant activity.

Shanghai, China). Premature ventricular beats, ventricular tachycardia and ventricular fibrillation during reperfusion were recorded. The severity of arrhythmias was scored using the Curtis arrhythmia scoring system [6]. This system uses a scale of 0-9, where 0 indicates occasional ectopic beats and 9 indicates ventricular fibrillation occurring during the first 60s of reperfusion. The time from the clamping of the atrial inflow and aortic outflow to the cessation of ventricular contractions was recorded as the time to arrest, and the time from the beginning of reperfusion to the start of ventricular contractions was recorded as the time to recovery. All hearts were allowed to beat spontaneously. After the 10 min normal buffer equilibration perfusion and 20 min pre-treatment normal buffer or hyperosmotic glucose perfusion (the total pre-ischemia period was 30 min), the hearts were subjected to 30 min global ischemia by clamping both atrial inflow and aortic outflow. The heart was thus in contact with hyperosmotic glucose buffer for a total of 50 min. The heart was kept warm during the ischemic period. At the end of this period, the above flow catheters were opened for a 30 min reperfusion period.

METHODS Animals This study was approved by the Animal Care and Use Committee of our institution (2011(LW)-13). Forty male Sprague-Dawley rats (originally weighing 220–280 g) were housed under standard conditions with free access to tap water and chow. Rats were randomly divided either to have their isolated hearts perfused with normal Krebs-Henseleit buffer solution (300 mOsm/L) or with Krebs-Henseleit buffer solution made hyperosmotic (360 mOsm/L) by addition of glucose. Isolated heart preparation and ischemia/reperfusion with normal buffer solution Rats were anaesthetized with sodium pentobarbital (60 mg/kg, i.p.), injected with 25 mg/kg heparin, and their hearts excised a few minutes later. The hearts were then placed in a Langendorff apparatus [5] and rapidly connected to the aortic cannula of this apparatus for retrograde perfusion with Krebs–Henseleit buffer containing (in mmol/L): NaCl 118.0; KCl 4.7; CaCl2 2.5; MgSO4 1.2; KH2PO4 1.2; NaHCO3 25.0; glucose 11.0 mM; Na2 -EDTA 0.5. The perfusate was maintained at 37˚C and aerated continuously with 95% O2 and 5% CO2. The left atrium was connected to a cannula and perfused in order to fill the left ventricle, and a catheter was inserted into the left ventricle to record left ventricular pressure (LVP), left ventricular end diastolic pressure (LVEDP), and maximal rate of LVP rise (dp/dtmax) and fall (dp/dtmin), using a data acquisition system (MPA 2000; Alcott Biotech, Shanghai, China). Aortic perfusion pressure was set at 70 mmHg and left atrial pressure at 15 mmHg throughout the experiment. However, cardiac output as it would occur in the living animal cannot be measured with this method. A catheter inserted into a small artery originating in the marginal or oblique branch of the left circumflex coronary artery was used for continuous measurement of coronary flow (calculated from the fluid fractions collected as volume/ time) in pre-ischemia perfusion, ischemia, and reperfusion periods. We used this location for catheter insertion because it enables more precise and clean collection of coronary effluent than effluent collected from other locations. The perfusate collected from the coronary artery was used to assay for creatine phosphokinase. Electrodes were inserted into the myocardium at the base and apex of the heart, and heart rate (HR) and electrocardiogram were recorded continuously with a data-acquisition system (MPA 2000; Alcott Biotech, 56

Hyperosmotic perfusion The procedure for the rat hearts in the hyperosmotic perfusion group was the same as that described above for normally perfused hearts except that the osmolarity of the Krebs–Henseleit buffer was increased to 360 mOsmol/L during the 20 min pre-treatment period by adding 60 mOsmol/L of glucose and thus increasing the glucose concentration to 71 mM. Biochemical determinations and Western blot analysis At the end of the 30 min reperfusion period, the front portions of the left ventricles were freeze-clamped for use in biochemical assays and Western blotting. Creatine phosphokinase (CPK) from the coronary artery, and superoxide dismutase (SOD) and catalase from myocardial tissue homogenate, were determined with assay kits (Jian-Cheng Biomedical Engineering, Nanjing, China) according to the instructions of the manufacturer. For Western blot analysis, the freeze-clamped sections of the left ventricle were homogenized in lysis buffer (pH 7.4) containing (in mmol/L): Tris-HCl 50; sucrose 150; EDTANa2 5; EGTA 2; Na3VO4 1; NaF 50; phenylmethanesulphonyl fluoride 0.1; leupeptin 1 mg/L. Actin was used as the protein standard. Protein samples were loaded onto 8% sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDSPAGE) acrylamide gels and transferred to polyvinylidene difluoride membranes. Blots were incubated with antibodies to either catalase (Calbiochem, San Jose, CA, USA) or SOD (Kagaard & Perry Laboratories). The membranes were then incubated with corresponding horseradish peroxidase-

Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts

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conjugated secondary antibody, and immunoreactive bands were visualized using electrochemoluminescence (Pierce; Thermo Fisher Scientific Inc., Rockford, IL, USA). Relative levels of proteins were semi-quantified with densitometry (Leica).

Ventricular function during ischemia and reperfusion Rat hearts perfused with hyperosmotic solution took a longer time (10.6±1.5 vs. 5.6±0.7 min) to stop beating during ischemia and a shorter time (13.0±2.5 vs. 19.2±1.5 sec) to resume beating during reperfusion than control hearts. In other words, hyperosmotic hearts were asystolic about 32 minutes as opposed to 43 minutes for control hearts. The reperfusion arrhythmia score (3.3±1.7) and ventricular tachycardiafibrillation period (15.0±1.2 min) were significantly reduced in hyperosmotic hearts compared to control hearts (5.3±1.2, 24.3±2 min respectively) (Table 1). There were no significant differences in pre-ischemia HR, LVP, LVEDP, dP/dtmax and dP/dtmin between the 2 groups. However, HR, LVP, dP/dtmax and dP/dtmin in both groups significantly decreased during reperfusion (P<0.05, Table 2).

Statistics Normally distributed continuous variables between control and hyperosmotic glucose groups were compared using an independent two sample t test. Differences between ischemia and reperfusion were determined using a paired t test. Repeated measurement of ANOVA was used for coronary flow. Data are presented as means ± SE. All statistical assessments were two-sided and evaluated at the 0.05 level of significant difference. Statistical analyses were performed using SPSS 15.0 statistics software (SPSS Inc, Chicago, IL).

Coronary flow and correlation with hyperosmotic perfusion Compared to normal osmotic perfusion, hyperosmotic glucose perfusion significantly increased pre-ischemia basal coronary flow in isolated rat heart after 5 and 10 minutes of perfusion (Figure 1). After ischemia and reperfusion treatment, coronary flow was also significantly higher with hyperosmotic glucose than normal osmotic perfusion over the 30 minutes of perfusion (Figure 2).

Creatine phosphokinase (CPK) leakage from myocardial tissue and myocardial anti-oxidant enzymes CPK leakage into the coronary artery, an indication of myocardial cell damage, was significantly reduced after reperfusion in hyperosmotic compared to control hearts, as shown by biochemical assays (360±115 vs. 860±124 U/g). From the two anti-oxidant enzymes measured, hyperosmotic hearts showed a significant increase in myocardial catalase in both biochemical assay and Western blotting (Table 1 and Figure 3A, C). However, myocardial contents of SOD in hyperosmotic hearts were similar to those of normal control hearts in both biochemical assay and Western blotting (Table 1 and Figure 3B, D).

Fig. 1 – The effects of normal and hyperosmotic glucose perfusion on pre-ischemia coronary flow in isolated rat heart . (mean±SE, n=20 in each time point)

Fig. 2 – The effect of reperfusion with normal and hyperosmotic glucose perfusate on post-ischemia coronary flow in isolated rat heart. (mean±SE, n=20 in each time point)

RESULTS

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Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts

Table 1. Ischemic arrest time, heartbeat recovery time, arrhythmia score and VT-VF time after ischemia/reperfusion with hyperosmotic glucose. Control 5.62±0.73 19.19±1.99 5.30±0.27 24.46±0.45 861.90±26.36 343±4.7 917±18.9

Ischemic arrest time (min) Heartbeat recovery time (sec) Arrhythmia score VT-VF duration (min) Creatine phosphokinase leakage (U/g ventricular weight) SOD (U/g wet weight) Catalase (U/g wet weight)

P value 0.005 0.056 <0.001 <0.001 <0.001 0.324 <0.001

Hyperosmotic glucose 10.60±1.50 11.24±2.40 3.20±0.33 14.91±0.28 340.10±24.88 354±10.0 1435±17.5

I/R ischemia/reperfusion; SOD, superoxide dismutase; VF, ventricular fibrillation; VT, ventricular tachycardia. Data are displayed as mean ± standard error. n=20

Table 2. Heart rate, contractility and relaxation before and after ischemia/reperfusion. HR (bpm) Pre 30 min LVP (mmHg) Pre 30 min LVEDP (mmHg) Pre 30 min dP/dtmax (mmHg/sec) Pre 30 min dP/dtmin (mmHg/sec) Pre 30 min

Control

Hyperosmotic glucose

P value

241.00±11.84 100.20±27.81a

249.70±15.82 198.50±17.23a

0.665 0.008

88.12±4.77 63.89±5.34a

86.08±3.50 69.92±3.42a

0.734 0.354

5.32±1.88 53.28±3.94a

5.87±1.21 37.16±3.74a

0.807 0.008

2476.5±218.6 345.0±105.8a

2538.0±129.3 1101.8±97.7a

0.811 <0.001

1657.5±137.5 303.0±61.1a

1881.3±121.6 834.0±46.55a

0.287 <0.001

dP/dtmax, maximum rate of left ventricular rise; dP/dtmin, maximal rate of left ventricular pressure fall; HR, heart rate; LVEDP, left ventricular end diastolic pressure; LVP, left ventricular pressure. a Significant difference between ischemia and reperfusion in each group using paired –t test. Data are displayed as mean ± standard error

Fig. 3 – Myocardial anti-oxidant enzymes in control and hyperosmotic glucose perfused ventricle. A. The myocardial catalase content was increased after hyperosmotic glucose perfusion. Data are the mean±SD (n = 20 in each time point). *P < 0.05 compared with control. B. There was no marked increase in SOD after hyperosmotic glucose perfusion. Data are the mean±SE (n = 20 in each time point). C. Western blot analysis also showed a marked increase in the levels of myocardial catalase after hyperosmotic glucose perfusion. D. No significant difference of SOD between control and hyperosmotic glucose group was found

Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts

DISCUSSION In the current study, hyperosmotic perfusion pretreatment with glucose of rat hearts subjected to global ischemia resulted in better ventricular contractile and electrophysiological function, increased coronary flow, and less myocardial damage than was seen in normal rat hearts. Hyperosmotic perfusion pretreatment also increased levels of catalase, although levels of a second anti-oxidant enzyme, SOD, were similar to those seen in control hearts. Endothelial nitric oxide (NO) production has previously been shown to be responsible for the increase in coronary blood flow seen after bolus injection of hypertonic saline in anaesthetized pigs [7]. This is a possible mechanism for the increased coronary flow seen with hypertonic perfusion pretreatment of glucose in our study, but we did not measure NO production. Previous research by others has shown that an important change responsible for ischemia/reperfusion damage is the increase in intracellular calcium that occurs during ischemia [8]. Anoxia decreases pH, and the increased Na/H exchange used by the cell to bring the pH back to normal affects Na/Ca exchange in a way that increases intracellular calcium [8]. Myocardial perfusion with fluid made hypertonic with either NaCl or sucrose has been shown to decrease intracellular calcium by decreasing the anoxia-induced increase in Na/H exchange [9]. Reactive oxygen species (ROS) have also been implicated in the pathogenesis of ischemia/reperfusion injury [8]. In our study, hyperosmotic hearts showed an increase in the activity of the anti-oxidant enzyme, catalase, but no increase in SOD, the second enzyme studied. A study of diabetic hearts of rats with severe hyperglycaemia also showed an increase in catalase, but not SOD, compared to normal hearts [4]. And a study of hyperosmotic sodium chloride perfusion of normal and stroke-prone spontaneously hypertensive rat hearts also showed increased catalase but not increased SOD, although in this study raising the osmolarity to 400 mOsm/L was able to increase SOD slightly [10]. In our study, levels of catalase were increased 20%, but levels of the marker of myocardial damage, CPK, however, were decreased 60%. It seems doubtful, therefore, that this modest increase in catalase activity could, by itself, cause such a profound lessening of myocardial damage. An unanswered question is whether beneficial effects for heart by solution made hypertonic by the addition of glucose differs in any way from that provided by solution made hypertonic by the addition of NaCl. Hyperosmotic glucose differs from hypertonic saline in that glucose is a substrate for energy metabolism in the myocardium. In normal conditions, myocardium utilizes fatty acids for aerobic metabolism but in anoxic conditions, it uses glucose

Rev Bras Cir Cardiovasc 2013;28(1):54-60

for anaerobic glycolysis. Anaerobic metabolism plays a crucial role in protecting myocardium from death [11]. Hyperosmotic glucose perfusate provides more glucose for the myocardium to produce ATP through glycolysis, an action beneficial for maintaining the activity of Na+-K+ATPase and the ATP-dependent K channel. This action may attenuate myocardium injury. However, because the manner in which the myocardium utilizes metabolic substrates is complex, the possibility that increases in extracellular glucose availability can be beneficial to heart needs further investigation. Chu et al. [12] also that ischemic myocardium in alloxaninduced-diabetic (DM) group displayed higher expression of cell survival proteins including phospho eNOS, heat shock protein 27, NFkB, and mTOR as compared with ischemic myocardium in normoglycemic (ND), whereas in non-ischemic tissue, expression of these proteins was similar or lower in the DM group. The expression of total Erk 1/2 was similar between ND and DM groups, whereas the expression of phospho-Erk 1/2(Thr202/Tyr204) was lower in the DM group as compared to the ND group [12]. The expression of SAPK/JNK was lower in the DM group [12]. The current study shows that normal rat hearts prefused with hyperosmotic glucose can provide beneficial effects to heart, but these beneficial effects could very well be due to the hyperosmolarity itself rather than glucose. In our study, rat hearts prefused with hyperosmotic glucose before ischemia/reperfusion increased coronary artery flow and decreased coronary artery resistance, increased left ventricular function, and increased levels of catalase but not SOD. In Shenâ&#x20AC;&#x2122;s et al. [10] study, prefused with hyperosmolar NaCl gave similar results: increased coronary artery flow and decreased coronary artery resistance, increased left ventricular function, and increased levels of catalase but not SOD. Shen et al. [10] also compared the effects of a 2 hour perfusion of rats hearts with solution made hyperosmolar with 4 different osmolytes (NaCl, glucose, mannitol, and raffinose) and found no significant differences in levels of the cellular constituents measured. They did not, however look at left ventricular function. Our findings and Shenâ&#x20AC;&#x2122;s et al. [10], therefore, may be due entirely to the hyperosmolarity. However, one must also consider the use for which a solution is intended. Studies comparing the success of solutions used to protect hearts used for transplantation have focused on protecting cellular energy metabolism [13,14]. Despite the crystalloid solutions studied are not fully able to suppress the deleterious effects of ischemia and reperfusion in the rat heart, Lima et al. [14] had also found that a solution may contain the mannitol, instead of glucose, and the concentrations of K+ (15 mmol/L) and Ca2+ (0.25 mmol/L) of solution can contribute to a better performance by promoting the depolarizing arrest without contributing to an overload of intracellular calcium during 59

Cao Y, et al. - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts

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the ischemic period. We were investigating hyperosmotic solutions might be beneficial to normal rat heart ex vivo to against ischemia/reperfusion injury during cardiac bypass surgery. In this situation, the physiologic effect of the hyperosmotic fluid used on non-cardiac tissue must be considered, and the use of glucose instead of NaCl as the osmolyte might have advantages. A limitation of this study is that we should compare the use of glucose to mannitol, an osmotically active but metabolically inactive compound, to see whether hyperosmolarity alone was responsible for the beneficial effects of glucose to heart or not. Perfusion with hypertonic mannitol has been shown to increase catalase levels in normal rat hearts [11] but there are no reports to date about its actions on ventricular function and enzymes during ischemia/reperfusion. Other limitations are that NO production, intracellular calcium, and ROS should be measured to elucidate the mechanism behind of these beneficial effects of hyperosmotic perfusion pretreatment. We also like to study the protein profiles of cell survival signaling and mitogen-activated protein kinase signaling to see whether changes in any of these parameters might be involved in beneficial effects of hyperosmotic perfusion pretreatment with glucose to normal rat heart. In summary, the present study had shown that hyperosmotic perfusion pretreatment may provide beneficial effects to heart from ischemia and reperfusion injury, increase coronary flow, and decrease reperfusion arrhythmia. The beneficial effects induced by hyperosmotic perfusion pretreatment with glucose may be attributed partly to the increased antioxidative activity. It is possible that hyperosmotic perfusion pretreatment may be able in the future to be applied during cardiac bypass surgery for its beneficial effects against ischemia/reperfusion injury.

2. Oliveira RP, Velasco I, Soriano FG, Friedman G. Clinical review: hypertonic saline resuscitation in sepsis. Crit Care. 2002;6(5):418-23.

ACKNOWLEDGEMENTS This study was supported by grants from the National Natural Science Foundation of China (No. 31171099, 30971154 and 30770848). CONFLICT OF INTEREST

4. Chen H, Shen WL, Wang XH, Chen HZ, Gu JZ, Fu J, et al. Paradoxically enhanced heart tolerance to ischaemia in type 1 diabetes and role of increased osmolarity. Clin Exp Pharmacol Physiol. 2006;33(10):910-6. 5. Skrzypiec-Spring M, Grotthus B, Szelag A, Schulz R. Isolated heart perfusion according to Langendorff: still viable in the new millennium. J Pharmacol Toxicol Methods. 2007;55(2):113-26. 6. Curtis MJ, Walker MJ. Quantification of arrhythmias using scoring systems: an examination of seven scores in an in vivo model of regional myocardial ischaemia. Cardiovasc Res. 1998;22(9):656-65. 7. Vacca G, Papillo B, Battaglia A, Grossini E, Mary DA, Pelosi G. The effects of hypertonic saline solution on coronary blood flow in anaesthetized pigs. J Physiol. 1996;491( Pt 3):843-51. 8. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88(2):581-609. 9. Ho HS, Liu H, Cala PM, Anderson SE. Hypertonic perfusion inhibits intracellular Na and Ca accumulation in hypoxic myocardium. Am J Physiol Cell Physiol. 2000;278(5):C953-64. 10. Shen WL, Chen LB, Zhao JX, Guo SJ, Chen YC, Wang LP, et al. Effects of hyperosmotic sodium chloride perfusion on ischemia/reperfusion injury in isolated hearts of normal and stroke-prone spontaneously hypertensive rats. J Clin Exper Cardiol. 2011;2(7):146. 11. Gong J, Li LH, Pei WD, Wang HY, Zheng YL, Zhou GY, et al. Glycolytic and fatty acid metabolic enzyme changes early after acute myocardial ischemia. Zhonghua Xin Xue Guan Bing Za Zhi. 2006;34(6):546-50.

No conflict of interest declared.

12. Chu LM, Osipov RM, Robich MP, Feng J, Oyamada S, Bianchi C, et al. Is hyperglycemia bad for the heart during acute ischemia? J Thorac Cardiovasc Surg. 2010;140(6):1345-52.

REFERENCES

13. Silveira Filho LM, Petrucci O Jr, Carmo MR, Oliveira PP, Vilarinho KA, Vieira RW, et al. Trimetazidine as cardioplegia addictive without pre-treatment does not improve myocardial protection: study in a swine working heat model. Rev Bras Cir Cardiovasc. 2008,23(2):224-34.

1. Gurfinkel V, Poggetti RS, Fontes B, Costa Ferreira Novo F, Birolini D. Hypertonic saline improves tissue oxygenation and reduces systemic and pulmonary inflammatory response caused by hemorrhagic shock. J Trauma. 2003;54(6):1137-45.

3. Chen LB, Liu T, Wu JX, Chen XF, Wang L, Fan CL, et al. Hypertonic perfusion reduced myocardial injury during subsequent ischemia and reperfusion in normal and hypertensive rats. Acta Pharmacol Sin. 2003;24(11):1077-82.

14. Lima ML, Fiorelli AI, Vassallo DV, Pinheiro BB, Stolf NA, Gomes OM. Comparative experimental study of myocardial protection with crystalloid solutions for heart transplantation. Rev Bras Cir Cardiovasc. 2012;27(1):110-6.

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Pfeifer PM, et al. - Coping strategies after heart transplantation: ORIGINAL ARTICLE psychological implications

Coping strategies after heart transplantation: psychological implications Estratégias de enfrentamento pós-transplante cardíaco: implicações psicológicas

Paula Moraes Pfeifer1, Patricia Pereira Ruschel2, Solange Bordignon3 DOI: 10.5935/1678-9741.20130010

RBCCV 44205-1443

Abstract Objectives: To investigate coping strategies used by patients submitted to heart transplantation and whether they are related to the perception of the disease and transplantation. Methods: Cross-sectional study with quantitative and qualitative analysis. The sample of 32 patients was assessed by the Ways of Coping Scale and socio-demographic questionnaire, and five of them were selected for interviews. The internal consistency of the scale was assessed, the variables and strategies involved were crossed and content analysis of interviews, investigating the existence of a relationship with the speech of the participants. Results: The individuals have used all coping styles, with a predominance of the problem-focused strategy. Psychologically prepared patients showed a statistically significant increase in the use of problem-focused coping and seek for social support. However, a significant increase in the use of emotion-focused coping was observed in patients who were not prepared. Analysis through the method of Bardin showed as categories: disease; reaction to call; transplantation; fantasies; postoperative; team and coping. Conclusion: Patients with a transplanted heart make use of all coping strategies, with a predominance of the problemfocused strategy. Psychologically prepared individuals used more active coping strategies, which highlights the importance of psychological support during the process.

Resumo Objetivos: Verificar as estratégias de enfrentamento utilizadas por indivíduos que tiveram o coração transplantado e suas relações com percepção da doença e do transplante. Métodos: Estudo transversal com análise quantitativa e qualitativa. A amostra de 32 pacientes foi avaliada pela Escala Modos de Enfretamento de Problemas e questionário sociodemográfico; e cinco deles foram sorteados para entrevista. Realizou-se a avaliação da consistência interna da escala, cruzamentos entre as variáveis e os estilos de enfrentamento e a análise de conteúdo das entrevistas, relacionando os resultados ao discurso dos participantes. Resultados: Os indivíduos utilizaram todos os estilos de enfrentamento, predominando o focalizado no problema. Nos participantes que receberam preparo psicológico, houve aumento estatisticamente significativo dos enfrentamentos focalizados no problema e na busca de suporte social. Entretanto, naqueles que não receberam preparo, houve aumento significativo da utilização do enfrentamento focalizado na emoção. Através do método de Bardin, revelaram-se como categorias: doença, reação ao chamado, transplante, fantasias, pós-operatório, equipe e enfrentamento. Conclusões: Os participantes utilizaram todos os estilos de enfrentamento, predominando a estratégia focalizada no problema. Os que receberam preparo psicológico usaram maior número de estratégias de enfrentamento ativas, o que evidencia a importância do acompanhamento psicológico durante o processo.

Descriptors: Heart transplantation. psychological. Sickness impact profile.

Adaptation,

Descritores: Transplante cardíaco. Adaptação psicológica. Perfil de impacto da doença.

1. Intern Psychologist at Instituto de Cardiologia; Specialized in Hospital Psychology, Porto Alegre, RS, Brazil. 2. Psychologist and Coordinator of the Psychology Service at Instituto de Cardiologia – Fundação Universitária de Cardiologia/ IC-FUC; Coordinator and Preceptor of Integrated Internship in Health: Cardiology – RISC, Porto Alegre, RS, Brazil. 3. Cardiologist at Instituto de Cardiologia - Fundação Universitária de Cardiologia/ IC-FUC, Porto Alegre, RS, Brazil.

Correspondence address: Paula Pfeifer Instituto de Cardiologia – Serviço de Psicologia Av. Princesa Isabel, 395 – Porto Alegre, RS, Brazil – Zip code: 90620-001. E-mail: paulabmpfeifer@gmail.com

Work carried out at Instituto de Cardiologia, Fundação Universitária de Cardiologia/ IC-FUC, Porto Alegre, RS, Brazil.

Article received on July 2nd, 2012 Article accepted on August 30th, 2012

Pfeifer PM, et al. - Coping strategies after heart transplantation: psychological implications

Abbreviations, Acronyms & Symbols HT WOCS

Heart transplantation Ways of Coping Scale

INTRODUCTION Heart transplantation (HT) can be seen as a process, since it does not imply a "cure", according to the popular conception of absence of disease. HT can significantly improve the quality of life, but the patient will have to adapt to multiple limitations and other health problems [1,2]. A heart transplant requires lifestyle changes, so that the individual may cope with the demanding postoperative protocol and side effects of the drugs used [3-5]. The patient is also confronted with feelings that are roused by the constant threat of rejection, uncertainty of long-term prognosis, ambivalent psychological acceptance of the transplanted organ and influence of the cultural symbolism of the heart [3-5]. These particularities can raise the levels of anxiety and stress and trigger depression, which is considered a relevant risk factor for mortality after HT [3,6,7]. The depressive reaction can influence the patient clinical situation and compromise good results during the rehabilitation phase, since it may combine with anxiety and directly affect treatment adherence [4]. Thus, it is extremely important that the patient is able to psychologically defend himself, using a range of coping strategies. These strategies include a hierarchy of flexible, purpose-oriented defense mechanisms, ranging from less adaptive to more evolved types of defense. They are defined as a stress response, which may be behavioral or cognitive, with the purpose of decreasing the aversive characteristics [8]. These strategies can be primarily focused on the problem, by modifying the relationship between the person and the environment, or on emotion, adapting the emotional response to the problem. They represent situational responses, influenced by the perception of environmental and personal systems and by the events of life. Evasive, emotive, fatalistic coping strategies are associated with a smaller capacity of personal control over the disease, increasing levels of depression and anxiety and decrease in treatment adherence [8-10]. The present study aims at the investigation of coping strategies used by patients who have had a HT and at analyzing if there is a relationship between the adoption of these strategies and the perception of the disease and transplantation. METHODS In this cross-sectional study with quantitative and qualitative analysis, sample size was calculated based on the 62

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study by Seidl et al. [11]. Thirty-two patients, who attended the Transplantation Service of Instituto de Cardiologia do Rio Grande do Sul (Porto Alegre, RS, Brazil), both males and females, aged over 18 years, were submitted to HT at least one month previously, were included in the study. The instruments used in this study included a demographic questionnaire, with basic data of the patient and information concerning the disease, transplantation and quality of life; a semi-structured-interview with thematic analysis for collecting information about the participant's perception in relation to disease and transplantation; the medical record for obtaining complementary data; and the Ways of Coping Scale (WOCS). The WOCS is a Likert type scale which assesses the magnitude of coping strategies used by the individual when confronted by stressors. The scale is composed of 45 items, with answers ranging from 1 (I never do that) to 5 (I always do it ), and was adapted for use in Brazil by Gimenes & Queiroz [8,11,12]. This study was approved by the Institutional Research Ethics Committee, and it is in accordance with the Declaration of Helsinki, and follows the Resolution 196, of October 10, 1996 [13]. Patients returning to the health center for consultation were informed about the study and invited to participate. Those who agreed to participate signed an informed consent and answered to a demographic questionnaire and the WOCS. Five of the patients were randomly selected for interviews, which were recorded with the permission of the participants. The data were tabulated and the interviews were fully transcribed. The results were analyzed in two steps. Firstly, the internal consistency of the WOCS factors was assessed using the Cronbach's alpha coefficient, with the statistical software SPSS version 17.0. Categorical variables were described by absolute and relative frequency, and quantitative variables, through the mean and standard deviation or median and interquartile range. Since coping is a situational concept, the variables and strategies involved were crossed. A difference was observed between participants who received or not psychological preparation for HT, and between those with or without psychiatric disorders. The participants were then assigned to groups according to the presence or absence of the analyzed variables, and the coping strategies were compared through Student's t-test for independent samples. P values lower than 0.05 were considered statistically significant. The variables were evaluated through the Pearson and Spearman correlation. The second step addressed the qualitative analysis of interviews, through the content analysis method described by Bardin [14]. The contents of interviews were separated into units of registry, such as phrases with specific themes, which reflect an individual perspective. Subsequently, they were grouped into categories and subcategories according to the recurring content in the speech of the participants,

Pfeifer PM, et al. - Coping strategies after heart transplantation: psychological implications

Rev Bras Cir Cardiovasc 2013;28(1):61-8

in order to articulate a group perspective [14]. The results of the two analyses were compared, for determination of the types of coping strategies used and relating the data obtained to the speech of individuals.

adopted (rs = - 0.471; P = 0.006). When the relationship of coping strategies among themselves was investigated, a moderate direct correlation was observed between coping focused on the problem and the search for social support (r = 0.450; P = 0.010). The comparison of coping strategies used between groups of participants who had or not received psychological preparation for HT is presented in Figure 1. The comparison of the strategies among the groups of patients with or without psychiatric disorders is presented in Figure 2.

RESULTS Descriptive results The main demographic and clinical characteristics of the sample are presented in Table 1. Data that indicate quality of life show that 93.8% of the participants have some type of leisure activity and 43.8% live with spouses and children. In relation to sleep, 81.3% of the patients sleep on average 5 to 8 hours per night; 87.5% report having dreams, and for 31.3% of them, dreams related to death.

Bardin's content analysis The qualitative analysis of the interviews content can be seen in Chart 1.

Evaluation of internal consistency WOCS reliability to assess coping strategies was acceptable. The results of the Cronbach alpha analysis of factors were: coping focused on the problem = 0.885; coping focused on emotion = 0.671; coping through religious/fantastic practices = 0.652; and coping aimed at seeking social support = 0.361. Coping strategies Participants used all types of coping strategies, with predominant focus on solving the problem. The coping strategies presented the following averages and standard deviations: (a) focused on the problem 3.78±0.77; (b) focused on emotion 0.54±2.11; (c) coping through religious/fantastic practices 0.86 ± 3.34; and (d) aimed at seeking social support 3.22±0.75. The analysis of age variables, time of HT and education showed that only the variable education presented a moderate inverse correlation with the coping strategy

Fig. 1 – Comparison of coping strategies among patients receiving or not psychological preparation for hearth transplantation (µ±SD). *P<0.05 significant

Table 1. Characterization of the sample (n=32) Age 58.5 (23-71) Gender-male 23 (71.9) Marital status-steady relationship 27 (84.4) Education – incomplete elementary school 14 (43.8) Professional status-inactive 19 (59.4) Cardiomyopathy-dilated 25 (78.1) Etiology-ischemic 16 (50) Transplant time* 105.5 (2-211) Psychological assessment 25 (78.1) Psychological preparation 21 (65.6) Duration of psychological follow-up 37 (0-243) Presence of psychiatric disorder 9 (28.1) Diagnosis of major depression 7 (21.9) Presence of suicidal ideation 4 (12.5) Data are presented in n(%); median and interquartile range. *Variables presented in months

Fig. 2 – Comparison of coping strategies among patients with or without psychiatric disorders (µ±SD). *P<0.05 significant

Pfeifer PM, et al. - Coping strategies after heart transplantation: psychological implications

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Chart 1. Analysis of the contents of patientsâ&#x20AC;&#x2122; speeches. Categories

Subcategories

Verbalizations

Disease

Invisibility Disabling symptoms Irreversibility

Who met me on the street though that I had nothing. So I couldn't walk well, or work. It was irreversible by the time it was decided for a transplantation.

Ambivalence Decision Coping

It is hard. One keeps thinking: Well, will I come back or not? There was the fear, then after that I started having that feeling that it was going to be all right. Then I must be decided and know that I'm leaving and I don't know if I'll come back. I was determined: take it or leave it. If I do not live I'll die. I'll try to live. The other time, they called me and I didn't got to come. Then when they called me last time, I did.

Reaction to calls

Transplantation

Solution Opportunity Happiness Gratitude Ambivalence Fear

Fantasies

Change of feelings Death of another Fate of the organ

Post-surgery

Fear of pain Happiness Suffering Recovery of autonomy Threat of rejection Adherence

Team

What helped to accept heart transplantation?

Receiving Trust Psychologist Will to live End the suffering Psychological preparation Personal characteristics

Then the doctor suggested entering a queue for transplants. When the transplantation was decided, there was no other solution. I was taking five medications and did not improve, had no perspective on life. I was disillusioned, and when I saw this light at the end of the tunnel I felt a great joy. A joy, a hapiness. How good it is to be alive. I thank you, because if I hadn't done it I would be no longer here. Sometimes, I would rather not have done. The fear that it does not work well. I have this concern that it can return. The wife of a future colleague cried and I asked why, and she replied: Because now, that he have a new heart, I keep thinking that he won't love me as much he did. I thought that someone had to die for me to live. One of my grandchildren asked what they had done with my heart that was taken away, and my wife said: they must have thrown it in the trash. I imagined a terrible pain after the surgery. I did not die. I'm alive. The feeling when I woke up was very good. I went through a lot, after I did the transplant, I heard voices. On the third day I got up, in the room I showered alone. I have take care of many things which need consideration, because if I stop taking cyclosporine or some other medication needed to avoid rejection, it is certain that I will die. The medication I do self medicate, because I already have separate everything, everything is already set. When I was admitted to the hospital, I was treated with great affection. This helped me a lot. When I came to have the transplant, everyone around me was worried. One day I will die. Now, if I'm get in, they will do everything to save my life. I had great faith, was sure that the doctors were going have success with my surgery. At that time, only a doctor worked, there was no follow-up with you as it is now. I changed my mind talking to a psychologist. She explained things to me, telling about what was going to happen, saying that I was not going to kill anyone. The will to live, for sure. I had to stop in the street because they had no more strength, it was bad. So this is what pushed me to go to fight. The psychologist helped a lot, because the first time I was called I didn't come. My way of seeing things. I do first to think later.

Pfeifer PM, et al. - Coping strategies after heart transplantation: psychological implications

DISCUSSION Several studies have examined coping strategies in the context of health. However, very few of them have investigated coping strategies used in the period after a HT, with virtually no research combining quantitative and qualitative designs [15]. Findings of the present study are consistent with previous reports. Early-stage heart disease is not always accompanied by symptoms, approaching the patient silently [5]. Unlike other diseases, such as certain types of cancer that modify the appearance of the individual, it is invisible, as can be inferred from the participant's speech: People who met me on the street thought that I was well. This aspect, coupled with emotional difficulties in dealing with the disease, may influence the delay in looking for treatment and poor adherence to treatment. The evolution of the disease leads to the development of heart failure and crippling symptoms [1]: So I couldn't walk well, or work. Thus, the indication for HT represents the possibility of survival and improvement in the quality of life [2,16]: I was disillusioned, and when I saw this light at the end of the tunnel I felt a great joy. I was taking five medications and did not have any improvement, had no perspective on life. At the same time, it arouses intense anxiety and fantasies: I thought that someone had to die for me to live. There is also a peculiarity in the influence of cultural symbolism of the heart, associated with life and emotions: A colleague's future wife cried and I asked why, and she replied: Because now, that he have a new heart, I keep thinking that he won't love me as much as he did. In addition to the physical suffering imposed by the disease, the patient is exposed to emotional distress by the uncertainty of survival and confrontation with death. Therefore, the reaction involves ambivalent feelings [3]: It is hard. One keeps thinking: Well, will I come back or not? HT requires from the patient a series of adaptive tasks [3]: I have to take care of many things which need consideration, because if I stop taking cyclosporine or some other medication needed to avoid rejection, it is certain that I will die. These events may generate high physical and psychosocial impact, because the transplant is seen as a new disease and not a cure: Sometimes, I think I would rather not have gone through this. In the immediate postoperative period, the participants relate a feeling of happiness for having survived: I did not die. I'm alive. The feeling when I woke up was very good. At the same time, it is a highly disorganizing experience:

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I went through a lot, after I had the transplant I heard voices. As in other studies, most of the survivors of a HT were male and were in a stable relationship, which indicates greater social support and is also considered a protective factor [15-17]. A high rate of professional inactivity was observed among the participants, which can be associated with the high emotional impact of the transplantation [18]. A high prevalence of dilated ischemic cardiomyopathy was also observed [19]. Considering the psychical elaboration of the HT, most participants remembered dreams, which is an important indicator of emotional capacity. It is important to observe that most dreams were related to death, highlighting again the high emotional impact of transplantation and the attempt of elaboration of the traumatic experience. The WOCS evaluates four types of coping strategies: coping focused on the problem, on emotion, in religious/ fantastic practice and in the search of social support. In the present study, the scale showed acceptable reliability to evaluate such strategies. In general, participants made use of all types of coping strategies, with a predominance of the strategy focused on solving the problem and, to a lesser extent, on emotion. The problem-focused strategies correspond to a cognitively active way of dealing with the situation, through behaviors of approaching the stressor in order to solve the problem. They are also related to positive thinking, such as a positive perception of the situation: I was determined: take it or leave it. If I do not live I'll die. I'll try to live. Strategies focused on emotion are a passive way of dealing with the situation, through the adoption of evasive and escape behavior in relation to treatment. They are related to negative emotional reactions and fantasy thoughts of self-guilt and or blaming other people [11,15]: The other time, they called me and I didn't get to come. Then when they called me the last time I did. Since coping strategy is a situational concept, and as such influenced by the individualâ&#x20AC;&#x2122;s internal and external environment, it was necessary to crossover and investigate correlations between variables and coping strategies. In this sample, no correlation was observed between the variables age and coping strategies [11], or between time of HT and coping strategies [15]. Therefore, the age variables and time of transplant did not influence the choice of coping strategy used by the patients. However, the variable education correlated inversely with coping by adoption of religious practices [11]. The coping strategy which uses the adoption of religious practices is related to 65

Pfeifer PM, et al. - Coping strategies after heart transplantation: psychological implications

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a range of feelings, from hope and faith (pertinent to the situation) to fantastic thinking, which can justify passive avoidance behaviors and the hope for a miracle (making treatment adherence more difficult). According to the literature, factors that may be responsible for poor treatment adherence include inadequate knowledge of the process, depression, anxiety, low social support, substance abuse, stress, persistence of psychological suffering, difficulty of access to medication and poor relationship with the team [8]. Therefore, a good relationship with the team can be fundamental [20]: When I was admitted to the hospital, I was treated with great affection. This helped me a lot. I had great faith, was sure that the doctors were going to be successful in my surgery. I changed my mind talking to a psychologist. She explained things to me, telling about what was going to happen, saying that I was not going to kill anyone in order to survive. In addition, the use of coping strategies focused on the problem and in seeking social support presented direct correlation, so the increase in coping with the problem is accompanied by greater search for support. The search for social support is related to the demand for instrumental and emotional support or information to assist in coping with the situation [11]. Thus, both strategies involve the adoption of an active posture of the patient in relation to treatment, thus favoring adherence, since they influence both the feelings of confidence in the health team, as the adoption of behaviors of search for health aid. Participants who had received psychological preparation used with higher frequency coping strategies focused on problem (P=0.008) and on the search of social support (P=0.01) than those without this preparation. In addition, there was a decrease in the use of emotion-focused coping (P=0.011). The differences were statistically significant. Taking into consideration that most of the participants had dilated ischemic cardiomyopathy before the HT and that the literature suggests that coronary patients have type "A" personality, these data show the relevance of psychological preparation. Individuals with type "A" personality are described as competitive, rigid, self-controlled, committed to the work and, often, unable to rest. They are described as persons who try to show independence, have difficulty in relating with others and in taking a passive and dependent stance. In addition, they have difficulty in identifying and dealing with their feelings, which makes them more fragile when sick [21]. According to these characteristics, individuals who are not well prepared for the transplant would use more frequently the emotion-focused coping strategy, due to

their emotional difficulties. Because of their difficulty in relating with other persons and assuming a dependent role, they would not use so frequently a coping strategy that relies on seeking social support. Similar results were observed for patients who did not receive psychological preparation. These behaviors deserve attention, since they can hinder treatment adherence as well as indicate a greater vulnerability of the patient [6,15]. Therefore, the data obtained from the group of patients psychologically prepared for the HT shows the relevance of this intervention. This preparation allows the patient a moment to talk about the transplant, so that he becomes aware of his fantasies and feelings, as well as the personal way of addressing the situation, a fact that enables a change of behavior and favors the adoption of coping modes more active and adapted to the situation, such as the confrontation focused on solving the problem and the search for social support [22]. These coping strategies are fundamental to the survival, since they influence the behavior of adherence to treatment [9,15]. In addition, the psychological treatment relieves feelings of stress, anxiety and depression, facilitating the process [15]. A comparison of strategies among patients with and without the presence of psychiatric disorder found that in seconds there is a predominance of problem-focused coping style (P=0.046) and less frequently the emotionfocused strategy (P=0.08). However, patients with psychiatric disorders showed a non-significant higher frequency of coping by religious practice (P=0.748), and a significant increase in the use of emotion-focused coping (P=0.352). These results suggest greater use of passive strategies, indicating an inability to deal with the post-transplant period, as pointed by other studies that emphasize the role of major depression as a risk factor in the post-transplantation period [6,7,15,23]. Taking into consideration these particularities, the role of the psychologist must start in the preoperative period and extend during the post-transplant period, according to the needs of each patient. In the pre-transplant period, the psychologist assesses how the patient processes information about his health, how he receives the indication for transplantation and what his level of knowledge of the process is. Therefore, the use of psychoprophylaxis â&#x20AC;&#x201C; a technique developed by psychoanalyst Arminda Aberastury â&#x20AC;&#x201C; emphasizes the importance of working the anxieties and fantasies related to the surgery. Therefore, it is necessary to explain every detail of the surgery, from the anesthesia to possible indispositions, decreasing in this way the postoperative anxiety and trauma by making it

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possible to elaborate fantasies, suffering and feelings of unsafety associated with transplantation, as well as the incorporation of a new body image [24]. In the period subsequent to the HT, psychological aspects related to the feeling of loss of the heart, acceptance of the new body and adaptation to changes in life habits should be addressed. In addition, the patient’s sense of autonomy, self-efficacy and responsibility for his own health care, as well as the stimulus to return to life activities, should be strengthened in order to increase adherence to the treatment [9,18,25]. One of the possible limitations of the present study is that the results cannot be generalized to the overall population, since the sample is small, despite being representative of the institutional reality – more than 55% of patients undergoing living transplantation – and reflecting clinical data already observed. In addition, the WOCS showed poor reliability in the analysis of coping strategy focused on seeking social support, highlighting the importance of further studies with more representative samples, with patients with psychiatric disorders and the need for a review of items that represent this factor in WOCS.

4. Pérez San Gregorio MA, Martín Rodríguez A, Pérez Bernal J. Psychological differences of patients and relatives according to post-transplantation anxiety. Span J Psychol. 2008;11(1):250-8.

CONCLUSION Individuals who underwent HT make use of all coping strategies, with a predominance of strategies focused on the problem. The use of this active coping strategy implies behaviors more adapted to the process and responsible for greater adherence to treatment. Participants who were psychologically prepared for HT used a greater number of active coping strategies, a fact that highlights the importance of psychological support during the process. These results indicate the relevance of further studies to investigate the influence of preparation in relation to coping strategies adopted in larger samples.

5. Stolf NAG, Sadala MLA. Os significados de ter o coração transplantado: a experiência dos pacientes. Rev Bras Cir Cardiovasc. 2006;21(3):314-23. 6. Burker EJ, Evon DM, Marroquin Losielle M, Finkel JB, Mill MR. Coping predicts depression and disability in heart transplant candidates. J Psychosom Res. 2005;59(4):215-22. 7. Sirri L, Potena L, Masetti M, Tossani E, Magelli C, Grandi S. Psychological predictors of mortality in heart transplanted patients: a prospective, 6-year follow-up study. Transplantation. 2010;89(7):879-86. 8. Savóia MG, Santana PR, Mejias NP. Adaptação do inventário de estratégias de coping de Folkman e Lazarus para o português. Psicologia USP. 1996;7(1/2):183-201. 9. Lisson GL, Rodrigues JR, Reed AI, Nelson DR. A brief psychological intervention to improve adherence following transplantation. Ann Transplant. 2005;10(1):52-7. 10. Telles-Correia D, Inês M, Barbosa A, Barroso E, Monteiro E. Coping nos doentes transplantados. Acta Med Port. 2008;21:141-8. 11. Seidl EMF, Tróccoli BT, Zannon C. Análise fatorial de uma medida de estratégias de enfrentamento. Psicologia: teoria e pesquisa. 2001;17(3):225-34. 12. Gimenes M, Queiroz B. A teoria do enfrentamento e suas implicações para sucessos e insucessos em psiconcologia. In: Gimenes M, Fávero M, eds. A mulher e o câncer. Campinas: Editorial Psi; 1997. p.111-47. 13. Ministério da Saúde B. Resolução nº 196/MS/CNS, de 10 de outubro de 1996. Diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. [cited 2011 30 Ago]. Available from: http://www.anvisa.gov.br/legis/ resol/196_96.htm. 14. Bardin L. Análise de conteúdo. Lisboa: LDA; 1991. 229p.

REFERENCES 1. Andrade J. II Diretriz brasileira de transplante cardíaco. Arq Bras Cardiol. 2010;94(1 supl 1):e16-e73. 2. Helito RAB, Branco JNR, D'Innocenzo M, Machado RC, Buffolo E. Qualidade de vida dos candidatos a transplante de coração. Rev Bras Cir Cardiovasc. 2009;24(1):50-7. 3. Costa S, Guerra MP. O luto no transplantado cardíaco. Psic, Saúde & Doenças. 2009;10(1):49-55.

15. Kaba E, Thompson DR, Burnard P. Coping after heart transplantation: a descriptive study of heart transplant recipients’ methods of coping. J Adv Nurs. 2000;32(4):930-6. 16. Evangelista LS, Dracup K, Moser DK, Westlake C, Erickson V, Hamilton MA, et al. Two-year follow-up of quality of life in patients referred for heart transplant. Heart Lung. 2005;34(3):187-93. 17. Assef MAS, Valbuena PFM, Neves Jr MT, Correia EB, Vasconcelos M, Manrique R, et al. Transplante cardíaco no Instituto Dante Pazzanese de Cardiologia: análise da sobrevida. Rev Bras Cir Cardiovasc. 2001;16(4):289-304.

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18. Kristen A, Katus H, Dengler T. Return to work after heart transplantation. Versicherungsmedizin. 2010;62(2):67-72.

22. Goetzinger AM, Blumenthal JA, O’Hayer CV, Babyak MA, Hoffman BM, Ong L, et al. Stress and coping in caregivers of patients awaiting solid organ transplantation. Clin Transplant. 2012;26(1):97-104.

19. Albanesi Filho FM. Cardiomiopatias. Arq Bras Cardiol. 1998;71(2):95-107. 20. Goetzmann L, Lieberherr M, Krombholz L, Ambühl P, Boehler A, Noll G, et al. Subjective experiences following organ transplantation: a qualitative study of 120 heart, lung, liver, and kidney recipients. Z Psychosom Med Psychother. 2010;56(3):268-82. 21. Friedman M, Rosenman RH. Association of specific overt behavior pattern with blood and cardiovascular findings; blood cholesterol level, blood clotting time, incidence of arcus senilis, and clinical coronary artery disease. J Am Med Assoc. 1959;169(12):1286-96.

23. Allman E, Berry D, Nasir L. Depression and coping in heart failure patients: a review of the literature. J Cardiovasc Nurs. 2009;24(2):106-17. 24. Aberastury A. História de una técnica: preparación psicoterapéutica en cirugía. El psicoanalisis de niños y sus aplicaciones. 2ª ed. ed. Buenos Aires: Paidós; 1972. p.34-43. 25. Frota Filho JD, Lucchese FA, Sales MC, Lobo RCM, Tanaka N, Correa Junior JM, et al. Mortality after partial left ventriculectomy in relation to contraindications for heart transplantation. Rev Bras Cir Cardiovasc. 2003;18(1):1-8.

Benfatti RA, et al. - Analysis of left ventricular function in patients with ORIGINAL ARTICLE heart failure undergoing cardiac resynchronization

Rev Bras Cir Cardiovasc 2013;28(1):69-75

Analysis of left ventricular function in patients with heart failure undergoing cardiac resynchronization Análise da função ventricular esquerda de pacientes com insuficiência cardíaca submetidos à ressincronização cardíaca

Ricardo Adala Benfatti1, Felipe Matsushita Manzano2, José Carlos Dorsa Vieira Pontes3, Amaury Edgardo Mont’Serrat Ávila Souza Dias4, João Jackson Duarte5, Guilherme Viotto Rodrigues da Silva6, Jandir Ferreira Gomes Junior7, Neimar Gardenal8

DOI: 10.5935/1678-9741.20130011

RBCCV 44205-1444

Resumo Fundamentos: O tratamento cirúrgico da insuficiência cardíaca padrão-ouro é o transplante cardíaco, porém, em decorrência das dificuldades desse tratamento, outras propostas cirúrgicas têm sido relatadas, entre elas o implante de ressincronizador cardíaco. Objetivo: Analisar a função ventricular esquerda, por meio da ecocardiografia, de pacientes portadores de insuficiência cardíaca avançada com dissincronia interventricular submetidos a implante de ressincronizador cardíaco. Métodos: Entre junho de 2006 a junho de 2012, foram avaliados 24 pacientes com idade média de 61,5 ± 11 anos, portadores de insuficiência cardíaca congestiva avançada em classe funcional III e IV (NYHA), dissincronia interventricular e tratamento medicamentoso otimizado. Esses pacientes foram submetidos ao implante de ressincronizador cardíaco e avaliados ecocardiograficamente no pós-operatório de seis meses.

Resultados: Houve melhora significativa dos parâmetros ecocardiográficos analisados. A média dos diâmetros diastólicos ventriculares esquerdos reduziu de 69,6 ± 9,8 mm para 66,8 ± 8,8 mm, diâmetros sistólicos de 58,6 ± 8,8 mm para 52,7 ± 8,8 mm e a fração de ejeção, média de 31 ± 8% para 40 ± 7% com nível de significância, respectivamente, de 0,019, 0,0004 e 0,0002, estatisticamente significativos com nível de significância de 0,05. Conclusão: Houve melhora da função ventricular esquerda analisada por meio da ecocardiografia, em seis meses, de pacientes portadores de insuficiência cardíaca avançada submetidos a implante de ressincronizador cardíaco.

1. Master of Science, Assistant Professor of Federal University of Mato Grosso do Sul (UFMS), Campo Grande, MS, Brazil – Main author. 2. Medical Doctor of UFMS, Campo Grande, MS, Brazil – Data collection. 3. Philosophy Doctor, Full Professor of UFMS, Campo Grande, MS, Brazil – Final review. 4. Assistant Professor of UFMS, Campo Grande, MS, Brazil – Performed surgeries and bibliographic research. 5. Master of Science of UFMS, Campo Grande, MS, Brazil – Performed surgeries and bibliographic research. 6. Resident Doctor of UFMS, Campo Grande, MS, Brazil – Bibliographic research, assistance in surgeries. 7. Master of Science, Campo Grande, MS, Brazil – Performed Surgeries. 8. Master of Science, Campo Grande, MS, Brazil – Co-author of the scientific paper.

Study carried out at the Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil.

Descritores: Insuficiência cardíaca. Terapia Ressincronização Cardíaca. Ecocardiografia.

Correspondence address Ricardo Adala Benfatti Av. Senador Filinto Muller, S/N – Hospital Universitário – UTI Cardiológica – Campo Grande, MS, Brazil. E-mail: ricardobenfatti@gmail.com

Article received on September 9th, 2012 Article accepted on December 18th, 2012

Benfatti RA, et al. - Analysis of left ventricular function in patients with heart failure undergoing cardiac resynchronization

Abbreviations, acronyms & symbols AAS ACE CRT DCM ECG EF HF LBBB LVDD LVEF LVSD NYHA RV SD SUS UFMS

Acetylsalicylic acid Angiotensin converting enzyme Cardiac resynchronization therapy Dilated cardiomyopathy Electrocardiogram Ejection fraction Heart failure Left bundle branch block Left ventricle diastolic diameter Left ventricular ejection fraction Left ventricle systolic diameter New York Heart Association Right ventricle Standard deviation Unified Health System Federal University of Mato Grosso do Sul

Abstract Background: The gold standard surgical treatment for heart failure is cardiac transplantation, however, due to difficulties of this treatment, other surgical proposals have been reported, including the implantation of cardiac resynchronizer.

INTRODUCTION Heart failure (HF) is one of the greatest clinical challenges in the current public health, and it is considered an epidemic in progress, diagnosed in 1% to 2% of developed countries population [1,2]. The HF is one of the most prevalent causes of hospital admissions in Brazil, at the Unified Health System (SUS). In 2007, there were 1.156.136 hospital admissions for cardiovascular diseases, representing the third leading cause of hospital admissions at the SUS, and HF is the main one [3]. The HF treatment has the purpose of symptoms improvement, reduction of mortality, decrease of hospital costs and prevention of readmissions. The treatment of heart failure consists of: nonpharmacological steps (diet, exercising, stress management, and others), drug therapy and surgery [3]. Studies show that medical treatment should always include a beta blocker and an angiotensin converting enzyme (ACE) inhibitor, composing the optimized medical treatment. For symptomatic patients, diuretics and digitalis are added. But if there is a disabling symptoms persistence, it is necessary to introduce aldosterone 70

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Objective: To analyze the left ventricular function by echocardiography in patients with advanced heart failure with interventricular dyssynchrony undergone implantation of cardiac resynchronizer. Methods: Between June 2006 and June 2012, 24 patients with average age of 61.5 ± 11 years were evaluated, carriers of advanced congestive heart failure functional class III and IV (NYHA), interventricular dyssynchrony and optimal drug therapy, and submitted implantation of cardiac resynchronizer and postoperative echocardiographically evaluated in six months. Results: There was significant improvement of the analyzed echocardiography parameters. The average left ventricular diastolic diameter decreased from 69.6 ± 9.8 mm to 66.8 ± 8.8 mm, systolic diameters from 58.6 ± 8.8 mm to 52.7 ± 8.8 mm, and ejection fraction, average of 31 ± 8% to 40 ± 7% with level of significance, respectively, of 0.019, 0.0004 and 0.0002, statistically significant with a significance level of 0.05. Conclusion: There was a significant improvement of left ventricular function analyzed by echocardiography at six months, in patients with advanced heart failure undergone implantation of cardiac resynchronizer. Descriptors: Heart failure. Cardiac resynchronization therapy. Echocardiography.

antagonists (functional class III heart failure by Criteria Committee of the New York Heart Association - NYHA) with strict control of serum potassium and combination of hydralazine + nitrate [3-6]. The search for alternative or complementary methods to drug treatment, which could change the course of the disease, is a major challenge of the researchers [7]. Surgical treatment should be considered for patients resistant to optimized medical treatment. Cardiac transplantation is the main treatment for patients with severe clinical and hemodynamic conditions, which represent significant changes in the prognosis of HF, but there are major obstacles to its achievement, as the low amount of donors, adverse responses to immunosuppressants, unfavorable clinical conditions and surgical risk, and other factors that are against the surgery [8]. Therefore, other alternative surgical techniques to heart transplantation, including surgical intervention of mitral valve in dilated cardiomyopathy [9], left ventricular aneurysmectomy and implanting a pacemaker of cardiac resynchronization [10,11] have been performed to improve the clinical conditions and reduce morbidity and mortality of HF patients. The cardiac interventricular dyssynchrony is presented

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as an electromechanical regional change, leading to delays in both contraction and relaxation in cardiac muscle. Among the possible mechanisms of worsening biventricular function, the dyssynchronous contraction of the right ventricle stands out, leading to a septal bulging towards the left ventricle. This can unleash a delay in the papillary muscles activation with consequent mitral valve insufficiency [11]. The interventricular dyssynchrony can be analyzed by echocardiography, using the Pulse Doppler, calculating the electromechanical delay between the ventricles by measuring the time interval between the R wave of the electrocardiogram and the beginning of the curve of flow speed and aortic pulmonary flow. In case when the difference between the two intervals is greater than 40 milliseconds, it is an indicative of interventricular dyssynchrony [12,13]. A cardiac resynchronization therapy plays an important role in treating patients with severe heart failure with conduction abnormalities and prolongation of the QRS complex, having as the main representative the left bundle branch block (LBBB), found in about 2550% of patients [14]. Among the indications for implantation of cardiac resynchronizer with or without internal defibrillator, patients with dilated cardiomyopathy with depressed left ventricular ejection fraction (LVEF) less than 35% are included, patients with ischemic heart disease without surgical or interventional treatment conditions, irreversible structural changes, functional class III or IV with electrocardiogram (ECG) showing QRS>150 milliseconds or QRS 120 to 150 milliseconds with dyssynchrony [15]. Studies show that biventricular resynchronization therapy provides a significant medical improvement with a reduction in the number of hospital admissions, improvement in functional class and quality of life. The assessment of ventricular function by echocardiography demonstrates improvement in systolic and diastolic function and ejection fraction [16-20]. The echocardiographic analysis, a cost-effective favorable, reproducible and affordable examination reveals itself as a method not only for indication, but also for postoperative evaluation of patients who underwent cardiac resynchronization therapy, evaluating parameters such as ejection fraction, cardiac synchrony, ventricular remodeling, reducing the degree of mitral valve incompetence and reversal of interventricular electromechanical delay [21-24]. We considered the severity of patients with advanced heart failure with optimized medical treatment in need of surgical treatment and with electrocardiographic criteria, medical and echocardiography for implantation of cardiac resynchronizer. The goal of this research is to analyze left ventricular function through echocardiography in patients

with advanced heart failure who underwent implantation of cardiac resynchronizer. METHODS Casuistry The echocardiographic data of 24 patients with severe congestive heart failure were analyzed, classified as NYHA functional class III and IV according to the Criteria Committee of the NYHA, underwent implantation of transvenous cardiac resynchronizer, by Cardiovascular Surgery Service of the discipline of Cardiothoracic Surgery of the Helio Mandetta School of MedicineFederal University of Mato Grosso do Sul (UFMS), between June 2006 to June 2012, with the approval of the UFMS Ethics Committee in humans in the approval letter - protocol number 2235-CAAE 0354.0.049.000 11, on November 9, 2011. The patients were between 34 and 86 years old, average 61.5 Âą 11.1 years old, eight (33%) were female and sixteen (67%) were male, according to Table 1. All patients were on maximum allowable drug therapy. Concerning etiology, idiopathic dilated cardiomyopathy, valvular diseases from mild to severe functional impairment and ischemic cardiomyopathy have been demonstrated. Table 1. General data of patients. Patients 1. E.M.S. 2. E.S.P. 3. H.R.S. 4. J.B.S. 5. J.C.C. 6. M.D.L. 7. M.L.A.T. 8. M.R.M. 9. P.M.L. 10.C.C.N. 11. D.B.K. 12. J.S.R. 13. S.R.O. 14. N.O.S. 15. S.L. 16. E.C.L. 17. B.F.S. 18. I.F.M. 19. E.L.F. 20. A.M. 21. M.A.S. 22. J.G.I. 23. E.A.O.S. 24. U.R.S.

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

Age (years) Functional Class 65 III 61 III 60 III 60 III 66 III 57 III 57 IV 54 IV 69 III 81 III 60 IV 69 IV 63 III 56 III 61 IV 74 III 86 IV 56 IV 42 III 69 III 34 IV 63 IV 48 III 66 III 61.5 Âą 11.1 years

M: male; F: female

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Inclusion Criteria The inclusion criteria were: 1) patients with dilated cardiomyopathy (DCM) and congestive heart failure functional class III or IV (NYHA) refractory to optimized drug therapy; 2) patients with DCM without possibility of surgery (coronary artery bypass grafting, valve replacement, left ventricular aneurysm resection or correction of congenital heart disease); 3) interventricular conduction of disturbance left and right standard bundle branch block, associated with anterosuperior or left branch induced by right ventricular cardiac pacing exclusive block; 4) interventricular dyssynchrony documented on echocardiography; 5) QRS complex duration higher or equal to 120 ms.

The study used the echocardiographic data with, a maximum of one month before the pacemaker implantation multisite, and after six months for postoperative evaluation, shown respectively on Tables 2 and 3. The following variables used were: Left Ventricular Diastolic Diameter, Left Ventricular Systolic Diameter and Ejection Fraction, in the standardized methods in the literature.

Echocardiographic assessment Echocardiographic evaluation was preoperatively and postoperatively performed by the same examiner with Medson EX 8008 Apparatus, transducers of frequency 2 and 3 MHz in conventional evaluation plans.

Table 2. Preoperative echocardiographic assessment of patients who underwent implantation of cardiac resynchronizer. Patients E.M.S. E.S.P. H.R.S. J.B.S. J.C.C. M.D.L. M.L.A.T. M.R.M. P.M.L. C.C.N. D.B.K. J.S.R. S.R.O. N.O.S. S.L. E.C.L. B.F.S. I.F.M. E.L.F. A.M. M.A.S. J.G.I. E.A.O.S. U.R.S. Mean SD

LVDD (mm) 80 79 63 85 65 65 56 72 81 68 49 80 65 67 77 78 64 70 78 55 86 69 58 72

LVSD (mm) 70 69 53 72 50 51 48 62 64 54 44 70 53 55 62 65 54 64 64 47 74 62 53 61

EF % 26% 23% 30% 31% 45% 43% 28% 29% 48% 43% 25% 24% 37% 33% 33% 34% 20% 20% 36% 30% 29% 22% 19% 31%

69.6 9.8

58.6 8.7

31% 8%

LVDD: left ventricle diastolic diameter; LVSD: left ventricle systolic diameter; EF: ejection fraction; mm: millimeters; SD: standard deviation

Operative technique The operative technique for implantation of cardiac resynchronizer starts with cardiac monitoring and degermation and antisepsis of the neck anterior chest wall. Local anesthesia is performed with 2% lidocaine in an area located in the middle third of the right infraclavicular fossa, measuring approximately 4 cm2. An incision of approximately 4 cm at the place above 1 cm below the right clavicle is made, with careful hemostasis. The first electrode was placed in the right ventricle (RV), followed by the right atrium lead, both by puncture of the right subclavian vein in which the guide wires were inserted, inserting the sheaths through which the endocavitary electrodes were passed (active fixation). They were placed in traditional sites (atrium into the right auricle and right ventricle at the end of it) or where the initiation of stimulation was obtained, with acceptable sensing and impedance. The last electrode was placed in the coronary sinus for left ventricular pacing. The electrodes used were: Corox OTW 75 DP (Biotronik速). The position obtained by the use of radiological anatomy with fluoroscopy in left anterior oblique, at an angle of 35 degrees in order to position the electrode of passive fixation on the lateral or posterior vein of the left ventricle. Afterwards, electrophysiological tests took place to verify basic viability and stability. The final stimulus generator is connected, and it immediately starts its activity verified by electrocardiogram tracing. Postoperative follow-up The days of observation and monitoring varied from November 2006 until June 2012. All patients were medicated in order to maintain the optimization of drug therapy for heart failure. The postoperative evaluation was performed by the Doppler echocardiogram in a 6-months postoperative period. Statistical analysis The analysis of quantitative variables was performed by comparing average (previously checked the normality of distributions), using the Student t test. The level of significance was P <0.05.

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Benfatti RA, et al. - Analysis of left ventricular function in patients with heart failure undergoing cardiac resynchronization

RESULTS The patients were discharged without complications during the perioperative period and no death on the early postoperative period. According to the needs of each patient, there was drug use in their highest tolerated doses, with frequent use of digoxin, furosemide, carvedilol, acetylsalicylic acid (AAS), amiodarone, enalapril, losartan, warfarin and espironalactona. Regarding postoperative data, according to Table 3, the mean left ventricular diastolic diameters were 66.8 ± 8.8 mm, systolic diameters, 52.7 ± 8.8 mm and ejection fraction 40 ± 7%. Comparing the pre-and postoperative data, according to Table 4, there was significant reduction in echocardiographic parameters and increase in the analyzed ventricular function. The left ventricular diastolic diameter average decreased from 69.6 ± 9.8 mm to 66.8 ± 8.8 mm, systolic diameters of 58.6 mm ± 8.8 to 52.7 ± 8.8 mm and there was an increase

Table 3. Postoperative echocardiographic assessment of patients who underwent implantation of cardiac resynchronizer Patients E.M.S. E.S.P. H.R.S. J.B.S. J.C.C. M.D.L. M.L.A.T. M.R.M. P.M.L. C.C.N. D.B.K. J.S.R. S.R.O. N.O.S. S.L. E.C.L. B.F.S. I.F.M. E.L.F. A.M. M.A.S. J.G.I. E.A.O.S. U.R.S. Mean SD

LVDD (mm) 87 79 62 77 64 69 66 67 70 65 53 71 58 72 75 78 58 60 73 53 76 61 54 63

LVSD (mm) 70 60 43 64 51 55 52 57 38 49 37 58 45 59 62 65 54 48 58 43 66 47 44 48

EF % 38% 39% 57% 34% 43% 40% 43% 31% 43% 48% 57% 37% 44% 36% 35% 28% 35% 40% 41% 39% 27% 45% 36% 47%

66.8 8.8

52.7 8.8

40% 7%

LVDD: left ventricle diastolic diameter; LVSD: left ventricle systolic diameter; EF: ejection fraction; mm: millimeters; SD: standard deviation

in ejection fraction, an average of 31% ± 8 to 40 ± 7% significance level, respectively, 0.019, 0.0004 and 0.0002, statistically significant with a significance level of 0.05.

Table 4. Preoperative and postoperative echocardiographic assessment of patients who underwent implantation of cardiac resynchronizer. Parameters LVDD LVSD EF%

Preoperative 69.6± 9.8 MM 58,6 ± 8,8 MM 31 ± 8%

Postoperative 66.8 ± 8.8 MM 52,7 ± 8,8 MM 40 ± 7%

SD 0.019 0.0004 0.0002

LVDD: left ventricle diastolic diameter; LVSD: left ventricle systolic diameter; EF: ejection fraction; mm: millimeters; SD: standard deviation

DISCUSSION Heart failure is a serious public health problem, with high annual mortality [25]. In order to decrease the symptoms, complications and increase life expectancy, several forms of treatment are considered, such as pharmacological and nonpharmacological steps with major therapeutic advances in recent decades. However, many patients remain with significant symptoms and a high number of hospital admissions, determining reserved prognosis and expensive treatments [26,27]. These are the cases when surgical treatment should be considered. The cardiac resynchronization therapy (CRT) has an important role in the treatment of patients with advanced heart failure with conduction abnormalities and prolongation of the QRS complex, as main representative the left bundle branch block (LBBB), present in approximately 25-50% patients [14,15,28,29]. Studies have shown the medical benefits of CRT. The tests MIRACLE [30] and MUSTIC [31], CONTAK CD [32] showed that CRT determines functional class improvement of HF patients, exercise tolerance (6 minutes walking test peak VO2), reduction in the rate of HF hospitalization and improved quality of life through the Minnesota questionnaire. However, decrease in mortality with CRT and echocardiographic parameters improving were not demonstrated. A meta-analysis of the CARE-HF [33], MUSTIC [31] and MIRACLE [30] studies, comparing biventricular pacing with optimized medical treatment alone showed a significant reduction in hospitalization rates, reducing the risk of death. McAlister et al. [34], in 2007, in an 11 month follow-up period, demonstrated the efficacy and safety of biventricular pacing in over 10,000 patients. They concluded that CRT reduced hospitalizations and all 73

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causes of mortality. An increase in ejection fraction was observed, improving quality of life for the Minnesota questionnaire and improvement in functional class. However, some studies have shown that CRT was able to significantly improve as from the third month of follow-up echocardiographic parameters, such as reduced cerebrovascular accidents and left ventricular end-diastolic volumes and increasing ejection fraction [26-28]. In contrast with the controversy in the literature regarding the improvement in echocardiographic parameters, this research has demonstrated an increase in ejection fraction of 31% ± 8 to 40 ± 7%, reducing of diastolic and left ventricular systolic diameter from 69.6 ± 9.8 mm to 66.8 ± 8.8 mm and 58.6 mm ± 8.9 to 52.7 ± 8.8 mm, respectively, all parameters statistically significant. This research may infer that transvenous CRT improves benefits in the biventricular systolic function with significant improvement in echocardiographic parameters such as ejection fraction and reduction of systolic and diastolic diameters.

5. Remme WJ, Swedberg K; European Society of Cardiology. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur J Heart Fail. 2002;4(1):11-22.

CONCLUSION In the present study, there was improvement in left ventricular function assessed by echocardiography in patients with advanced heart failure who underwent implantation of cardiac resynchronizer.

REFERENCES 1. McAlister FA, Teo KK, Taher M, Montague TJ, Humen D, Cheung L. Insights into the contemporary epidemiology and outpatient management of congestive heart failure. Am Heart J. 1999;138(1 Pt 1):87-94. 2. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al; MIRACLE Study Group. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-53. 3. Bocchi EA, Braga FGM, Ferreira SMA, Rohde LEP, Oliveira WA, Almeida DR, et al. Sociedade Brasileira de Cardiologia. III Diretriz Brasileira de Insuficiência Cardíaca Crônica. Arq Bras Cardiol. 2009;93(1 supl.1):1-71. 4. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al; ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008;10(10):933-89.

6. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al; American College of Cardiology/ American Heart Association. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38(7):2101-13. 7. Stolf NAG, Jatene AD. História do transplante cardíaco. Rev Soc Cardiol Estado de São Paulo. 1995;5(6):609-13. 8. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Deng MC, Keck BM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report-2005. J Heart Lung Transplant. 2005;24(8):945-55. 9. Benfatti RA, Pontes JC, Gomes OM, Dias AE, Gomes Júnior JF, Gardenal N, et al. Mitral valve replacement with crossed papillopexy and annular constriction in heart failure patients. Rev Bras Cir Cardiovasc. 2008;23(3): 372-7. 10. Horwich T, Foster E, De Marco T, Tseng Z, Saxon L. Effects of resynchronization therapy on cardiac function in pacemaker patients “upgraded” to biventricular devices. J Cardiovasc Electrophysiol. 2004;15(11):1284-9. 11. Leclercq C, Hare JM. Ventricular resynchronization: current state of the art. Circulation. 2004;109(3):296-9. 12. Silva CES, Barretto ACP. Avaliação ecocardiográfica da terapia de ressincronização cardíaca. Arq Bras Cardiol. 2005;84(6):503-7. 13. Veiga VC, Abensur H, Rojas SS. Echocardiography in cardiac resynchronization therapy. Arq Bras Cardiol. 2009;93(3):441-5. 14. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95(12):2660-7. 15. Filho MM. Terapia de ressincronização cardíaca (TRC). Jornal Diagnósticos em Cardiologia. 38a Ed. Nov/Dez 2008. 16. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltislice STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol. 2002;40(1):111-8.

Benfatti RA, et al. - Analysis of left ventricular function in patients with heart failure undergoing cardiac resynchronization

Rev Bras Cir Cardiovasc 2013;28(1):69-75

17. Reuter S, Garrigue S, Bordachar P, Hocini M, Jaïs P, Haïssagueree M, et al. Intermediate-term results of biventricular pacing in heart failure: correlation between clinical and hemodynamic data. Pacing Clin Electrophysiol. 2000;23(11 Pt 2):1713-7.

26. Auricchio A, Abraham WT. Cardiac resynchronization therapy: current state of the art: cost versus benefit. Circulation. 2004;109(3):300-7.

18. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873-80. 19. Bakker PF, Meijburg HW, de Vries JW, Mower MM, Thomas AC, Hull ML, et al. Biventricular pacing in end-stage heart failure improves functional capacity and left ventricular function. J Interv Card Electrophysiol. 2000;4(2):395-404. 20. Soares MJF, Oliveira MAB, Braile DM. Marcapasso multisítio no tratamento da insuficiência cardíaca: evolução e resultados. Reblampa. 2007;20(1):31-5. 21. Kawaguchi M, Murabayashi T, Fetics BJ, Nelson GS, Samejima H, Nevo E, et al. Quantitation of basal dyssynchrony and acute resynchronization from left or biventricular pacing by novel echo-contrast variability imaging. J Am Coll Cardiol. 2002;39(12):2052-8. 22. Breithardt OA, Stellbrink C, Herbots L, Claus P, Sinha AM, Bijnens B, et al. Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle branch block. J Am Coll Cardiol. 2003;42(3):486-94. 23. Breithardt OA, Stellbrink C, Kramer AP, Sinha AM, Franke A, Salo R, et al. Echocardiographic quantification of left ventricular asynchrony predicts an acute hemodynamic benefit of cardiac resynchronization therapy. J Am Coll Cardiol. 2002;40(3):536-45. 24. Yu CM, Fung WH, Lin H, Zhang Q, Sanderson JE, Lau CP. Predictors of left ventricular reverse remodeling after cardiac resynchronization therapy for heart failure secondary to idiopathic dilated or ischemic cardiomyopathy. Am J Cardiol. 2003;91(6):684-8. 25. McAlister FA, Teo KK, Taher M, Montague TJ, Humen D, Cheung L. Insights into the contemporary epidemiology and outpatient management of congestive heart failure. Am Heart J. 1999;138(1 Pt 1):87-94.

27. Kadish A, Mehra M. Heart failure devices: implantable cardioverter-defibrillators and biventricular pacing therapy. Circulation. 2005;111(24):3327-35. 28. Souza FSO, Braile DM, Vieira RW, Rojas SO, Mortati NL, Rabelo AC, et al. Aspectos técnicos do implante de eletrodo para estimulação ventricular esquerda através do seio coronariano, com a utilização de anatomia radiológica e eletrograma intracavitário, na terapia de ressincronização cardíaca. Rev Bras Cir Cardiovasc. 2005;20(3):301-9. 29. Kalil C, Nery PB, Bartholomay E, Albuquerque LC. Tratamento com cardioversor-desfibrilador implantável e ressincronização cardíaca: isolados ou associados? Rev Bras Cir Cardiovasc. 2006;21(1):85-91. 30. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-53. 31. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al; Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344(12):873-80. 32. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, et al. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol. 2002;39(12):2026-33. 33. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-50. 34. McAlister FA, Ezekowitz J, Hooton N, Vandermeer B, Spooner C, Dryden DM, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: a systematic review. JAMA. 2007;297(22):2502-14.

Almeida RMS, et al. - The use of cell saver system in cardiac surgery with ORIGINAL ARTICLE cardiopulmonary bypass

Rev Bras Cir Cardiovasc 2013;28(1):76-82

The use of cell saver system in cardiac surgery with cardiopulmonary bypass O uso de recuperador de sangue em cirurgia cardíaca com circulação extracorpórea

Rui M. S. Almeida1, Luciano Leitão2

DOI: 10.5935/1678-9741.20130012

RBCCV 44205-1445

Abstract Introduction: The use of cell saver (CS) in cardiac surgery is proposed to reduce the use of units of packed red blood cells stored (UPRBC), which increases morbidity, mortality and causes inflammatory reactions. Objective: The objective is to evaluate whether the use of CS decreases the use UPRBC, is cost / effective and beneficial to the patient. Methods: In a prospective study, between November 2009 and October 2011, 100 consecutive patients who underwent cardiovascular surgery with CPB, hemodilution and hemofiltration, were enrolled. Patients were divided into group 1 (no CS) and 2 (CS). The criteria for the replacement of RBC were hemodynamic instability and hemoglobin (Hb) <7-8g/dl. Demographic data, as well as Hb and hematocrit, mediastinal drainage, number of URBC and CPB, ICU and hospital time, were analysed. Results: In groups 1 and 2 the average age was 64.1 and 60.6 years; predominantly male; the logistic EuroSCORE 10.3 and 9.4; mortality 2% and 4%. Group 2 had a higher incidence of reoperations (12% versus 6%), but the average

of UPRBC used (4.31 versus 1.25) and mean length of hospital stay (10.8 versus 7.4 days) was lower. Univariate and multivariate analysis, were performed, which showed no statistically significant values, except in the use of UPRBC. The relationship between the CS and the cost of RBC was not cost / effective and length of stay was shorter. Conclusion: The use of CS decreases the number of used UPRBC, is not cost / effective but has shown benefits for patients.

1. Coordinator of the Medicine Course of Assis Gurgacz College (FAG), President of the Deliberative Council of BSCVS and Editorial Board Member of BJCVS - Associate Professor at the State University of Western Paraná (UNIOESTE), Cascavel, Paraná, Brazil. Methodology, data collection, article writing and article revision. 2. Cardiovascular Surgeon of the Institute of Cardiovascular Surgery of Paraná, Cascavel, Paraná, Brazil. Participation in surgery, discussion of methodology and article revision.

Correspondence address: Rui Manuel Sequeira de Almeida 740 Maranhão Street, Apt 202 - Cascavel, Paraná, Brazil – Zip code: 85806-050. E-mail: ruimsalmeida@iccop.com.br

Work performed at the Institute of Cardiovascular Surgery of Paraná, Cascavel, Paraná, Brazil.

Article received on May 9th, 2012 Article accepted on December 26th, 2012

Descriptors: Operative blood salvage. Blood component transfusion. Cell separation. Resumo Introdução: O uso de recuperador de sangue (RS) em cirurgia cardíaca é proposto para diminuir o uso de unidades de concentrado de hemácias estocadas (UCH), que aumenta morbidade, mortalidade e reações inflamatórias. Objetivo: O objetivo deste estudo é avaliar se o uso do RS diminui o emprego de UCH, é custo/efetivo e traz benefícios ao paciente.

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Almeida RMS, et al. - The use of cell saver system in cardiac surgery with cardiopulmonary bypass

Abbreviations, Acronyms & Symbols ANS CPB CABG Hb Ht BMI PO BSA UPRBC ICU

National Agency of Supplemental Health Cardiopulmonary bypass Coronary artery bypass grafting Hemoglobin Hematocrit Body mass index Postoperative Body surface area Units of store packed red blood cells Intensive care unit

Métodos: Estudo prospectivo realizado entre novembro de 2009 e outubro de 2011, em 100 pacientes consecutivos, submetidos à cirurgia cardiovascular com circulação extracorpórea (CEC), hemodiluição mínima e hemofiltração. Os pacientes foram divididos em grupo 1 (sem RS) e 2 (com RS). Os critérios para a reposição de UCH foram

INTRODUCTION Several methods have been used to decrease the use of homologous blood with the progress and increased knowledge of the pathophysiology of cardiopulmonary bypass. This has been a path, with the highest incidence of use in patients for religious reasons and those who do not wish to make use of units of stored packed red blood cells (UPRBC). The use of this strategy varies from services to services in different continents, between 15% and 60% [1]. In recent years, efforts have been made to decrease more and more the use of homologous blood, with recovery of autologous blood during surgery and sometimes even in the postoperative period [2], along with a more hemostasis strict protocols throughout the surgical procedures. Cell savers machines (CS) have been used [3] in adult patients with high risk of bleeding, due to the fact that they decrease the inflammatory response to cardiopulmonary bypass. The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists [4], in its guidelines for 2007, considered as class I the use of CS. However, several

instabilidade hemodinâmica e hemoglobina (Hb) <7-8g/ dl. Foram analisados dados demográficos, Hb, hematócrito (Ht), drenagem mediastinal e reposição de UCH, em diversos intervalos, e tempos de CEC, UTI e hospital. Resultados: Nos grupos 1 e 2, a idade média foi de 64,2 e 60,6 anos, com predominância do sexo masculino, o EuroSCORE logístico de 10,3 e 9,6 e a mortalidade de 2% e 4%, não relacionada ao estudo. O grupo 2 apresentou incidência de reoperações superior (12 x 6%), mas o número de UCH usado (4,31x1,25) e o tempo de internamento hospitalar (10,8x7,4) foram menores. Realizada análise uni e multivariada, que não demonstrou valores estatisticamente significativos, exceto no uso de UCH. A relação entre o custo do RS e das UCH foi custo/efetiva e o tempo de internamento, menor. Conclusão: O uso de RS diminui o número de UCH usadas, não é custo/efetivo e mostrou benefícios ao paciente. Descritores: Recuperação de sangue operatório. Transfusão de componentes sanguíneos. Separação celular.

authors have shown that the use of CS is not as beneficial as stated [5,6] and is not cost-effective [7-9]. In order to clarify this issue, the authors devised this work, which aims to verify that the primary use of CS in cardiovascular surgery with cardiopulmonary bypass (CPB), is cost-effective. As a secondary objective, we sought to identify a reduction in the use of units of UPRBC in patients who used CS, and morbidity resulting from the use of this protocol. METHODS This is a non-randomized prospective cohort study that was held at the Institute of Cardiovascular Surgery of Paraná, in a group of 100 consecutive patients operated on by the same surgeon (RMSA) from November 2009 to October 2011 . All patients undergoing cardiovascular surgery with CPB were included, without any established exclusion criteria. The patients were divided into two groups of 50 patients: Group A - without using CS, Group B - with 77

Almeida RMS, et al. - The use of cell saver system in cardiac surgery with cardiopulmonary bypass

Rev Bras Cir Cardiovasc 2013;28(1):76-82

the use of CS. Both groups made use of the CPB, partial hemodilution and hemofiltration. The criterion for the use of UPRBC was hemoglobin (Hb) below 7 or 8 g/100 ml, with hemodynamic instability. The number of units of plasma, platelets and cryoprecipitate used was not taken into consideration, for not being the objective of this study. All patients underwent induction of anesthesia with the use of midazolam and remifentanil and its maintenance was carried out with servoflurano. After median sternotomy and manufacturing of cannulation pouches, the patients were heparinized with a dose of 300 U / kg in order to obtain activated clotting time exceeding 400 seconds; controls were performed every 60 minutes. In all cases, an adult membrane oxygenator was used (Braile Biomedica®, São José do Rio Preto, SP, Brazil) with a total of 500 ml filling volume. Blood and antegrade infusions were used. In Group B, the CS used was autolog Autotransfusion System (Medtronic, Minnesota, USA), throughout the surgery, with the CPB blood being pumped and processed by the CS system at the end of the surgery. Hb and hematocrit (Ht) were obtained on the day of hospital admission, upon arrival to the intensive care unit (ICU), on the first postoperative day and on the day of discharge, the volume aspirated and infused by CS were also recorded, as well as Hb and Ht of infused blood. The number of UPRBC used was recorded. The package prices of disposables CS and UPRBC were obtained for the purchase by a company belonging to the National Health Agency (ANS). At current prices, UPRBC was R$ 400.00 and the package of disposable CS was R$ 1,650.00. The study was approved by Assis Gurgacz Ethics Committee under the protocol number 154/2012.

The continuous variables are statistically represented by their mean and standard deviation and median. Student’s t-test, Mann Whitney test and Fisher’s exact test were used to analyze the variables in this study. We used statistics for the variables in the preoperative period (age, gender, weight, type of surgery, CPB and aortic clamping time and packed cell volume), to verify whether the sample of the two groups was comparable or not. RESULTS The patients' ages ranged from 26 to 84 years old, and the average age of patients in Group A was 64.15 ± 9.99 years and 60.55 ± 12.01 in Group B. There was a predominance of males in both groups. The demographic data are shown in Table 1. In Group A, 60% of patients underwent coronary artery bypass grafting, while in Group B 68%; the logistic EuroSCORE was similar in both groups, as well as the additive EuroSCORE, by subgroups (Table 2). Age, weight, gender, type of surgery (in two subgroups with larger number of patients), CPB and aortic clamping time, and Hb and preoperative PCV were statistically analyzed to see if the two groups were comparable. There was no statistical difference between the two groups except in the variable weight (Table 3). Two patients in Group B were reoperations (4%), and a fifth surgery, and one in Group A (2%). The CPB, aortic clamping time and the various stages of hospitalization are shown in Table 4. The incidence of reoperation for bleeding was 6% in Group A and 12% in Group B.

Table 1. Both groups clinical characteristics.

EuroSCORE

Age

Mean ± Median SD

Group A 64.15 ± 9.99 65

Group B 60.55 ± 12.01 63

Gender

Male

56%

84%

Additive

0a2 2a5 >5 Logistic

9 19 22 10.28

10 21 19 9.55

Weight Height Body Surface Body Index Mass

kg cm cm2

75.61 ± 14.85 166.31 ± 9.35 185.86 ± 23.75 27.25 ± 3.86

78.36 ± 16.59 169. 92 ± 8.48 187.48 ± 20.02 26.72 ± 4.26

CPB Aortic clamping time

min min

73.06 ± 20.97 38.70 ± 13.91

66.62 ± 15.69 37.43 ± 9.73

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Almeida RMS, et al. - The use of cell saver system in cardiac surgery with cardiopulmonary bypass

Table 2. Type of surgery.

CABG Associated CABG Aortic Valve Replacement Mitral Valve Replacement Aortic Valve Plasty Mitral Valve Plasty Ascending Aortic Aneurysm Myxoma LV Aneurysm Aortic Valve Replacement Mitral Valve Replacement Aortic Valve Plasty Mitral Valve Plasty Ascend. Aor. Aneur. Mixoma Atrial Septal Defect Ventricular Septal Defect

Group A 30

Arterial Graft 34

1 1 2

2 1 4 3 1

APS 67

Metal Prosthesis

Biological Prosthesis

Group B 34

Arterial Graft 43

APS

3 1

4 1

2 4

1 5

3 3

3 1

1 1

2 1

Metal Prosthesis

2 2

Table 3. Table of comparative variables. With Cell Saver (n=50) 63.72±12.21 79.58±16.43 38/12

Without Cell Saver (n=50) 60.56±9.90 76.10±15.04 27/23

P-Value P=0.1587 P=0.2722 P=0.0233

(Aortic/non-aortic)

6/44

9/41

P=0.4195

(Coronary x non-coronary)

41/9

36/14

P=0.2476

67.10±20.05 38.28±13.82 13.70±3.67 41.10

73.10±21.23 38.36±13.82 12.80±1.69 38.40

P=0.1517 P=0.9787 P=0.1397 P=0.1397

Variables Age(years) Weight(Kg) Male/Female Type of Surgery

CPB time (minutes) Clamping time (minutes) Preoperative Hb Preoperative PCV (%)

The hospital mortality was 2% in group A (patient who underwent CABG with mitral valve replacement for multiple organ failure), and 4% in group B (patient who undewent CABG with aortic valve replacement and porcelain aorta due to cerebrovscular accident, and patient with CABG with ventricular septal defect because of multiple organ failure). No deaths occurred during the follow-up period. The daily bleeding during postoperative days, and the use of UPRBC are shown in Table 3. The mean total volume of aspirated fluid was 1657.00 ± 2309.65 ml, in which 474.58 ± 160.66

ml were used for infusion, with a mean Hb and Ht of 18.58 ± 4.51 g/100 ml and 52.31 ± 11.28%, respectively. Bleeding average was 642.51 ± 193.30 ml in group A, and 685.65 ± 210.36 mL in Group B. Body surface area (BSA) and body mass index (BMI) were, respectively, 3.46 and 3.66 ml/cm2 and 23.58 and 25.66 ml/cm2 in Groups A and B, with no significant difference. A total of 194 UPRBC was used for Group A and 62 in Group B. The average use of RBC in Group A was 2.42 ± 1.37, and 0.70 ± 0.93 in Group B. On 0° postoperative day, 123 and 29 UPRBC 79

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Almeida RMS, et al. - The use of cell saver system in cardiac surgery with cardiopulmonary bypass

Table 4. CPB, aortic clamping time e other times. Time

CPB Aortic clamping time

min min

73.06 ± 20.97 38.70 ± 13.91

66.62 ± 15.69 37.43 ± 9.73

Time

Preoperative

Mean ± SD Median Mean ± SD Median Mean ± SD Median Mean ± SD Median

2.98 ± 2.86 2 4.24 ± 5.87 2 10.79 ± 14.70 7 13.77 ± 15.23 9

2.37 ± 1.73 2 3.66 ± 5.36 2 7.43 ± 6.97 6 9.80 ± 7.33 8

ICU Postoperative Hospital Stay 1st Postoperative Period

Hb Ht

g/100 ml %

9.41 ± 1.09 28.27 ± 5.33

9.85 ± 1.27 29.64 ± 3.86

Hospital Discharge

Hb Ht

g/100 ml %

10.10 ± 1.32 30.41 ± 4.16

9.48 ± 1.20 28.71 ± 3.65

0 Postoperative Period 1st Postoperative Period 2nd Postoperative Period After 0 Postoperative Period 1st Postoperative Period 2nd Postoperative Period After

ml ml ml ml

428.57 ± 214.10 175.51 ± 134.64 25.67 ± 77.33 12.77 ± 133.76

443.20 ± 271.65 231.84 ± 190.47 10.61 ± 64.19 0.00 ± 0.00

n° n° n° n°

2.51 ± 1.20 1.05 ± 1.00 0.37 ± 0.78 0.38 ± 1.07

0.58 ± 1.48 0.39 ± 0.92 0.27 ± 0.63 0.02 ± 0.14

Bleeding

uPRBC

Table 5. Table analysis of statistically significant variables. Variables Hb after CPB (g/dl) Hb in the 1° Postoperative Period (g/dl) Hb during Hospital Discharge (g/dl) Bleeding (ml) Transfusion (ml)

With Cell Saver (n=50) 10.55±1.80 9.85±1.28 9.47±1.21 443.2±274 174±449

were used, on the 1st postoperative day, 42 and 19, on the 2nd postoperative day, 14 and 13, until hospital discharge 15 and 1 in Groups A and B, respectively (Table 3). All patients from Group A were infused with at least two UPRBC (2-13) during hospitalization, 28 patients in group B received no UPRBC, while the rest of them used 2.81. In the analysis of variables between the two groups that were statistically significant, we observed that hemoglobin at hospital discharge and the number of UPRBC transfused were the only statistically significant differences (Table 5). Regarding the cost, taking into account only the price of all UPRBC in Group A, and in Group B, the RBC added to the material cost of CS system, we can conclude that in 80

Without Cell Saver (n=50) 10.29±1.48 9.40±1.09 10.09±1.33 431.6±216 526±468

P-Value P=0.4645 P=0.0846 P=0.0247 P=0.8149 P=0.002

the first group there was a cost / patient of R$ 1,552.00 and in the second one, R$ 1,946.00. DISCUSSION Studies have shown that the use of homologous blood in cardiovascular surgery increases not only mortality but also morbidity [10-12] The use of cell saver machines began in the 1970s, due to an increasing demand by patients not to use blood. These requests were prompted by a religious group, which did not allow the use of stored blood to be infused into their worshipers. According to the guidelines used by the National Health Service, the use of CS in

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cardiovascular surgery with CPB, should be performed at the surgeonâ&#x20AC;&#x2122;s discretion and can be cost-effective [13]. The main objective in using CS is to have the ability to decrease the use of UPRBC in patients and thereby reduce inflammatory reactions and morbimortality. This care must be taken simultaneously with perfect hemostasis in both initial dieresis and before synthesis in cardiovascular surgeries. In the early 1980s, some authors already had their opinion against the indiscriminate use of CS, because it would neither decrease the costs nor the necessity of homologous blood [14]. However, several studies have shown advantages in the use of CS, as an increase in hemoglobin concentration and less time in ICU [15], less use of UPRBC, as long as the blood lost during surgery be reused [16], and poor results with low Ht in postoperative period of cardiovascular surgery [17]. Data from this study show shorter hospitalization time in ICU, one day less and less use of UPRBC during the hospital stay. There was no difference regarding postoperative complications between the two groups, since they were not related to the use of RBC, but the underlying disease and its treatment methods. A major difference in this study in relation to Reyes et al. [18], one of the last articles published in the literature, is that they considered consecutive patients, without any exclusion (real life study), and on the other, the authors excluded patients with: concomitant surgeries, aortic surgery, reoperations, emergencies, high levels of creatinine, and patients with anemia BS<1.6 m2, as well as patients with a EuroSCORE> 10% and high risk of bleeding. This study showed 21% of patients with a EuroSCORE above that percentage, and the group that made use of CS, 6% of patients were operated on duration while using clopidogrel and a patient was being subjected to a fourth reoperation (fifth procedure). Still comparing criteria, the combination of procedures performed in 90% of patients (6% in Group B), and 55.6% of them underwent surgical exploration for bleeding, which corresponds to 5% of the entire group. Attaran et al. [19], in a group of 1871 patients using CS, obtained percentage of re-exploration for bleeding that varied with the type of surgery, similar to that shown previously. These authors also concluded that regular use of CS does not bring any benefit to the patient, and this decision should be made individually. We can see that there was no economic advantage when comparing the cost of the amount of RBC used per patient in Group A, with the amount of disposable material of CS in Group B. The higher cost was observed in Group B, R$ 394.00 more. Several authors have also come to this conclusion [7- 9,11] and, therefore, its indication has been made for specific cases in which bleeding is above normal [10]. However, we must take into consideration that the group using CS, 28 patients did not have UPRBC infusionn infusion, the total of 1.25 RBC / patient / hospitalization,

and in Group A, 4.31. Several authors have demonstrated that the non-use RBC in the postoperative period decreases not only the morbidity but also trans and postoperative mortality [4,5]. This device has the advantage of reducing the use of UPRBC in cardiac surgery, but only in selected cases, therefore, its benefits are not the same for all patients. More studies should be conducted so that we can have a response in relation to inflammatory markers and advantages of its use in daily practice. CONCLUSION This study demonstrated that the use of CS is not costeffective, which decreased the number of UPRBC in the group using CS and there was no morbidity related to this protocol implementation.

REFERENCES 1. Reyes G, Prieto M, Alvarez P, Orts M, Bustamante J, Santos G, et al. Cell saving systems do not reduce the need of transfusion in low-risk patients undergoing cardiac surgery. Interact Cardiovasc Thorac Surg. 2011;12(2):189-93. 2. Klein AA, Nashef SA, Sharples L, Bottrill F, Dyer M, Armstrong J, et al. A randomized controlled trial of cell salvage in routine cardiac surgery. Anesth Analg. 2008;107(5):1487-95. 3. Carless PA, Henry DA, Moxey AJ, Oâ&#x20AC;&#x2122;Connell DL, Brown T, Fergusson DA. Cell salvage for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2006;(4):CD001888. 4. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD, et al; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83(5 Suppl):S27-86. 5. Jakobsen CJ, Ryhammer PK, Tang M, Andreasen JJ, Mortensen PE. Transfusion of blood during cardiac surgery is associated with higher long-term mortality in low-risk patients. Eur J Cardiothorac Surg. 2012;42(1):114-20.

Almeida RMS, et al. - The use of cell saver system in cardiac surgery with cardiopulmonary bypass

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6. Scott BH. Blood transfusion in cardiac surgery: is it appropriate? Ann Card Anaesth. 2007;10(2):108-12.

Committee Royal Brompton & Harefield Hospitals. DisponĂvel em: http://www.transfusionguidelines.org.uk/docs/pdfs/rtcscent_policy_rcs.pdf

7. Attaran S, McIlroy D, Fabri BM, Pullan MD. The use of cell salvage in routine cardiac surgery is ineffective and not costeffective and should be reserved for selected cases. Interact Cardiovasc Thorac Surg. 2011;12(5):824-6.

14. Winton TL, Charrette EJ, Salerno TA. The cell saver during cardiac surgery: does it save? Ann Thorac Surg. 1982;33(4):379-81.

8. Klein AA, Nashef SA, Sharples L, Bottrill F, Dyer M, Armstrong J, et al. A randomized controlled trial of cell salvage in routine cardiac surgery. Anesth Analg. 2008;107(5):1487-95.

15. Marcoux J, Rosin M, McNair E, Smith G, Lim H, Mycyk T. A comparison of intra-operative cell-saving strategies upon immediate post-operative outcomes after CPB-assisted cardiac procedures. Perfusion. 2008;23(3):157-64.

9. Serrano FJ, MoĂąux G, Aroca M. Should the cell saver autotransfusion system be routinely used in elective aortic surgery? Ann Vasc Surg. 2000;14(6):663-8.

16. Wang G, Bainbridge D, Martin J, Cheng D. The efficacy of an intraoperative cell saver during cardiac surgery: a meta-analysis of randomized trials. Anesth Analg. 2009;109(2):320-30.

10. Scott BH. Blood transfusion in cardiac surgery: is it appropriate? Ann Card Anaesth. 2007;10(2):108-12.

17. Hannan EL, Samadashvili Z, Lahey SJ, Culliford AT, Higgins RS, Jordan D, et al. Predictors of postoperative hematocrit and association of hematocrit with adverse outcomes for coronary artery bypass graft surgery patients with cardiopulmonary bypass. J Card Surg. 2010;25(6):638-46.

11. Basran S, Frumento RJ, Cohen A, Lee S, Du Y, Nishanian E, et al. The association between duration of storage of transfused red blood cells and morbidity and mortality after reoperative cardiac surgery. Anesth Analg. 2006;103(1):15-20. 12. Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-67. 13. Kelleher AA, Pepper J, Boecoe M, Shuldham C. Policy for the provision of perioperative red cell salvage. Joint Transfusion

18. Reyes G, Prieto M, Alvarez P, Orts M, Bustamante J, Santos G, et al. Cell saving systems do not reduce the need of transfusion in low-risk patients undergoing cardiac surgery. Interact Cardiovasc Thorac Surg. 2011;12(2):189-93. 19. Attaran S, McIlroy D, Fabri BM, Pullan MD. The use of cell salvage in routine cardiac surgery is ineffective and not costeffective and should be reserved for selected cases. Interact Cardiovasc Thorac Surg. 2011;12(5):824-6.

Sá MPBO, et al. - Five-year outcomes following PCI with DES versus REVIEW ARTICLE CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients

Rev Bras Cir Cardiovasc 2013;28(1):83-92

Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and meta-regression of 2914 patients Desfechos de 5 anos do tratamento de lesões de TCE por stents farmacológicos versus CRM: metaanálise e meta-regressão de 2914 pacientes

Michel Pompeu Barros de Oliveira Sá1, Paulo Ernando Ferraz2, Rodrigo Renda Escobar2, Eliobas Oliveira Nunes2, Alexandre Magno Macário Nunes Soares2, Frederico Browne Correia de Araújo e Sá2, Frederico Pires Vasconcelos2, Ricardo Carvalho Lima3

DOI: 10.5935/1678-9741.20130013

RBCCV 44205-1446

Abstract Objective: To compare the safety and efficacy at long-term follow-up of coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) using drug-eluting stents (DES) in patients with unprotected left main coronary artery (ULMCA) disease. Methods: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were searched for clinical studies that reported outcomes at 5-year follow-up after PCI with DES and CABG for the treatment of ULMCA stenosis. Five studies (1 randomized controlled trial and 4 observational studies) were identified and included a total of 2914 patients (1300 for CABG and 1614 for PCI with DES). Results: At 5-year follow-up, there was no significant difference between the CABG and PCI-DES groups in the risk for death (odds ratio [OR] 1.159, P=0.168 for random effect) or the composite endpoint of death, myocardial infarction, or stroke (OR 1.214, P=0.083). The risk for target vessel revascularization (TVR) was significantly lower in the CABG group compared to the PCI-DES group (OR

0.212, P<0.001). The risk of major adverse cardiac and cerebrovascular events (MACCE) was significantly lower in the CABG group compared to the PCI-DES group (OR 0.526, P<0.001). It was observed no publication bias about outcomes and considerably heterogeneity effect about MACCE. Conclusion: CABG surgery remains the best option of treatment for patients with ULMCA disease, with less need of TVR and MACCE rates at long-term follow-up.

1. MD, MSc – Author. 2. MD – Co-author. 3. MD, MSc, PhD, ChM – Co-author.

Correspondence address: Michel Pompeu Barros de Oliveira Sá. Av. Eng. Domingos Ferreira, 4172/405 Recife, PE, Brazil – Zip code: 51021-040. E-mail: michel_pompeu@yahoo.com.br

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

Descriptors: Meta-analysis. Myocardial revascularization. Drug-eluting stents. Resumo Objetivo: Comparar segurança e eficácia do seguimento a longo prazo da cirurgia de revascularização miocárdica (CRM) com intervenção coronária percutânea (ICP), utilizando stents farmacológicos (SF) em pacientes com lesão de tronco de coronária esquerda não-protegida (TCE). Métodos: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar e listas de referências de

Article received on September 23rd, 2012 Article accepted on November 13th, 2012

Sá MPBO, et al. - Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients

Abbreviations, Acronyms & Symbols CABG CENTRAL/CCTR CI DES EuroSCORE LILACS MACCE MeSH OR PCI PRISMA SciELO TVR ULMCA

Coronary artery bypass graft Cochrane Central Register of Controlled Trials Confidence interval Drug-eluting stents European System for Cardiac Operative Risk Evaluation Literatura Latino-Americana e do Caribe em Ciências da Saúde Major adverse cardiac and cerebrovascular events Medical subject heading Odds ratio Percutaneous coronary intervention Preferred Reporting Items for Systematic Reviews and Meta-Analyses Scientific Electronic Library Online Target vessel revascularization Unprotected left main coronary artery

artigos relevantes foram escaneados para estudos clínicos que relataram resultados em 5 anos de seguimento após ICP-SF e CRM para o tratamento de lesão de TCE. Cinco estudos (um

INTRODUCTION Rationale Current guidelines recommend percutaneous coronary intervention (PCI) of unprotected left main coronary artery (ULMCA) with stents as a Class IIa or IIb alternative to coronary artery bypass graft (CABG) in patients with conditions that are associated with a low risk of PCI procedural complications and/or increased risk of adverse surgical outcomes [1]. Capodanno et al. [2] recently published a meta-analysis of 4 randomized controlled trials and suggested, boldly, that “based on that study, revision of the guidelines regarding left main PCI is warranted, raising the level of evidence of current recommendations from B to A”. Although recent randomized controlled trials have suggested that PCI with drug-eluting stents (DES) could be a non-inferior strategy that might be used safely [3,4], sample sizes are small (and some conclusions may be affected by this aspect) and observational studies ("realworld" studies) should not be ignored in meta-analyses. Recently, Sá et al. [5] published a new meta-analysis with 16 studies (three randomized and 13 observational) with 1-year follow up results. This one argued against the “non-inferiority” of PCI with DES in comparison 84

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ensaio clínico randomizado e quatro estudos observacionais) foram identificados e incluíram um total de 2914 pacientes (1300 para CRM e 1614 para ICP-SF). Resultados: Aos 5 anos de seguimento, não houve diferença significativa entre os grupos CRM e ICP-SF no risco de morte (odds ratio [OR] 1,159, P=0,168) ou desfecho composto de morte, infarto do miocárdio , ou AVC (OR 1,214, P=0,083). O risco de necessidade de nova revascularização foi significativamente menor no grupo CRM em comparação com o grupo de ICP-SF (OR 0,212, P<0,001). O risco de eventos adversos cardíacos maiores e cerebrovasculares (EACMC) foi significativamente menor no grupo CRM em comparação com o grupo de ICP-SF (OR 0,526, P<0,001). Não foi observado viés de publicação sobre os resultados e considerável heterogeneidade dos efeitos sobre EACMC. Conclusão: CRM continua sendo a melhor opção de tratamento para pacientes com lesão de TCE, com menos necessidade de novas revascularizações e EACMC no seguimento a longo prazo. Descritores: Metanálise. Revascularização miocárdica. Stents farmacológicos.

to CABG surgery and against the idea that PCI could be considered a reasonable choice in elective cases (not mentioning prohibitive risk patients, acute patients and those who reject surgery), given that, although the rates of death between both strategies were not statistically different, the need of new procedures and major adverse cardiac and cerebrovascular events rates were clearly lower in patients treated with CABG surgery. Sá et al. [5] emphasized that the length of follow-up considered for their study may have been too short (1-year) to truly detect differences between the treatment groups, and so was the study of published by Capodanno et al. [2]. Performing a quick search on medical literature, we found no meta-analyses that evaluated the long-term results regarding this topic (PCI with DES versus CABG in ULMCA disease). Taking into considerations all these aspects, it is necessary to evaluate the long-term results of CABG surgery versus PCI with DES in scenario of ULMCA disease, using the highest level of existing evidence. Objective We performed a meta-analysis of randomized controlled trials and observational studies to compare

Sá MPBO, et al. - Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients

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CABG to PCI with DES for the treatment of patients with ULMCA disease, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [6].

or exclusion of studies was decided unanimously. When there was disagreement, a third reviewer took the final decision.

METHODS Eligibility Criteria Using PICOS studies were considered if: (1) population comprised patients with ULMCA disease; (2) compared efficacy or effectiveness between CABG and PCI with DES; (3) outcomes studied included myocardial infarction, cerebrovascular events, death, target vessel revascularization (TVR) or combined outcomes (MACCE – major adverse cardiac and cerebrovascular events); (4) presented follow-up of at least 5 years. Information Sources The following databases were used (until July 2012): MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), ClinicalTrials.gov, SciELO (Scientific Electronic Library Online), LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde – The Latin American and Caribbean Health Sciences), Google Schoolar and reference lists of relevant articles. Search We conducted the search using Medical Subject Heading (MeSH) terms “coronary artery bypass graft” OR “coronary artery bypass grafting” OR “coronary artery bypass surgery” OR “coronary bypass surgery” OR “coronary artery bypass graft surgery” OR “coronary artery bypass” OR “coronary bypass” AND “drug-eluting stent” OR “sirolimus-eluting stent” OR “paclitaxeleluting stent” AND “unprotected left main” OR “left main stenting” OR “left main coronary artery disease” OR “left main PCI” OR “unprotected left main coronary artery” OR “left main stenosis” OR “left main coronary artery stenting” OR “unprotected left main stenting”. Study Selection The following steps were done: (1) identification of titles of records through databases searching; (2) removal of duplicates; (3) screening and selection of abstracts; (4) assessment for eligibility through full-text articles; (5) final inclusion in study. One reviewer followed the steps 1 to 3. Two independent reviewers followed step 4 and selected studies. Inclusion

Data Items The primary endpoint was the Odds Ratio (OR) for mortality after PCI or CABG, up to 5 years. Secondary end points were the OR for composite endpoint of death, myocardial infarction or stroke; TVR (target vessel revascularization – repeat revascularization of the treated vessel) after the procedure; and MACCE (major adverse cardiac and cerebrovascular events – composite endpoint of death, myocardial infarction, stroke or TVR). Data Collection Process Two independent reviewers extracted the data. When there was disagreement about data, a third reviewer (the first author) checked the data and took the final decision about it. From each study, we extracted patient characteristics, study design, and outcomes at 5-year after treatment of ULMCA stenosis. When possible, actual probabilities of mortality and death after 5-year following PCI or CABG were used to calculate odds ratios. Alternatively, probabilities of mortality or MACCE were estimated from published Kaplan-Meier survival curves. We also extracted TVR from the total MACCE events and reported this outcome as a separate measure. When MACCE was not reported, we calculated it using the events of death, myocardial infarction, stroke and TVR and reported this outcome as a separate measure. Risk of Bias in Individual Studies Included studies were assessed for the following characteristics: design (prospective or retrospective), randomization (yes or no), multicenter enrollment (yes or no), characteristics of participants and personnel (performance bias), outcome assessment (detection bias), incomplete outcome data addressed (attrition bias) and adequation of multivariate adjustment for possible confounders. Two independent reviewers assessed risk of bias. Agreement between the two reviewers was assessed using kappa statistics for full text screening, and rating of relevance and risk of bias. When there was disagreement about risk of bias, a third reviewer (the first author) checked the data and took the final decision about it. Summary Measures The principal summary measures were OR’s with 85

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95% Confidence Interval (CI) and P values (that will be considered statistically significant when <0.05). The metaanalysis was completed using the software Comprehensive Meta-Analysis version 2 (Biostat Inc., Englewood, New Jersey, USA).

(Kappa=0.84). Agreement for decisions related to study validity was very good (Kappa=0.81). The search strategy can be seen in Figure 1.

Synthesis of Results Forest plots were generated for graphical presentations for clinical outcomes and we performed the I2 test and Chi2 statistics for assessment of heterogeneity across the studies [7]. Each study was summarized by the OR for PCI compared to CABG. The OR’s were combined across studies using DerSimonian-Laird random effects model [8] and with the fixed effects model using the MantelHaenszel model [9]. Both models were weighted by number of events in each study. Risk of Bias Across Studies To assess publication bias, a funnel plot was generated (for each outcome), being statistically assessed by Begg and Mazumdar’s test [10] and Egger’s test [11]. Meta-regression Analysis Meta-regression analyses were performed to determine whether the effects of CABG were modulated by prespecified factors. Meta-regression graphs describe the effect of CABG on the outcome (plotted as a log OR on the y-axis) as a function of a given factor (plotted as a mean or proportion of that factor on the x-axis). Meta-regression coefficients show the estimated increase in log OR per unit increase in the covariate. Since log OR >0 corresponds to OR >1 and log OR <0 corresponds to OR<1, a negative coefficient would indicate that as a given factor increases, the OR decreases. The pre-determined modulating factors for all outcomes to be examined were: sex, age, diabetes and prior PCI. Sex was represented as the proportion of females in the studies. Age was represented as the mean age of the patients participating in the studies. Diabetes was represented as the proportion of diabetics in the studies. Prior PCI was represented as the proportion of patients who underwent PCI before any interventions in the studies.

Study Characteristics Characteristics of each study are shown in Table 1. A total of 2914 patients were studied with 1300 receiving CABG and 1614 receiving PCI with DES. Of the 5 studies, one was randomized controlled trial [14], one matched the treatment cohorts using European System for Cardiac Operative Risk Evaluation (EuroSCORE) [16], two used other propensity scores to guarantee like-to-like comparisons [12,15], Four studies mostly used Cypher stent (sirolimus) or Taxus stent (paclitaxel) and one study did not report which DES was used. The overall internal validity was moderate risk of bias and is illustrated in Table 2. Synthesis of Results The OR of the risk of death in the CABG group compared with the PCI-DES group in each study, at the 5-year time point, is reported in Figure 2. There was no evidence for heterogeneity of treatment effect among the studies for death. The overall OR (95% confidence interval) of mortality showed no difference between CABG and PCIDES at 5-year (fixed effect model: OR 1.159, P=0.168; random effect model: OR 1.159, P=0.168).

RESULTS Study Selection A total of 14.705 citations were identified, of which 31 studies were potentially relevant and retrieved as full-text. Five publications fulfilled our eligibility criteria [12-16]. Interobserver reliability of study relevance was excellent 86

Fig. 1 – Flow diagram of studies included in data search

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Sá MPBO, et al. - Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients

Table 1. Study characteristics. Study

PCI (n)

DES

Complete revascularization with PCI (%) NR

CABG (n)

LIMA to LAD (%)

Off-pump (%)

309

Complete revascularization with CABG (%) NR

Chang et al. 2012 [12]

556

Terazawa et al. 2012 [13]

Boudriot et al. 2011 [14]

Unadjusted risk

Method of Adjustment

CABG higher risk clinical profile; EuroSCORE higher risk profile; SYNTAX score higher risk profile

Propensity matched

Cypher (88%) Taxus (12%)

CABG higher risk clinical profile; EuroSCORE higher risk profile

Multivariate logistic regression and multivariable Cox regression

100

Cypher (98%) Taxus (2%)

101

Randomized, same risk

Unneeded

MAINCOMPARE registry 2010 [15]

396

Cypher (79%) Taxus (21%)

396

Propensity score matched

Unneeded

Chieffo et al. 2010 [16]

107

Cypher (51.4%) Taxus (48.2%)

142

CABG higher risk clinical profile

Propensity score adjusted (EuroSCORE)

CABG: coronary artery bypass grafting; DES: drug-eluting stent; LAD: left anterior descending; LIMA: left internal mammary artery; PCI: percutaneous coronary intervention; NR: non-reported Table 2. Analysis of risk of bias – internal validity.

NP, NR, M

Selection bias B

Performance bias B

Attriction bias C

Dettection bias B

Multivariate adjustment for possible confounders Probably adequate

Terazawa et al. 2012 [13]

NP, NR, NM

Probably adequate

Boudriot et al. 2011 [14]

P, R, M

Probably adequate

P, NR, M

Probably adequate

NP, NR, NM

Probably adequate

Study Chang et al. 2012 [12]

MAIN-COMPARE registry 2010 [15] Chieffo et al. 2010 [16]

Study design

This was performed by 2 independent reviewers. The overall bias of the combined studies was considered moderate. A: risk of bias is low; B: risk of bias is moderate; C: risk of bias is high; D: incomplete reporting

Fig. 2 – Odds ratio and conclusions plot of mortality associated with CABG versus DES

Sá MPBO, et al. - Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients

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Fig. 3 – Odds ratio and conclusions plot of composite endpoint (death, myocardial infarction or stroke) associated with CABG versus DES

Fig. 4 – Odds ratio and conclusions plot of target vessel revascularization (TVR) associated with CABG versus DES

The OR of the risk of composite endpoint of death, myocardial infarction or stroke in the CABG group compared with the PCI-DES group in each study, at the 5-year time point, is reported in Figure 3. There was evidence of low heterogeneity of treatment effect among the studies for this composite endpoint. The overall OR (95% confidence interval) of composite end point showed no difference between PCI-DES and CABG at 5-year (fixed effect model: OR 1.215, P=0.061; random effect model: OR 1.214, P=0.083). The OR of the risk of TVR in the CABG group compared with the PCI-DES group in each study, at the 5-year time point, is reported in Figure 4. There was no evidence for heterogeneity of treatment effect among the studies for TVR. The overall OR (95% confidence interval) of TVR showed an important difference between CABG and PCIDES at 5-year (fixed effect model: OR 0.212, P<0.001; 88

random effect model: OR 0.212, P<0.001), which favors the CABG strategy. The OR of the risk of MACCE in the CABG group compared with the PCI-DES group in each study, at the 5-year time point, is reported in Figure 5. There was a considerably evidence for heterogeneity of treatment effect among the studies for MACCE. The overall OR (95% confidence interval) of MACCE showed an important difference between CABG and PCI-DES at 5-year (fixed effect model: OR 0.543, P<0.001; random effect model: OR 0.526, P<0.001), which favors the CABG strategy. Risk of Bias Across Studies Funnel plot analysis (Figure 6) disclosed symmetry around the axis for the treatment effect in all outcomes, which means we probably do not have publication bias related to these end points.

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Fig. 5 – Odds ratio and conclusions plot of major adverse cardiac and cerebrovascular events (MACCE) associated with CABG versus DES

Fig. 6 – Publication bias analysis by funnel plot graphic

Meta-regression Analysis We observed a statistically significant coefficient for 2 situations: (1) MACCE and proportion of diabetic patients (coefficient -0.04, 95% CI -0.07 to -0.01, P=0.016); (2) MACCE and proportion of prior PCI (coefficient -0.03, 95% CI -0.05 to -0.01, P=0.010). It

means that the greater the proportion of diabetic patients and prior PCI in a population undergoing CABG, the lower the OR for MACCE in CABG group, i.e., the greater the protective effect of CABG for diabetic patients and/or submitted to prior PCI in relation to the incidence of MACCE (Figure 7). 89

Sá MPBO, et al. - Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and metaregression of 2914 patients

Fig. 7 – Meta-regression analysis by representative plots

DISCUSSION Summary of Evidence The results of this meta-analysis demonstrate that CABG remains the best option for ULMCA disease. At 5-year follow-up, although there was no difference in the risk for death and composite endpoint of death, myocardial infarction and stroke, there was a significantly higher risk for TVR and MACCE (this last one under the influence of heterogeneity of the effects) associated with PCI with DES, with no publication bias of the summary measures of all outcomes. Considerations About this Meta-Analysis To our knowledge, this is the first meta-analysis of studies with 5-years follow-up performed to date about PCI-DES versus CABG in ULMCA disease, providing incremental value by demonstrating that CABG reduces the incidence of TVR and MACCE compared with PCIDES. Furthermore, this analysis suggests that PCI-DES does not significantly reduce the incidence of long-term all-cause mortality and composite endpoint of death, myocardial infarction and stroke in comparison with 90

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CABG. The potential benefits of CABG on these outcomes appear to be influenced by diabetes and previous PCI. Diabetes mellitus is a powerful independent predictor of cardiovascular events. It is associated with extensive coronary artery disease, increased mortality regardless of revascularization mode and unfavorable prognosis if treated medically [17]. The SYNTAX trial [18] has shown in the diabetic subset of patients at 1 year, similar death/ infarction/stroke rates between the two revascularization groups, increased risk across all SYNTAX terciles and higher mortality and MACCE in diabetic patients with SYNTAX score ≥33 with PCI over surgery. As we can see by meta-analysis and meta-regression, the total population of patients with ULMCA disease benefit from surgery (in comparison with PCI-DES) and the population of diabetics benefit more, since the presence of diabetes modulate the effect toward the protective effect (lesser odds ratio). In case of prior PCI, the severity of the progression of coronary atherosclerotic disease may justify the greater MACCE in PCI-DES group previously submitted to PCI, making CABG appears to be more protective. Currently, patients undergoing initial PCI with a stent have severe atherosclerotic disease, but not as severe as those undergoing initial surgical treatment; when treatment with stents fails, these patients are referred for surgical revascularization, however the atherosclerotic disease is then more severe and diffuse [19]. At present, the totality of evidence suggests that CABG appears better for the “sicker” patients, i.e., those with multivessel disease or ULMCA disease and characteristics indicative of extensive atheroma burden with or without depressed left ventricle ejection fraction [20]. We should not forget that SYNTAX trial showed the undoubted benefits of surgery (in comparison with PCI-DES) in the group with higher SYNTAX score, i.e., more extensive and complex lesions [4]. Risk of Bias and Limitations Another limitation is the heterogeneity of the strategies across the studies. Among PCI strategies, studies used many combinations of sirolimus-stent and paclitaxelstents (one did not report). Among CABG strategies, there is variability in rates of use of internal thoracic artery (two did not report), use of cardiopulmonary bypass (on-pump versus off-pump CABG; two did not report), etc. And among both studies, an important aspect to consider is the rate of complete revascularization (not reported in four studies), which reflects in outcomes. There are inherent limitations with meta-analyses, including the use of cumulative data from summary

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estimates. Patient data were gathered from published data, not from individual patient follow-up. Access to individual patient data would have enabled us to conduct further subgroup analysis and propensity analysis to account for differences between the treatment groups. This metaanalysis included data from nonrandomized observational studies, which reflects the “real world” but are limited by treatment bias, confounders, and a tendency to overestimate treatment effects. Patient selection alters outcome and thus makes nonrandomized studies less robust. We tried to analyze the influence of surgical risk profile and profile of lesion complexity; however, it was not possible because studies did not report these issues more systematically and broadly; it would be interesting, for example, that studies always evaluate SYNTAX score of groups, as this would allow further analysis of outcomes with respect to this variable, including meta-analyzes on this topic. A final limitation is the absence of adequate published comparative data for the third therapeutic option, medical therapy. PCI with DES has not been compared with medical therapy alone when we consider ULMCA disease, but CABG has been shown to be superior to medical therapy in this set.

surgery and against the idea that PCI can be considered a reasonable choice in elective cases (not mentioning prohibitive risk patients, acute patients and those who reject surgery), given that, although the rates of death and composite endpoint (death, myocardial infarction or stroke) between both strategies were not statistically different, the need of new procedures and MACCE rates were clearly lower in patients treated with CABG surgery. However, careful analysis of the data shows that no definite conclusion can be drawn from the evidence available due to the heterogeneity of studies with respect to some outcomes, heterogeneity of strategies (different drugeluting stents, different ways to perform surgery, etc) and heterogeneity of coronary lesions complexity. Rigorous studies are necessary to define the best way to treat each subset of ULMCA disease. Based on our findings, we conclude that there is not clear evidence that left main PCI presents non-inferiority to CABG surgery and revision of the guidelines regarding left main PCI must be viewed with caution, and we still do not have enough evidences that make the level of evidence of current recommendations raises from B to A”.

Perspectives Ongoing and planned trials (Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease - PRECOMBAT 1 and 2; Evaluation of Xience Prime versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization - EXCEL) will further facilitate evidence-based clinical decisions for ULMCA disease. Furthermore, the 5-year SYNTAX results (not published yet) will provide us a valuable extension of the 3-year information and possibly elucidate whether PCI should be further performed even in high-risk, very complex coronary disease by experienced teams in large volume centers. Others important registries (as CUSTOMIZE registry [11]) did not report their 5-year results yet. We hope that with the publication of all these studies, we will have more evidence about the long-term results, which will enable new meta-analyses with larger samples and other meta-regression analyses, in search of other factors that modulate the results. CONCLUSIONS We found evidence that argues against the “noninferiority” of PCI with DES in comparison to CABG

REFERENCES 1. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association Association for Cardio-Thoracic Surgery (EACTS), Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010;31(20):2501-55. 2. Capodanno D, Stone GW, Morice MC, Bass TA, Tamburino C. Percutaneous coronary intervention versus coronary artery bypass graft surgery in left main coronary artery disease: a meta-analysis of randomized clinical data. J Am Coll Cardiol. 2011;58(14):1426-32. 3. Park SJ, Kim YH, Park DW, Yun SC, Ahn JM, Song HG, et al. Randomized trial of stents versus bypass surgery for left main coronary artery disease. N Engl J Med. 2011;364(18):1718-27. 4. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961-72. 5. Sá MP, Soares AM, Lustosa PC, Martins WN, Browne F, Ferraz PE, et al. Meta-analysis of 5674 patients treated with percutaneous coronary intervention and drug-eluting stents for coronary artery bypass graft surgery for unprotected

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left main coronary artery stenosis. Eur J Cardiothorac Surg. 2013;43(1):73-80.

15. Park DW, Seung KB, Kim YH, Lee JY, Kim WJ, Kang SJ, et al. Long-term safety and efficacy of stenting versus coronary artery bypass grafting for unprotected left main coronary artery disease: 5-year results from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry. J Am Coll Cardiol. 2010;56(2):117-24.

6. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-9. 7. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60. 8. DerSimonian R, Kacker R. Random-effects model for metaanalysis of clinical trials: an update. Contemp Clin Trials. 2007;28(2):105-14. 9. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997;127(9):820-6. 10. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088-101. 11. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-34. 12. Chang K, Koh YS, Jeong SH, Lee JM, Her SH, Park HJ, et al. Long-term outcomes of percutaneous coronary intervention versus coronary artery bypass grafting for unprotected left main coronary bifurcation disease in the drug-eluting stent era. Heart. 2012;98(10):799-805. 13. Terazawa S, Tajima K, Takami Y, Tanaka K, Okada N, Usui A, et al. Early and late outcomes of coronary artery bypass surgery versus percutaneous coronary intervention with drug-eluting stents for dialysis patients. J Card Surg. 2012;27(3):281-7. 14. Boudriot E, Thiele H, Walther T, Liebetrau C, Boeckstegers P, Pohl T, et al. Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis. J Am Coll Cardiol. 2011;57(5):538-45.

16. Chieffo A, Magni V, Latib A, Maisano F, Ielasi A, Montorfano M, et al. 5-year outcomes following percutaneous coronary intervention with drug-eluting stent implantation versus coronary artery bypass graft for unprotected left main coronary artery lesions the Milan experience. JACC Cardiovasc Interv. 2010;3(6):595-601. 17. Flaherty JD, Davidson CJ. Diabetes and coronary revascularization. JAMA. 2005;293(12):1501-8. 18. Banning AP, Westaby S, Morice MC, Kappetein AP, Mohr FW, Berti S, et al. Diabetic and nondiabetic patients with left main and/or 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-eluting stents. J Am Coll Cardiol. 2010;55(11):1067-75. 19. Borges JC, Lopes N, Soares PR, G贸is AF, Stolf NA, Oliveira SA, et al. Five-year follow-up of angiographic disease progression after medicine, angioplasty, or surgery. J Cardiothorac Surg. 2010;5:91. 20. Smith PK, Califf RM, Tuttle RH, Shaw LK, Lee KL, Delong ER, et al. Selection of surgical or percutaneous coronary intervention provides differential longevity benefit. Ann Thorac Surg. 2006;82(4):1420-8. 21. Caggegi A, Capodanno D, Capranzano P, Chisari A, Ministeri M, Mangiameli A, et al. Comparison of one-year outcomes of percutaneous coronary intervention versus coronary artery bypass grafting in patients with unprotected left main coronary artery disease and acute coronary syndromes (from the CUSTOMIZE Registry). Am J Cardiol. 2011;108(3):355-9.

Oliveira IM, et al. - Criss-cross heart: Report of two cases, anatomic and REVIEW ARTICLE surgical description and literature review

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Criss-cross heart: report of two cases, anatomic and surgical description and literature review Coração entrecruzado (Criss-cross heart): relato de dois casos, descrição anatomocirúrgica e revisão de literatura

Ítalo Martins de Oliveira1, Vera Demarchi Aiello2, Marcela Maria Aguiar Mindêllo3, Yasmin de Oliveira Martins4, Valdester Cavalcante Pinto Jr5

DOI: 10.5935/1678-9741.20130014

RBCCV 44205-1447

Resumo Coração entrecruzado (criss-cross heart) é uma anomalia extremamente rara, caracterizada por rotação anormal da massa ventricular ao longo do seu eixo maior e pode estar associada com qualquer malformação dos segmentos e das conexões entre as câmaras cardíacas. Devido às alterações estruturais complexas e à raridade da anomalia, essa anomalia de rotação é muitas vezes mal diagnosticada. Neste trabalho são relatados dois casos de coração entrecruzado com ênfase no diagnóstico morfológico e nas técnicas cirúrgicas utilizadas. Foi também realizada revisão da literatura sobre o assunto, que, embora escassa, foi enfatizada quanto à morfologia, diagnóstico, abordagem cirúrgica e possíveis complicações.

Abstract Criss-cross heart is an extremely rare anomaly, characterized by an abnormal rotation of the ventricular mass along its major axis. It may be associated with any malformation of the heart segments and connections. Due to the complex structural changes and rarity of the anomaly, the rotation of ventricular axis is often misdiagnosed. In this paper, two cases of criss-cross heart are reported, with emphasis on diagnostic and surgical techniques used to corrected the main defects. A literature review on the subject is also presented which, although sparse, emphasized on the morphologic, diagnostic and surgical aspects of the anomaly.

Descritores: Anormalidades congênitas. Procedimentos cirúrgicos cardíacos. Coração entrecruzado.

Descriptors: Congenital abnormalities. Cardiac surgical procedures. Crisscross heart.

1. PhD in Cardiology at Faculty of Medicine in the University of São Paulo, Research Coordinator at Hospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, Ceará 2. Pathologist-in-chief, Surgical Pathology Section, Laboratory of Pathology at the Heart Institute of Sao Paulo University School of Medicine 3. Physician, graduated at State University of Ceará 4. Medicine Student at Fortaleza University. 5. Master's Degree in Public Politics Assessment at Federal University of Ceará, Head of the Pediatric Cardiac Surgery Service at Hospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza, Ceará.

This study was carried out at: Hospital de Messejana Dr. Carlos Alberto Studart Gomes. Fortleza, CE, Brazil. Correspondence address: Ítalo Martins de Oliveira Av. Frei Cirilo, 3480 – Messejana Fortaleza, CE, Brazil. Zip code: 60846-190 E-mail: italomartins@cardiol.br Article received on May 9th, 2012 Article accepted on December 26th, 2012

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Oliveira IM, et al. - Criss-cross heart: Report of two cases, anatomic and surgical description and literature review

Abbreviations, acronyms & symbols Ao DORV EF HF ICU LV LVOT MeSH MRI PA PDA PVS RV RVOT VSD

aorta double outlet right ventricle ejection fraction heart failure intensive care unit left ventricle left ventricular outflow tract Health Sciences Descriptors magnetic resonance image pulmonary artery patent ductus arteriosus pulmonary valve stenosis right ventricle right ventricular outflow tract ventricular septal defect

most of the mass placed on the left, with transposition of the great vessels. In the other case the right atrium was connected to the morphologically left ventricle, with discordant atrioventricular connection as will be described below. This study was approved by the Research Ethics Committee of the institution, case number 473/07 on 25/09/2007.

INTRODUCTION Congenital heart defects are present in about 8 cases per 1000 newborns at term. This index increases if premature and stillbirths were considered. Criss-cross heart anomaly is extremely rare, accounting for less than 0.1% of all congenital heart defects, not exceeding 8 per 1,000,000 births [1]. The morphological essence of the criss-cross heart is a rotation of the ventricular mass along its major axis [1]. This conformational change may be associated with any malformation described in cardiac segments, resulting in different relationships and connections between the atria, ventricles and great vessels (Figure 1)[2]. Although translated by Health Sciences Descriptors (MeSH) as “criss-cross heart”, there is no fully accepted and standardized translation to Portuguese for this word from the English language, which is why we use it in its original form throughout this study[3]. In French, some authors refer to this anomaly as “coeur croisé” or as “coeur avec ventricules entrecroisés” [4]. Due to the complex structural changes and the rarity of the disease, this anomaly of rotation is often misdiagnosed due to lack of awareness of the medical team, bringing potential harm to appropriate surgical approach [5]. Depending on the associated anomalies, surgical treatment includes from palliative correction to definitive anatomic correction. In this study, we performed a literature review, based on the report of two cases of criss-cross heart where the pulmonary and systemic circulations intersect at the atrioventricular level. Both present situs solitus or usual arrangement of the organs. In one of them the right atrium was morphologically connected to the right ventricle with 94

Fig. 1 - A: Schematic view of the right ventricular chambers with criss-cross, with double outlet right ventricle (VD). The VD is located anterosuperior and to the left to the left. B: Right atrium (AD) connected to the VD through the tricuspid valve. C: Left atrium (AE) connection with the Left ventricle (VE). In D it is represented the VD inlet, crossing anteriorly the VE inlet. Ao = aorta, AP = pulmonary artery. Reproduced with permission of Cavellucci et al. Braz J Echocardiogr Cardiovasc Imag. 2012;25(4):292-7.

CASE REPORT Case 1 Clinical data A 12-day-old male newborn presented with progressive dyspnea and acrocyanosis from the first day of life. On examination, he presented severe dyspnea with retraction of sternal notch, subcostal and intercostal indrawing and

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nasal flaring, diaphoresis, cyanosis ++/4+, afebrile, with a heart rate of 140 beats per minute, respiratory rate of 120 breaths per minute. Cardiac auscultation showed systolic murmur ++/6+ at the left sternal edge and accentuated P2 heart sound. His abdomen presented palpable liver two inches below the right costal margin. Peripheral pulses were present and symmetric and the saturation was 85.5% in oxihood (oxygen hood or helmet). Clinical evaluation started from birth at neonatal Intensive Care Unit (ICU).

in the new aorta, associated with correction of septal defects. In the immediate postoperative period, the patient developed systemic inflammatory response syndrome, reversed by standard therapy. During postoperative period he also presented the following complications: respiratory infection associated with prolonged mechanical ventilation and atelectasis of the left upper lobe. He was discharged on the thirty-sixth day postoperatively using furosemide and amiodarone. Discharge echocardiogram showed the criss-cross heart and post-Jatene's correction condition. There was no evidence of dysfunction of the neopulmonary or the neoaorta. It was also observed a foramen ovale with leftright shunt, small perimembranous VSD and preserved contractile function in both ventricles. After six months of correction, another evaluation showed that the patient presented pulmonary branches supravalvular stenosis, confirmed by cardiac catheterization. At the age of one year and ten months, the patient underwent atrioventriculosseptoplastia and expansion of the right ventricular outflow tract using valved tube. Clinical follow-up was performed every six months and the patient remained asymptomatic, without drugs. New hemodynamic study performed at five years of age, indicated supravalvular stenosis in neopulmonary artery with RV- pulmonary artery (PA) gradient of 38 mmHg.

Tests The transthoracic echocardiography showed situs solitus. There were concordant atrioventricular connections and most of the morphologically left ventricle mass stood on the right. There was transposition of great arteries with a left-sided and anterior aorta originating from the morphologically right ventricle. The posterior pulmonary trunk was located at right and posteriorly to the aortic root. There was a significant gradient in the right ventricular outflow tract (RVOT), and at the left ventricular outflow tract (LVOT) we observed the presence of mild posterior deviation of the infundibular portion of the interventricular septum without evidence of LVOT obstruction (subpulmonary). There was no significant atrioventricular valve regurgitation. Presence of muscular ventricular septal defect (VSD) of 3.6 mm with right ventricle (RV) flow to left ventricle (LV) (aortopulmonary), and large atrial septal defect (ASD) of ostium secundum type, measuring about 7mm with flow from left to right (L-R) and arterial channel of 4.5 mm with L-R continuous flow. Biventricular systolic function was qualitatively normal. Diagnosis This is a case of criss-cross heart with concordant atrioventricular connections, ventriculo-arterial discordance, large ASD, VSD and patent ductus arteriosus (PDA) with continuous flow predominantly L-R. Approach The presence of associated malformations and the patient's clinical outcome characterize the severity of the condition. Jatene's surgical technique was indicated due to the patientâ&#x20AC;&#x2122;s age at the time of diagnosis. Surgical procedure The proposed surgery was performed in March 2007. We performed the switch operation, sectioning just above the arterial valves, and thecoronary arteries were reimplanted

Case 2 Clinical data A seven year-and-11-month-old female child, 19kg, with a history of progressive exertional dyspnea and cyanosis of the extremities since the age of three. On physical examination, the patient was afebrile and mildly cyanotic, with systolic murmur ++/6+ in the lower left sternal border and presence of digital clubbing. Tests A transthoracic echocardiogram showed discordant atrioventricular connections, double outlet right ventricle (DORV), large VSD, criss-cross heart, and pulmonary valve stenosis (PVS) with a peak gradient of 96 mmHg. Hemodynamic study was performed which showed double outlet right ventricle with mild infundibular stenosis, discordant atrioventricular connections, perimembranous VSD, and well developed pulmonary branches and right ventricle decreased in size. Oximetry showed blood oxygen saturation in LV of 87%, aorta (Ao) 91% and right ventricle of 100%, 10mmHg RA pressure, LV 107x15mmHg and AO 107x65x81mmHg. 95

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Diagnosis Criss-cross heart with discordant atrioventricular connections, DORV, large VSD and VPS. The presence of associated malformations characterized the severity of the cardiac defect. A Fontan procedure was indicated, obeying the following criteria: age above 2 years, absence of pulmonary stenosis, mean pulmonary artery pressure less than 15 mmHg, pulmonary vascular resistance below 4 Wood units, preserved left atrioventricular valve and ventricular function. The biventricular repair was contraindicated due to the small size of the right ventricle.

Clinical follow-up was performed every six months for 11 years. At the last visit, the patient was asymptomatic, with normal psychomotor development, without changes in physical examination and under no drug therapy. The last echocardiogram showed mild mitral regurgitation, hypertrophy and mild RV dilatation, cavo-pulmonary connections with diameters and normal flows, with an EF of 69%. â&#x20AC;&#x192; DISCUSSION

Surgical procedure The surgical procedure was performed starting the right atriotomy approximately 1 cm above the insertion of the superior vena cava extending to the inferior cava. Thus, it was possible to make the tunnel, suturing the patch to the interatrial septum leaving the coronary sinus to the left and performing tunnel fenestration. After the completion of the tunnel, suture of the anterior patch over this was performed (Figure 2). Postoperatively, the patient presented as complications: heart failure (HF) and right pleural effusion, resolved using increased diuretic use. Later, she remained unchanged, with no other complications. He was discharged by making use of digoxin, furosemide, captopril and spironolactone. A transthoracic echocardiogram 3 months after surgery showed left ventricle with good contractility and venous connections (cavopulmonary) with fair functioning, ejection fraction (EF) of 71%, LV diastolic diameter of 21mm and 13mm systolic.

Fig. 2 - A: Suture of an anterior atrial patch on the IC-SC tunnel. (Adapted from Pinto Jr et al. [78]. B: Confection of the inferior tunnel cava â&#x20AC;&#x201C; superior cava

Description and anatomy The criss-cross heart is an extremely rare malformation but well described morphologically. In descriptive report of a collection of 81 hearts with congenital malformations collected over two decades and published in 1999, only one specimen with criss-cross was found, representing only 1.2% of cases [6]. This congenital defect was first described by Lev & Rowlatt [7] in 1961, but it was only in 1974 that Anderson et al. [4] first used the term criss-cross heart. From this publication, about 300 cases of the anomaly have been reported in articles cited in Pubmed to date (2012) [8-43]. The diagnosis of criss-cross heart is based on the intersection of the axes of the ventricular entries. In a normal heart these axes are virtually parallel. This condition is characterized by a spatial change of the ventricular mass that guides or appears to guide, each ventricle in a contralateral position in relation to the corresponding atrium. While the base of the heart remains unchanged in its spatial position, the ventricles appear to have been twisted along their longitudinal axis. This promotes a change in hemodynamics characterized by crossing flows through the atrioventricular valves, resulting in the false impression that each atrium is being directed to the contralateral ventricle [1]. (Figure 1) The criss-cross heart may present with concordant or discordant atrioventricular connections (Figure 3). These connections were demonstrated in 1961 by Lev & Rowlatt [7] through the study of the anatomy of two hearts presenting atria in solitus position communicating with morphologically discordant ventricles in normal position.- a morphologically right atrium draining to the morphologically left ventricle situated to the left. Another case of criss-cross heart was described by Van Praagh in 1962 [43], in which the morphologically right atrium connected to the morphologically right ventricle on the left side, in a case example with concordant atrioventricular connections.

Oliveira IM, et al. - Criss-cross heart: Report of two cases, anatomic and surgical description and literature review

Fig. 3 - Examples of the types of atrioventricular connections in criss-cross hearts: discordant (A) and concordant (B)

There are cases of criss-cross heart described in the literature with discordant atrioventricular connections associated with transposition of the great vessels which results in a corrected physiological circulation, since the presence of â&#x20AC;&#x153;double mismatchâ&#x20AC;? results in the direction of venous blood to the lungs and arterial blood into the systemic circulation. Patients with this type of anomaly, which represents 0.05% of congenital heart diseases [44] may be symptomatic not because of the criss-cross heart, but by the presence of other associated anomalies such as VSD, pulmonary outflow obstruction, tricuspid valve abnormalities [45]. Often the criss-cross heart is associated with other cardiac malformations. A review of the literature revealed no cases of of this anomaly occurring in isolation. Most patients have ventricular septal defects, transposition of the great arteries, double-outlet right ventricle, hypoplastic right ventricle, pulmonary stenosis and tricuspid hypoplasia, the latter present in most patients. Other associated defects, although less frequent, are straddling mitral or tricuspid valve, subaortic stenosis, aortic arch obstruction and mitral stenosis [1,45-47]. Anomalies of the coronary circulation may be present and usually related to the ventricular position, and in these cases, magnetic resonance image (MRI) and angiography are useful tools in the diagnosis and approach [47]. In literature there are some studies linking the Cx43 gene mutation to pathogenesis of the criss-cross heart. Deletion of gene would result in a delay in establishing heart dextroposition, which makes the right ventricle to maintain a craniomedial position, resulting in a 90Â° rotation of the atrioventricular mass [48]. The Cx43 gene is responsible for the production of a type of the protein connexin. These proteins are

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known to compose gap junctions, and the decrease in their expression has been associated with various genetic alterations, with increased cell proliferation and carcinogenesis [49]. Reaume et al. [50] in 1995 reported that animals with deletions in both alleles of Cx43 died shortly after birth, with no major phenotypic differences compared to controls, except for cyanotic appearance. Necropsy revealed cardiac defects, thereby revealing vital importance of this protein in cardiac development during embrionary development. Ya et al. [48] in 1998 reported that, on the 9th day of development, animals with deletion of Cx43 showed delayed development of the ascending looping of the heart tube, causing malformation of the tricuspid valve patch and changes in conformation and cardiac death of animals shortly after birth with cyanotic appearance. Clinical, supplementary and differential diagnosis Due to the complex structural changes, this anomaly is often not recognized. The diagnosis becomes more difficult due to the similarity of the clinical presentation of the different connections abnormalities [51,52]. The anatomic and physiologic diagnosis of this anomaly can be established by echocardiography, along with other diagnostic methods, such as MRI and cardiac catheterization if necessary [53]. The transthoracic echocardiography can be used to identify the position and morphology of all cardiac chambers, AV valves, in addition to the connections between chambers and vessels. The subcostal window will determine the location of the heart apex and assess mainly the ventricles characteristics. The trabeculae morphological features, will determine the morphologic ventricle characteristics [51]. The great arteries connections are better visualized in the paraesternal window [54,55]. MRI, when showing the heart in the axial, coronal and sagital planes makes such additional examination an important tool for diagnosis of complex congenital heart diseases [56]. MRI, when compared to other imaging tests, has the advantage of providing a wide field of vision and the ability to reconstruct the image in 3 dimensions [57]. The images acquired with the MRI show in detail all the heart components and simultaneously clarifies the changes in the AV connections by being able to diagnose abnormalities of heart rotation [58]. The indications for cardiac catheterization are currently limited, since the images obtained with echocardiography and magnetic resonance imaging better delimit the anatomy, 97

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ventricular function and atrioventricular relationships [51]. Cardiac catheterization may be necessary only to obtain pressure and oximetry data and discard additional septal ventricular defects [53]. Some indications for the invasive study were assessment of pulmonary vascular resistance, angiographic analysis of coronary arteries, presence of pulmonary valve atresia or pulmonary anomalous veins [53]. The differential diagnosis of criss-cross heart should include straddling atrioventricular valve, double atrial outlet where an outlet orifice apparently crosses the other valve, and severe forms of Ebstein anomaly on which the tricuspid valve opens to the infundibulum, giving the appearance of crossing the valves [54].

defect, the presence of flow through the ductus arteriosus and the LV outflow tract obstructions can be assessed, in addition to the determination of the ventricles mass [63]. For cases of dTGA and IAC, according to most authors, the primary anatomic correction should be performed until the 15th day of life, and this period may be extended with relative safety until the end of the 1st month [64]. The approach after the neonatal period is controversial and published experiences generally have a small number of patients. Lacourt-Gayet et al. [65] and Lyer et al. [66] advocate for clinical and echocardiographic selection correction in 1 or 2 stages in these cases. Davis et al. [67] and Ducan et al. [68] indicate primary anatomic correction in all patients until the 2nd month of life, based on an aggressive vasodilator therapy and occasional use of ventricular assistance postoperatively. Yacoub et al. [69] in 1980 reported 20 cases who had undergone late staging, with an immediate mortality of three patients, and 14 of them directed to the 2nd stage, when there were four deaths (29%). The main advantage of the ventricular preparation would be related to better LV conditioning, which could provide better long term outcomes. Moreover, the long interval between stages can be a source of problems related to the presence of pulmonary artery banding, such as distortions of the trunk and branches of the pulmonary artery and an increased incidence of late aortic insufficiency and fibroelastosis [63]. The difficulty of proper control after discharge of some patients also contributes to early correction with rapid preparation. Most children who underwent Jatene's operation have normal physical, psychomotor and cardiovascular development. However, some problems can be found in late development. Among these, pulmonary or RVOT stenoses are the most common and can be directly related to surgical technique and patient's age at the time of correction. The incidence of RVOT obstruction varies from 7%-40% [70], and is the main cause of reoperation after discharge [70,71]. The obstructive process may occur in the infundibular or annular region (proximal obstructions) or supravalvular region (distal obstructions). In the first case described here, the patient developed supra-valvular stenosis in neopulmonary and in pulmonary branches after six months postoperatively, being treated with implantation of a valved tube. In the second case, due to right ventricular hypoplasia the choice was for the Fontan procedure which, over the past 40 years, goes through technical enhancements to the optimization of hemodynamic status. Studies show lack of atrial contractility, over time, since it tends to dilation,

Surgical treatment The natural history of patients is unfavorable without surgical treatment, 64% of deaths occurring in childhood, with 50% still in the neonatal period [58,59]. The surgical management of patients with criss-cross heart consists of the repair of major and limiting malformation, not being ventricular rotation itself the reason for the correction. The initial management is determined by the presence or absence of pulmonary stenosis, and its severity. On those where the pulmonary flow is inadequate, early intervention with prostaglandin E1 is indicated for maintaining the patency of the ductus arteriosus. When anatomic correction fails, balance in pulmonary flow can be achieved with the construction of systemic-pulmonary shunt. The corrective surgery is determined by the potential use of both ventricles. Only some patients are candidates for biventricular repair, due to hypoplasia of the tricuspid valve and right ventricle, atrioventricular valve straddling [60-62]. In these cases the Fontan correction is indicated as a palliative repair option. The case studies reflect the size of the treatment of structural abnormalities associated with the criss-cross heart. In the first, the association with transposition of the great arteries, VSD, ASD and PDA, was defined as a surgical option the Jatene's operation. The surgery is usually performed in the neonatal period and may be performed in patients with VSD and maintains left ventricular mass characteristics compatible to support the systemic resistance. Several factors may contribute to the loss of left ventricular mass, and the reduction of pulmonary arteriolar resistance, the most important. Echocardiographic selection is the primary method for defining the surgical treatment. With this assessment, the size of the atrial septal 98

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turning the flow turbulent with consequent arrhythmia and thrombosis [72]. The use of prosthetic material as part of the tunnel excludes pulsatile mobility of the conduit. Several authors [73,74] have shown that TCP anastomosis, because it excludes the right atrium and makes the inferior cava flow occurs through a tunnel, avoids turbulence, thus reducing the risk of thrombosis and arrhythmias. The use of bovine pericardium for the atrial level tunneling is worrisome because retractions with minimal obstructions can cause significant hemodynamic effects. Rossi et al. [75] in 1986 and Arbustini et al. [76] in 1983 showed calcification in this type of graft, with a clear relation with time. In 1997, Pires et al. [77] demonstrated that bovine pericardial tissue implanted in the atrium calcifies, retracts and promotes thrombus formation. The variation proposed by Van De Wal et al, without the use of prosthetic material, using the retail from the own right atrial wall by confection of the tunnel [72], aimed to improve the outcome in the short term, because it keeps the tunnel contraction, allowing improved systemic venous drainage. On the other hand, in the long-term, as a prosthetic material was not used, a proper growth of this conduit was obtained, without calcification, resulting in lower risk of retraction, embolization and anti-coagulation problems [59]. CONCLUSION

caso e revisão de literatura. Rev Bras Ecocardiogr Imagem Cardiovasc. 2012;25(4):292-7.

The study of these two cases and the extensive literature review on the subject show that the rotation anomalies of the ventricular mass are associated with changes in general connections between the cameras and large arteries and that the surgical approach depends on the morphology of the main defect. The presence of crossed ventricles in the reported cases had no impact alone on the surgical intervention.

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58. Fantini FA, Gontijo B, Martins C, et al. Operação de Fontan: uma técnica em evolução. Rev Bras Cir Cardiovasc 2009;24(4):463-9. 59. Carotti A, Iorio FS, Amodeo A, Giamberti A, Marianeschi S, Nava S, et al. Total cavopul-monary direct anastomosis: a logical approach in selected patients. Ann Thorac Surg. 1993;56(4):963-4. 60 Sato K, Ohara S, Tsukaguchi Yyasui K, Nakata T, Tamai M, et al. A criss-cross heart with concordant atrioventriculo-arterial connection. Report of case. Circulation. 1978;57(2):396-400. 61. Danielson GK, Tabry IF, Ritter DG, Fulton RE. Surgical repair of criss-cross heart with straddling atrioventricular valve. J Thorac Cardiovasc Surg. 1979;77(6):847-51. 62. Kashiwagi J, Imai Y, Aoki M, Shin’oka T, Hagino I, Nakazawa M. An arterial switch oper-ation for a concordant crisscross heart with the complete transposition of the great arteries. J Thorac Cardiovasc Surg. 2002;124(1):176-8. 63. Gontijo Filho B, Fantini FA, Martins C, Lopes RM, Pereira RST, Rabelo SM, et al. Estra-tégia cirúrgica na transposição das grandes artérias com septo interventricular intacto após pe-ríodo neonatal. Arq Bras Cardiol. 2005;85(1):39-44. 64. Plaché C, Bruniaux J, Lacour-Gayet F, Kachaner J, Binet JP, Sidi D, et al. Switch operation for transposition of the great arteries in neonates. A study of 120 patients. J Thorac Cardiovasc Surg. 1988;96(3):354-63. 65. Lacourt-Gayet F, Piot D, Zoghbi, Serraf A, Gruber P, Macé L, et al. Surgical management and indication of left ventricular retraining in arterial switch for transposition of the great arteries with intact ventricular septum. Eur J Cardiothoracic Surg. 2001;20(4):824-9. 66. Iyer KS, Sharma R, Kumar K, Bhan A, Kothari SS, Saxena A, et al. Serial echocardiog-raphy for decision making in rapid two-stage arterial switch operation. Ann Thorac Surg. 1995;60(3):658-64. 67. Davis AM, Wilkinson JL, Karl TR, Mee RB. Transposition of the great arteries with intact ventricular septum. Arterial switch repair in patients 21 days of age or older. J Thoracic Cardi-ovasc Surg. 1993;106(1):111-5. 68. Ducan BW, Poirier NC, Mee RB, Drummond-Webb JJ, Qureshi A, Mesia CI, et al. Selec-tive timing for the arterial switch operation. Ann Thorac Surg. 2004;77(5):1691-6. 69. Yacoub MH, Radley-Smith R, Maclaurin R. Two-stage operation for anatomical correction of transposition of the great arteries with intact interventricular septum. Lancet. 1977;1(8025):1275-8.

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Lucchese FA & Koenig HG - Religion, spirituality and cardiovascular SPECIAL ARTICLE disease: research, clinical implications, and opportunities in Brazil

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Fernando A. Lucchese1, Harold G. Koenig2

DOI: 10.5935/1678-9741.20130015

RBCCV 44205-1448

Abstract In this paper we comprehensively review published quantitative research on the relationship between religion, spirituality (R/S), and cardiovascular (CV) disease, discuss mechanisms that help explain the associations reported, examine the clinical implications of those findings, and explore future research needed in Brazil on this topic. First, we define the terms religion, spirituality, and secular humanism. Next, we review research examining the relationships between R/S and CV risk factors (smoking, alcohol/drug use, physical inactivity, poor diet, cholesterol, obesity, diabetes, blood pressure, and psychosocial stress). We then review research on R/S, cardiovascular functions (CV reactivity, heart rate variability, etc.), and inflammatory markers (IL-6, IFN-γ, CRP, fibrinogen, IL-4, IL-10). Next we examine research on R/S and coronary artery disease, hypertension, stroke, dementia, cardiac surgery outcomes, and mortality (CV mortality in particular). We then discuss mechanisms that help explain these relationships (focusing on psychological,

social, and behavioral pathways) and present a theoretical causal model based on a Western religious perspective. Next we discuss the clinical applications of the research, and make practical suggestions on how cardiologists and cardiac surgeons can sensitively and sensibly address spiritual issues in clinical practice. Finally, we explore opportunities for future research. No research on R/S and cardiovascular disease has yet been published from Brazil, despite the tremendous interest and involvement of the population in R/S, making this an area of almost unlimited possibilities for researchers in Brazil.

1. M.D., F.A.C.C. Director, Hospital São Francisco (Cardiology and Transplants), Professor and Chairman, Cardiovascular Medicine and Surgery; Faculdade Federal de Ciências Medicas, Porto Alegre, RS, Brazil. 2. M.D. Professor of Psychiatry & Behavioral Sciences; Associate Professor of Medicine, Director, Center for Spirituality, Theology and Health Duke University Medical Center, Durham, North Carolina, USA; Distinguished Adjunct Professor - King Abdulaziz University, Jeddah, Saudi Arabia.

Correspondence address: Harold G. Koenig Box 3400 – Duke University Medical Center – Durham, North Carolina, USA – 27710 E-mail: harold.koenig@duke.edu (also, see website: http://www. spiritualityandhealth.duke.edu)

Descriptors: Religion. Spirituality. Cardiovascular diseases. Cardiac surgical procedures. Research. Mortality. Descritores: Religião. Espiritualidade. Doenças cardiovasculares. Procedimentos cirúrgicos cardíacos. Pesquisa. Mortalidade.

Article received on December 5th, 2012 Article accepted on February 12th, 2013

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Abbreviations, acronyms & symbols ABI BAR BP CABG CAC CAD CC-IMT CD CHF CRP CVD HRV LOS LVM MI MM PTSD R/S SES TIA

Ankle brachial index Arterial baroreflex sensitivity Blood pressure Coronary artery bypass graft Coronary artery calcium Coronary artery disease Common carotid intima-media thickness Cerebrovascular disease Congestive heart failure C-reactive protein Cardiovascular disease Heart rate variability Length of stay Left ventricular mass Myocardial infarction Mindfulness meditation Post-traumatic stress disorder Religion and spirituality Socioeconomic status Transient ischemic attack

INTRODUCTION A growing research database documents a link between religion, spirituality and cardiovascular disease (CVD). Given that Brazil is a highly religious country (87% of the population says that religion is important [1]), cardiologists and cardiac surgeons need to know about this research and the clinical applications that might follow. In this paper, we explore (1) definitions of the terms religion and spirituality (R/S) for conducting research and carrying out applications at the bedside; (2) relationships between R/S and CVD risk factors; (3) R/S, cardiovascular functions, and inflammatory markers (cardiovascular reactivity, C-reactive protein, fibrinogen, etc.); (4) R/S and coronary artery disease; (5) R/S and hypertension; (6) R/S and cerebrovascular disease; (7) R/S and cardiac surgery outcomes; (8) R/S and cardiovascular mortality; (9) mechanisms by which R/S might influence cardiovascular outcomes; (10) some clinical implications of this research; and (11) future research in this area that Brazilian researchers are ideally positioned to take the lead on. 1. DEFINITIONS The area of definitions is one of the most controversial areas in R/S and health research. Terms that need defining are religion, spirituality, secular humanism, and religious coping. Many researchers and clinicians have erred by combining all of these terms under "spirituality." We 104

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will argue that the choice of which term to use may be quite different when conducting research (understanding relationships between R/S and CVD and how R/S impact CVD outcomes) compared to when discussing these issues at the bedside in clinical settings. We define religion as "…beliefs, practices, and rituals related to the transcendent, where the transcendent is God, Allah, HaShem, or a Higher Power in Western religious traditions, or Brahman, manifestations of Brahman, Buddha, Dao, or ultimate truth/reality in Eastern traditions. This often involves the mystical or supernatural. Religions usually have specific beliefs about life after death and rules about conduct within a social group. Religion is a multi-dimensional construct that includes beliefs, behaviors, rituals, and ceremonies that may be held or practiced in private or public settings, but are in some way derived from established traditions that developed over time within a community. Religion is also an organized system of beliefs, practices, and symbols designed (a) to facilitate closeness to the transcendent, and (b) to foster an understanding of one's relationship and responsibility to others when living together in a community [2]”. In contrast to religion is secular humanism, which we define as follows: "The secular or secular humanist has no belief in, connection with, or desire to connect to the transcendent, the sacred, God, or the supernatural. The secular involves beliefs, behaviors, and social relationships that have value and importance on their own intrinsic merit that is not connected with anything outside of the human experience or nature. The attitude is, 'this is all we have so let’s make the best of it together.' That which is real can be observed and verified, and anything that cannot be observed and verified does not exist and does not matter. The world is viewed in a rational, logical, scientific manner. Human relationships, moral values, and ethical standards are very important, and forgiveness, altruism, and gratefulness are often emphasized and practiced, all without any transcendent reference. Atheists, agnostics, and secular humanists would fall into this category. If there is any seeking or searching, then it is for purely secular objects or goals. Most would not refer to themselves as religious, and probably not as spiritual either [3]”. Finally, there is the term spirituality. This is the term over which there is the most disagreement and lack of consensus. Spirituality is a popular expression today preferred over religion. Spirituality is considered personal, something individuals define for themselves. It is often free of rules, regulations, and responsibilities associated with religion. One can be spiritual, but not religious. In fact, a “secular spirituality” is often emphasized today in circles where religion is in disfavor. Thus, spirituality is seen as non-divisive and common to all, both religious and secular. This is an excellent term to use when discussing these

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issues with patients (who can define for themselves what the term means). However, trying to measure spirituality has created a real problem for quantitative researchers, who must work with terms that are clear, agreed upon, distinct and non-overlapping. The goals of quantitative research are to measure and quantify a construct and then relate that construct to similarly quantified health outcomes. The ultimate aim is to compare those with the construct (or who have more of the construct) to those without the construct (or who have less of the construct), and if there is a relationship, then develop an intervention that takes advantage of that connection to improve health outcomes. This is not possible with a construct like spirituality, especially when defined in such a nebulous, diffuse manner. The definition of spirituality that we use in this paper is similar to religion, since religion is a distinct construct that can be measured and quantified and examined in relationship to health outcomes. We define spirituality, then, by saying that it "…is distinguished from all other things – humanism, values, morals, and mental health – by its connection to that which is sacred, the transcendent. The transcendent is that which is outside of the self, and yet also within the self – and in Western traditions is called God, Allah, HaShem, or a Higher Power, and in Eastern traditions may be called Brahman, manifestations of Brahman, Buddha, Dao, or ultimate truth/reality. Spirituality is intimately connected to the supernatural, the mystical, and to organized religion, although also extends beyond organized religion (and begins before it). Spirituality includes both a search for the transcendent and the discovery of the transcendent, and so involves traveling along the path that leads from non-consideration to questioning to either staunch non-belief or belief, and if belief, then ultimately to devotion and finally, surrender.” [4]. As can been seen, our definition of spirituality is very similar to our definition of religion. In the studies we will cite in this article, spirituality has been assessed either using (1) measures of religious belief and practice, (2) measures of positive psychological states (i.e., meaning and purpose, deep inner peace, harmony, well-being, social connections), or (3) measures of positive character traits (i.e., being forgiving or altruistic, having high moral standards). Unfortunately, assessing spirituality using positive psychological states or positive character traits creates a situation where the predictor (spirituality) is contaminated by the outcome (mental health), which results in tautological relationships between spirituality and mental health outcomes (and probably physical health outcomes as well, given the mind-body relationship). The result of such research is meaningless, un-interpretable findings. Thus, only when spirituality is measured using measures of religious involvement (a construct that is

distinctive and non-overlapping with mental health) does it provide meaningful results. For a thorough discussion of the issue of measurement overlap and contamination, which is beyond the scope of the present article, see the following cited resources [5-8]. In reviewing the research below, then, we use spirituality and religion synonymously (i.e., R/S). Furthermore, we have distinguished studies that assess spirituality using contaminated measures by assigning quality scores to each of the studies. In the original review of this research, we usually assigned quality scores of 7 or higher (on a 1 to 10 scale) only to studies that measured spirituality or religion using religious variables that were distinct from mental health outcomes and thus avoided measurement tautology [9]. Religious coping is another term that deserves definition, given its importance as a mechanism by which R/S could affect CVD risk (see section "Understanding Mechanisms" below). By religious coping we mean, " the use of religious beliefs or practices as a way of adapting to the physical, psychological, and social challenges caused by medical illness. For example, in Western religious traditions, religious coping may involve praying to God for strength and comfort, wisdom and direction, health or healing, or help for loved ones. It may involve reading inspirational materials, such as the Holy Scriptures (Torah, Christian Bible, or Holy Qur’an) or reading popular books or magazines on religious topics. R/S coping may involve getting together with members of one’s faith tradition for worship services, singing hymns, prayer, or scripture study. It also may involve the practice of religious rituals related to health and healing, such as lighting candles or participating in sacraments, such as the Eucharist or Confession, or the practice of immersion in a Mikveh or wearing of Tefillin. R/S coping may involve asking others to pray for oneself, praying for others, seeking religious counseling, providing religious support to others, or participating in religious rituals focused on healing."[10]. In discussing the research, we will rely heavily on our systematic review of the literature conducted in 2010 that searched the major online databases (PsycINFO, MEDLINE, etc.) using the terms “religion,” “religiosity,” “religiousness,” and “spirituality” to identify original quantitative data-based research on R/S and health. The online database search was supplemented by asking researchers in the field of R/S and health for any published reports of research that they had conducted on this topic. Furthermore, studies that were cited in the reference lists of the reports identified in this manner were tracked down and included in the review. In this way, the systematic review identified over 3,200 studies that reported data on the relationship between R/S and health. Nearly two-thirds of this research was published between the year 2000 and mid-2010 (e.g., more research on this topic was published 105

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during that 10-year period than in the previous 128 years). Each of these studies, particularly those summarized below on R/S and CVD, is described in the appendices of the the two editions of the Handbook of Religion and Health [11,12]. For both positive and negative findings summarized below, we provide the original citations for a sample of the studies included in the review. However, given the very large number of studies, we cite only a few of the higher quality ones that examine relationships between R/S and cardiovascular risk factors (section 2). In contrast, we try to cite all studies that examine relationships between R/S and specific CVD functions or outcomes (sections 3-8). We also cite more recent research that either confirms or contradicts earlier reports identified in the systematic review.

relationship [24]. The results from studies examining R/S and drug use parallel those on R/S and alcohol. Among 185 studies on the relationship between R/S and drug use, 84% (155 studies) found inverse relationships. Only two studies of the 185 found significant relationships with greater drug use. Of the 112 better designed studies (rated 7 or higher in quality), 96 (86%) reported this finding [2527], wherease only one study found a positive relationship [28]. Most of these studies were conducted in younger adults, typically high school or college students, a time when alcohol and drug use habits are just beginning to develop and will affect their cardiovascular systems for the remainder of their lives. 2c. Physical inactivity. A sedentary lifestyle is known to increase the risk of CVD, and regular exercise is known to decrease that risk [29,30]. Research shows that those who are more R/S are more likely to be physically active or more likely to exercise. Of 37 studies that have examined the association between R/S and physical activity, 25 (68%) found greater exercise or physical activity among those who were more R/S. Of the 21 methodologically most rigorous studies, over three-quarters (76% or 16 studies) reported positive relationships [32,33] whereas only two (10%) found negative relationships [34,35]. 2d. Poor diet/nutrition. Numerous studies have linked diets high in saturated fat, low in omega-3 fatty acids, and low in fruits, vegetables, nuts, and whole grains to increased CVD morbidity and mortality [36-38]. By healthy we mean a high intake of fiber, green vegetables, fruit, fish, and a low intake of processed foods and fat. Regular vitamin intake, eating breakfast, and overall better nutrition are also part of a healthy diet. Again, many studies show that persons who are more R/S consume a healthier diet. Our systematic review uncovered 21 studies that examined this relationship. Nearly two-thirds (62% or 13 studies) found a positive link between R/S and a healthier diet, and only one study reported a worse diet [39]. Of the 10 highest quality studies, seven (70%) reported an association between greater R/S and a healthier diet [4042]; no high quality study reported a worse diet among those who were more R/S. 2e. High cholesterol. A healthier diet might also be expected to affect the level of cholesterol in the blood. Serum cholesterol is strongly linked with all types of CVD. For example, a 10% decrease in LDL is associated with a 10% reduction in risk of myocardial infarction [43]. In our systematic review, we identified 23 studies that had examined associations between R/S and serum cholesterol. The majority (12 of 23) reported significantly lower cholesterol among those who were more R/S. Similarly, of the nine highest quality studies, five (56%) found either lower cholesterol in those who were more R/S [44,45] or reported that a R/S intervention lowered cholesterol [46-

2. CARDIOVASCULAR RISK FACTORS Standard modifiable risk factors for CVD are cigarette smoking, excess alcohol, physical inactivity, poor diet/ nutrition, high blood cholesterol, obesity, diabetes mellitus, high blood pressure, and psychosocial stress (including depression, anxiety, and personality traits such as hostility) [13]. Each of these risk factors is related in one way or another to R/S. 2a. Cigarette smoking. The risk factor most strongly related to both CVD and R/S is tobacco use, a habit that contributes to 30% of all coronary heart disease deaths each year in the U.S. [14]. The problem is of similar or greater magnitude in Brazil, where 18% of adults smoke and this contributes to 45% of all deaths from coronary heart disease [15]. We uncovered 137 studies that had examined the relationship between R/S and smoking, and of those, 123 (90%) reported inverse relationships. No studies found positive relationships. When examining the 83 methodologically most rigorous studies (ratings of 7 or higher on a 1 to 10 quality scale), 75 of those (again 90%) reported inverse relationships with R/S involvement [16-18]. If those who are more R/S smoke less, then this should influence their risk for developing CVD. 2b. Alcohol and drug use. Heavy alcohol use is known to affect cardiac function (alcoholic cardiomyopathy, arrhythmias), blood pressure, and increase risk of stroke [19]. A similar relationship has been found with chronic use of illicit drugs [20]. At least 278 studies have now examined relationships between alcohol use, abuse, or dependence and R/S. The vast majority of those (86%, i.e., 240 studies) found inverse relationships with R/S involvement. Only four of 278 (1%) studies reported positive relationships. The higher quality studies are even more likely to report this finding. Of the 145 studies that were rated 7 or higher in quality, 90% (i.e., 131 studies) found inverse relationships [21-23]; only one study reported a positive 106

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48]; one study reported higher cholesterol, but only in a subgroup of the sample (Mexican-American men) [49]. 2f. Obesity. Many studies show that those who are overweight have an increased risk of CVD [50]. The one characteristic of R/S persons that increases their risk of CVD is heavier weight. We located 36 studies examining associations between weight and R/S involvement, of which 14 (39%) found that R/S was associated with greater weight or higher body mass index. In contrast, only seven studies (19%) found that R/S was associated with lower weight. The findings from more rigorouly designed studies support this conclusion. Of the 25 best studies, 11 (44%) reported greater weight [51,52] and five (20%) found lower weight (or less underweight) [53,54] among those who were more R/S. 2g. Diabetes. Two-thirds of diabetics die of CVD, and the risk of coronary artery disease alone is up to four times higher in those with diabetes [55]. Despite their heavier weight, those who are more R/S do not have a greater risk of being diabetic. At least 14 studies conducted between 2000 and 2010 examined this relationship. Of those, five (36%) found less diabetes, lower blood sugar, a lower HgbA1C [56,57], or improvement in response to a R/S intervention [58-60], four (29%) reported more diabetes [61] or higher indicators of diabetes [62-64], and the remaining studies reported mixed findings [65] or no association. Thus, overall, the research finds no consistent relationship between R/S and diabetes. Perhaps a better diet, or perhaps better compliance with treatment, makes up for the heavier weight of those who are more R/S (neutralizing the risk of diabetes that heavier weight confers). 2h. Blood pressure. The majority of studies find that R/S involvement is related to lower blood pressure. See section 5 on hypertension. 2i. Psychosocial stress. High emotional stress, loneliness, and social isolation are associated with atrial and ventricular arrhythmias [66], left ventricular dysfunction, myocardial ischemia [67], recurrent myocardial infarction [68], and increased risk of cardiac death [69], as well as other cardiac abnormalities. Likewise, personality traits such as cynical hostility [70], and emotional states such as depression [71] and anxiety [72], are linked to increased risk of CVD and worse prognosis. Lower risk, however, has been found for optimism, [73] agreeableness, 74 and other positive emotions [75]. Our systematic review identified 75 studies that examined relationships between R/S and stress level. Of those, 46 (61%) reported lower levels of psychological stress in those who were more R/S and 12% reported higher levels of stress. We also identified 74 studies examining R/S and social support, of which 61 (82%) found significant positive relationships and none found negative relationships; of the 29 best studies, 27 (93%)

reported significantly greater social support among those who were more R/S [76-78]. We also identified 27 studies examining R/S and hostility, of which 18 (67%) reported inverse relationships [79-81]. Our review uncovered many studies examining connections between R/S, depression, and anxiety. Of 444 studies assessing relationships between R/S and depression, 272 (61%) reported lower depression among the more R/S, including 119 (67%) of the 178 highest quality studies [82-84]. Of 299 studies examining relationships with anxiety, 147 (49%) reported inverse associations with R/S, and of the 67 highest quality studies, 38 (55%) did so [85-87]. With regard to optimism, at least 32 studies examined relationships with R/S, and of those, 26 (81%) reported significant positive associations [88-90], and none found the opposite. Concerning the personality trait â&#x20AC;&#x153;agreeableness,â&#x20AC;? 30 studies have examined associations with R/S, and of those, 26 (87%) found that R/S was related to greater agreeableness [91-93]. Finally, with regard to well-being and happiness, we identified 326 quantitative studies examining associations with R/S, and of those, 256 (79%) found positive relationships; of the 120 highest quality studies, 98 (82%) reported that those who were more R/S experienced higher well-being, happiness, or life satisfaction [94-96] and only one study found lower well-being [97]. Thus, in the vast majority of studies, greater R/S is related to fewer negative emotions that predict an increased risk of CVD disease and to more positive emotions that predict a reduced risk of CVD. Likewise, other than being heavier in terms of weight and neutral in terms of diabetes, those who are more R/S are less likely to smoke cigarettes, use or abuse alcohol/drugs, be physically inactive, consume a poor diet, have high cholesterol, and have high blood pressure, each of which is related to a greater risk of CVD morbidity and mortality. 3. CARDIOVASCULAR FUNCTIONS AND INFLAMMATORY MARKERS Given the relationship between R/S and the CVD risk factors above, we would predict that those who are more R/S might also have better cardiovascular functions when tested in the laboratory (i.e., lower cardiovascular reactivity, brachial artery vasoreactivity, peripheral resistance) and lower levels of inflammatory markers (proinflammatory cytokines, C-reactive protein, fibrinogen). 3a. Cardiovascular reactivity. Regarding cardiovascular reactivity (a known risk factor for CVD[98]), at least eight studies have examined relationships with R/S, and of those, four (50%) found inverse relationships [99101] or a reduction in cardiovascular reactivity with a R/S intervention [102]. One study reported a positive relationship (in a situation of unresolved justice) [103], 107

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two studies reported mixed findings (significant positive or significant negative relationships, depending on R/S characteristic) [104,105], and one study found that transcendental meditation had no effect on brachial artery vasoreactivity [106]. 3b. Heart rate variability and other cardiovascular functions. Reduced heart rate variability (HRV) is a known risk factor for CVD [107]. At least four studies have examined relationship between R/S and HRV or assessed the effects of a R/S intervention on HRV. Three of these studies reported positive findings (one showing a positive relationship between R/S and HRV [108] and two finding that Eastern forms of meditation increased HRV [109,110]), whereas one study found that transcendental meditation had no effect [111]. Two additional studies have assessed other cardiac functions. One study examined the effects of saying the Ave Maria (rosary prayer) in Latin or a Tibetan Buddhist mantra (in the original language) on arterial baroreflex sensitivity (BAR) [112]. A reduction in BAR is known to predict future coronary artery disease and heart failure. Results indicated an increase in BAR with both forms of meditation. The second study examined relationships between R/S, coronary artery calcium, and left ventricular mass, finding no relationship [113]. 3c. Inflammation. High levels of inflammatory markers in the blood are known to increase the risk of CVD [114117]. The relationship between R/S and inflammatory markers is a complex one, since the mechanism by which R/S affects inflammatory markers is indirect acting through psychological, social, and behavioral pathways. Furthermore, psychological states (and certain mental disorders) may influence inflammatory marker levels in opposite directions; for example, depression is associated with high levels of the pro-inflammatory marker IFN-γ [118], whereas PTSD and acute stress have been associated with low levels of IFN-γ [119]. As a result, treatments for these mental disorders may either decrease or increase IFN-γ in order to normalize levels. With these complexities mind, we review studies that have examined relationships between R/S and inflammatory markers or have assessed the effects of a R/S intervention on pro-inflammatory cytokines such as interluekin-6 (IL6) or interferon gamma (IFN-γ), other pro-inflammatory markers such as C-reactive protein (CRP) and fibrinogen, and the anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10). 3c.1. Interleukin-6. At least nine studies have examined relationships between R/S and blood levels of IL-6. Of those, five (56%) reported significant inverse relationships [120,121] or a reduction in IL-6 in response to a R/S intervention [122-124]. In contrast, IL-6 levels appear to be increased in cardiac surgery patients undergoing existential stress related to religious struggles [125] or

may be increased in response to a spiritual intervention [126]. 3c.2. Interferon gamma. As noted above, IFN-γ is increased in major depression [127] and decreases in response to treatment [128]. However, IFN-γ is suppressed by cortisol [129], decreases in response to acute psychological stress [130], and may actually increase in response to treatment in those with low INF-γ levels [131,132]. Three studies have examined the effects of R/S interventions on INF-γ levels in blood. All three found that the R/S intervention significantly increased INF-γ levels [133-135]. 3c.3. C-reactive protein. There is strong evidence that pro-inflammatory CRP plays a role in the development of atherosclerosis and coronary heart disease [136]. Eight studies have now examined relationships with R/S. Of those, four (50%) reported significant inverse relationships [137-139] or a reduction in CRP in response to a R/S intervention [140]; the other four studies found no association. More recent research supports an inverse relationship between R/S and CRP [141]. 3c.4. Fibrinogen. Only one study, to our knowledge, has examined relationships between serum fibrinogen (a key factor in the development of CVD [142]) and R/S. That study examined the relationship between frequency of religious attendance (as part of a two-item social index) and fibrinogen levels, finding a significant inverse relationship after controlling for multiple covariates [143]. 3c.5. Anti-inflammatory cytokines. Anti-inflammatory cytokines such as IL-4 and IL-10 have the opposite effect of pro-inflammatory cytokines on the development of atherosclerotic plaque [144]. At least two studies have now examined the relationship between R/S and antiinflammatory cytokines. In our systematic review, we identified one study that examined the effects of Buddhistbased mindfulness meditation (MM) on IL-4 and IL-10 levels in 66 women recently diagnosed with breast cancer [145]. Those receiving MM experienced a significant reduction in IL-4 and IL-10 levels compared to controls (approximating that of women without breast cancer) during the 8-week follow-up. Note, however, that antiinflammatory cytokines may be increased in situations of acute stress [146]. A more recent study examined cytokine levels in 33 very elderly persons with cardiovascular disease (mean age 87) who participated in weekly 30-minute sermons by chaplains over 20 months [147]. Plasma IL-10 and IL-6 levels were compared to 26 age-matched controls (mean age 85) without the intervention. Results indicated that the IL-10/IL-6 ratio was significantly higher in those listening to the sermons compared to controls (3.96 vs. 1.79, P<0.05). In summary, the majority of studies find that cardiovascular reactivity and other cardiovascular

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responses are healthier (lower risk in terms of CVD) in those who are more R/S or receiving R/S interventions. Likewise, except in situations of acute psychological stress, the majority of studies find that R/S or R/S interventions are associated with lower levels of inflammatory markers known to be involved in CVD pathogenesis.

on this measure of religious orthodoxy) experienced a significantly lower mortality rate from CAD over the 23year follow-up compared to the least religious group (those scoring in the bottom one-fifth on the religious measure). There were 38 deaths from CAD in the most religious group during follow-up, compared to 61 deaths in the least religious group. There were 135 deaths from other causes in the most religious group, compared to 168 deaths in the least religious group. Overall, the risk of dying from CAD in the most religious group was 20% lower than in the least religious group. Controlling for age, systolic blood pressure, cholesterol, smoking, diabetes, body mass index, and baseline CAD could not explain these results. Overall, then, our systematic review identified 19 studies that examined associations between R/S and CAD. Of those, 12 (63%) reported a significant inverse relationship. Of the 13 most rigorously designed studies, nine (69%) reported inverse relationships [150-158] and one found a positive relationship [159]. The latter study was an 8-year follow-up of 92,395 women ages 50-79 participating in the U.S. Women’s Health Initiative Observational Study. R/S was measured with three questions: religious affiliation, attendance at religious services, and strength/comfort derived from religion. Only the uncontrolled analysis was reported. Women who indicated a religious affiliation at baseline (93% of the sample) were more likely than those with no religious affiliation to experience a coronary event during follow-up (2.7% vs. 1.9%, P<0.0001). Those attending religious services weekly or more (44% of the sample) were also more likely than those attending less than weekly to experience a coronary event (2.7%, vs. 2.5%, P=0.03). Finally, those who received “a great deal” of of strength/comfort from religion were more likely than those receiving no strength/comfort from religion to have a coronary event during follow-up (2.8% vs. 2.0%, P<0.0001). Note that these findings, unlike other studies, did not control for race or age. Older women and women from minority groups (African-American or Hispanic) tend to be much more religious (and at greater risk for CVD) than young or white women. Therefore, controlling for these factors may have explained the association.

4. CORONARY ARTERY DISEASE We have been focusing on R/S and risk factors for CVD. We now shift to examine research that has directly measured relationships between R/S and specific cardiovascular disorders, beginning first with coronary artery disease (CAD). One of the first studies demonstrating an association between R/S and CAD was published in 1986. Friedlander et al. compared the religious orthodoxy of 539 patients in Israel experiencing their first myocardial infarction (MI) with a matched control group of 686 patients without heart disease [148]. Among those with MI, 51% of men and 50% of women described themselves as secular (vs. religious) compared with 21% of men and 16% of women controls. Controlling for age, ethnicity, education, smoking, physical exercise, and body mass index, researchers found that secular men were over four times more likely to have MI compared to religious men (OR=4.2, 95% CI 2.6-6.6) and secular women were over seven times more likely than religious women (OR=7.3, 95% CI 2.3-23.0). Even before that report, Comstock et al. had published a study in 1971 that found significantly fewer deaths from atherosclerotic cardiovascular disease in those attending religious services weekly or more compared to those attending less than weekly [149]. During this 3-year follow-up of 378 white males ages 45-64 in Washington county, Maryland (USA), there were 189 deaths due to artherosclerotic or degenerative heart disease. Those who died were matched by age, race, and sex with men who did not die from heart disease. The risk of dying from atherosclerotic heart disease was over twice as great in men attending church less than once per week, compared to those attending services once weekly or more (RR 2.02, P<0.01). Even after controlling for smoking, SES, hard water, and other risk factors, the increased risk for less frequent attendees remained significantly higher. In a 23-year follow-up of 10,000 middle-aged men employed in civic or municipal occupations in Israel (the Israel Ischemic Study), investigators examined the relationship between religious orthodoxy and death rate from myocardial infarction. Religious orthodoxy was measured using a three-item scale: having a religious vs. secular education, self-identified as orthodox, traditional, or secular, and frequency of synagogue attendance. The most religious group (those scoring in the top one-fifth

5. HYPERTENSION Given the relationship between blood pressure (BP) and psychological stress [160] and the influence that R/S has in helping people to cope with stress, we expect R/S and BP to be related. The systematic review identified 63 studies that measured degree of religious involvement and BP or diagnosis of hypertension. Of those, 36 (57%) reported lower BP or less hypertension in those who were more R/S, whereas seven (11%) reported higher BP. When 109

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examining the higher quality studies (those rated 7 or higher on a 1-10 scale), 24 (62%) reported lower BP or less hypertension among those who were more R/S [161-173] or in response to a R/S intervention [174-184] (including two reports from a single study, one reporting results for the overall sample and one for the sample stratified by race). In contrast, seven studies reported higher blood pressure among the more religious, including two lower quality studies [185,186] and five high-quality studies (13%) [187-191]. Why would R/S would be associated with higher blood pressure? Perhaps in some populations, greater religious involvement might be associated with higher stress, anxiety or guilt, which in turn might increase BP. There is another explanation, however. Note that three of the five studies linking R/S to higher BP included a large proportion of African-Americans (36% to 100% of the sample). Research shows that nearly 40% of AfricanAmericans have high blood pressure [192]. Research also shows that African-Americans are very religious (much more religious than white Americans). Efforts to statistically control for such a powerful confound, then, may not always be successful. Thus, the majority of studies find that R/S is related to lower BP and less hypertension. A smaller number of studies including high quality ones, however, find that R/S is related to higher BP, which needs to be better understood.

measured R/S. Four of those (44%) reported a lower risk of stroke among the more religious, and all of these were high quality studies [193-196]. Of the remaining five studies, four found no association and one reported greater carotid artery thickening in those who were more R/S, placing them at higher risk for stroke [197]. In that cross-sectional study (n=5,474), researchers found that those who attended religious services were 12% to 64% more likely (depending on frequency of attendance) than those who never attended to be above the 90th percentile in common carotid intima-media thickness (CC-IMT). Results were controlled for hypertension, diabetes, smoking, hypercholesterolemia, obesity, age, gender, race, education, and income. Frequency of attendance was also positively associated with obesity. Again, note that 30% of the sample were African-American, who also frequently attended religious servies (50% of those who attended religious services daily were African-American). Although race was controlled for, the latter may have influenced the results. Interestingly, no association was found between religious attendance and coronary artery calcium (CAC), left ventricular mass (LVM), or ankle brachial index (ABI). Furthermore, religious attendance was the only R/S characterisic associated with greater CCIMT; neither frequency of prayer/meditation nor frequency of daily spiritual experiences were related to CC-IMT, CAC, LVM, or ABI. Likewise, when participants were followed for three years, none of the religious variables predicted incident CVD events (myocardial infarction, unstable angina, CAD death, stroke, TIA, CHF, or other CVD death). With regard to dementia, which is often the result of multiple strokes, a number of studies have examined associations with R/S. The systematic review uncovered 21 studies examining R/S and dementia or level of cognitive functioning. Nearly half (48% or 10 studies) reported less dementia or better cognitive functioning in those who were more R/S. Of the 14 studies with the most rigorous designs, eight (57%) reported positive relationships with better cognitive function [198-205]. Three studies, however, reported worse cognitive funcitoning in those who were more R/S [206-208]. The latter may be due to the fact that R/S persons tend to live longer than less religious individuals, increasing the likelihood that they will live to an older age when cognitive problems tend to develop. Recent research supports a positive relationship between R/S and better cognitive function in those with dementia [209] and in those of advanced age [210].

6. CEREBROVASCULAR DISEASE Much less attention has been paid to the relationship between R/S and cerebrovascular disease (CD). We know that CAD and hypertension are related to CD, and so there may also be a relationship between R/S and CD. This is particularly likely given that R/S is related to many of the other risk factors for CD (high serum cholesterol, poor diet, physical inactivity, cigarette smoking, heavy alcohol or drug use, and psychological factors such as stress, anxiety and depression). Of course, heavier weight and perhaps emotional excitement during religious services might also increase the risk of CD. Alternatively, an inverse relationship between R/S and CD (particularly in cross-sectional studies) may simply indicate that those disabled with CD are simply less able to engage in R/S activities, particularly when this involves attending religious services. Finally, those who are disabled by CD may also turn to R/S for comfort in order to cope with their disability, increasing the likelihood of a positive correlation between R/S and CD. Thus, numerous factors need to be considered when studying his relationship. Our systematic review identified a number of studies that had examined relationships between R/S and two cerebrovascular disorders: stroke and dementia. With regard to stroke, there are at least nine studies that 110

7. CARDIAC SURGERY OUTCOMES Psychological stress is known to influence the speed of wound healing. Research shows that it can delay healing

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by up to 60% in older animals and humans [211]. Adverse effects of stress on wound closure can also be demonstrated in young [212] and middle-aged adults [213], as well as in persons undergoing surgical operations [214]. Some investigators have explained this phenomenon as being due to changes in pro-inflammatory cytokines IL-1B, IL-6, and TNF-alpha at the wound site, perhaps the result of higher levels of cortisol stimulated by the stress response [215]. If R/S helps to reduce psychological stress and improve coping, it might also influence the speed of wound healing and successful recovery from cardiac surgery. Unfortunately, very little research has examined the relationship between R/S and either speed of wound healing or recovery from surgery. However, several studies have examined relationships between R/S and infection, a factor that strongly influences the speed of wound healing. Our systematic review identified 12 studies that examined relationships between R/S and susceptibility to infection or concentration of infectious agents in blood (viral load). Of those, eight (67%) reported lower infection rates or lower viral load in those who were more R/S, and no study found greater infection or higher viral load. Of the 10 best studies, seven (70%) found significant inverse associations between R/S and infection or viral load [216-222]. There is also a wealth of research linking R/S involvement or interventions to better immune function (14 of 27 studies) [223] and endocrine function (lower cortisol levels in 19 of 29 studies) [224], both of which are known to influence both infection risk and speed of wound healing. Thus, given the impact that psychological stress may have on wound healing by increasing susceptibility to infection and adversely affecting immune/endocrine functions â&#x20AC;&#x201C; and the relationships between R/S and lower psychological stress, lower susceptibility to infection, and better immune and endocrine functions â&#x20AC;&#x201C; there is every reason to predict that R/S involvement might influence the speed of wound healing and surgical outcomes. As noted above, there is little research examining the direct impact of R/S on outcomes from cardiac surgery. However, we located five studies that have examined this relationship (four observational studies and one clinical trial), which we now describe. In the first study, published in 1995, researchers at Dartmouth Medical Center in Lebanon, New Hampshire (USA), examined the effects of religious attendance, importance of religion, and comfort/support from religion on 6-month mortality rates in 232 patients following coronary artery bypass graft (CABG) surgery [225]. Most of participants were either Protestant (63%) or Catholic (25%), and all were age 55 or older. Among those attending religious services at least once every few months, only 5% died; among those who never or rarely attended, 12%

died (P=0.06). Among those who described themselves as deeply religious (n=37), mortality was 0% compared to 11% in other patients (P=0.04). Finally, mortality in those who indicated they obtained strength/comfort from religion was 6%, compared to 16% in those who did not receive strength/comfort from religion (P=0.01). When logistic regression was used to control for other covariates, such as history of previous cardiac surgery, impairments of physical functioning, age, and frequency of group social activity, patients who said they did not receive strength/ comfort from religion were three times more likely to die than those who said they received strength/comfort from religion (OR=3.25, 95% CI 1.09-9.72). There was also an interaction between social participation and receiving strenght/comfort from religion, such that those who said they neither received strength/comfort from religion nor participated in social groups were over 14 times more likely to die (OR=14.32, 95% CI 2.37-86.56), controlling for other risk factors. In a second observational study, researchers from Rutgers University in New Brunswick, New Jersey (USA) followed 142 patients hospitalized for elective cardiac surgery (coronary artery bypass grafting, CABG), examining the relationship between religiosity and post-operative surgical complications [226]. Surgical complications, assessed by medical record review, were determined only during the time the patient was in the hospital. Religiosity was measured by frequency of religious attendance, frequency of prayer or meditation, and a 5-item scale assessing intrinsic religious commitment. After controlling for demographic, biomedical, and psychosocial variables, scores on intrinsic religious commitment were inversely related to complications following surgery (B=-0.32, P<0.01). No effect was found for frequency of religious attendance or prayer/meditation. In a second and separate study by this Rutgers University research group, they examined the relationship between religiosity and length of stay (LOS) in 405 patients undergoing elective CABG [227]. Patients were interviewed an average of 5 days prior to surgery, and LOS was determined by medical record review. Religiosity was assessed using a 6-item devotional activities scale and a 7-item beliefs scale. After controlling for social support and depressive symptoms, neither measure of religiosity predicted LOS (effect on other surgical outcomes and complications were not examined). In a fourth study, a randomized clinical trial, researchers at the University of Nebraska Heart Institute (USA) examined the effects of listening to prayer during surgery [228]. They randomized 78 cardiac surgery patients to one of three groups: (1) patients who listened to a CD that played a generic prayer, (2) patients who 111

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listened to a CD with a standard relaxation technique, or (3) patients who listened to a tape with no sound (placebo). The CD’s were played starting with the beginning of the unconscious anesthetic period prior to surgery and continued throughout the surgical procedure. The prayer was the following: “Dear God, Please come to my aid. Help me to be at peace during this surgery and in my recovery. Strengthen me and help me to remember you are always present, that your healing love and spirit surround me at all times, and that I am held in your tender care. Amen.” Mortality, sepsis, supraventricular tachycardia, and amount of pain medication (assessed in hospital and 30-days post surgery) were compared between the three groups. No significant differences were found on any outcome between groups. Since the tapes were played while patients were under anesthesia, they were not conscious of the tapes’ contents. The mechanism by which R/S is thought to influence health outcomes is through concious cognitive processes that reduce stress levels and improve coping. Thus, we would not expect that a religious intervention during an unconscious period to have an impact on surgical outcomes. If prayer has an effect on cardiac outcomes following surgery, this study suggests that it probably doesn't have its effect through unconscious processes. The last and final study (to our knowledge) is one conducted by researchers at the University of Michigan (UM) that examined the effects of religious involvement on post-operative complications following CABG at the UM Medical Center in Ann Arbor, Michigan (USA) [229]. A total of 177 patients undergoing CABG were assessed two weeks prior to surgery when data were collected on frequency of religious attendance, private prayer, and importance of religion. The 9-item INSPIRIT and a 4-item religious reverence scale were also administered at that time prior to surgery. Cardiac surgery complications were assessed using a standard measure (Thorasic Surgeons Database). Controlling for other significant predictors of post-operative complications, researchers found that patients who prayed frequently prior to surgery were 45% more likely to have no postoperative complications (OR=1.45, 95% CI 1.03-2.06). No other religious variables significantly predicted postoperative complications when frequency of prayer was controlled for in the model. Thus, three of five studies examining outcomes following cardiac surgery found that R/S predicted significantly better health outcomes and two studies found no effect. These results are positive enough to warrant further studies to examine the effects of R/S or R/S interventions on outcomes following cardiac surgery – especially in other countries. To date, no research has been published from countries outside the United States. 112

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8. OVERALL MORTALITY AND CARDIOVASCULAR MORTALITY In our systematic review, we identified 121 studies on R/S and mortality, of which 82 (68%) found that greater R/S predicted significantly greater longevity [230]. Six studies (5%) reported shorter longevity. Considering the 63 methodologically most rigorous studies, 47 (75%) found greater longevity. With regard to CVD mortality in particular, we identified 12 studies that had examined relationships with R/S. Of those, eight (67%) reported significance inverse relationships during periods of follow-up that ranged from 6 months to 31 years [231238]. In addition, two found no association [239,240] (one study with a follow-up of only 19 months), one reported mixed results [241] (CVD as a cause of death was greater among Catholic sister radiology technicians compared to other female radiology technicians, but was significantly lower compared to US females in general), and one reported greater mortality (although uncertain if statistically significant) in women reporting they received comfort/strength from religion [242]. In several of these studies, all cause mortality was the primary focus (not CVD), but when investigators examined the disease in which the inverse relationship between R/S and mortality was strongest, it was CVD [243,244]. Furthermore, in an independent systematic quantitative review of this research, investigators reported the effects of R/S on mortality were greater in CVD than in any other disease (HR=0.72, 95% CI 0.58-0.89) [245]. No studies of cardiovascular morbidity or mortality have been published from Brazil. 9. EXPLANATORY MECHANISMS As emphasized throughout this article, the way that R/S affects the cardiovascular system must be through psychological, social, or behavioral pathways. At least these are the pathways that we can study using the methods of science that researchers have available to them, i.e., through observational studies, experimental studies, and clinical trials. 9.1. Psychological pathways. By decreasing the probability of stressful life events (by influences on behavior), by providing meaning and purpose to stressful life events that do occur, and by providing role models in sacred scriptures of exemplary individuals dealing with adversity, R/S provides psychological resources that facilitate coping and adaptation. The result is the experience of more positive emotions (well-being, happiness, optimism, meaning and purpose) and fewer negative emotions (depression, anxiety, low self-esteem, hopelessness). These psychological benefits of R/S

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are known to affect immune, inflammatory, endocrine, and autonomic functions, which in turn influence cardiovascular health. Based on the amount of variance in health outcomes explained by R/S factors in regression models, we estimate that psychological factors account for about 50% of the effect of R/S on cardiovascular outcomes. 9.2 Social pathways. By encouraging involvement in the faith community, promoting forgiveness, and nurturing pro-social attitudes and activities, R/S provides social resources to build and maintain family, marital, and friendship networks that will be available to facilitate adaptation and coping (thereby positively influencing mental health). Social support of this kind also influences attitudes and behaviors that affect the ability to obtain an education and a job, influence work ethics, and help persons obtain financial stability that will enable them to access health resources. Finally, social contacts from involvement in a faith community will increase the flow of health information, increasing awareness of the latest research findings, disease screening opportunities, and available medical treatments. We estimate that social pathways account for about 15% of the effects of R/S on cardiovascular outcomes (again, based on regression models). 9.3. Behavioral pathways. By doctrines that promote care for the physical body (as the "temple of the Holy Spirit" in the Christian tradition, for example), R/S affects health behaviors such as cigarette smoking, alcohol and drug use, exercise and physical activity, and diet. Likewise, R/S doctrines discouraging sexual activity outside of marriage and delinquent or criminal activities will influence development of sexually transmitted diseases and risk of motor vehicle crashes and other accidents that could lead to the development of CVD. Our systematic review of research in this area revealed that of 95 studies examining relationships between R/S and risky sexual activities, 82 (86%) found inverse relationships. Likewise, of 104 studies examining associations between R/S and delinquency/crime, 82 (79%) reported inverse relationships. Finally, R/S attitudes encourage honesty and accountability, influencing compliance with medical treatments and adherence to disease screening practices (blood pressure monitoring, blood glucose checks, etc.). In the systematic review, we found that 27 studies examined relationships between R/S and compliance with medical treatments; of those, 15 (56%) reported positive associations. Furthermore, of 44 studies that examined relationships with disease screening, 28 (64%) found that those who were more R/S were more likely to engage in disease screening activities. Thus, a major pathway by which R/S may influence cardiovascular functions and risk of CVD is though health behaviors, lifestyle choices, compliance with medical treatments, and participation

in disease screening. We estimate that these pathways account for about 35% of the total effects of R/S on cardiovascular outcomes. 9.4. Supernatural pathways. Some researchers have sought to explain the relationship between R/S and CVD by invoking mechanisms that lie outside of the natural world (i.e., Divine or supernatural pathways). Classic examples are double-blinded intercessory prayer studies conducted in patients undergoing CABG, including the Byrd study [246] at San Francisco General Hospital, the Kansas City Mid-America Heart Institute study [247], and the multi-site Harvard study [248]. In the latter study, Harvard investigators randomized 1800 CABG patients to prayer or no prayer (a study published in the American Heart Journal). To the disappointment of the researchers in the Harvard study, the findings of this multi-million dollar project indicated that being prayed for made no difference in cardiac outcomes and, in fact, if patients were told they were being prayed for, they actually did significantly worse (i.e., they were more likely to have atrial arrhythmias). This resulted in an article published in Newsweek magazine that was titled "Don't pray for me! Please! [249]”. These studies are neither theologically nor scientifically credible, and so we have not discussed them in this paper. Interested readers are referred elsewhere for a thorough treatment of these studies and why they should not be done [250,251]. 9.5 Comprehensive theoretical model. We present here a theoretical causal model (Figure) adapted from a model presented in the Handbook [252]. The ultimate driving "source" of the cardiovascular benefits (and health benefits more generally) from R/S, according to the three major Western monotheistic traditions, is attachment to God. In Judaism, it is the 1st commandment of the 10 commandments ("Thou shalt have no other gods before Me" [Exodus 20:3]) and emphasized by Moses as the core of the Jewish faith ("Thou shalt love the Lord thy G-d with all thy heart, and with all thy soul, and with all thy mind" [Deuteronomy 6:5]). In Islam, it is in the opening stanza of the Qur'an ("You [alone] we worship, You [alone] we ask for help [for each and everything]" [Al-Fatihah 1:5]," and repeated many times elsewhere (e.g., "…those who have attained to faith Love God more than all else" [AlBaqara 2:165], and "…worship God [alone], and do not ascribe divinity, in any way, to aught beside Him" [AnNisa 4:36]). In Christianity, Jesus said (quoting Moses) that it is the first and greatest commandment and necessary to inherit eternal life ("Thou shalt love the Lord thy God with all thy heart, and with all thy soul, and with all thy mind" [Matthew 22:37]; this teaching is repeated twice more in Mark 12:30 and Luke 10:27). There is no debate here. Belief in, attachment to, and relationship with God is at the core of the monotheistic traditions above. 113

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This relationship with God is then manifested in terms of the theological virtues (love of God, faith or trust in God, hope in God). These virtues are taught and nourished within a religious community, although influenced by peers, education, and training. They are manifested in a person's life by public religious practices (attending religious services and other social group related religious activity), private religious activity (prayer or meditation, reading religious scriptures, watching religious TV, listening to religious music), intrinsic religious beliefs or commitments, religious experiences, and religious coping. The latter we call "religion" or "spirituality" (used synonymously in this paper – see earlier discussion). Religion/spirituality is then seen as influencing day-today decisions made at work, in the family, with friends and colleagues, as well as affecting life-style choices and health behaviors, which in turn influence mental and social health. R/S is also viewed as promoting the "human virtues" (as distinct from the theological virtues) that include forgiveness, honesty, courage, self-discipline, altruism (caring for others), humility, gratefulness, patience, and dependability. The human virtues, in turn, enhance social relationships, increase positive emotions, and reduce negative emotions. R/S has both "indirect" and “direct” effects on health

outcomes. This includes the indirect effects through positive emotions (well-being, meaning and purpose, optimism, hope, etc.), through negative emotions (mental disorders such as depression, suicide, anxiety, substance abuse), and through social relationships (social support, marital stability). R/S also indirectly influence mental, social, and physical health outcomes by effects on decisionmaking, lifestyle choices, and health behaviors, as well as through encouraging human virtues. Besides indirect effects, R/S also has "direct" effects on positive emotions, negative emotions, and social relationships. Mental health (positive and negative), social health, and health behaviors (including diet, exercise, smoking, etc.) are seen as the key factors that influence physiological systems on which healthy cardiovascular functions depend (immune/ inflammatory, endocrine, sympathetic/parasympathetic nervous systems), ultimately affecting rates of CVD. Note that R/S has no "direct" influences on cardiovascular functions or on cardiovascular health/disease. Rather, R/S always operates through psychological, social, and behavioral pathways. This entire system, rests on genetic influences, early developmental experiences during childhood and adulthood, and personality influences that result from an interaction of genetics and developmental forces. Note that

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these genetic and environmental factors (and the interaction of genetics and environment) influence the development of human virtues, decision-making and health behaviors, positive emotions (set-point for happiness and wellbeing), negative emotions (tendencies toward depression or anxiety or vulnerability to alcoholism or drug use), social connections (sociability, extroversion, etc.), and of course, physiological systems underlying cardiovascular functions and cardiovascular diseases themselves. Genetic and environmental factors also influence the person's capacity for religious or spiritual experiences, such that it may be "easier" for some individuals to be spiritual or religious because of their genetic makeup, temperament, or environmental experiences (including race, gender, education, economic situation). For example, the presence of genetic polymorphisms of the promoter region of the serotonin transporter gene may convey an emotional sensitivity to life events that makes an individual more likely to have spiritual or religious experiences, or more vulnerable to emotional distress, which in turn causes people to turn to R/S for comfort and emotional regulation. Indeed, there is growing interest in and research now being done on the genetic basis of spirituality. Thus, the relationship between R/S and cardiovascular health and disease is extremely complex, involving decision-making that is under the individualâ&#x20AC;&#x2122;s control as well as genetic and environmental factors over which the individual has no control. Concluding that a person has a cardiovascular disease (myocardial infarction, cardiac arrhythmia, atherosclerosis, high blood pressure, stroke or vascular dementia) because he or she is "not religious enough," then, is not possible because of the huge amount of information that is needed on which to base such a conclusion (including knowledge about the personâ&#x20AC;&#x2122;s genetic makeup).

10.1. Take a spiritual history. Cardiologists and cardiovascular surgeons should consider taking a brief spiritual history on all seriously ill patients whom they admit to the hospital. This also applies to patients seen for the first time in the outpatient setting, particularly those with chronic cardiovascular disorders that challenge ability to cope. The "screening" spiritual history is quite different from the comprehensive assessment that a chaplain would do when evaluating a patient. The screening spiritual history performed by the physician should take no more than 2-3 minutes, and usually consists of asking the patient about (1) his or her religious denomination, (2) R/S beliefs that assist with coping (or that might be causing distress), (3) R/S beliefs that might influence treatment decisions or conflict with medical care, (4) participation in a faith community and whether supportive, and (5) any other spiritual needs that are present and related to the patient's health or healthcare [254,255]. Besides gathering crucial information that will assist in the medical and surgical care of the patient, a spiritual history sends an important message to the patient: that the doctor is open to discussing these issues and will not avoid them or delegate them to others. When the physician takes a spiritual history, this has been shown to enhance the doctor-patient relationship [256]. However, before taking a spiritual history, the physician should prepare the patient by explaining why he or she is asking these questions. The reason for the questions has nothing to do with the severity of the patient's cardiac condition. Rather, the intention is to provide culturally sensitive care that addresses the whole person â&#x20AC;&#x201C; mind, body and spirit. If the doctor fails to provide such an explanation beforehand, the patient may get the wrong impression, i.e., that the reason the doctor is asking these questions is because the end of life is near and their condition is hopeless. 10.2. Value and support. When taking a spiritual history or discussing R/S matters, the doctor should always communicate to patients that he or she values and respects their R/S beliefs, and is supportive of them. This is true when the doctor has different religious beliefs than the patient, and even if the R/S beliefs of the patient conflicts with medical or surgical treatments. In the latter case, respecting and showing support for the patient's R/S beliefs will enhance the doctor-patient relationship and will likely increase the patient's adherence to medical treatments more generally and increase the likelihood that he will either ultimately comply or at least tell the physician if he doesn't comply. Rejecting or arguing with patients about firmly held R/S beliefs that conflict with treatment is usually disastrous, putting a wedge between the doctor and the patient and increasing the likelihood of resistance or subtle non-compliance. 10.3. Refer to chaplain services. If any but the most

10. CLINICAL APPLICATIONS Although scientific exploration on the influences that R/S has on cardiovascular health and disease is only in its infancy, and much further research is needed to better understand these relationships and effects, there is probably enough known already for us to make some suggestions on how to apply this knowledge to clinical practice. Bear in mind that the suggestions we provide here are largely based on common sense and clinical experience caring for patients with CVD, rather than on systematic research. Furthermore, space limitations allow us only to summarize our recommendations here and do so quite briefly. For a more detailed and comprehensive description of clinical recommendations (and limitations/boundaries), the reader is referred elsewhere [253]. In brief, here is what we would suggest:

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simple of R/S needs come up during the spiritual history, the doctor should refer the patient to a chaplain or pastoral counselor for further evaluation. The physician doesn't have the time or the training to address most patients' spiritual needs, and so should refer patients to experts in this area, especially if there are complex issues at stake. For example, a patient may tell the doctor that she feels that God is punishing her or doesn't care about her, or may even feel that she is going to hell. This is something that chaplains are trained to deal with. Doctors are not. Sometimes, however, if the patient refuses to see a chaplain, then the doctor will have to listen to these concerns and try to understand them (not argue about or dismiss them). 10.4. Engage. Should cardiologists or cardiac surgeons engage in religious or spiritual activities with patients? The most likely issue that comes up is praying with patients. Many religious patients (and even some non-religious patients), particularly when serious medical illness is present, would like to pray with their doctors, especially after hearing a bad diagnosis or prior to undergoing cardiac surgery. We believe it is appropriate for cardiologists and cardiac surgeons to pray with their patients â&#x20AC;&#x201C; if this is something they feel comfortable doing. However, the doctor should only do so after taking a spiritual history and if the patient asks them to pray. If the doctor asks patients to pray, this increases the risk of coercion (i.e., the patient may not want to pray with their doctor, but feel forced to do so in order not to offend or disappoint the doctor). Thus, if doctors are open to praying with patients, they should inform patients that they are willing to do so, but tell patients to ask for prayer at a later time if they wish to do so. In this way, the patient is free to either ask the doctor to pray (if the patient really wants prayer) or not, and no coercion will be involved. 10.5. Prescribe. Given the potential health benefits of R/S, should cardiologists or cardiac surgeons prescribe religious beliefs or activities to patients who are not currently engaged in them [257]? The answer is a resounding "no." Prescribing R/S is not appropriate and possibly unethical. When patients are sick and vulnerable, this is not a time to introduce new R/S beliefs or practices. However, in the vast majority of cases, patients will already be religious or spiritual, and no prescription is necessary. Supporting and encouraging the R/S beliefs and practices of the patient, though, may help to boost the effectiveness of those beliefs in helping the patient cope with their illness. 10.6. Limitations and boundaries. There are limitations to what physicians can do and boundaries across which they should not cross. First, as noted above, doctors should not prescribe R/S beliefs or practices to non-religious patients. Second, physicians should not force a spiritual history if the patient is not R/S (instead, switch the topic to

a discussion of what gives life meaning and purpose in the context of their illness and ask how this can be supported). Third, don't coerce patients in any way regarding R/S; this is a very sensitive and important topic to most patients and they need to feel in control. Fourth, do not pray with patients before taking a spiritual history and unless patients ask for prayer. Fifth, the doctor should not try to spiritually counsel patients unless he or she has the training to do so. Finally, the doctor should not do any activity related to R/S that is not patient-centered and patient-directed. Patient-centered medicine is now considered the standard of medical care, and this especially applies to addressing R/S issues. 10.7. Medical education. A recent survey of medical deans at Brazilian medical schools reported that many schools are beginning to address spiritual issues in the medical curriculum [258]. Researchers surveyed 86 of Brazil's 180 medical schools, finding that 5% had a required course dedicated to R/S and health and 6% had an elective course of this type (combined, nine of 86 schools with required or elective dedicated courses). In addition, 14 other medical schools said that they included a lecture on R/S and health at some point in the curriculum, and 12 more schools said that while they did not have a specific course or lecture on R/S and health, the topic was integrated into another course or lecture. Thus, 41% of the schools surveyed (35 of 86) had some type of content on R/S and health in the curriculum, either on a required or elective basis. Furthermore, when medical deans were asked whether their institution considered R/S and health important for their students, 54% said "very important", 36% "somewhat important", 11% "of little importance," and 0% "not important". These findings are similar to a recent survey of 122 medical schools in the U.S. that found that 7% of the 115 schools that responded had a dedicated required course on R/S and health, and 34% said they offered an elective course dedicated to R/S and health [259]. Likewise, about 40% of medical deans said that including R/S and health in the medical curriculum is important. Thus, many medical schools in both Brazil and the U.S. are now exposing students to spirituality and health in their curricula and there is a growing desire among medical school deans to include more such content in the future.

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11. FUTURE RESEARCH NEEDS Because of the influences that psychological, social, and behavioral factors have on cardiovascular health and disease (influences that are stronger than in most other medical conditions), and the influence that R/S has on those psychological, social and behavioral factors, the potential for R/S affecting cardiovascular health and

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disease is more likely than in any other organ system. The possible avenues for research on R/S and cardiovascular disease are almost endless, especially in Brazil where no research on this topic has yet been published in the peerreview literature. Given the religiousness of the population of Brazil and interest in R/S, particularly among those who are sick with CVD who use R/S to cope with illness, there is a huge opportunity to systematically study these relationships in Brazil. This also means opportunity to conduct research on the benefits or harm of physicians addressing R/S issues in the care of patients with CVD. Below are the types of studies that are needed. 11.1. Observational studies. Both cross-sectional and longitudinal cohort studies are needed on the relationship between R/S and all types of CVD. Prospective studies are needed to determine whether R/S involvement influences coronary artery calcification, left ventricular mass, ankle brachial index, carotid artery intima-media thickness, etc., over time, or predicts negative cardiovascular events. A model study is that of Feinstein et al. [260], but the design should follow patients over a longer time period and assess exposure to R/S across the lifespan rather than only R/S activity at baseline. Of particular importance are studies examining the interaction between R/S and pharmaceutical, biological, and surgical treatments for CVD. In other words, do highly R/S patients respond more quickly to treatment and with fewer complications, and maintain their response longer, compared with patients who are less R/S? Such studies are relatively simple and inexpensive to conduct. For example, if an investigator plans to study the effects of either a medication or a surgical procedure on cardiac outcomes, then measures of R/S could be added to the baseline interview and the effects assessed over time in terms of response to the treatment. There would be no additional cost to such a study, other than adding a few questions to the baseline interview. Time and expertise, however, would be needed to conduct the statistical analysis after the project is completed, and then write up the results for publication. The benefits of R/S to treatments for coronary artery disease, valve problems, heart failure, hypertension, peripheral vascular disease, or stroke could all be assessed using this low cost research strategy. 11.2. Experimental studies. Single group experimental studies conducted in the laboratory are also needed to determine whether prior R/S involvement or current R/S spiritual activities influence basic cardiovascular functions (cardiovascular reactivity, heart rate variability, ejection fraction, etc.) in response to an experimentally induced psychological or physical stressor. While a few studies have been done, more of these are needed that involve larger samples, that measure R/S in greater detail, and that more precisely assess cardiovascular functions. 11.3. Randomized clinical trials. Randomized clinical

trials are also needed that examine the effects of a R/S intervention on medical or surgical outcomes. The intervention might involve a religious cognitive-behavioral therapy that influences attitudes toward and coping with CVD, particularly among seriously ill, chronically disabled cardiac patients. Alternatively, an intervention could be designed that involves chaplain or clergy visits before and after cardiac surgery, followed by an examination of shortterm and long-term surgical outcomes (complications, hospital stay, re-admission rates, speed of wound healing, infection rates, need for pain medication, and mortality, for example). Another intervention might involve studying the effects of cardiac surgeons praying with patients (vs. no prayer with surgeon) on patient satisfaction, other psychological and behavioral outcomes, and surgical outcomes described above. A similar randomized clinical trial could examine the effects of medical cardiologists praying with patients, perhaps following a first-time acute myocardial infarction or a re-infarction. We have discussed here a few high priority areas that might be of interest to cardiovascular researchers. For a more comprehensive resource that outlines and ranks in priority the studies that are needed and their likely cost, and exhaustively describes how to conduct research on spirituality and health, the reader is referred to another resource [261]. This resource includes a description of the different research methodologies, R/S measurement tools, ways of conducting statistical analyses, writing up the results, and publishing the findings, as well as ways of funding this type of research. 12. SUMMARY Given the mechanism by which we think religion/ spirituality influences physical health, i.e., through psychosocial and behavioral pathways, and the strong influence that psychosocial and behavioral factors have on risk of developing cardiovascular disease, there is no medical condition that R/S is more likely to influence than CVD. Compared to the massive volume of research on R/S and health overall (over 3,200 quantitative studies), relatively little research has examined the effects of R/S on cardiovascular morbidity or mortality. Thus, there is a wide-open door for cardiovascular researchers in Brazil â&#x20AC;&#x201C; one of the most religious countries in the world â&#x20AC;&#x201C; to conduct groundbreaking research that establishes (or refutes) the effects that R/S may have on CVD. The fact is that in developed countries, cardiovascular diseases are now the most common cause of both death and functional disability [262]. If R/S beliefs and practices have any influence on CVD, no matter how small, then demonstrating this through research may lead to both a higher quality and longer life for millions worldwide. 117

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218. Tully J, Viner RM, Coen PG, Stuart JM, Zambon M, Peckham C, et al. Risk and protective factors for meningococcal disease in adolescents: matched cohort study. BMJ. 2006;332(7539):445-50. 219. Pereira DB, Christian LM, Patidar S, Bishop MM, Dodd SM, Athanason R, et al. Spiritual absence and 1-year mortality after hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2010;16(8):1171-9. 220. Gillum RF, Holt CL. Religious involvement and seroprevalence of six infectious diseases in US adults. South Med J. 2010;103(5):403-8. 221. Ironson G, Stuetzle R, Ironson D, Balbin E, Kremer H, George A. View of God as benevolent and forgiving or punishing and judgmental predicts HIV disease progression. J Behav Med. 2011;34(6):414-25. 222. Ironson G, Stuetzle R, Fletcher MA. An increase in religiousness/spirituality occurs after HIV diagnosis and predicts slower disease progression over 4 years in people with HIV. J Gen Intern Med. 2006;21(Suppl 5):S62-8. 223. Koenig HG, King DE, Carson V. Immune functions (ch 20), in Handbook of Religion and Health. 2nd ed. New York: Oxford University Press;2012. p.394-419. 224. Koenig HG, King DE, Carson VB. Endocrine functions. In: Handbook of religion and health, 2nd ed. New York: Oxford University Press;2012. p.420-38.

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246. Byrd RC. Positive therapeutic effects of intercessory prayer in a coronary care unit population. South Med J. 1988;81(7):826-9. 247. Harris WS, Gowda M, Kolb JW, Strychacz CP, Vacek JL, Jones PG, et al. A randomized, controlled trial of the effects of remote, intercessory prayer on outcomes in patients admitted ot the coronary care unit. Arch Intern Med. 1999;159(19):2273-8. 248. Benson H, Dusek JA, Sherwood JB, Lam P, Bethea CF, Carpenter W, et al. Study of the Therapeutic Effects of Intercessory Prayer (STEP) in cardiac bypass patients: a multicenter randomized trial of uncertainty and certainty of receiving intercessory prayer. Am Heart J. 2006;151(4):934-42. 249. Spirituality: don't pray for me! Please! Newsweek, Apr 9. Available at: http://www.thedailybeast.com/ newsweek/2006/04/10/spirituality-don-t-pray-for-me-please. html Accessed on: 9/3/2012. 250. Chibnall JT, Jeral JM, Cerullo MA. Experiments on distant intercessory prayer: God, science, and the lesson of Massah. Arch Intern Med. 2001;161(21):2529-36. 251. Bishop JP, Stenger VJ. Retroactive prayer: lots of history, not much mystery, and no science. BMJ. 2004;329(7480):1444-6. 252. Koenig HG, King DE, Carson VB. Handbook of religion and health. 2nd ed. New York: Oxford University Press;2012. p.587. 253. Koenig HG. Spirituality in patient care. 3rd ed. Conshohocken: Templeton Press; 2013. 254. Koenig HG. An 83-year-old woman with chronic illness and strong religious beliefs. JAMA;288(4):487-93. 255. Koenig HG. Taking a spiritual history. J Am Med Assoc. 2004;291:2881. 256. Kristeller JL, Rhodes M, Cripe LD, Sheets V. Oncologist Assisted Spiritual Intervention Study (OASIS): patient acceptability and initial evidence of effects. Int J Psychiatry Med. 2005;35(4):329-47. 257. Sloan RP, Bagiella E, VandeCreek L, Hover M, Casalone C, Jinpu Hirsch T, et al. Should physicians prescribe religious activities? N Engl J Med. 2000;342(25):1913-6.

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SPECIAL ARTICLE

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Cardiac surgery: the infinite quest. Part II Cirurgia cardíaca: a busca infinita. Parte II

Rodolfo A. Neirotti1 Publicamos, abaixo, a segunda parte do artigo “Cardiac surgery – the infinte quest”. Apesar de mais complexo que a anterior, este texto vai além das habilidades técnicas e tem conceitos modernos de como lidar com os sistemas complexos da atual prática da nossa profissão e especialidade. Domingo Braile Editor-Chefe/BJCVS/RBCCV

DOI: 10.5935/1678-9741.20130016

Part II Cardiac surgery: issues around and beyond the operating room Ultramini-abstract: In addition to our clinical and technical work, there is a need to cross boundaries searching for collaboration as well as lessons from other complex systems that has identified common solutions for common problems, indicating that the general theory is independent of any particular industry or activity. Cardiac surgery: a complex system Heart surgery has much in common with other high technology systems in which performance and outcomes depend on multifaceted interactions of individual, technical and organizational factors. In addition, our specialty often functions as a chaotic/emergent system since the initial circumstances vary in patients with the same medical condition resulting in uncertainty and lack of predictability [1]. Complexity: The American Heritage Dictionary defines complex and complicated as “things whose parts are so interconnected or interwoven as to make the whole perplexing”. If we add rarity and small numbers to complexity, the results is a distinctiveness that explains many aspects of our profession and specialty such as variability with institutional differences in outcomes; inconsistency of results in treating rare diseases and uncertainty on any inference about results of complex rare lesions [2]. 1. MD, MPA, PhD, FETCS, Honorary Member of the Brazilian Society of Cardiovascular Surgery.

RBCCV 44205-1449

A system is a set of interdependent elements that are interacting, or working together, to accomplish a common goal. All systems, at the “atomic” level, consist of individuals, activities, connections, and pathways with the following characteristics, qualities or peculiarities in complex systems: • Heterogeneity of the parties (diverse nature and multiple); • Cause-and-effect relationships may be nonlinear and obvious only in retrospect; • Richness of interaction between them (including their contradictory character); • Multidimensional and multi-referential; • Many variables commonly present; • Provide information that by itself reveals the extent of its complexity; • Under an apparent simplicity, they often hide the true dynamics of these processes and interactions between its parts • Vulnerability — Are influenced by factors and surprising circumstances that may affect, cause, or facilitate a change in behavior and expected results, altering all or changed significantly “Complex business generates complex services. Regardless of how much effort and brain power go into designing their complex operations (‘system of work’), it is impossible to do it perfectly and to predict how it will behave under every circumstance” [3]. Complex systems are rich in multiple and interdependent Correspondence address: 1199 Beacon St, Unit 2. Brookline MA 02446 USA E-mail: ra_neirotti@ksg06.harvard.edu Article received on January 31st, 2013 Article accepted on February 28th, 2013

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events that usually manifest unforeseen consequences that are nonlinear and often asymmetric — frequently called black swans. Why call big surprises black swans? It goes back to the second century when Roman poet Juvenal said that some events are “as rare as a black swan” [4]. History is shaped by events that seem impossible until they occur changing predictions and planning. Surprises are by definition unexpected and therefore well beyond the limit of our experience, not allowing us to pick the “next disaster”. Why can’t we foresee these events? Blame it on the way humans make sense of the world — most of their experience falls within a tightly bounded range called “the norm”. Focusing on that narrow array carries the risk of preparing us only for events we are familiar with [5]. Rare diseases — rare as Black swans — are a challenge for the Science of Cardiac Surgery because of their infrequency at any single institution, and thus the gaps in knowledge. Because of this, there is little chance that randomized comparison can be accomplished. In this setting, highly variable outcomes are predictable given the scarceness of skill-based, rule-based, and knowledge-based foundations for performance that avoids and compensates for human errors, the inevitable breakdowns due to complexity and uncertainty. Statistics to determine risk are not available; we just do not have them due to their rarity. Complexity thus calls for experimentation. Once patterns become apparent, it is possible to attempt to destabilize undesirable interactions [6]. By contrast, in chaotic situations — highly sensitive to initial conditions — there are no trends to monitor. Sometimes complexity is at the "edge of chaos” without a pattern to differentiate. Clayton Christensen reminds us that “Theory is often associated with the word theoretical, which, among practical people, has a connotation of impracticality. However, a well researched theory is practical because it allow us to know what cause what and why, and to predict the result of an action. The key to developing a theory that is valid internally and externally is to seek anomalies, to find instances in which the explanation of causality does not yield the result that the theory predicts. The scientific method requires to search for instances in which the theory does not work” [6]. “As the circle of science grows larger, it touches paradox at more places” Nietzsche. Managing complexity: Steven Spear aptly describes the problem and manner of managing complexity: “There are high velocity organizations — whom everyone chases but never catches — that manage to stay ahead because 130

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of their endurance, responsiveness, and an exceptionally high velocity in self correction. They see and seize opportunities and, by the time rivals responded, the leaders have raced on to further opportunities — these systems pose both the capacity to retain their viability and the capacity to evolve” [3]. “These organizations — complex adaptive, selfimprovement systems — face a common problem and have identified a common solution, which keeps them performing way ahead of the pack and always getting better — the two go together. The solution has been used successfully by a wide variety of organizations indicating that the general theory is independent of any particular industry or activity” [3,7]. “And this leads to collaborative rationality, of getting better together, which is a different way of knowing and generating, of making and justifying decisions based on diversity, interdependence and authentic dialogue — not always accepted by the chain of command despite of the limitations of acting unilaterally. The agents interact dynamically, exchanging information and the effects of these connections flow through the system. There are many direct and indirect feedback loops; the overall system is open. The behavior of the system is determined by these interactions, not the components; and the behavior of the system cannot be understood by looking only at the components” [7,8]. Diversity: "Diversity implies that a collaboratively rational process must include not only agents who have power but also those who have needed information or could be affected by outcomes of the process". As in direct democracy, their success depends on the amount and quality of the information available to those involved in the decision making process [9,10]. Interdependence: “Agents must depend to a significant degree on other agents, considering that each stakeholder has something that the others want. This condition ensures that participants maintain a level of interest and energy required to engaging each other and pushing for consensus — such interdependence means that players cannot achieve their interests on their own” [10]. Authentic dialogue: “Deliberations must be characterized by direct engagement so that the parties can test to be sure that claims are accurate, comprehensible, and sincere. Deliberations cannot be dominated by those with power outside the process, and everyone involved must have equal access to all the relevant information and an equal ability to speak and be listened to. In authentic dialogue, nothing is off the table” [10].

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Structure and dynamics of successful high velocity organizations Structure: Managing and integrating the functions as part of the process. Dynamics: “Continually Improving the Parts and the Process, by engaging those closest to the work in the continual improvement, their speed of detecting and problem solving, learning, and discovering better ways of how to produce. Any snapshot will reveal where they are today but not where they are headed determined by their DNA”. “These organizations, share four capabilities that can be adapted to medical situations: a) specifying design to capture existing knowledge and building in tests to reveal problems and improve a process; b) detecting and rapidly solving problems to build new knowledge avoiding memory perishability; c) sharing new knowledge throughout the organization; d) leading by developing the above mentioned capabilities by allowing enough time and resources for staff/team training, turning employees into problem solvers. Operations are designed to continually let them know that it does not know all there is to know. When the operations speak, these organizations listen, learn, improve, and wait for the next lesson. The lesson learned here and now is spread throughout the organization. The high velocity set themselves apart in how they deal with the problem of unknowable unpredictable systems, understanding, learning and recovering from failures” [3]. How complex systems fail: in those systems that fail, their pieces come together through hard work, goodwill, and improvisation. Their components are managed as if they operated independently; in fact they are quite interdependent. Although it could be a "Sisyphean task" some of them fail wisely learning from their mistakes and try again. However, the choices are often both clear and stark: organizations must either modify their forms and structures (reinvent) in ways appropriated to the emergent environment or, over a period of time, cease to exist. Occasionally, disruptive innovations, creating new organizations are necessary rather than transformation of existing outdated institutions. Like in our profession, the first step to treatment is diagnosis. If one considers that a system has an illness — dysfunction — the first step should be to make a diagnosis to uncover its root causes. Often, administrators and managers have a tendency to prescribe treatment without a proper diagnosis that would allow identifying the systemspecific problems. Policies that work in some setting may not be effective in a different context. A chart constructed

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by combining a diagnostic tree with the National Diamond Model allows displaying the components of the system and pinpointing the potential binding constraints affecting performance and growth before implementing reforms. A similar approach, with different factors, can be used in program evaluations [11,12]. There are many factors which contribute to failed or failing institutions [13]. Reasons people fail • Personal weakness — failure to reach a minimum required performance; • Poor people skills — inability to relate to others; • Deviance — violating an agreed process or practice; • Negative attitude — in reacting to adverse circumstances of life; • Bad fit — mismatched abilities required to execute the job, interests, personality, values; • Lack of focus and attention — priorities not well established leading to inadvertent departure from stipulations; • Weak commitment — not giving the task our very best; • Unwillingness to change — major enemy of success; • Shortcut mind-set — take the shorter road to success; • Excessive confidence — it is not beyond my scope or skills. I can do no wrong → Ego; • Relying on talent alone — avoiding hard work to improve it; • Response to poor information — not feeling you need more information; • No goals — lack of a dream with a time limit; • Frustration — not learning from failures; • Anger: according to Aristotle, “Anyone can become angry, that is easy — but to be angry with the right person, in the right degree, at the right time, for the right purpose, and in the right way — that is not easy”. Rationally speaking, it is a very important emotion and a huge driver of human behavior. In some cases it is even welcome; however, those that can control it — i.e., those who have emotional intelligence or are emotionally astute — avoid being an angry decision maker and may have an advantage in their daily life. In sum, showing your anger conveys a toughness that can help you get what you want. But beware: When your counterpart has better information than you do, your anger could work against you [14]. Human behavior and errors: Medical errors cause 90-120,000 preventable deaths per year in the USA — far more than in car crashes — costing the industry somewhere between $9 billion and $15 billion a year. 131

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Furthermore, only 50% of US patients receive adequate quality of care, altogether enough to take the necessary actions to reduce risk the factors. It is a basic principle of systems that every one of them is perfectly designed to achieve the results it attains. Academics, by studying these systems, could contribute to a better understanding of how the components relate to one another in designing a self improving process that prevents mistakes from occurring. In addition, medical schools should consider building up awareness of the importance of prevention of medical errors among students early on their career [6]. The fact that complexity makes errors inevitable should not be an excuse; we should to do our best to avoid them. Human factors research has been a major contributor to safety, enhanced reliability and error avoidance in those complex socio-technical systems such as the aviation industry. Their long used safety check list looks like a simple and helpful tool to reduce errors, complications and deaths in medicine, as well as in other professions [15]. Unfortunately, industry and watchdogs often rely far too much on a patchwork of retroactive rules, with inspectors adding the negative event to their checklist each time a trouble is found in one of the components, decreasing its usefulness, particularly if thereafter the new norm is looked at with the old lenses. Imperfect outcomes are caused not only by lack of knowledge — ignorance — but by imperfect selection of treatment, imperfect performance, and are too often caused by human errors. Mistakes are the result of either the misapplication of good rules — ineptitude — or the application of bad rules. Most mistakes can be traced back not just due to flawed execution but to flawed thinking of people trying to do a good work, and a tendency to make absurd decisions [16]. Team communication, organization, and mutual supervision are crucial to minimize the chance of making a mistake. Technical failure and human error led to the loss of an Air France flight over the Atlantic in June 2009 and the deaths of 228 people, according to the final report of the French air accident investigation agency (Pilot Linked to Air France Atlantic Plunge, BBC News, July 5, 2012). Similarly, the Fukushima nuclear plant was "a profoundly man-made disaster that could and should have been foreseen and prevented" and its effects "mitigated by a more effective human response" according to the report of the Japanese parliamentary panel. The report catalogued serious deficiencies in both the government and plant operator response adding that regulators should "go through an essential transformation process" to ensure 132

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nuclear safety in Japan (Japan panel: Fukushima nuclear disaster 'man-made'. BBC News, July 5, 2012). It is important to recognize that medicine is so complex that no human being can be in control of everything without some sort of compensation for bounded rationality or hyper rationality. Furthermore, over the last decades, science has filled in an enormous amount of knowledge, challenging even more the human mind’s limited capacity to evaluate and process the information available, considering the time constraint to make some decisions. We have to achieve near perfection in the shortest possible time avoiding the “let's-get-home-itis”, a disease in judgment that has negative impacts on a number of surgeons who sing the praise of speed and quick operations. It may be part of human nature to err, but it is also part of human nature to develop solutions, find better alternatives, and meet the challenges ahead. Rather than punishing those that make mistakes, it is more effective to find out why they made the mistakes in order to act on the system to diminish the odds of repetition [17]. Negative events in complex systems Minor Events are subtle, insidious, except to human factors observers, and many of them largely overlooked by the operator and the team members. As a result, no attempt to correct them is made. In isolation, they have little impact, but their multiplicative effect can lead to negative outcomes. Near Misses can cause severe temporary or permanent complications. By paying attention to close calls, it is possible to recognize them, learn and eventually predict and prevent major events. Unfortunately, decision makers have often a tendency to view near-disasters as successes! Major Events, without compensation, are likely to lead to death. Because they are more obvious, they can be recognized, triggering rescue actions to avoid catastrophic consequences. Risk Factors for Complications are more related to patient variables than to structural hospital characteristics. The highest quality, lowest risk hospitals have a higher prevalence of rescue from complications. It is the failure to compensate that leads to a negative outcome [18]. Individual and organizational factors and their interactions Individuals: Exchanges with highly qualified individuals concerning change often involve negotiation and compromise, since they would not comply with the instructions without adequate rationale. It is not a matter

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of who is right or who is wrong; the focus must be on what professionals should care about: the patient. Though silence is associated with many virtues, it can exact a high price on individuals, generating feelings of humiliation, paralysis, anger and resentment, and eventually, if unexpressed, can seriously damage an organization. Silence can also be the result of cultural conventions and a reluctance to question authority. The message throughout the organization should be: STOP! Any question from the team? “If you see something that concerns you please speak up”. It is difficult to manage secrets! This approach thwarts the blame game, helping to build a culture that promotes participation, and encourages detecting, analyzing, and learning from failures [19]. Organizational factors: Team work in which all components of the cardiovascular services — a cluster of people with similar interests, all focused on excellence — contributes to the quality of the final outcome with an integrated approach. Using an orchestra as a paradigm of team work, a conductor — the chief cardiac surgeon in most centers — leading from the front and by example is needed, working out the problems collectively with the individual orchestra members. He does not produce the sound but he can inspire, teach, and persuade. It is about how to play rather than what, an excellent example of the importance of coaching something that surgeons seldom do. After all, “Music fills a gap in life like nothing else — and brings serenity when other things cannot” [20]. Interaction, negotiation and compromise: In an ideal world, after an operation, patients stay in the intensive care unit where the physician on duty must synthesize information from various sources and personnel into a sound plan of care. When another physician, such as the cardiovascular surgeon — when they participate, though often they do not — collaborates with the critical care specialist to manage a patient, the relationship requires mutual respect and cooperation, without patient ownership, in order for optimal patient care to occur. If the dialog starts with someone saying: this is my patient! It is a bad start. Every agreement in the ICU involving two physicians is a negotiation as much as it is collaboration. Each person concerned approaches the interaction with a defined (and possibly different) idea of what he wants to happen, and therefore there is an urgent need to reach agreement on a plan of action. If you approach a negotiation thinking you know everything, you may not make the best decisions. You could be missing out on information, insight and suggestions that may be critical to the outcome. A leader

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who doesn't nurture an atmosphere where ideas are welcome is shortchanging his or her effectiveness. In addition, team members who are discouraged from giving opinions or input will be ineffective players. It is prudent to approach these discussions with a few ground rules in mind. First, there are certain basic principles of care known to be true that should not be compromised. Second, both parties will learn something from the interaction. Third, there is much in medicine that is either uncertain or can be approached in more than one-way. Ultimately, the best plan more often than not results from honest open communication between physicians and the melding of the best of both points of view. If beyond winning, both physicians enter into the negotiation accepting that give and take is essential to the process, then a well reasoned design of care is achieved and the patient benefits greatly. An analogous approach is applicable to the interactions among surgeons, cardiologists, anesthesiologists and perfusionists. It is difficult to have a team unless every member has respect for people who have different skills [21,22]. The power of a positive NO: “No is perhaps the most important and certainly the most powerful word in the language. Every day we find ourselves in situations where we need to say No — to people at work, at home, and in our communities — because No is the word we must use to protect ourselves and to stand up for everything and everyone that matters to us”. “Saying No the right way is crucial. A wrong one, a clear a resounding NO! can also destroy what we most value by angering and alienating people. The secret to saying No, clearly, respectfully, and effectively, without destroying relationships lies in the art of the Positive No, a technique that anyone can learn. The Positive NO can help you to get not just any Yes but to the right yes the one that truly serves your interests” [23]. Quality: “An essential and distinguishing attribute of something or someone” (Word Net Dictionary). It is difficult to define, but you know it when you see it! Quality is measurable and requires appreciation to recognize the quality, its significance or magnitude and appreciation requires knowledge. In medicine as in many other businesses precision equals precise diagnosis plus doing the right thing (effectiveness) plus doing it right the first time (efficiency). Precision in medicine not only improves outcomes but also can dramatically cut costs. In health care, cost is not a proof of high quality and low cost comes from focus. Value added procedures are possible only after a precise definitive diagnosis has been made [6,24]. 133

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Quality comes from correct integration to get the job done. As we improve the technology of medicine, we also need to include the patient’s story in the equation: Quality of care equals technical quality (precise diagnostic, doing the right thing and doing it correctly) plus service quality, both throughout a process that cannot be turned off at five o’clock. Adopting the quality equation is a decision and a commitment one makes every day that never goes away, that needs to be sustained all year long to become a habit. Institutional quality and qualified people are the key to making quality products, with the best possible use of the ordinary distribution of human talent and a permanent awareness of personal and institutional limitations [25]. Service quality: The privilege to assist in preserving and improving life provides us with much professional satisfaction. But, do we have the necessary background to fulfill the humanistic demands of our profession? Often, one recognizes professionals who have mastered scientific facts and surgical techniques but who lack interpersonal skills and respect for the dignity of man, empathy, and humility. Remember that our attitude often trickles down to the entire team! [26]. To achieve this, a combined approach is necessary, inducing change from the top, by influence or persuasion and commitment to education, and encouraging bottomup grassroots involvement and cooperation. Promoting bottom-up chances is an important component of Edwards Deming’s principles of total quality management. Both the top-down and the bottom-up approaches are not mutually exclusive but rather complementary and are what is meant by Total Quality Management. • Total Quality Management (TQM) is a business strategy aimed at embedding awareness of quality in all organizational processes making it the responsibility of all employees. • TQM requires a re-organization of the work process and the workplace by application of principles of “teamwork” and work “teams” that are supposed to involve the workers and give them greater control in their work Quality problems and categories of poor quality: Overuse, underuse and misuse of funds due to: defensive medicine, ignorance, the culture of money, poor attitude, lack of knowledge, resources, or technology, as well as corruption, greed, etc. Reforms such as revisions to the fee-for service reimbursement and the incentive it provides for overuse can result in significant savings [27,28]. In other words, health care providers who ensure quality care, customer satisfaction, cost control, and efficient and appropriate use of resources, are preferred. 134

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Reporting of quality • Lay media: Anecdotal; substantiation not required; short-lived; • Professional literature/media: Scientific process; scrutinized data; longer lasting; • Value of representation in both lay and professional media: Credible evidence-based outcomes, that are recognized in the professional literature and attract the interest of the lay media provides the best of both worlds. Quality of care: Using “network science”, a method of analysis that examines webs of connections in complex systems, it is possible to map the “Product Space” by depicting clusters of capabilities/products grouping them according to their relatedness. The concept of “proximity” formalizes the intuitive idea that the ability of a center to generate an outcome depends on its ability to produce other ones — “structure of production”. When a center with many complex capabilities adds a new capability, it can create a range of new possible products — new complex procedures. Conversely, adding a single new capability in a center that has few to begin with won’t leverage an existing matrix of capabilities in the same way, indeed it might not produce any new products at all [29]. Systems of care, their impact on quality: Although the knowledge and practice of individual clinicians are important for high-quality care, today we realize that no health care professional can deliver high quality alone; therefore, health care professionals prefer to practice within groups — proximity — and systems of care. Systems of Care equal institution plus staff partnership plus product space plus structure of production [29,30]. Institutional variations in hospital mortality associated with inpatient surgery • Rates of death vary across hospitals, from 3.5% in low-mortality hospitals to 6.9% in high-mortality hospitals; • High mortality hospitals have complications rates similar to those of low mortality hospitals (24.6% and 26.9%, respectively) and of major complications (18.2% and 16.2%, respectively); • Mortality in patients with major complications was almost twice as high in hospitals with high mortality than in those with low mortality — high velocity organizations — (21.4% vs. 12.5%, P<0.001). Hospitals with higher mortality rates — the pack — are less effective in rescuing patients from complications; • Timely recognition and effective management of complications are important in reducing deaths after surgery;

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• The value of avoiding complications is obvious. The quality of care once complications have occurred is crucial for reducing mortality [30]. Business intelligence: how are we doing? Business intelligence — the systematic use of information about one’s business — is vital to understand, report on, and to predict different aspects of performance. High quality intelligence capabilities and analytic skills play crucial roles in the most competitive sectors of the global economy because it can avert bad events providing that the dots are properly linked. How are we doing? Due to the current demand for excellence and transparency, hospitals should start collecting and analyzing data — a method to evaluate future improvements — about outcomes calling for quality from their practitioners in preparation for a not too distant future. Implementing an independent measurement and a reporting system — business intelligence — focused on patient safety with a view to eventually making the information available to the public, will have an impact on quality, as well as on consumer and patient satisfaction. An accurate and unbiased statistical analysis of surgical outcomes allows for an intelligent search of the risk factors, continuous improvement through responsiveness of the parts and the course of actions, as well as for a valid comparison with other institutions. The truth is the truth wherever it is found and to dismiss it because it comes from people with different views is a mistake. Undoubtedly, gathering accurate information is vital also because politicians, bureaucrats and company officials are often wary about alarming citizens. The systematic use of information requires good data and commitment of executives to fact-based and analytical decision-making as a way to learn rather that doing it out of gut feeling or intuition — cognitive illusions, illusion of validity [31]. Gathering solid data, working analytically, and leaving emotions aside all help those on the top to reflect critically on their own behavior, and then change how they act to make better decisions. Efforts to develop fact-based decision-making capabilities are likely to fail unless they are closely supported by top management. High performance organizations adapt and thrive by rapidly making choices that others do not by moving the decision making process down, close to the generation of information and around the needs of the user, instead of moving the information up to the executive suite. The people who construct statistics are very often not the same kind of people needed to publicize them. An

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effective leader should be able to comprehend numberladen reports, evaluate the information provided to him, and draw conclusions from data, rather than be dependent on others to interpret for him. Altogether, evidence-based medicine improves patient care using metrics and evaluations as a tool for learning rather than accounting. Two categories: Reporting: Those providing services to the public, needs to report accurately on what is going on in their business. By getting a relatively early warning on their performance they can fix the problems and educate the team members encouraging their participation with a button up plus horizontal approach. Analytics: This is more understanding-oriented in terms of knowing what factors are really driving your business performance, or prediction-oriented, looking forward instead of backward. Inferences • Cardiac Surgery is not immune to the waves of innovations — Kondratieff waves — sweeping the world at large over the past fifty years starting with disruptive new technologies that have tranformed industries, societies and economies beyond recognition. Developing economies have been spared this technological onslaught, but they might soon have this same problem [32]. As President J. F. Kennedy put it, “Great change dominates the world, and unless we move with change, we will become its victims”. • An innovative partnership among the government, the private sector and foundations can led to major advancement of the health system. • Listening to customers is in general a good idea, but it is not the whole story; in order to innovate smart companies should sometimes ignore what the market says it wants today, relying on inspiration and even distorting reality for the genesis of new products. • We should be prepared for changes in the patient population requiring surgery. Conventional surgical procedures are expected to diminish. Hybrid procedures, requiring special facilities and team work with the participation of people with different skills will be more often adopted. ► Part III will be published in the next issue of the RBCCV Pediatric Cardiac Surgery: a discipline on its own Ultramini-abstract: Although there are common grounds with adult cardiac surgery, it is important to 135

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understand the differences in the business plan, paths, manpower, mindset, training, and infrastructure that are essential in those institutions where pediatric cardiac surgery can and should be performed. Time to start thinking, it is not what we can do, but should we do it?

16. Blackstone E. Cleveland Clinic Foundation, personal communication.

18. De Leval MR, Carthey J, Wright DJ, Farewell VT, Reason JT. Human factors and cardiac surgery: a multicenter study. J Thorac Cardiovasc Surg. 2000;119(4 Pt 1):661-72.

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1. Neirotti R. Paediatric cardiac surgery in less privileged parts of the world. Cardiol Young. 2004;14(3):341-6. 2. Blackstone EH. The challenge of rare diseases. Joint Meeting of the Congenital Heart Surgeons Society and the European Congenital Heart Surgeons Association. Montreal, October 2-4, 2004. 3. Spear SJ. Chasing the rabbit. New York: Mc Graw Hill; 2009. 4. Taleb NN. The Black Swan: the impact of the highly improbable. New York: Random House; 2007. 5. Fugate C. Federal Emergency Management Agency in Preparing for the Next Disaster: The future of crisis data The Nonprofit Technology Network Oct 13, 2010 13:17. 6. Christensen CM, Grossman JH, Hwang J. The innovator’s prescription. a disruptive solution for health care. New York: Mc Graw Hill; 2009. 7. Christensen C. Foreword. In: Spear SJ, ed. Chasing the rabbit. New York: Mc Graw Hill; 2009. 8. Susskind's L. blog on Innes JE, Booher DE. February 20, 2010 about the Book Planning with complexity: an introduction to collaborative rationality for public policy. New York: Routledge; 2010. 9. Innes JE, Booher DE. Planning with complexity: an introduction to collaborative rationality for public policy. New York: Routledge; 2010. 10. Democracy in California. The Economist, April 23rd-29th; 2011. 11. Hausmann R, Rodrik D, Velasco A. Competitive advantage of nations growth diagnosis. Boston: Harvard University; 2004. 12. Porter M. Competitive advantage of nations. New York: The Free Press; 1998. 13. Maxwell JC. Failing forward: turning mistakes into stepping stones for success” Thomas Nelson Inc, April 3; 2007. 14. PON Staff. Tempering your temper. the downside of anger. The Negotiation newsletter. Program on Negotiation at Harvard Law School, April 5, 2011. 15. Gawande A. The checklist manifesto. New York: Metropolitan Books; 2010.

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17. Leape L. Medical errors, public health challenges of the 21st century. Health care think tank. Advanced leadership initiative. Boston: Harvard University; 2009.

19. Edmondson A. Strategies for learning from failures. Harvard Business Review 2011;48-55. 20. Newman M. Life trustee. Boston Symphony Orchestra;2011. 21. Neirotti RA. Cardiac surgery: complex individual and organizational factors and their interactions. Concepts and practices. Rev Bras Cir Cardiovasc. 2010;25(1):VI-VII. 22. Hackbarth R. DeVos Children Hospital. Grand Rapids MI, Personal communication; 2006. 23. Ury W. The power of the positive no. New York: Bantam Books;2007. 24. Meeting of the Joint Committee of Primary Care Trusts (JCPCT) United Kingdom, 16th February, 2011. 25. Shore MF. Harvard Medical School, Personal communication, 2007. 26. Castañeda A. Perspectives on Success in Congenital Heart Surgery. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2008; 88-90. 27. Mello MM, Chandra A, Gawande A, Studdert D. National costs of the medical liability system. Health Aff. 2010;29(9):1569-77. 28. Chassin MR, Galvin RW. The urgent need to improve health care quality. Institute of Medicine National Roundtable on Health Care Quality. JAMA. 1998;280(11):1000-5. 29. Hausmann R, Hidalgo C. In: Jonathan Shaw on “Complexity and the wealth of nations” Harvard Magazine. March-April 2010. 30. Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality associated with inpatient surgery. N Engl J Med. 2009;361(14):1368-75. 31. Davenport T. Research sees business intelligence emerging as crucial competitive advantage. Babson College MA; News room release date: 4/12/2005. 32. Šmihula D. Waves of technological innovations and the end of the information revolution. J Economics Int Finance. 2010;2(4):58-67.

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Dallan LAO, etSPECIAL al. - Myocardial revascularization in the XXI century ARTICLE

Myocardial revascularization in the XXI century Revascularização miocárdica no século XXI

Luís Alberto Oliveira Dallan1, Fabio Biscegli Jatene2

Always concerned with the historic rescue of cardiovascular surgery, the Brazilian Journal of Cardiovascular Surgery (BJCVS) publishes the following article, written by Dr. Luis Dallan and Fábio Jatene, respectively, Associate Editor and former Editorin-Chief of BJCVS. In a text rich in detail, they write about the history of CABG, from its beginnings until prospects of the currently consecrated technique and that should be aware of all cardiovascular surgeons.

DOI: 10.5935/1678-9741.20130017 Descriptors: Myocardial revascularization. Coronary artery bypass. Cardiac Surgical Procedures/History. History.

HEART: BODY THAT UNTOUCHABLE Despite the acceptance and routine use of cardiac surgery nowadays, i was not always so. In the late 19th century and early 20th century, the surgical treatment of heart was considered beyond any question. One of the clearest examples of this view was the declaration by Theodor Billroth in the meeting of the Medical Society of Vienna, 1881, who stated: “The surgeon who wished to preserve the respect of his colleagues would ever attempt to suture the wound of the heart” [1]. Even in the early decades of the 20th century heart surgery gained great expression. Proof of this is the absence

1. Associate Professor at Faculty of Medicine at University of São Paulo. Director of the Coronary Disease Surgery Unit of the Heart Institute (InCor) at Faculty of Medicine at University of São Paulo, São Paulo, SP, Brazil. 2. Titular Professor of the Cardiovascular Surgery Discipline at Faculty of Medicine at University of São Paulo, São Paulo, SP, Brazil.

RBCCV 44205-1450 Descritores: Revascularização miocárdica. Ponte de artéria coronária. Procedimentos Cirúrgicos cardíacos/ História. História.

of any mention of it in the classic book “The Century of the Surgeon”, published in 1957 by Jurgen Thorwald [2]. However, from the years 1950, cardiopulmonary bypass has gained great development and became progressively employed in clinical practice. This allowed the real principle of heart surgery and generated its fantastic boost, which did not cease until the present day. THE PRESTIGE OF CARDIAC SURGERY Despite a timid start to the second half of the 20th century, from the 1960s the cardiac surgery has gained tremendous visibility. The figure of the cardiovascular surgeon came to

Correspondence address: Luís Alberto Oliveira Dallan Av. Enéas Carvalho Aguiar, 44 – Cerqueira César – São Paulo, SP, Brasil. Zip code: 05403-000 - E-mail: dcidallan@incor.usp.br Article received on November 24th, 2012 Article accepted on October 1st, 2012

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be celebrated publicly, with much prestige as astronauts. Names like Dr. Christiaan Barnard, Denton Cooley, Michael DeBakey and Norman Shumway became known for the huge audience, especially after the advent of heart transplantation. In Brazil it was no different. It was up to teachers as Euryclides Zerbini and Adib Jatene assume this leadership [3]. ARTERY BYPASS GRAFTING: ADVANCES ESTABLISHED Today, surgical treatment of coronary artery disease is probably the most studied topic among all medical specialties. This fact certainly makes the method more attractive and greatly honors who proceeds. Moreover, it also keeps the surgeon under constant stress and challenge. Historically, CABG is involved in a huge visibility. Besides the possibility of imminent death compared to procedures that manipulate the coronary arteries, the alternatives available today, such as angioplasty, contribute to the debate about what is the best procedure for coronary disease. BEGINNINGS OF ARTERY BYPASS GRAFTING The notion of coronary artery disease was brought to the Royal College of Physicians in 1768 by William Heberden and published in 1772 in the Transactions of the Medical College. However, the relationship between this disease and angina was not completely elucidated, and only in 1876 Adam Hammer [4] suggested that the angina pectoris and myocardial infarction could be attributed to the reduction or interruption in coronary blood flow when at least one of the arteries of the heart was compromised. This allowed better understanding of coronary artery disease, enabling the programming of its treatment. The methods of myocardial revascularization were not established from day to night, neither linearly. Initially, the procedures used were abandoned to be later reproduced again and sometimes were considered ideal. In the first decades of the 20th century countless procedures on the heart were used, seeking the relief of angina symptoms. These methods were all indirect and ineffective. Among them, the one proposed by Beck et al. [5] at the Cleveland Clinic in 1935, which sought to obtain collateral circulation with the involvement of structures such as pericardial fat, pectoral muscle or omentum on the chiseling epicardium. Only in 1951 Vineberg et al. [6], after extensive experimental study involving the development of collateral circulation, proposed the implant of the internal thoracic artery in the left ventricle muscle. For that, they performed a tunnel amid the ventricular wall, which was posited within 138

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the internal thoracic artery. The branches of this artery were kept bleeding, aiming to establish future connections with ischemic myocardial arterioles. This technique achieved good results and was an important treatment of angina for several years. DIRECT MYOCARDIAL REVASCULARIZATION: A CONTROVERSIAL START Certainly the great impetus to the development of myocardial revascularization was the advent of coronary angiography in 1958, assigned to Sones et al. [7] at the Cleveland Clinic. However, the idea of directly revascularize the myocardium met resistance until the mid 1960s. On May 2, 1960, Goetz et al. [8] performed the first successful coronary artery bypass grafting. They anastomosed the right internal thoracic artery with the right coronary artery, using mechanical suture with tantalum ring. Despite the patency be maintained for 1 year, they were strongly criticized by fellow clinicians and surgeons and the procedure was deemed unsafe and of experimental nature. Goetz never performed any revascularization [9]. In 1962, David Sabiston performed a saphenous vein graft with a patient who died after three days of neurological complications. The case was only reported in 1974. In 1964, Garrett et al. [10] performed at Methodist Hospital in Houston, the first successful coronary artery bypass grafting with saphenous vein after failure in coronary artery endarterectomy. An angiogram after seven years demonstrated graft patency and the case was reported in 1973. ARTERY BYPASS GRAFTING: EXCELLENCE TECHNICIANS THAT HAVE PERPETUATED Internal Thoracic Arteries In Leningrad, Russia, Kolessov [11] performed on 25 February 1964, the first anastomosis of the left internal thoracic artery to the anterior interventricular branch of the left coronary artery. The technique involved the left thoracotomy without the use of cardiopulmonary bypass. At the time, the method was not well received in the international media. One reason was the observation that the immediate flow of the left internal thoracic artery was lower than that of saphenous vein graft. Since 1967, René Favaloro, working in line with Mason Sones at the Cleveland Clinic, popularized and gave a scientific mark to the saphenous vein graft in the treatment of coronary heart disease [12]. After just one year, in 1968, this procedure for myocardial revascularization was also performed in Brazil by Dr. Zerbini and Adib Jatene rapidly being reproduced by many groups across the country [13,14].

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Again, it fell to a study performed at the Cleveland Clinic in 1986, by Loop et al. [15], promote strong impact on the history of coronary artery bypass grafting. In it, the authors found the long-term superiority of the left internal thoracic artery when comparing to the saphenous vein, when anastomosed to the anterior interventricular branch of the left coronary artery. After 10 years of follow-up, the observation of patency over 90% chose the left internal thoracic artery as the standard procedure to revascularize this branch of the left coronary artery. More recently, Lytle et al. [16] extended similar studies for a longer period. The observation of 90% of patent grafts over 20 years after surgery gave the left internal thoracic artery the condition of most reliable therapy that is known for treating coronary artery disease. The right internal thoracic artery when used for the right coronary artery and its branches, showed no similar patency results to those obtained when used for the left coronary artery system. A major advance in CABG was its use in situ by retroaortic via in branches of the left coronary artery. This technique was described in our midst by Puig et al. [17] in 1984. This thoracic artery also came to be used for branches of the circumflex artery as a composed arterial graft with the left internal thoracic artery, or as a free graft. Recently, various studies have demonstrated the possibility of using the right internal thoracic artery in situ by anterograde via in the anterior interventricular branch of the left coronary artery, with excellent immediate results [18-21]. ALTERNATIVE ARTERIAL GRAFTS Radial, gastroepiploic, inferior epigastric and lateral circumflex femoral arteries In 1971, Carpentier had already introduced the radial artery as a graft for coronary revascularization alternative, however, the initial results were disappointing. Currently, its use was restored, especially after the advent of antispasmodic drugs. [22] This also motivated the development of alternative proposals to prevent its spasm [23]. With the dissection, a graft from 15 to 20 cm can be obtained, which can be used by means of proximal aortic anastomosis, or in â&#x20AC;&#x153;Yâ&#x20AC;? with the internal thoracic artery. Its dissection can be simultaneous with the chest opening and often is ready before the end of the internal thoracic artery dissection. That was one of the reasons that led to the temporary abandonment of its use because its tissue structure suffered significant damage when subjected to prolonged ischemia. Today is consensus that after the dissection, one should keep it in its bed, covered with gauze soaked in papaverine to reverse any spasms, until its use. Alternatively, it can be removed only after the systemic administration of heparin immediately before making its proximal anastomosis. Thus, it gets expanded with the

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systemic pressure, without manipulation, and therefore less risk of injury to its layers (particularly the endothelium), decreasing the chance of perioperative spasm. Today we know that, given its feature of spasticity, its use should be avoided in coronary arteries with lesions smaller than 70%, due to the risk of flow competition, which could eventually lead to the occurrence of string sign (diffuse tapering throughout graft) [24]. The hypothesis that the proximal anastomosis could interfere with the graft flow has not been proven [25]. In 1987, Pym et al. [26] described the use of gastroepiploic artery segments. It originates, respectively, from hepatic, gastroduodenal and pancreaticoduodenalÂ arteries. Located on the anterior surface of the greater gastric curvature, being responsible for the irrigation of the lower two-thirds of this curvature. Its use in cardiac surgery reserves mainly to cases where one seeks the exclusive use of arterial grafts in CABG. Usually, it is used in situ to coronary branches of the underside of the heart, or in combination with other arteries such as the internal thoracic and radial. In the 1990s, Puig et al. [27] introduced the inferior epigastric artery. Anatomically, originates from the external iliac artery, and is situated in the lower third of the abdominal wall, between the rectus abdominis muscle and its posterior sheath. In this region, it enters the rectus abdominis muscle, dividing into several branches, which will anastomose with branches of the superior epigastric artery. It is indicated in young patients, or the unavailability of normal grafts, as grafted patients or patients with varicose veins in the lower limbs. The descending branch of the lateral femoral circumflex artery has also been studied in this line alternative. In 2003, Fabrocini et al. [28] studied by cineangiography 81 among 147 patients in which the graft was employed. The patency at the end of 1 and 3 years was respectively 97% and 93%. A similar study in Brazil also showed high short-term patency (92% at 90 days) and positive remodeling of the luminal diameter [29]. The authors concluded that the descending branch of the lateral femoral circumflex artery is a promising option for arterial graft. GRAFTS USING SAPHENOUS VEIN The use of saphenous vein devoted the coronary artery bypass grafting and is still used in many centers to complement the revascularization of determined coronary arteries. It is known that the patency of saphenous vein is less than that of human internal thoracic arteries. This is due in part to the fact that the structure of the saphenous vein can be affected by high pressures of distension, either in its preparation or when positioned as coronary artery bypass graft [30,31]. 139

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The dissection of the saphenous vein should be performed through small incisions, approximately 4 cm in length, leaving a bridge between each of intact skin incision. There are also auxiliary devices that allow withdrawal of a less invasive manner, with mini-incisions of a few millimeters. Modern techniques of dissection demonstrated that reduced distention pressure of the veins during preparation minimize the risk of endothelial lesions, further improving the results [32]. Furthermore, drugs that reduce systemic rates of fat and platelet adhesion have demonstrated an influence on long-term patency of these grafts. MINIMALLY INVASIVE TECHNIQUES Revascularization without cardiopulmonary bypass The search for less invasive procedures led to the development of techniques of revascularization without cardiopulmonary bypass. The possibility of performing coronary artery bypass grafting without its use was strengthened in the 1990s. Buffolo et al. [33] and Benetti et al. [34] as well as other groups began to emerge in the world demonstrating the benefit of this technique in reducing morbidity and mortality, especially by the reduction of neurological problems. Initially reserved for treatment of coronary lesions only and located on the anterior wall of the heart, this tactic was quickly extended to patients with injuries in two or more vessels. We developed different models of heart stabilizers, which allowed the reduction of regional cardiac motion. It was also used in shunts that enabled the maintenance of irrigation during the distal anastomosis, avoiding eventual ischemia and hemodynamic deterioration. This provided more comfort for the anastomosis in these surgeries[35]. The issue became controversial and numerous comparative studies have been developed, with conflicting results. Most of them relied on less inflammatory reaction surrounding the procedure. But certainly, the great benefit of the method is to avoid excessive manipulation of the ascending aorta. Thus, although it is desirable to minimize the use of cardiopulmonary bypass on myocardial revascularization, it is still a major challenge for modern heart surgery to avoid it in all cases. Myocardial revascularization by miniaccess In seeking to maintain the benefits of surgical treatment of coronary artery disease, with less invasive techniques with less surgical trauma, we have sought to achieve myocardial revascularization with the internal thoracic artery by minithoracotomy, avoiding cardiopulmonary bypass and sternotomy. The first report of myocardial revascularization by this miniaccess was described by Benetti & Ballester [36] in 1995. In two patients, the authors managed to dissect the left internal thoracic artery to left 140

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anterior minithoracotomy, with the aid of videothoracoscopy and anastomosed it to the anterior interventricular coronary artery. Subramanian et al. [37] also reported experience with CABG minithroracotomy, but with direct dissection of the left internal thoracic artery, without using a thoracoscope. A major concern of this new technique was the quality of the anastomosis of the internal thoracic artery to the coronary artery, without cardiopulmonary bypass and minimal access surgery. At the beginning of the experiment, some authors have reported problems in coronary anastomosis and early reoperation between 10% and 15% of patients [38,39]. With the advent of regional coronary stabilizers, coronary anastomosis on the beating heart began to be performed more safely and myocardial revascularization without cardiopulmonary bypass with full sternotomy or miniaccess now has greater acceptance by cardiovascular surgeons [40-42 ]. ROBOTIC SURGERY IN CORONARY ARTERY BYPASS GRAFTING Various techniques of minimally invasive CABG have been facilitated by appropriate endoscopic view during dissection of the internal thoracic artery. The use of these techniques in cardiovascular surgery has provided a less invasive new alternative for patients with coronary heart disease. The surgery can be performed with better aesthetics, enabling faster recovery, less hospital stay [43]. In Brazil, the robotic dissection of left internal thoracic artery was initiated in 2001 with the use of videothoracoscopy guided by robotic arm (AESOP), integrated with the drive system of the optical fiber, through voice communication [44]. Importantly, the improvement and application of these techniques require a training step and an intensive learning curve [45,46]. Several recent studies have demonstrated the advantages of these minimally invasive procedures. In our environment, Milanez et al. [47] demonstrated the possibility of dissection of the left internal thoracic artery through robotics, with better outcomes compared to those obtained by its traditional dissection. The ultimate goal would be the feasibility of complete myocardial revascularization with the aid of thoracoscopy, which is performed without opening the chest [48-50]. In this sense, robotic assistance has gradually gaining ground in clinical practice, aiding in dissection of the internal thoracic artery and performance of coronary anastomosis [51,52]. CABG robotic surgeries with chest fully enclosed are a reality in some centers in the United States and Europe, and the anastomoses performed with the use of mechanical devices, without the use of cardiopulmonary bypass. Despite initial reports with favorable results, the high cost of such equipment and the great difficulty in learning curve of

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these procedures are limited to a few specialized centers worldwide. All these innovations aim to optimize the results already achieved, with less aggression and less patient morbidity and mortality; some, however, still need to be incorporated routinely in daily clinical practice, making procedures more efficient, safe and reproducible. HYBRID SURGICAL ROOM The development and recent changes of cardiac surgery and interventional cardiology have demonstrated the need for installation of integrated catheterization laboratory to the operating room. These hybrid or high-tech rooms, as they are more commonly known, began to be idealized from the growth of minimally invasive cardiac surgery and the need for interventional cardiology in performing increasingly invasive and more complex procedures. The hybrid room is generally located within the operating room and used in less invasive, video-assisted or robotic surgeries requiring more sophisticated and complex imaging modality. They provide security for the surgery and allow the surgeon rapid assessment of the surgical outcome. More invasive and complex interventional procedures requiring rapid action of the cardiovascular surgeon and mechanical assistance are also performed in this room. Currently, the hybrid operating room is a reality, not only in academic and research institutions, but also in general hospitals. The recent interest in these rooms has raised important questions about the use, standardization, dimensions and organization of material and personnel in these units. CORONARY ARTERY BYPASS GRAFTING: CURRENT CONSIDERATIONS Even today, the CABG remains an excellent therapeutic option for treatment of obstructive coronary artery disease, even in diabetic patients [53,54], in elderly patients [55,56] and in patients with low left ventricular ejection fraction [57]. Alternative procedures, such as using laser beams [58], stem cells [59] and even variations in the use of internal thoracic artery [60] have been described, but are part of the treatment of a special group of patients, which is certainly not fit into the daily routine. It is clear that CABG surgery is a moment of transformation, as we can observe: surgery using only arterial grafts without the use of cardiopulmonary bypass, performed in a minimally invasive way, if possible with the help of robotics. The aims of this surgery are basically relief in anginal symptoms, with consequent improvement in quality of life and increased survival. Especially in young patients, it seeks

a type of intervention alternative to drug or percutaneous therapy to maintain long-term outcomes, thus avoiding the recurrence of angina or cardiac events, thus minimizing the need for reoperation or reintervention. Despite the tendency of employment the greatest possible number of arterial grafts in coronary artery bypass graft, due to higher patency internal thoracic artery and other arterial grafts, saphenous vein continues to be used due to the very good size and easy to obtain. Limitations such as graft failure in the long term have been circumvented by its proper preparation and systemic treatment of the patient, especially with controlling his blood pressure, and glycemic indices by using statins. Moreover, the ITAs rarely develop atherosclerosis, their diameters are usually compatible with the coronary artery to be revascularized and its limitations in length can be overcome through skeletonization or employment as a free graft [61]. However, the use of both internal thoracic arteries requires more refined technique and increases the surgical time. Thus, the use of both internal thoracic arteries is not routinely performed on all services and in many subgroups of patients. This makes the utilization rates of internal thoracic arteries vary from 4% to 30%, even in countries like the U.S., Japan and some countries of Europe [62,63]. Currently, we know that in the long-term there is the remodeling of the internal thoracic arteries, which eventually suit their flow to myocardial bed receptor. Thus, the right internal thoracic artery has been preferred as a second arterial graft compared to the radial artery. Therefore, the use of left and right internal thoracic arteries, supplemented or not by arterial grafts or saphenous vein, is still the condition therapy used in the treatment of obstructive coronary artery disease. In a nutshell, an achievement at low cost and minimally invasive manner (video-assisted or robotic) can be considered ideal in CABG, without the use of cardiopulmonary bypass, using arterial grafts and, if necessary, associated to hybrid procedures (minimally invasive surgery complemented by percutaneous performance).

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58. Dallan LAO, Gowdak LH, Lisboa LAF, Schettert I, César LAM, Oliveira SA, et al. Terapia celular associada à revascularização transmiocárdica a laser como proposta no tratamento da angina refratária. Rev Bras Cir Cardiovasc. 2008;23(1):46-52. 59. Gowdak LH, Schettert IT, Rochitte CE, Lisboa LA, Dallan LA, Cesar LA, et al. Early increase in myocardial perfusion after stem cell therapy in patients undergoing incomplete coronary artery bypass surgery. J Cardiovasc Transl Res. 2011;4(1):106-13. 60. Dallan LAO, Gowdak LH, Lisboa LAF, Milanez AMM, Platania F, Moreira LFP, et al. Modificação de antigo método (Vineberg) na era das células tronco: nova tática? Arq Bras Cardiol. 2009;93(5):79-81. 61. Lisboa LAF, Dallan LAO, Puig LB, Abreu Filho C, Leca RC, Dallan LAP, et al. Seguimento clínico a médio prazo com uso exclusivo de enxertos arteriais na revascularização completa do miocárdio em pacientes com doença coronária triarterial. Rev Bras Cir Cardiovasc. 2004;19(1):9-16. 62. Kappetein AP. Bilateral mammary artery vs. single mammary artery grafting: promising early results: but will the match finish with enough players? Eur Heart J. 2010;31(20):2444-6. 63. Kinoshita T, Asai T. Bilateral internal thoracic artery grafting: current state of the art. Innovations (Phila). 2011;6(2):77-83.

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Pontes JCDV, et al.COMMUNICATION - Endovascular repair of ascending aortic dissection SHORT

Endovascular repair of ascending aortic dissection Correção endovascular de dissecção de aorta ascendente

José Carlos Dorsa Vieira Pontes1, Amaury Mont’Serrat Ávila Souza Dias2, João Jackson Duarte3, Ricardo Adala Benfatti3, Neimar Gardenal4 DOI: 10.5935/1678-9741.20130018

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Abstract Woman, 84 years-old, with Stanford type A thoracic aortic dissection committing aortic arch and descending aorta. Proposed and accepted endovascular treatment according to the severity of the clinical picture. Common femoral artery dissection bilaterally was done. Aortography confirmed the exclusion of the false lumen and patency of the coronary ostia.

Resumo Paciente de 84 anos com dissecção de aorta torácica tipo A de Stanford comprometendo todo o arco aórtico e aorta descendente. Proposto e aceito o tratamento endovascular em função da gravidade do quadro clínico. Procedeu-se à dissecção das artérias femorais comum bilateralmente. A aortografia confirmou a exclusão da falsa luz e a patência dos óstios coronarianos.

Descriptors: Aneurysm, procedures. Stents.

Descritores: Aneurisma endovasculares. Stents.

dissecting.

Endovascular

INTRODUCTION There is a consensus that the treatment for type A dissections is immediate surgery in order to prevent fatal complications such as cardiac tamponade, aortic rupture, myocardial infarction, acute aortic insufficiency and neurological complications [1]. However, the conventional surgical treatment, with a mortality rate of 10% to 30%, has its own complications arising from surgical trauma, the patient undergoing cardiopulmonary bypass, the extent of the aortic lesion and vessel impairment as well as complications related to the natural progression of the disease. Furthermore, conventional surgical treatment has a high mortality rate when associated with serious systemic diseases such as emphysema, diabetes and renal failure, and advanced age.

1 - Doctorate (Managing Director at Núcleo do Hospital Universitário – Universidade Federal do Mato Grosso do Sul-UFMS) 2 - Specialist in Cardiovascular Surgery 3 - Masters in Cardiovascular Surgery 4 - Masters in Cardiovascular Surgery – Cardiovascular Surgeon

dissecante.

Procedimentos

Endovascular treatment has been widely used to treat diseases of the thoracic aorta and isolated cases of the endovascular approach for repairing ascending aortic dissection have described in the literature. The present paper describes an endovascular repair of a patient with ascending aortic dissection. CASE REPORT An 84-year-old patient from Mato Grosso do Sul suffering from chest pain and dyspnea was admitted to a hospital in Campo Grande, MS in October, 2011. The patient was diagnosed with chronic obstructive pulmonary disease, diabetes mellitus, decompensated congestive heart failure, pneumonia and chronic renal failure.

Correspondence address: José Carlos Dorsa Vieira Pontes Hospital Universitário-UFMS Avenida Senador Filinto Muller 355, Vila Ipiranga, Campo Grande, MS, Brazil. Zip code: 79080-190 E-mail: carlosdorsa@uol.com.br Article received on June 20th, 2012 Article accepted on August 27th, 2012

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Abbreviations, acronyms & simbols ASD ITU

Atrial Septal Defect Intensive Therapy Unit

Chest radiography showed meadiastinal enlargement. Bedside echocardiogram showed dilated myocardiopathy (FE 0.4) in addition to an image typical of ascending aortic dissection. A CT angiogram was performed showing “Stanford type A aortic dissection compromising the aortic arch and descending aorta” without damage to the supra-aortic branches and the beginning of the dissection at 1.0 cm from the right coronary ostium (Figure 1). No reentry points were observed. According to the severity of the patient’s clinical picture, conventional surgical treatment was deemed unfeasible due to her comorbidities and a high risk of death (EuroSCORE 83%). Thus, the patient and her relatives consented to the endovascular treatment suggested. The manufacture of a 40-mm-diameter stent graft, containing an 8-cm covered segment and a 2-cm uncovered free flow segment, was ordered. The uncovered segment allows for increased anchoring area since it is fixed in the aortic arch without the risk of occlusion of its branches. The patient underwent bilateral femoral artery dissection under general anesthesia and in a hemodynamic environment. Since it was an exception and a high risk procedure, the contralateral femoral artery was dissected in case a sudden emergency cardiopulmonary bypass was needed.

Fig. 1 – Stanford type A thoracic aortic dissection, compromising the aortic arch and the descending aorta

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The left femoral artery was catheterized to insert the aortography catheter and locate the coronary ostia. The right femoral artery was dissected, exposed, and the guidewire was inserted, with its end passing through the aortic valve and entering the left ventricular chamber. The patient was put under induced hypotension and the stent was placed above the coronary ostia. The coronary ostia were only marked, not catheterized, as to better visualize the correct placement of the stent directly above the right ostium. Therefore, the coronaries were not selected, but rather contracted in the ASD acquisition mode to determine the distance from the right coronary to the dissection entry point. The rigid guidewire was placed inside the left ventricle, since the device had to be in a transvalvular position (Figure 2). The aortography confirmed the exclusion of the false lumen and the patency of the coronary ostia. The patient was extubated in the operating room and sent to the ITU.

Fig. 2 – Rigid guidewire positioned inside the left ventricle

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Pontes JCDV, et al. - Endovascular repair of ascending aortic dissection

Patient’s progress was satisfactory and she was discharged from the hospital. As requested by the nephrology team, no contrast exams were performed prior to the discharge. During follow-up, since the patient was well and her creatinine clearance was below 25%, imaging exams with contrast were not performed, as they would have been just for control purposes and not for a prescribed medical reason, outweighing cost effectiveness.

which could compromise, in case of ostial lesions, the occlusion of the false lumen, and obstruct the supra-aortic branches. Endovascular repairs for ascending aorta diseases are still emerging and they are not statistically significant in terms of medium-term mortality rates, as a longer follow-up period of patients who underwent these new procedures is needed to prove their success.

DISCUSSION The use of a custom-made stent graft has been studied as an alternative approach to ascending aorta lesions, hence, being reserved for patients who have are not able to withstand conventional surgery, but still need an immediate solution to this serious aortic disease. Endovascular treatment for aortic diseases is widely used for Stanford type B dissections [1]; however, its use for the treatment of the ascending aorta is a challenge. The procedure has a highly specific technique that demands preparation, refinement and sharp skills. The first report of the use of a stent graft for Stanford type A aortic dissection was published in October, 2007 [3]. The literature is limited to examples of isolated cases where a stent was used in ascending dissection as part of a hybrid procedure. In 2007, a stent implant was reported; however, the patient was under cardiopulmonary bypass [4]. Recent cases have shown the use of endovascular therapy for ascending aorta in the treatment of pseudo-aneurysms [5]. Recently, in 2012, a case of type A ascending aortic dissection was published, in which the treatment was a stent implant and exclusion of the false lumen. Our work shows that this technique is feasible and promising, and training of the surgical team is essential to its execution. A well trained surgical team can use this technique to approach complex aortic lesions, such as the one described, with an entry point at 1.0 cm from the coronary ostium. CONCLUSION The surgical outcome depends not only on the training of the team, but also on the attention paid to the stent itself, such as the appropriate radial force used for its setting and non-displacement,

REFERENCES 1. Albuquerque LC, Braile DM, Palma JH, Saadi EK, Almeida RMS, Gomes WJ, et al. Diretrizes para o tratamento cirúrgico das doenças da aorta da Sociedade Brasileira de Cirurgia Cardiovascular: atualização 2009. Rev Bras Cir Cardiovasc. 2009;24(2 supl. 1):7-33. 2. Borst HG, Heinemann MK, Stone CD. Surgical treatment of aortic dissection. New York: Churchill Livingstone; 1996. p.357. 3. Senay S, Alhan C, Toraman F, Karabulut H, Dagdelen S, Cagil H. Endovascular stent-graft treatment of type A dissection: case report and review of literature. Eur J Vasc Endovasc Surg. 2007;34(4):457-60. 4. Dias RR, Silva IA, Fiorelli AI, Stolf NAG. Tratamento híbrido com endoprótese não recoberta nas dissecções agudas da aorta tipo A. Rev Bras Cir Cardiovasc. 2007;22(4):495-7. 5. Saadi EK, Moura L, Zago A, Zago A. Endovascular repair of ascending aorta and coronary stent implantation. Rev Bras Cir Cardiovasc. 2011;26(3):477-80.

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Mistakes inSCIENTIFIC Brazilian papers are more from concepts than of expression DIFFUSION

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Mistakes in Brazilian papers are more from concepts than of expression Erros em artigos científicos brasileiros são mais conceituais do que de expressão

Elton Alisson

DOI: 10.5935/1678-9741.20130019 FAPESP Agency - The scientific writing is still the “Achilles heel” of many Brazilian researchers. The mistakes made when writing a thesis or research paper are much more related to problems of research methodology than to lack of ability with words to present the results in a clear, concise and interesting way. The analysis of Gilson Volpato, Professor at Department of Physiology, Institute of Biosciences, Universidade Estadual Paulista (Unesp), on Botucatu campus, is the sixth revised and expanded edition of the book Ciência: da filosofia à publicação (Original name in Portuguese). Launched in early December, the edition adds four new chapters to the nine of the first edition, published in 1998. One of them presents a brief summary of the history of philosophy in order to explain why science is done as it is today - only accepting conclusions based on empirical evidence (experimentally proved). The idea of this chapter, according to Volpato, is to show the reader the inseparable character from the practice of science and philosophical and theoretical questions, and you can only do good science and write articles for publication in journals of high impact factor when you have a good philosophical training and a very precise understanding of scientific concepts. “You must have a very clear understanding of what is doing science to perform good research, resulting in solid articles to be published in high-levels journals. You can not only fix the end of this process - the scientific writing - without having a well-founded basis behind it", said Volpato to FAPESP Agency. Specialist in writing and scientific publication, the author who teaches courses in the area and has already helped Brazilian researchers to rewrite more than 250 scientific articles in the field of human, exact and biological knowledges – states that some of the articles published by scientists in Brazil have many structural problems. Among these are introductions that do not fulfill their function, incomprehensible tables, graphs and figures, questionable methods and data that do not support the authors’ conclusions but, in most cases, according to Volpato, errors inherent to the present study.

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RBCCV 44205-1452 “If the research has started in a wrong way and it is bad, doing magic in the article is quite impossible. If the researcher studied an irrelevant question, even with good results, they never result in scientific papers that will stand out in their labs and let alone in Brazil”, he said. A major conceptual error in some papers published by Brazilian scientists, according to Volpato, is willing to do science to solve specific and localized problems, without addressing the general phenomenon, that just has the ability to solve specific problems. According to the expert, what prooves this fact is that many very titles of some published papers still show the name of the institution or the city where the survey was conducted and data were collected, reinforcing the idea that the study is limited to that site. “In order to do science, we really need data collected from somewhere. But the problem is that some Brazilian researchers collect data from a particular place and only care about that place, especifically”said Volpato. “It’s very different to get the data from a certain place and build a general science that addresses particular issues, as can be seen in articles published by foreign scientists in major international journals. This learning and some scientific daring is still missing in our Brazilian researchers” the autor compares. Timely issues According to Volpato, some of the factors responsible for the absence of general science is the lack of philosophical training on what is necessary to build knowledge and the fact that Brazil was long closed to the world. Some fields were separated from the science done abroad. Moreover, according to Volpato, other areas related to basic science, such as immunology, cell biology and physics have always had a natural international integration that had greater projection in the 1990s with the advent of globalization and the internet. According to the researcher, it is necessary to review the concept of doing science under a strictly local perspective so

Mistakes in Brazilian papers are more from concepts than of expression

that we can improve the quality of scientific papers published by Brazilian and thereby increase the publication in journals of high impact factor and international citation. “The scientific writing is a strong indicator of authors scientific concepts so, to improve it, it is necessary, first, to correct the reasearches concepts of what it is like to do science”, he said. Volpato is also author of the books “Método lógico para a redação científica”, “Bases teóricas da redação científica”, “Publicação científica”, “Bases teóricas para redação científica”, “Administração da vida científica”, “Pérolas da redação

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científica”, “Dicas para redação científica”, “Lógica da redação científica” e “Estatística sem dor!”. ( All titles in Portuguese). The Professor also publishes his work at www.gilsonvolpato. com.br where you can find articles, tips and reflections on scientific writing, education, and ethics in science. The site provides access to online classes in the course “Theoretical Bases for Scientific Writing,” presented by Volpato at Unesp. Published by FAPESP Agency on January 3rd, 2013. URL: http://agencia.fapesp.br/16655

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Letter to the Editor

DOI: 10.5935/1678-9741.20130020

Impact on Early and Late Mortality after Blood Transfusion in CABG Surgery “Lamb’s blood was used for the transfusion, and the man had a violent reaction, the horrible symptoms being chills and fever and black urine.” Jean Baptiste Denis, 1665 Dear Editor, I've read with great interest the article by Santos et al. [1]: “Impact on early and late mortality after blood transfusions in coronary artery bypass surgery”, to be published in the Brazilian Journal of Cardiovascular Surgery [1]. The matter is very relevant, but some important considerations are worth being discussed. The first attempt at blood transfusion to humans occurred in France in 1665, when sheep blood was used for treating a psychosis. The aim was to restore sanity to the patient, however, what it was observed was the first reaction to blood incompatibility. The first report of blood transfusion using human blood occurred in the year 1665 in London by Richard Lower. The clotting problems, compatibility and storage of blood were later resolved. During armed conflicts (especially after World War II), blood transfusions were widely used [2]. The indication of blood products transfusion in patients undergoing cardiac surgery, measures to limit its use (fibrinolytic drugs, extracorporeal circuits coated with heparin), reuse of blood lost during surgery and non-use of cardiopulmonary bypass (CPB), all contributed to reduce the number of transfusions [3]. Actually, it is not always possible not to use blood products. Concerns exist when performing blood transfusions: infections (viral, bacterial), incompatibility and a silent complication, the immunosuppressive effects [4]. 150

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When assessing the outcome mortality related to blood transfusions in coronary artery bypass grafting, Santos et al. [1] reinforced the observations on the early and immediate impact. Koch et al. [5] reported, actually, that blood stored for more than 14 days would be more related to postoperative complications. Newer blood (less than 14 days of storage) has a lower relative risk (30%) compared to postoperative mortality. At 1 year, mortality was 11% for older blood (over 14 days of storage) [5]. Would this data be a new limitation to the study? When we assessed only blood transfusion and its adverse events, we can not forget the efficacy and safety in the use of autotransfusion [6]. If, as noted by Koch et al. [5], the stored blood has a higher risk, so probably the same would be true for stored autotransfusion. But, if it is used early or even during surgery before CPB, would that impact on early and late mortality observed by Santos et al. [1] also occur? The study in question does not provide such data. Hélcio Giffhorn Cardiovascular Surgeon, Master's Degree in Surgical Clinics, Curitiba, PR, Brazil

REFERENCES 1. Santos AA, Sousa AG, Thomé HOS, Machado RL, Piotto RF. Impacto na mortalidade precoce e tardia após transfusão de hemácias em cirurgia de revascularização miocárdica. Rev Bras Cir Cardiovasc. 2013;28[1]1-XXX. 2. Sturgis CC. The history of blood transfusion. Bull Med Libr Assoc. 1942;30(2):105-12. 3. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK; Society of Cardiovascular Anesthesiologists

Letter to the Editor

Special Task Force on Blood Transfusion, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83(5 Suppl):S27-86. 4. Dellinger EP, Anaya DA. Infectious and immunologic consequences of blood transfusion. Crit Care. 2004;8(Suppl 2):S18-23. 5. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229-39. 6. Martin K, Keller E, Gertler R, Tassani P, Wiesner G. Efficiency and safety of preoperative autologous blood donation in cardiac surgery: a matched-pair analysis in 432 patients. Eur J Cardiothorac Surg. 2012;37(6):1396-401.

ANSWER Dear Editor, Initially, we would like to thank the observations and comments made by Prof. Dr. Hélcio Giffhorn about the article “Impact on early and late mortality after blood transfusions in coronary artery bypass surgery” [1]. Red cells stored in blood bags develop a series of structural and functional changes with the passage of time, known as “storage lesion” [2]. A meta-analysis involving 21 studies: 18 observational studies and three randomized clinical trials, with a predominance of cardiac surgery patients (6) and trauma (6), concluded that the use of blood stored for longer time was associated with increased mortality when compared the use of blood stored for less time [3]. Hajjar et al. [4] published a prospective randomized controlled clinical trial, comparing restrictive versus liberal strategy in 502 patients undergoing cardiac surgery. Regardless of the transfusion strategy used, transfusion of a single unit of blood was associated with significantly increased morbidity and postoperative mortality. Nevertheless, this study used only bags of blood with little storage time (less than 10 days of storage), with an average of only 3 days of storage in both groups. Therefore, “new” blood transfusion is also associated with higher

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mortality. One of the possible causes of an adverse clinical outcome even with the use of new blood is the fall of the bioactivity of nitric oxide in stored red blood cells, resulting in decreased oxygen delivery in the microcirculation. It was observed that this reduction occurs rapidly with only a few hours of storage [5,6]. Also, another critical factor is the immunomodulatory effect of transfusion, which results in reducing the number of circulating lymphocytes, T helper cells modification and activation of immune cells [7]. Evidently, this effect depends solely on the charge of transfused antigens and not storage time of red blood cells. One limitation of our study, which was retrospective, was the inability to assess the storage time of each 4936 bags of transfused blood. It is possible, as suggested by PhD Hélcio Giffhorn that longer storage of blood bags may have influenced a higher mortality rate in this study. Currently, in most institutions, it is common for patients who require blood transfusion units preferentially receive blood from their blood type with the greatest storage time. This practice aims a better storage of the limited supplies of blood [3]. Anyway, the fact that the storage time of transfused blood bags was not taken into account does not invalidate the final conclusion of this study, which showed numbers very similar to those found in the international literature. Furthermore, this study exemplifies the typical transfusion behavior employed by a large hospital in Brazil. We believe that the increased storage time of the blood bags could have further strengthened the final conclusion of our study. One of the techniques used to decrease the use of allogeneic blood during the perioperative period is the autotransfusion, on which a preoperative donation is performed weeks before surgery and storage. Such a method would have as advantages the prevention of viruses transmission, such as HIV and hepatitis C as well as deleterious effects caused by immunological phenomena resulting from the use of allogenic blood [8]. A systematic review of randomized controlled trials on the effectiveness of autotransfusion, published with collaboration of Cochrane, involved 14 randomized clinical trials and observed reduced risk of receiving an allogeneic blood transfusion [9]. However, the risk of receiving a transfusion of any type (autologous or allogeneic) was higher using the autotransfusion, and it is not possible to the authors to establish whether the benefits of autotransfusion were larger than its risks. Furthermore, the autotransfusion in the form of preoperative donation and storage does not provide, theoretically prevention as the development of storing injury. On the other hand, preoperative acute normovolemic hemodilution involves removing blood from the surgical patient immediately before or after induction of anesthesia and its simultaneous replacement with appropriate volumes of crystalloid or colloids solutions. The collected blood 151

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is then reinfused to replace blood loss occurred during surgery [10], without the inconvenience of storing injury. Goodnough et al. [11] suggest that acute hemodilution could replace benefits with the use of autotransfusion. The intraoperative cell recovery is another technique used to minimize the use of allogeneic blood and consists of retrieve, filter and reinfuse blood lost by the patient intraoperatively with the aid of special equipment [12]. A systematic review of randomized clinical trials on the efficacy of intraoperative cell recovery, published by Cochrane, included 75 trials and concluded that it was effective in reducing the use of allogeneic blood in adult patients undergoing elective cardiac surgery, without causing adverse clinical effects [13]. This study did not assess the use of preoperative acute normovolemic hemodilution or intraoperative cell recovery and its impact on morbidity and mortality, but both techniques are excellent prospects for the development of future studies. Again we appreciate the comments of PhD Hélcio Giffhorn. Dr. Antonio Alceu dos Santos Cardiologist, São Paulo, SP, Brazil

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physiological activity in banked blood. Proc Natl Acad Sci U S A. 2007;104(43):17058-62. 7. Blajchman MA. Immunomodulation and blood transfusion. Am J Ther. 2002;9(5):389-95. 8. Martin K, Kaller E, Gertler R, Tassani P, Wiesner G. Efficiency and safety of preoperative autologous blood donation in cardiac surgery: a matched-pair analysis in 432 patients. Eur J Cardiothorac Surg. 2012;37(6):1396-401. 9. Henry DA, Carless PA, Moxey AJ, O'Connell D, Forgie MA, Wells PS, et al. Pre-operative autologous donation for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2002;(2):CD003602. 10. Shander A, Rijhwani TS. Acute normovolemic hemodilution. Transfusion. 2004;44(12 Suppl):26S-34S. 11. Goodnough LT, Monk TG, Brecher ME. Acute normovolemic hemodilution should replace the preoperative donation of autologous blood as a method of autologous-blood procurement. Transfusion. 1998;38(5):473-6. 12. Esper SA, Waters JH. Intra-operative cell salvage: a fresh look at the indications and contraindications. Blood Transfus. 2011;9(2):139-47. 13. Carless PA, Henry DA, Moxey AJ, O'Connell D, Brown T, Fergusson DA. Cell salvage for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2010;(4):CD001888.

REFERENCES 1. Santos AA, Sousa AG, Thomé HOS, Machado RL, Piotto RF. Impacto na mortalidade precoce e tardia após transfusão de hemácias em cirurgia de revascularização miocárdica. Rev Bras Cir Cardiovasc. 2013;28[1]1-9. 2. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229-39. 3. Wang D, Sun J, Solomon SB, Klein HG, Natanson C. Transfusion of older stored blood and risk of death: a metaanalysis. Transfusion. 2012;52(6):1184-95. 4. Hajjar LA, Vincent JL, Galas FR, Nakamura RE, Silva CM, Santos MH, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-67. 5. Kor DJ, Van Buskirk CM, Gajic O. Red blood cell storage lesion. Bosn J Basic Med Sci. 2009;9(Suppl 1):21-7. 6. Reynolds JD, Ahearn GS, Angelo M, Zhang J, Cobb F, Stamler JS. S-nitrosohemoglobin deficiency: a mechanism for loss of

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Second edition of the book Cardiology and Pedriatic Cardiac Surgery is available On November 29, 2012, during the XXII Brazilian Congress of Pediatric Cardiology in Foz do Iguaçu, Paraná, its second edition was officially launched celebrating the unity between the Brazilian Society of Cardiology and the Brazilian Society of Cardiovascular Surgery, represented by their respective departments of pediatric cardiology and pediatric cardiac surgery. The second edition had 178 authors who sought to present the very best in the specialty. The text is illustrated with 1649 images distributed in 1240 pages, which practically became a book-atlas.

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Letter to the Editor

Coordinators claimed to believe that this work is an important contribution to the development of cardiology and also the pediatric cardiac surgery in our country, as well as demonstrating the high level of knowledge, involvement and capacity of those professionals working in the area. "Many young doctors can study and learn the most basic and important points in this book," said the book general coordinator, Professor Ulisses Alexandre Croti.

would be interested to know what feedback you get from the readership. And I look forward to the next chapters. All the best, and congratulations. Miles Frederick Shore Cambridge/MA, USA Rodolfo, I just finished reading part II of " Cardiac Surgery, the Infinite Quest" - it's beautifully written and very provocative. You are on a trajectory to become the "master of missives" in cardiac surgery! All the best, James K. Kirklin Birmingham/AL, USA

(From left to right.) Maria Del Pilar Paya (Roca Editorial Manager – National Editorial Group - GEN), Vera Demarchi Aiello (nomenclature coordinator), Sandra da Silva Mattos (clinical coordinator), Ulisses Alexandre Croti (general coordinator) Valéria de Melo Moreira (images coordinator). Valdester Cavalcante Pinto Jr. (surgical coordinator) is not in the photo because he was in another event abroad

Following the global trend, the book was also presented in e-book plataform which can be purchased at http:// grupogen.com.br. There are also many images and videos to be accessed for free, confirming once again, one of the main goals of the book, which is knowledge dissemination.

100 citations Dear friends I received a notification of the Google Scholar with the information that our article (Basics notions of heart rate variability and its clinical applicability - Luiz Carlos Marques Vanderley, Carlos Marcelo Pastre, Rosangela Akemi Hoshi, Tatiana Dias de Carvalho and Moacir Fernandes de Godoy, published in issue 24.2 of BJCVS) reached the significant milestone of 100 citations!! Congratulations to all and a special thanks to Prof. Domingo Braile for enabled us to have this published in a journal with so great expressiveness and penetration as the Brazilian Journal of Cardiovascular Surgery. A hug to everyone. Moacir Godoy São José do Rio Preto -SP

Cardiac surgery: the infinite quest Hi Rodolfo -- I finally got the time to go over your very ambitious paper. I am impressed that a specialty journal would have the leadership to publish such a farreaching piece. And it is also impressive that you are able to integrate so much relevant and important material. I

Accessing Google Scholar, I watched the Moacir reported by prof Moacir. The paper was designed for us from an internal strategy from laboratories aiming a scientific update on HRV and this idea was catalyzed on post-doctoral meetings, strongly encouraged by Professor Moacir and finally started from the action of Luiz Carlos. 153

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Letter to the Editor

From that, every search for references and organization of data were made by Rosangela and Tatiana. The outcome was, in my point of view, extremely impressive, and by the way, for the academic community as well. I'm sure that was not the view of Professor Domingo, such information would not have such a movement and projection. I reiterate the importance of BJCVS in this context! I sincerely thank for the privilege to have worked on this project: my academic brother Luiz, my dear teachers and Teachers Moacir and Braile and especially Memi and Tatiana, who were tireless and patient to answer any requirements, including mine. It was worth it and I think we're ready for a new challenge!! A brotherly hug!! Marcelo Pastre São José do Rio Preto-SP

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Reflections of a translator in the Human Anatomy area Dear Editor, I've sent an article “Reflections engendered as a practicing translator concerning the language of Anatomy - Reflections of a translator in the Human Anatomy area”, which was published in Brazilian Journal of Cardiovascular Surgery 2012;27(3):453-6. In this article, my mistake, was omitted the name of co-author: PhD Fernando Batigália, MD Human Anatomy Tutor, Health Sciences Stricto Sensu Post-Graduate Programme; São José do Rio Preto Medical School (FAMERP). I request the issue of an erratum to correct the error. With nothing further to add at this time, I count on your support. Sincerely, Alexandre Lins Werneck São José do Rio Preto-SP

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Erratum DOI: 10.5935/1678-9741.20130021

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In the article “Reflections engendered as a practicing translator concerning the language of Anatomy”, published in issue 27.3, pages 453-6, the name of co-author Fernando Batigália, MD Human Anatomy Tutor, Health Sciences Stricto Sensu Post-Graduate Programme; São José do Rio Preto Medical School (FAMERP) was not included.

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Reviewers RBCCV 28.1 Below follows a list of the names of those who evaluated the papers published in this issue of the Brazilian Journal of Cardiovascular Surgery ( BJCVS). My special thanks to all of them.

Domingo Braile Chief Editor BJCVS

Alfredo Inácio Fiorelli

Marcos Rogério Joaquim

Alfredo José Rodrigues

Mauricio de Nassau Machado

Eduardo Keller Saadi Ellen Hettwer Magedanz

Melchior Luiz Lima Neide Micelli Domingos

Guilherme Succi Orlando Petrucci João Galantier José Glauco Lobo Filho Luciana da Fonseca

Paulo Slud Brofman Roberto Gomes de Carvalho

Luiz César Guarita-Souza

Rubens Toffano de Barros

Marcelo N Nakazone

Tomas Salerno

156

RBCCV em números

27 anos de circulação ininterrupta Fator de Impacto 1,239 Consultada por leitores de mais de 110 países

www.rbccv.org.br www.scielo.br/rbccv www.bjcvs.org

788.564 acessos no site próprio (www.rbccv.org.br) em 2012 709.180 acessos no site da SciELO (www.scielo.br/rbccv) em 2012 4092 visitantes diariamente 469,65 gigabytes (GB) transferidos, média de 1,28 GB por dia 47.232.073 impressões de páginas em 2012 (requisição do navegador de um visitante para uma página web que possa ser exibida), média diária de 129.049,38. Presente em nas bases de dados EBSCO, Lilacs, Scielo, Latindex, Index Copernicus, Scopus, PubMed, Thomson Scientific (ISI), Google Scholar

Fig.1 – Número de acessos ao site da RBCCV em 2012

Fig. 2 – Transferência de bytes no site da RBCCV durante 2012

Fig. 3 – Número de impressões de páginas da RBCCV em 2012