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www.arquivosonline.com.br Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 105, Nº 4, October 2015 Figure 1 – Thematic maps of the mean mortality rate from cardiovascular diseases (MMRCD) per thousand inhabitants in each Brazilian state and gender in the periods from 1996 to 2000 and from 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics the Unified Health System (DATASUS)/ Ministry of Health, 2015. Page 375 Editorial Development and Validation of Predictive Models of Cardiac Mortality Cardiovascular Risk Factors: From Consolidated Knowledge to a Call and Transplantation in Resynchronization Therapy for Action Special Article Executive Summary of the Guidelines on Stable Coronary Disease Changes in Medical Management after Coronary CT Angiography Review Article A Systematic Review on Sleep Duration and Dyslipidemia in Original Articles Adolescents: Understanding Inconsistencies Acute Coronary Syndrome Treatment Costs from the Perspective of the Viewpoint Supplementary Health System Patient Management with Metallic Valve Prosthesis during Pregnancy The Benefits of Prone SPECT Myocardial Perfusion Imaging in and Postpartum Period Reducing Both Artifact Defects and Patient Radiation Exposure Anatomopathological Session Palliative Senning in the Treatment of Congenital Heart Disease with Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to Severe Pulmonary Hypertension Restrictive Cardiomyopathy Anxiety, Depression, and General Psychological Distress in Patients Case Report with Coronary Slow Flow Percutaneous Treatment of Mitral Paraprosthetic Regurgitation: an Mortality from Cardiovascular Diseases in the Elderly: Comparative Analysis of Two Five-year Periods Sex-Specific Equations to Estimate Maximum Oxygen Uptake in Cycle Ergometry A Novel Algorithm to Quantify Coronary Remodeling Using Inferred Normal Dimensions Alternative to Surgery Image Persistent Left Superior Vena Cava in Permanent Pacemaker Implantation Erratum A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948 Contents Editorial Cardiovascular Risk Factors: From Consolidated Knowledge to a Call for Action Guilherme Brasil Grezzana e Lucia Campos Pellanda .....................................................................................................................................................................page 325 Special Article Executive Summary of the Guidelines on Stable Coronary Disease Luiz Antonio Machado César, Antonio de Pádua Mansur, João Fernando Monteiro Ferreira .....................................................................................................................................................................page 328 Original Articles Coronary Angioplasty with and without Stent Acute Coronary Syndrome Treatment Costs from the Perspective of the Supplementary Health System Vanessa Teich, Tony Piha, Lucas Fahham, Haline Bianca Squiassi, Everton de Matos Paloni, Denizar Vianna Araújo, Paulo Miranda .....................................................................................................................................................................page 339 Nuclear Cardiology and PET The Benefits of Prone SPECT Myocardial Perfusion Imaging in Reducing Both Artifact Defects and Patient Radiation Exposure Maria Stathaki, Sophia Koukouraki, Emmanouela Papadaki, Angeliki Tsaroucha, Nikolaos Karkavitsas .....................................................................................................................................................................page 345 Cardiac Surgery – Adults Palliative Senning in the Treatment of Congenital Heart Disease with Severe Pulmonary Hypertension Juliano Gomes Penha, Leina Zorzanelli, Antonio Augusto Barbosa-Lopes, Edimar Atik, Leonardo Augusto Miana, Carla Tanamati, Luiz Fernando Caneo, Nana Miura, Vera Demarchi Aiello, Marcelo Biscegli Jatene .....................................................................................................................................................................page 353 Chronic Acute Coronary Syndrome Anxiety, Depression, and General Psychological Distress in Patients with Coronary Slow Flow Mehmet Baran Karataş, Ebru Şahan, Kazım Serhan Özcan, Yiğit Çanga, Barış Güngör, Tolga Onuk, Göktürk İpek, Yasin Çakıllı, Emre Arugaslan, Osman Bolca .....................................................................................................................................................................page 362 Arquivos Brasileiros de Cardiologia - Volume 105, Nº 4, October 2015 Epidemiology Mortality from Cardiovascular Diseases in the Elderly: Comparative Analysis of Two Five-year Periods Grasiela Piuvezam, Wilton Rodrigues Medeiros, Andressa Vellasco Costa, Felipe Fonseca Emerenciano, Renata Cristina Santos, Danilo Silveira Seabra .....................................................................................................................................................................page 371 Ergospirometry Sex-Specific Equations to Estimate Maximum Oxygen Uptake in Cycle Ergometry Christina G. de Souza e Silva e Claudio Gil S. Araújo .....................................................................................................................................................................page 381 Hemodynamics - Adults A Novel Algorithm to Quantify Coronary Remodeling Using Inferred Normal Dimensions Breno A. A. Falcão, João Luiz A. A. Falcão, Gustavo R. Morais, Rafael C. Silva, Augusto C. Lopes, Paulo R. Soares, José Mariani Jr, Roberto Kalil-Filho, Elazer R. Edelman, Pedro A. Lemos .....................................................................................................................................................................page 390 Resynchronization Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy Eduardo Arrais Rocha, Francisca Tatiana Moreira Pereira, José Sebastião Abreu, José Wellington O. Lima, Marcelo de Paula Martins Monteiro, Almino Cavalcante Rocha Neto, Camilla Viana Arrais Goés, Ana Gardênia P. Farias, Carlos Roberto Martins Rodrigues Sobrinho, Ana Rosa Pinto Quidute, Maurício Ibrahim Scanavacca .....................................................................................................................................................................page 399 Cardiovascular Computed Tomography Changes in Medical Management after Coronary CT Angiography Vânia Mairi Naue, Gabriel Camargo, Letícia Roberto Sabioni, Ronaldo de Souza Leão Lima, Maria Eduarda Derenne, Andréa Rocha de Lorenzo, Monica Di Calafiori Freire, Clério Francisco Azevedo Filho, Elmiro Santos Resende, Ilan Gottlieb .....................................................................................................................................................................page 410 Review Article A Systematic Review on Sleep Duration and Dyslipidemia in Adolescents: Understanding Inconsistencies Gabriela de Azevedo Abreu, Laura Augusta Barufaldi, Katia Vergetti Bloch, Moyses Szklo .....................................................................................................................................................................page 418 Viewpoint Patient Management with Metallic Valve Prosthesis during Pregnancy and Postpartum Period Juliane Dantas Seabra Garcez, Vitor Emer Egypto Rosa, Antonio Sergio de Santis Andrade Lopes, Tarso Augusto Duenhas Accorsi, João Ricardo Cordeiro Fernandes, Pablo Maria Pomerantzeff, Walkiria Samuel Avila, Flavio Tarasoutchi .....................................................................................................................................................................page 426 Anatomopathological Session Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to Restrictive Cardiomyopathy Sumaia Mustafa, Alice Tatsuko Yamada, Fabio Mitsuo Lima, Valdemir Melechco Carvalho,Vera Demarchi Aiello e Jussara Bianchi Castelli .....................................................................................................................................................................page 430 Arquivos Brasileiros de Cardiologia - Volume 105, Nº 4, October 20X15 Case Report Percutaneous Treatment of Mitral Paraprosthetic Regurgitation: an Alternative to Surgery Roney Orismar Sampaio, Alessandra Gomes de Oliveira, George Barreto Miranda, Pedro Alves Lemos Neto, Marcelo Luiz Campos Vieira, Flávio Tarasoutchi .....................................................................................................................................................................page 440 Image Persistent Left Superior Vena Cava in Permanent Pacemaker Implantation Jerson Hernando Quitián, José Julian Carvajal, Mariana Soto, Guillermo Mora .....................................................................................................................................................................page 443 Erratum .....................................................................................................................................................................page 445 Arquivos Brasileiros de Cardiologia - Volume 105, Nº 4, October 2015 www.arquivosonline.com.br A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948 Scientific Director Maria da Consolação V. Moreira Interventionist Cardiology Pedro A. Lemos Chief Editor Luiz Felipe P. Moreira Pediatric/Congenital Cardiology Antonio Augusto Lopes Associated Editors Arrhythmias/Pacemaker Mauricio Scanavacca Clinical Cardiology José Augusto Barreto-Filho Non-Invasive Diagnostic Methods Carlos E. Rochitte Surgical Cardiology Paulo Roberto B. Evora Basic or Experimental Research Leonardo A. M. Zornoff Epidemiology/Statistics Lucia Campos Pellanda Arterial Hypertension Paulo Cesar B. V. Jardim Ergometrics, Exercise and Cardiac Rehabilitation Ricardo Stein First Editor (1948-1953) † Jairo Ramos Editorial Board Brazil Aguinaldo Figueiredo de Freitas Junior (GO) Alfredo José Mansur (SP) Aloir Queiroz de Araújo Sobrinho (ES) Amanda G. M. R. Sousa (SP) Ana Clara Tude Rodrigues (SP) André Labrunie (PR) Andrei Sposito (SP) Angelo A. V. de Paola (SP) Antonio Augusto Barbosa Lopes (SP) Antonio Carlos C. Carvalho (SP) Antônio Carlos Palandri Chagas (SP) Antonio Carlos Pereira Barretto (SP) Antonio Cláudio L. Nóbrega (RJ) Antonio de Padua Mansur (SP) Ari Timerman (SP) Armênio Costa Guimarães (BA) Ayrton Pires Brandão (RJ) Beatriz Matsubara (SP) Brivaldo Markman Filho (PE) Bruno Caramelli (SP) Carisi A. Polanczyk (RS) Carlos Eduardo Rochitte (SP) Carlos Eduardo Suaide Silva (SP) Carlos Vicente Serrano Júnior (SP) Celso Amodeo (SP) Charles Mady (SP) Claudio Gil Soares de Araujo (RJ) Cláudio Tinoco Mesquita (RJ) Cleonice Carvalho C. Mota (MG) Clerio Francisco de Azevedo Filho (RJ) Dalton Bertolim Précoma (PR) Dário C. Sobral Filho (PE) Décio Mion Junior (SP) Denilson Campos de Albuquerque (RJ) Djair Brindeiro Filho (PE) Domingo M. Braile (SP) Edmar Atik (SP) Emilio Hideyuki Moriguchi (RS) Enio Buffolo (SP) Eulógio E. Martinez Filho (SP) Evandro Tinoco Mesquita (RJ) Expedito E. Ribeiro da Silva (SP) Fábio Vilas-Boas (BA) Fernando Bacal (SP) Flávio D. Fuchs (RS) Francisco Antonio Helfenstein Fonseca (SP) Gilson Soares Feitosa (BA) Glaucia Maria M. de Oliveira (RJ) Hans Fernando R. Dohmann (RJ) Humberto Villacorta Junior (RJ) Ínes Lessa (BA) Iran Castro (RS) Jarbas Jakson Dinkhuysen (SP) João Pimenta (SP) Jorge Ilha Guimarães (RS) José Antonio Franchini Ramires (SP) José Augusto Soares Barreto Filho (SE) José Carlos Nicolau (SP) José Lázaro de Andrade (SP) José Péricles Esteves (BA) Leonardo A. M. Zornoff (SP) Leopoldo Soares Piegas (SP) Lucia Campos Pellanda (RS) Luís Eduardo Rohde (RS) Luís Cláudio Lemos Correia (BA) Luiz A. Machado César (SP) Luiz Alberto Piva e Mattos (SP) Marcia Melo Barbosa (MG) Maria da Consolação V. Moreira (MG) Mario S. S. de Azeredo Coutinho (SC) Maurício I. Scanavacca (SP) Max Grinberg (SP) Michel Batlouni (SP) Murilo Foppa (RS) Nadine O. Clausell (RS) Orlando Campos Filho (SP) Otávio Rizzi Coelho (SP) Otoni Moreira Gomes (MG) Paulo Andrade Lotufo (SP) Paulo Cesar B. V. Jardim (GO) Paulo J. F. Tucci (SP) Paulo R. A. Caramori (RS) Paulo Roberto B. Évora (SP) Paulo Roberto S. Brofman (PR) Pedro A. Lemos (SP) Protásio Lemos da Luz (SP) Reinaldo B. Bestetti (SP) Renato A. K. Kalil (RS) Ricardo Stein (RS) Salvador Rassi (GO) Sandra da Silva Mattos (PE) Sandra Fuchs (RS) Sergio Timerman (SP) Silvio Henrique Barberato (PR) Tales de Carvalho (SC) Vera D. Aiello (SP) Walter José Gomes (SP) Weimar K. S. B. de Souza (GO) William Azem Chalela (SP) Wilson Mathias Junior (SP) Exterior Adelino F. Leite-Moreira (Portugal) Alan Maisel (USA) Aldo P. Maggioni (Italy) Cândida Fonseca (Portugal) Fausto Pinto (Portugal) Hugo Grancelli (Argentina) James de Lemos (USA) João A. Lima (USA) John G. F. Cleland (England) Maria Pilar Tornos (Spain) Pedro Brugada (Belgium) Peter A. McCullough (USA) Peter Libby (USA) Piero Anversa (Italy) Sociedade Brasileira de Cardiologia Presidente Angelo Amato V. de Paola Diretora de Pesquisa Fernanda Marciano Consolim Colombo Vice-Presidente Sergio Tavares Montenegro Editor-Chefe dos Arquivos Brasileiros de Cardiologia Luiz Felipe P. Moreira Presidente-Eleito Marcus Vinícius Bolívar Malachias Diretor Financeiro Jacob Atié Assessoria Especial da Presidência Fábio Sândoli de Brito Governador - ACC Brazil Chapter Antonio Carlos de Camargo Carvalho Diretora Científica Maria da Consolação V. Moreira Coordenadorias Adjuntas Diretor Administrativo Emilio Cesar Zilli Editoria do Jornal SBC Nabil Ghorayeb e Fernando Antonio Lucchese Diretor de Qualidade Assistencial Pedro Ferreira de Albuquerque Diretor de Comunicação Maurício Batista Nunes Diretor de Tecnologia da Informação José Carlos Moura Jorge Diretor de Relações Governamentais Luiz César Nazário Scala Diretor de Relações com Estaduais e Regionais Abrahão Afiune Neto Diretor de Promoção de Saúde Cardiovascular – SBC/Funcor Carlos Costa Magalhães Diretor de Departamentos Especializados Jorge Eduardo Assef Coordenadoria de Educação Continuada Estêvão Lanna Figueiredo Coordenadoria de Normatizações e Diretrizes Luiz Carlos Bodanese Coordenadoria de Integração Governamental Edna Maria Marques de Oliveira Coordenadoria de Integração Regional José Luis Aziz SBC/DF - Wagner Pires de Oliveira Junior SBC/ES - Marcio Augusto Silva SBC/GO - Thiago de Souza Veiga Jardim SBC/MA - Nilton Santana de Oliveira SBC/MG - Odilon Gariglio Alvarenga de Freitas SBC/MS - Mércule Pedro Paulista Cavalcante SBC/MT - Julio César de Oliveira SBC/NNE - Jose Itamar Abreu Costa SBC/PA - Luiz Alberto Rolla Maneschy SBC/PB - Helman Campos Martins SBC/PE - Catarina Vasconcelos Cavalcanti SBC/PI - João Francisco de Sousa SBC/PR - Osni Moreira Filho SBC/RJ - Olga Ferreira de Souza SBC/RN - Rui Alberto de Faria Filho Presidentes das Soc. Estaduais e Regionais SBC/RO - João Roberto Gemelli SBC/AL - Carlos Alberto Ramos Macias SBC/RS - Carisi Anne Polanczyk SBC/AM - Simão Gonçalves Maduro SBC/SC - Marcos Venício Garcia Joaquim SBC/BA - Mario de Seixas Rocha SBC/SE - Fabio Serra Silveira SBC/CE - Ana Lucia de Sá Leitão Ramos SBC/SP - Francisco Antonio Helfenstein Fonseca SBC/CO - Frederico Somaio Neto SBC/TO - Hueverson Junqueira Neves Presidents of the Specialized Departaments and Study Groups SBC/DA - José Rocha Faria Neto SBCCV - Marcelo Matos Cascudo GECHOSP - Evandro Tinoco Mesquita SBC/DECAGE - Josmar de Castro Alves SBHCI - Hélio Roque Figueira GECO - Roberto Kalil Filho SBC/DCC - José Carlos Nicolau SBC/DEIC - Dirceu Rodrigues Almeida SBC/DCM - Maria Alayde Mendonça da Silva GERTC - Clerio Francisco de Azevedo Filho SBC/DCC/CP - Isabel Cristina Britto Guimarães GAPO - Danielle Menosi Gualandro SBC/DIC - Arnaldo Rabischoffsky GEECG - Joel Alves Pinho Filho SBC/DERC - Nabil Ghorayeb GEECABE - Mario Sergio S. de Azeredo Coutinho SBC/DFCVR - Ricardo Adala Benfatti GECETI - Gilson Soares Feitosa Filho SBC/DHA - Luiz Aparecido Bortolotto GEMCA - Álvaro Avezum Junior GEMIC - Félix José Alvarez Ramires SOBRAC - Luiz Pereira de Magalhães GECC - Mauricio Wajngarten GEICPED - Estela Azeka GECIP - Gisela Martina Bohns Meyer GECESP - Ricardo Stein GECN - Ronaldo de Souza Leão Lima GERCPM - Artur Haddad Herdy GETAC - João David de Souza Neto Arquivos Brasileiros de Cardiologia Volume 105, Nº 4, October 2015 Indexing: ISI (Thomson Scientific), Cumulated Index Medicus (NLM), SCOPUS, MEDLINE, EMBASE, LILACS, SciELO, PubMed Address: Av. Marechal Câmara, 160 - 3º andar - Sala 330 20020-907 • Centro • Rio de Janeiro, RJ • Brasil Phone.: (21) 3478-2700 E-mail: [email protected] www.arquivosonline.com.br SciELO: www.scielo.br Commercial Department Phone: (11) 3411-5500 Graphic Design and Diagramming SBC - Internal Design Department E-mail: [email protected] Print IMOS Editora e Gráfica Editorial Production Circulation 1.500 copies SBC - Internal Publication Department Affiliated at the Brazilian Medical Association The ads showed in this issue are of the sole responsibility of advertisers, as well as the concepts expressed in signed articles are of the sole responsibility of their authors and do not necessarily reflect the views of SBC. This material is for exclusive distribution to the medical profession. 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SUPPORT Back to the Cover Editorial Cardiovascular Risk Factors: From Consolidated Knowledge to a Call for Action Guilherme Brasil Grezzana1 and Lucia Campos Pellanda1,2 Fundação Universitária de Cardiologia do Rio Grande do Sul1 – ICFUC; Universidade Federal de Ciências da saúde de Porto Alegre2 – UFCSPA, Porto Alegre, RS – Brazil Since the decade of 1950, the most prominent journal in cardiology in Brazil, Arquivos Brasileiros de Cardiologia (ABC), has been indexed in Medline1. A total of 7,102 articles have been published since then, on various subjects related to clinical, invasive, surgical cardiology, as well as diagnostic methods. We performed a systematic review of articles published in ABC during the period from January 2001 to June 2015 containing the MeSH term “cardiovascular risk factors”. Of the 3,087 titles of articles published in the period, 116 articles were identified. The abstracts of these articles were reviewed, and 107 articles, in which assessment of cardiovascular risk factors was the main topic, were included. The sample was composed by 102 original articles, 3 letters and 2 editorials. When specific topics were assessed, “cardiovascular factor or cardiovascular risk” was generally described in 88 articles, 6 articles focused on quality of life and cardiovascular risk factor, 4 articles described epidemiological factors and risk factors, 5 articles specifically explored systemic arterial hypertension and risk factors, 3 were guidelines on risk factors and 1 articles related risk factor with public health. However, when we focused only on isolated risk factors, there has been a clear preponderance of articles involving arterial hypertension (18% between 2010 and 2013) and a trend of increase in the number of articles on diabetes (approximately 10%) published on ABC in the last years. The average annual number of articles focused on cardiovascular risk factors published on ABC has been Keywords Risk Factors; Cardiovascular Diseases; Prevention; Epidemiologic Studies; Data Interpretation Statistical; Journals Articles. Mailing Address: Lucia Campos Pellanda • Av. Princesa Isabel, 370, Santana Postal Code 90620-000. Porto Alegre, RS – Brazil E-mail: [email protected] DOI: 10.5935/abc.20150128 325 consistent in the last 15 years, with a mean of 3.47% of total publications per year, and no significant differences between years (p = 0.195) (Table 1). Considering SciELO database and the number of accesses to the articles selected between January 2014 and June 2015, the 2 most accessed articles were cross-sectional studies on metabolic syndrome and systemic arterial hypertension (Table 2)2,3. In 2005, an ABC editorial discussed the cardiovascular risk factors in Brazil and the perspective of cardiovascular epidemiology in the next 50 years4. National data published at that time (one study conducted in São Paulo metropolitan region and the AFIRMAR study)5,6, and a study with students about life style and cardiovascular disease7 revealed that predictive factors of atherosclerosis in Brazil were not different from those in Europe and North America8. In addition, there is a relationship between early mortality caused by cardiovascular disease and social inequality9. However, ten years after publication of this editorial, which clarified the definitions of cardiovascular risks in Brazil, most studies about this topic published on ABC have had an observational design. This trend may be found in a review of articles published on ABC in the last 60 years10. Therefore, the current scenario is of consolidation and confirmation of traditional risk factors for cardiovascular events, associated with results of mortality rates for ischemic and cerebrovascular disease in different regions of the country. Therefore, the challenge of cardiovascular epidemiology and of academic publishing in the next years is to promote the development of interventional studies. This approach, in line with primary and secondary prevention measures, may contribute to changes in the epidemiology of cardiovascular risks in Brazil in the coming years. Thus, the role of the leading journal in cardiology in Brazil is to support solid evidence that serve as the basis for practices in our society. Grezzana & Pellanda Cardiovascular risk factors: from consolidated knowledge to call to action Editorial Table 1 – Total of publications on cardiovascular risk factors between 2001 and 2015 identified by search of MeSH term and revision of the articles’ title and abstract Year N N-Reviewed % N-Reviewed/N 2001 134 4 2.98% 2002 168 3 1.78% 2003 160 5 3.12% 2004 184 2 1.08% 2005 224 8 3.57% 2006 274 11 4.05% 2007 244 9 3.68% 2008 172 5 2.9% 2009 259 11 4.24% 2010 331 18 5.43% 2011 235 5 2.12% 2012 209 4 1.91% 2013 236 10 4.23% 2014 227 9 3.96% 2015 30 3 10% Total 3087 107 3.47% N: Number of articles published; N-Reviewed: Articles selected from the review of abstracts; % N-Reviewed/N: % of articles on cardiovascular risk factors in relation to total number of articles published. Table 2 – List of articles selected in 2014 and 2015 and the number of accesses accroding to SciELO database (date of access 06/23/15) Access Year Vol/N/Pags Article title Design Country Study City 100 2014 V 102, n 4, p 345-354 Dietary interventions and blood pressure In Latin America: systematic review and meta-analysis SR Curitiba Brazil 280 2014 V 102,n 4, p 374-382 Alimentary habits, physical activity, and Framingham global risk score in metabolic syndrome CSS Porto Alegre Brazil 119 2014 V 103,n 21; p 1-31 South American gruidelines for cardiovascular disease prevention and rehabilitation G – Brazil 168 2014 V 103,n 6, p 493-501 Comparison of cardiovascular risk factors in different areas of health care over a 20-year period CS Goiânia Brazil 107 2014 V 102,n 5, p 473-480 Prevalence of cardiovascular risk factors in hemodialysis patients – The CORDIAL study CSS Porto Alegre Brazil 235 2014 V 102,n 6, p 571-578 Blood pressure control In hypertensive patients in the “Hiperdia Program”: a territory-based study CSS Porto Alegre Brazil 151 2014 V 102,n 5, p 420-431 l cardiovascular prevention guideline of the BSC – executive summary D – Brazil CSS: Cross-sectional study; G: Guidelines; CS: cohort study; SR: Systematic review; BSC: Brazilian Society of Cardiology Arq Bras Cardiol. 2015; 105(4):325-327 326 Grezzana & Pellanda Cardiovascular risk factors: from consolidated knowledge to call to action Editorial References 1. Stein R, Araújo CG. Heart, exercise and the Brazilian Archives of Cardiology. Arq Bras Cardiol. 2011;97(6):446-8. 2. Soares TS, Piovesan CH, Gustavo Ada S, Macagnan FE, Bodanese LC, Feoli AM. Alimentary habits, physical activity, and Framingham global risk score in metabolic syndrome. Arq Bras Cardiol. 2014;102(4):374-82. 3. Souza CS, Stein AT, Bastos GA, Pellanda LC. Blood pressure control in hypertensive patients in the “Hiperdia Program”: a territory-based study. Arq Bras Cardiol. 2014;102(6):571-8. 4. Polanczyk CA. [Cardiovascular risk factors in Brazil: the next 50 years!]. Arq Bras Cardiol. 2005;84(3):199-201. 5. Avezum A, Piegas LS, Pereira JC. [Risk factors associated with acute myocardial infarction in the São Paulo metropolitan region: a developed region in a developing country]. Arq Bras Cardiol. 2005;84(3):206-13. 327 Arq Bras Cardiol. 2015; 105(4):325-327 6. Piegas LS, Avezum A, Pereira JC, Neto JM, Hoepfner C, Farran JA, et al; AFIRMAR Study Investigators. Risk factors for myocardial infarction in Brazil. Am Heart J. 2003;146(2):331-8. 7. Lancarotte I, Nobre MR, Zanetta R, Polydoro M. Lifestyle and cardiovascular health in school adolescents from São Paulo. Arq Bras Cardiol. 2010;95(1):61-9. 8. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937-52. 9. Bassanesi SL, Azambuja MI, Achutti A. Premature mortality due to cardiovascular disease and social inequalities in Porto Alegre: from evidence to action. Arq Bras Cardiol. 2008;90(6):370-9. 10. Evora PR, Nather JC, Rodrigues AJ. Prevalence of heart disease demonstrated in 60 years of the Arquivos Brasileiros de Cardiologia. Arq Bras Cardiol. 2014;102(1):3-9. Back to the Cover Special Article Executive Summary of the Guidelines on Stable Coronary Disease Luiz Antonio Machado César, Antonio de Pádua Mansur, João Fernando Monteiro Ferreira Instituto do Coração (InCor) HC-FMUSP, São Paulo, SP – Brasil Part I – Diagnosis and risk stratification Diagnosis Introduction Diagnosis of subclinical coronary artery disease The risk of atherosclerotic disease may be measured by the sum of individual risks and by the synergism between the known risk factors for cardiovascular disease. Due to these complex interactions, an intuitive approach of risk attribution frequently lead to underestimation or overestimation of cases with higher or low risk, respectively. These guidelines aim to assist physicians, particularly cardiologists, to identify adults at high risk of coronary disease as early as possible, and to highlight its most common symptoms, especially coronary arery disease (CAD) symptoms. According to Brazilian’s Unified Health System database (DATASUS), cardiovascular causes represent nearly 30% of all causes of death in Brazil1. Recommendation levels: • Class I: conditions for which there is conclusive evidence or general agreement that the procedure is useful/effective; • Class II: conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of the procedure; • Class IIa: weight of evidence/opinion in favor of usefulness/efficacy. Approved by the majority of the professionals; • Class IIb: safety and usefulness/efficacy is less well established, with no predominance of opinion in favor of the procedure; • Class III: conditions for which there is evidence and/or general agreement that the procedure is not useful or effective and in some cases may be harmful; Evidence level: • Level A: data derived from multiple consistent, large randomized clinical trials and/or robust systematic meta‑analysis of randomized clinical trials. • Level of evidence B: data derived from a less robust meta-analysis, a single randomized trial or nonrandomized (observational) studies. • Level of evidence C: data derived from consensus opinion of experts. Keywords Coronary Artery Disease; Diagnosis; Risk Factors; Physical Examination; Atherosclerosis. Mailing Address: Luiz Antonio Machado César • Av. Dr. Enéas de Carvalho Aguiar, 44. Cerqueira Cesar, Postal Code 05403-000. São Paulo, SP – Brazil Email: [email protected] Manuscript received September 23, 2015; revised manuscript September 23, 2015; accepted September 23, 2015. DOI: 10.5935/abc.20150136 328 Diagnosis of symptomatic patients The approach proposed by Diamond and Forrester2,3 (Table 1): Level of recommendation I, evidence level B was considered for diagnosis. For the assessment of cardiovascular risk, the Brazilian Guidelines for Atherosclerosis Prevention and the V Brazilian Guidelines on Dyslipidemia and Atherosclerosis Prevention were used4,5. (Level of recommendation IIa, evidence level B). Diagnosis of manifest coronary artery disease History, physical examination, differential diagnosis Definition of angina Angina is a clinical syndrome characterized by pain or discomfort in any of the following regions: chest, epigastrium, mandible, shoulder, dorsum, or upper limbs. It is triggered or aggravated by physical activity or emotional stress and attenuated by nitroglycerin and its derivatives. Clinical assessment of patients with chest pain a) Clinical history: Detailed clinical history. Some characteristics should be carefully investigated to determine the probability of the presence of angina: quality: constriction, tightness, heaviness, distress, suffocation, discomfort, burning, and stabbing; location: precordium, retrosternal area, shoulder, epigastrium, neck, hemithorax and dorsum; irradiation: upper limbs (right, left, or both), shoulder, mandible, neck, dorsum, and epigastrium; duration: seconds, minutes, hours, or days; triggering factors: exertion, sexual activity, position, eating habits, breathing, emotional component , and spontaneous; relieving factors: rest, sublingual nitrates, analgesic, food, antacids, position, and apnea; associated symptoms: sweating, nausea, vomiting, pallor, dyspnea, hemoptysis, cough, presyncope, and syncope. An episode of angina lasts for a few minutes. It is generally triggered by exertion of emotional stress, and relieved by rest. The use of nitroglycerin, such as sublingual nitrate, relieves César et al Summary of the guidelines on stable coronary disease Special Article Table 1 – Pre-test probability of coronary artery disease in symptomatic patients by age and sex (Diamond/Forrester e CASS Data) Age (years) Nonanginal chest pain Male Female 35 3-35 45 9-47 55 65 Atypical angina Typical angina Male Female Male Female 1-19 8-59 2-39 30-88 10-78 2-22 21-70 5-43 51-92 20-79 23-59 4-25 25-79 10-47 80-95 38-82 49-69 9-29 71-86 20-51 93-97 56-84 angina within approximately 1 min. Pain in the chondrosternal joints is rarely of cardiac origin. The Canadian Cardiovascular Society (CCS) grading of angina pectoris6 is the most widely used classification of angina (Chart 1). b) Physical examination: Physical examination is usually normal in patients with stable angina. However, during an episode of angina, it may provide important evidence about the presence of absence of CAD. When physical examination is performed during an episode of pain, third heart sound (S3), fourth heart sound (S4) or gallop, mitral regurgitation, paradoxical splitting of the second heart sound (S2), and bibasilar crackles are suggestive and predictive indicators of DAC7. The occurrence of atherosclerosis in other regions, including decreased pulse in lower limbs, arterial hardening, and abdominal aneurysm, increase the likelihood of CAD. Differential diagnosis of chest pain: associated conditions, and provoking and relieving factors of angina In all patients, especially in those with typical angina, associated (simultaneous) diseases that can precipitate “functional” angina, i.e. myocardial ischemia in the absence of significant anatomic coronary obstruction, should be considered. These diseases generally cause myocardial ischemia either by increasing myocardial oxygen consumption or by decreasing the oxygen supply. An increase in oxygen consumption may be caused by hyperthermia, hyperthyroidism, and cocaine use. Obstructive sleep apnea should be seriously considered in patients with significant nocturnal symptoms. Electrocardiogram The test is indicated when a cardiac cause of chest pain is suspected (level of recommendation I, evidence level B). Chest radiography Chest radiography is indicated for patients with CAD and signs or symptoms of congestive heart failure (level of recommendation I, evidence level B), and patients with signs and symptoms of pulmonary disease (level of recommendation IIa, evidence level B). Exercise treadmill test The most predictive variables in the diagnosis of coronary obstruction are ST-segment depression ≥ 1 mm (measured at 0.80 seconds from the J-point), with a horizontal or descending pattern, and presence of anginal pain. Exercise treadmill test for the diagnosis of coronary obstruction Level of recommendation I, evidence level B 1. Intermediate probability Level of recommendation IIa, evidence level B 1. Suspected vasospastic angina. 2.Coronary angiography for assessment of intermediate lesions. 3. Asymptomatic individuals with more than two risk factors. Level of recommendation IIb, evidence level B 1. A high or low pretest probability of coronary obstruction, based on age, sex and symptoms. 2.Risk assessment for noncardiac surgery (in low cardiovascular risk). Noninvasive tests Additional tests in stable angina are based on the probability of CAD. After estimating the probability, it is categorized as low, intermediate, or high according to established values: 10%–90% in intermediate probability, < 10% in low probability, and > 90% in high probability cases. Level of recommendation III: abnormalities: preexcitation syndrome or Wolff-Parkinson-White syndrome, pacemaker rhythm, ST-segment depression >1 mm at rest, and complete left bundle-branch block. Since overall mortality of patients with stable angina varies from 1.2% to 2.4% per year8, a diagnostic method that leads to a higher incidence of complications and death would be inappropriate. Echocardiography Echocardiography may help in the diagnosis9, by showing reversible and irreversible abnormalities in segmental motion in patients with clinical features of CAD. Arq Bras Cardiol. 2015; 105(4):328-338 329 César et al Summary of the guidelines on stable coronary disease Special Article Chart 1 – Canadian Cardiovascular Society grading of angina pectoris Class I Habitual physical activity, such as walking and climbing sairs, does not cause angina. Angina occurs during prolonged or strenuous physical activity. Class II Slight limitation for habitual activities. Angina during walking or climbing stairs rapidly, walking uphill, walking or climbing stairs after meals or in the cold, in the wind or under emotional stress, or within a few hours after waking up. Angina occurs after walking two blocks or climbing more than 1 flight of stairs in normal conditions. Class III Limitation of habitual activities. Angina occurs after walking one block or climbing 1 flight of stairs. Class IV Unable to carry on any habitual physical without discomfort. Angina symptoms may be present at rest. a) Stress echocardiography in chronic coronary atherosclerotic disease: the test is used in diagnosis and prognosis, to assess the impact of revascularization therapies and myocardial viability, and to support therapeutic decisions. The test has good accuracy for induced myocardial ischemia in patients with intermediate or high pretest probability, with higher diagnostic sensitivity and specificity as compared with the exercise treadmill test10. Level of recommendation IIa, evidence level B Asymptomatic individuals at low risk using the overall risk score and family history of early CAD. Level of recommendation IIIa, evidence level B 1.Asymptomatic patients at high risk of CAD or with known CAD. 2. Follow-up of coronary calcification progression. b) Preoperative evaluation: according to recommendations of the American College of Cardiology/American Heart Association (ACC/AHA) and the European Association of Cardiovascular Imaging (EACVI), dobutamine stress echocardiography has been valuable in preoperative risk stratification in patients with CAD11. Radioisotopes Aspects of myocardial perfusion, cellular integrity, myocardial metabolism, myocardial contractility, and global or segmental ventricular function are evaluated 12. The radioisotope thallium-201 is less frequently used because of its association with higher radiation, and is indicated for the detection of ischemia concomitant with viable myocardium. Coronary angiography Coronary lesions are significant when one or more epicardial arteries are obstructed, with at least 70% stenosis and/or stenosis greater than 50% of the left main coronary artery. Assessment and measurement of obstructions are performed using coronary angiography (Chart 2). 3. Symptomatic patients. b) Coronary computed tomography angiography Coronary computed tomography angiography enables the noninvasive evaluation of the lumen of coronary arteries14. The test is clinically indicated for symptomatic patients with conflicting results between ischemia and clinical tests. Level of recommendation IIa, evidence level A Suspected chronic CAD using: a) Previous conflicting or inconclusive ischemia tests; b) Continuous symptoms and ischemia tests with normal or inconclusive results. Level of recommendation IIa, evidence level B 1.To assess the patency of grafts for myocardial revascularization in symptomatic individuals with pretest probability. Level of recommendation IIb, evidence level B Cardiac computed tomography There are two main modes of examinations using cardiac computed tomography that use different techniques and provide different information: the calcium score and coronary computed tomography angiography. 1. Symptomatic individuals with intermediate probability of CAD and positive ischemia tests. 2. Symptomatic individuals with low probability of CAD and negative ischemia tests. 3.Assessment of in-stent restenosis in symptomatic individuals with intermediate pretest probability. a) Calcium score Quantification of coronary artery calcification using calcium score correlates with the atheroscleroctic load13. Level of recommendation I, evidence level A Asymptomatic individuals at intermediate risk using the overall risk score. 330 Arq Bras Cardiol. 2015; 105(4):328-338 Level of recommendation III, evidence level B 1. Symptomatic individuals with high probability of CAD. 2. Initial evaluation of CAD in asymptomatic individuals, able to exercise and with interpretable electrocardiogram. 3.Follow-up of coronary atheroscleroctic lesions in asymptomatic individuals. César et al Summary of the guidelines on stable coronary disease Special Article Chart 2 – Recommendations for coronary angiography in patients with coronary artery disease Stable angina (CCS III or IV) despite clinical treatment (B) Class I High risk in noninvasive tests, regardless of angina (B) Angina and cardiac arrest or severe ventricular arrhythmia survivors (B) Angina and symptoms/signs of congestive heart failure (C) Patients with uncertain diagnosis after noninvasive tests, when the benefits of an accurate diagnosis outweigh the risks and costs of coronary angiography (C) Class IIa Unable to undergo noninvasive tests due to physical disability, illness, or obesity (C) High-risk jobs that require an accurate diagnosis (C) Patients with uncertain prognostic information after noninvasive tests (C) Class IIb Multiple hospitalizations for chest pain, when a definitive diagnosis is considered necessary (C) Significant comorbidities, when the risks of angiography outweigh the benefits of the procedure (C) Class III Stable angina (CCS I or II) that responds to drug treatment and no evidence of ischemia in noninvasive tests (C) Preference to avoid revascularization (C) CCS: Canadian Cardiovascular Society. Cardiovascular magnetic resonance imaging Magnetic resonance imaging is an excellent diagnostic method; it allows the assessment of cardiac and vascular anatomy, ventricular function, myocardial perfusion, and tissue characterization in an accurate, reproducible manner, in a single test15. a) Myocardial ischemia The protocols for the investigation of ischemia by magnetic resonance with myocardial perfusion are similar to those used in scintigraphy. b) Delayed enhancement The diagnosis and characterization of areas of myocardial infarction/necrosis/fibrosis using CMR is based on the delayed enhancement technique16-18. c) Coronary magnetic resonance angiography The clinical use of the test has been focused on the assessment of congenital anomalies and the origin and course of the coronary arteries19. Recommendations for magnetic resonance imaging Level of recommendation I, evidence level A Evaluation of the global (left and right) ventricular function, volume, and mass Detection of ischemia: • Assessment of myocardial perfusion under stress using vasodilators. • Assessment of ventricular contractility using dobutamine stress magnetic resonance. • Detection and quantification of myocardial fibrosis and infarction. • Assessment of myocardial viability. Level of recommendation I, evidence level B Differentiation between ischemic and nonischemic cardiopahty • Coronary magnetic resonance angiography: • Assessment of congenital anomalies. Cardiovascular risk stratification in CAD The strategies and methods used in the diagnosis of CAD also provide information on disease severity, with implications for complementary invasive methods, including coronary angiography, and therapeutic decision-making. Exercise treadmill test for the prognosis of coronary atherosclerosis Level of recommendation I, evidence level B Patients with intermediate or high probability of CAD after initial evaluation; patients showing changes in symptoms. Level of recommendation IIb, evidence level B Patients with pre-excitation, ST-segment depression > 1 mm in echocardiogram at rest, pacemaker rhythm, and complete left bundle-branch block. Level of recommendation IIa, evidence level C Revascularized patients with symptoms suggestive of ischemia. Level of recommendation III, evidence level C Patients with severe comorbidities. In patients with CAD who are able to reach stage 3 of the Bruce protocol, the annual mortality rate is approximately 1%, whereas in those unable to exceed 5 METs, the annual mortality rate is approximately 5%20. Arq Bras Cardiol. 2015; 105(4):328-338 331 César et al Summary of the guidelines on stable coronary disease Special Article Other high-risk variables include ST-segment depression in multiple leads, persistent ST-segment depression in recovery phase > 5 min, inadequate chronotropic response, fall in systolic blood pressure during physical exertion or a flat curve, and severe ventricular arrhythmia at low level of exercise in the presence of ST-segment depression or anginal pain. Stress echocardiography Echocardiography for CAD prognosis takes into account mainly the left ventricle function, and the presence or absence of myocardial ischemia induced by physical or pharmacological stress on echocardiography. In asymptomatic patients who have successfully undergone coronary artery bypass graft surgery (CABG), routine evaluation using stress echocardiography is not indicated. Other important variables for risk stratification include pulmonary uptake of thallium in myocardial perfusion scintigraphy, and the transient increase in the left ventricle. Strategies for the diagnosis and stratification of coronary artery disease The prognosis of CAD may also be based on the direct anatomical visualization of the coronary lesion by coronary angiography. Normal functional testing, performed with appropriate stress protocol yields the same prognosis as compared with the standard coronary angiography test. For specific situations and after implantation of antiproliferative drugs-coated stent, follow the Brazilian Guidelines of Antiplatelet Agents and Anticoagulants in Cardiology. Secondary prevention: Hypolipidemic agent Lifestyle change (LC) is recommended for all patients with CAD (Chart 3). Blockade of the renin–angiotensin system a) ACE inhibitors: the benefits of ACE inhibitors in the treatment of CAD have been shown in clinical trials involving asymptomatic patients with reduced ejection fraction21 and patients with ventricular dysfunction after acute myocardial infarction21,22. They should be used routinely for ventricular dysfunction, and/or heart failure, and/or diabetes mellitus management23,24. Level of recommendation I, evidence level A. It should be used routinely in all patients with CAD: Level of recommendation IIa, evidence level A. Part II – Drug Treatment b) Angiotensin receptor blockers: alternative therapy for patients intolerant to ACE inhibitors, since no study has been conducted on the use of this group of drugs in stable coronary disease. In other situations, angiotensin receptor blockers have provided no additional benefits over those of ACE inhibitors, which can decrease the incidence of infarction. The main objectives of the treatment of CAD are to prevent myocardial infarction and decrease mortality, and to reduce symptoms and the incidence of myocardial ischemia, providing a better quality of life. Treatment to reduce symptoms and myocardial ischemia Drug treatments to reduce the risk of myocardial infarction and mortality Antiplatelet drugs a) Acetylsalicylic acid (ASA): Level of recommendation I, evidence level A. b) Thienopyridine derivatives: Clopidogrel: Level of recommendation I, evidence level B. Indicated when aspirin is absolutely contraindicated, and associated with aspirin after stent implant for at least 30 days. Ticlopidine: Level of recommendation IIa, evidence level B. Indicated when aspirin is absolutely contraindicated, and associated with aspirin after stent implant for at least 30 days. c) Dipyridamole: Level of recommendation III, evidence level B. d) Anticoagulants: should be used in combination with aspirin in case of high risk of thrombosis, especially after myocardial infarction. Level of recommendation I, evidence level A. 332 As an alternative to aspirin intolerance: Level of recommendation IIa, evidence level A. Arq Bras Cardiol. 2015; 105(4):328-338 a) Beta-blockers: beta-blockers are drugs of choice, to be administered alone or in combination with other antianginal drugs. Indicated as first-line agents in patients with stable angina without previous myocardial infarction and/or left ventricle dysfunction25. Level of recommendation I, evidence level B. – First-line agents in patients with stable angina within 2 years of myocardial infarction and/or left ventricle. Level of recommendation III, evidence level C. – For symptomatic relief in patients with vasospastic angina: Level of recommendation III, evidence level C. b) Calcium-channel blockers: heterogeneous group of drugs with pharmacological effects that include smooth muscle relaxation, afterload reduction, and negative inotropic effects (some formulations). On the other hand, they are contraindicated in case of ventricular dysfunction (verapamil and diltiazem)26. – First-line agents for symptomatic relief in patients with vasospastic angina. Level of recommendation IIa, evidence level B. – In symptomatic patients with stable angina on betablockers (dihydropyridines). Level of recommendation I, evidence level B. – In symptomatic patients with stable angina on beta-blockers (verapamil or diltiazem). Level of recommendation III, evidence level B. César et al Summary of the guidelines on stable coronary disease Special Article Chart 3 – Recommendations for drug therapy in dyslipidemias Indications Class-level of evidence Statins are first choice treatment in primary and secondary prevention I-A Fibrate monotherapy or in combination with statins to prevent microvascular diseases in type 2 diabetes patients I-A Associations of ezetimibe or resins with statins when LDL-C target levels are not achieved IIa-C Association of niacin with statins III-A Omega-3 fatty acids for cardiovascular prevention IIII-A Source: Brazilian guidelines for cardiovascular disease prevention10. – In patients with stable angina and contraindications to beta-blockers (preferably verapamil or diltiazem). Level of recommendation I, evidence level B. – In symptomatic patients with stable angina (fastacting ihydropyridines). Level of recommendation III, evidence level B. c) Nitrates: – Fast-acting nitrates: for symptomatic relief of acute angina. Level of recommendation I, evidence level B. – Long-acting nitrates: continuous use of long-acting nitrates leads to drug tolerance. – First-line agents in patients with stable angina. Level of recommendation III, evidence level C. – Third-line agents in stable angina patients who still have symptoms even after using other antianginal agents associated. Level of recommendation IIa, evidence level B. – For symptomatic relief in patients with vasospastic angina after using calcium-channel blockers. Level of recommendation IIa, evidence level B. d) Trimetazidine: drug with metabolic and anti-ischemic effects and no effect on cardiovascular hemodynamics27. – In symptomatic patients with stable angina on beta-blockers alone or in combination with other antianginal agents. Level of recommendation IIa, evidence level B. – In patients with stable angina and left ventricle dysfunction associated with optimized medical therapy. Level of recommendation IIa, evidence level B. – In patients with stable angina during myocardial revascularization procedures (percutaneous or surgical). Level of recommendation IIa, evidence level B. – In symptomatic patients with stable angina who are intolerant to beta-blockers alone or with other antianginal agents. Level of recommendation IIb, evidence level B. – In patients with stable angina, left ventricle dysfunction (LVEF < 40%) and heart rate ≥ 70 bpm under optimized medical therapy. Level of recommendation IIa, evidence level B. f) Ranolazine: piperazine derivative. Similar to trimetazidine, it protects patients from ischemia by increasing glucose metabolism and decreasing fatty acids oxidation. However, its major effect appears to be the inhibition of late sodium current29. Figures 1 and 2 depict algorithms that facilitate understanding of drug therapy options in stable CAD. Part III – Treatment with invasive measures Treatment with invasive measures Direct surgical revascularization The Guidelines on Myocardial Revascularization30 cover the procedure techniques, alternatives, and current practices. They also briefly review classic studies, comparing surgical treatment strategies with clinical treatment and percutaneous coronary intervention. Main indications for direct revascularization Level of recommendation I Left main coronary artery stenosis ≥ 50% or equivalent conditions (left descending anterior and circumflex arteries in the ostium, or before the exit of important branches). Evidence level A. e) Ivabradine: a specific sinus node If current i inhibitor, which specifically decreases the heart rate28. Proximal stenosis (> 70%) in the three main arteries with or without involvement of proximal left anterior descending artery, especially in patients with ejection fraction < 50% or functional evidence of moderate to severe ischemia. Evidence level B. – In symptomatic patients with stable angina on betablockers alone or with other antianginal agents, and heart rate > 70 bpm. Level of recommendation IIa, evidence level B. Stenosis in two main vessels, with proximal left anterior descending artery lesion in patients with ejection fraction < 50% or functional evidence of moderate to severe ischemia. Evidence level B. Arq Bras Cardiol. 2015; 105(4):328-338 333 César et al Summary of the guidelines on stable coronary disease Special Article Figure 1 – Algorithm for drug treatment of stable angina with antianginal drugs to relieve symptoms and improve quality of life. Details, levels of recommendation and evidence level: see the corresponding text. Level of recommendation IIa Left internal mammary artery graft in patients with significant stenosis (> 70%) in proximal left anterior descending artery and evidence of extensive ischemia, aiming to improve survival. Evidence level B. Coronary artery by-pass surgery instead of percutaneous coronary intervention in patients with multivessel CAD and diabetes mellitus, particularly in those who underwent internal mammary artery grafting with revascularization to the left anterior descending artery. Evidence level B. functional lesions (e.g., fractional flow reserve > 0.8 or mild ischemia in noninvasive tests). Evidence level C. Involvement of one or two arteries, except for the proximal left anterior descending artery, with no evidence of relevant ischemia in functional tests, and presence of perfusion in small areas of viable myocardium. Evidence level B. Moderate lesions (between 50% and 60%) except in left main coronary artery, without moderate ischemia in functional tests. Insignificant lesions (< 50%). The “Heart Team” concept for myocardial revascularization Level of recommendation III Asymptomatic patients with normal ventricular function, without extensive areas of ischemia or involvement of the left anterior descending artery. Evidence level C. Asymptomatic patients without significant anatomical lesions (< 70%, or < 50% of the left main coronary artery) or 334 Arq Bras Cardiol. 2015; 105(4):328-338 Class I A team made up of clinical cardiologists, cardiac surgeons and interventional cardiologists is recommended to individualize the indication for the treatment of left main coronary artery lesions or complex CAD. Evidence level C31. César et al Summary of the guidelines on stable coronary disease Special Article Figure 2 – Algorithm for reduction of cardiovascular events in the presence of left ventricular dysfunction. Details, levels of recommendation and evidence level: see the corresponding text. ASA: Acetylsalicylic acid; AH: Arterial hypertension; ACE inhibitors: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin receptor blocker I; AP: Arterial pressure; HR: Heart rate. Catheter-based revascularization: clinical indications Indications for myocardial revascularization Revascularization vs. drug treatment (Figure 3) Comparison of revascularization strategies in diabetic patients with multi-vessel CAD Percutaneous coronary intervention vs. clinical treatment Sensitivity analysis showed that the superiority of coronary artery bypass surgery was more evident in individuals with high Syntax score (> 33), with no significant difference between the low score and intermediate score groups33. To date, no study has demonstrated that percutaneous coronary intervention in patients with CAD improves survival rates32. Appropriate use of revascularization Patients with three-vessel disease The coronary artery bypass surgery is the preferred strategy for three-vessel disease patients with increased age, low ejection fraction, renal dysfunction, peripheral vascular disease, diabetes mellitus, or Syntax score > 22. Special situations Aspects of percutaneous coronary intervention in diabetes mellitus patients Drug-eluting stents are recommended to reduce restenosis and the need of a new target vessel revascularization34,35. The dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is an essential component of drug regiments for perioperative and postoperative periods. Patients who receive drug-eluting stents should use the therapy for 12 months, and those who receive non-drug-eluting stents should use it for 1 month. Patients with diabetes mellitus Diabetes mellitus is an increasingly prevalent condition associated with increased risk of cardiovascular complications, especially late mortality. Patients with previous revascularization The main indications for revascularization are persistence of symptoms, despite optimized medical therapy and/or prognosis. Arq Bras Cardiol. 2015; 105(4):328-338 335 César et al Summary of the guidelines on stable coronary disease Special Article Figure 3 – Percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) in stable coronary atheroscleroctic disease without involvement of left main coronary artery. a≥ 50% stenosis and confirmation of ischemia, lesion > 90% confirmed by two physicians or fractional flow reserve of 0.80; bCABG is the preferred option in most patients, unless in case of comorbidities or other particularities that require discussion with the Heart Team. Adapted from: 2010 Guidelines on myocardial revascularization of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery. Author contributions Writing of the manuscript and Critical revision of the manuscript for intellectual content: César LAM, Mansur AP, Ferreira JFM. advisory board member or director of a Servier e Astra-Zeneca; Committees participated in completion of research sponsored by Servier e Astra-Zeneca; Personal or institutional aid received from Servier e Astra-Zeneca; Produced scientific papers in journals sponsored by Servier e Astra-Zeneca. Potencial conflito de interesse Sources of Funding Drs. Luiz Antonio Machado César and João Fernando Monteiro Ferreira participated in clinical studies and / or experimental trials supported by Servier e Astra-Zeneca. There were no external funding sources for this study. 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Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, et al; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. J Am Coll Cardiol. 2007;49(6):734-9. Arq Bras Cardiol. 2015; 105(4):328-338 337 César et al Summary of the guidelines on stable coronary disease Special Article 338 Arq Bras Cardiol. 2015; 105(4):328-338 Back to the Cover Original Article Acute Coronary Syndrome Treatment Costs from the Perspective of the Supplementary Health System Vanessa Teich1, Tony Piha2, Lucas Fahham1, Haline Bianca Squiassi1, Everton de Matos Paloni3, Paulo Miranda2, Denizar Vianna Araújo4 MedInsight1, São Paulo, SP; AstraZeneca Brasil2, Cotia, SP; Orizon3, São Paulo, SP; Departamento de Clínica Médica da Universidade do Estado do Rio de Janeiro4, Rio de Janeiro, RJ – Brazil Abstract Background: Acute coronary syndrome (ACS) is defined as a “group of clinical symptoms compatible with acute myocardial ischemia”, representing the leading cause of death worldwide, with a high clinical and financial impact. In this sense, the development of economic studies assessing the costs related to the treatment of ACS should be considered. Objective: To evaluate costs and length of hospital stay between groups of patients treated for ACS undergoing angioplasty with or without stent implantation (stent+ / stent-), coronary artery bypass surgery (CABG) and treated only clinically (Clinical) from the perspective of the Brazilian Supplementary Health System (SHS). Methods: A retrospective analysis of medical claims of beneficiaries of health plans was performed considering hospitalization costs and length of hospital stay for management of patients undergoing different types of treatment for ACS, between Jan/2010 and Jun/2012. Results: The average costs per patient were R$ 18,261.77, R$ 30,611.07, R$ 37,454.94 and R$ 40,883.37 in the following groups: Clinical, stent-, stent+ and CABG, respectively. The average costs per day of hospitalization were R$ 1,987.03, R$ 4,024.72, R$ 6,033.40 and R$ 2,663.82, respectively. The average results for length of stay were 9.19 days, 7.61 days, 6.19 days and 15.20 days in these same groups. The differences were significant between all groups except Clinical and stent- and between stent + and CABG groups for cost analysis. Conclusion: Hospitalization costs of SCA are high in the Brazilian SHS, being significantly higher when interventional procedures are required. (Arq Bras Cardiol. 2015; 105(4):339-344) Keywords: Acute Coronary Syndrome / economy; Health Care Costs; Health Expenditures; Data Interpretation, Statistical; Prepaid Health Plans. Introduction Acute coronary syndrome (ACS) is defined by the American Heart Association as a “group of clinical symptoms compatible with acute myocardial ischemia”. Its clinical spectrum includes unstable angina and acute myocardial infarction (AMI) with or without ST-segment elevation. According to Polanczyk and Ribeiro1, prevalence data in Brazil estimate that 5% to 8% of adults older than 40 years old have ACS1. The disease is the leading cause of mortality in Brazil2 and developed countries3. It is estimated that for every 5 to 7 cases of myocardial infarction there is one death4,5. Thus, coronary heart disease is the leading cause of death worldwide, making it one of the diseases with the highest clinical and financial impact4. Mailing Address: Vanessa Teich • Rua Ministro Jesuíno Cardoso, 454. Postal Code 04544-051, São Paulo, SP – Brazil E-mail: [email protected], [email protected] Manuscript received February 20, 2015; revised manuscript April 26, 2015; accepted April 30, 2015. DOI: 10.5935/abc.20150129 339 Several types of interventions have been shown to be beneficial for the management of ACS, including the use of medications such as antiplatelet agents, beta-blockers, heparin, glycoprotein IIb/IIIa inhibitors and the use of procedures such as catheterization and thrombolytic therapy such as coronary angioplasty and revascularization6. Currently in Brazil there are no studies comparing the costs of different types of treatment for ACS in SHS. Studies such as this are needed to make it possible to evaluate the economic impact a disease such as ACS has on society. Thus, the objective of this article is to evaluate the costs and the length of hospital stay between groups of patients that were treated for ACS, submitted to angioplasty with or without stenting (stent + / stent-), revascularization (CABG) and treated only clinically (Clinical), from the perspective of the Brazilian Supplementary Health System (SHS). Methods A retrospective analysis was carried out of medical claims from beneficiaries of health care provided by private institutions in all Brazilian regions (excluding the states of Tocantins, Roraima and Mato Grosso do Sul), through a Teich et al. Economic evaluation of acute coronary syndrome Original Article database obtained from Orizon, a health care company responsible for the management of information processes from 110 health insurance companies, representing more than 18 million beneficiaries in Brazil. This database included data from patients undergoing hospital treatment for ACS and costs related to hospitalization by type of procedure (food, exams, medical gases, hygiene/cosmetics, fees, materials, drugs, procedures and taxes) and length of hospital stay. The period considered for the analysis was between January 2010 and June 2012. Orizon carried out the preliminary analysis of the data and MedInsight performed the statistical analysis. The treatments included in the analysis for the ACS episode management were: medical treatment, angioplasty with stenting, angioplasty without stenting (balloon angioplasty) and coronary artery bypass grafting (CABG). Quantitative variables such as cost and length of stay were described by the mean, median and mode. An exploratory analysis through Q-Q Plots method was performed to define the normality of the extracted data, and the Shapiro-Wilk normality test was applied to determine the adherence of the sample to a normal distribution. In cases of non-normal distributions, the nonparametric Kruskal-Wallis test was applied, used to determine equality between groups, and the Nemenyi-Damico-Wolfe-Dunn post-hoc Test, to test the difference between groups after the Kruskal-Wallis test. Analyses were performed using the R Statistical Software, version 3.1.17. A significance level of 5% was used. Results A total of 2,876 patients were identified in the period between 1/2010 and 6/2012, being divided into four groups: patients treated by angioplasty with stenting (stent+) patients treated by angioplasty without stenting (stent-) patients undergoing revascularization (CABG) and patients treated clinically (Clinical), all of them using antiplatelet agents. The mean age of patients in each group ranged between 55 and 65 years (55 years in the Clinical group, 59 years in the CABG group, 62 years in the stent+ group and 65 years in the stent- group), whereas the percentage of female patients ranged from 18% to 24% (22% in the Clinical group, 20% in the CABG group, 24% in the stent+ group and 18% in the stent- group; p = 0.51). Patient characteristics were similar between groups, with significant difference in the mean age between the Clinical group and patients from groups submitted to angioplasty with or without stent (Clinical vs stent-, p = 0.003; Clinical vs stent+, p = 0.016). After the sample selection, total hospital costs for the same period (between 1/2010 and 6/2012) were extracted and divided by procedure, as shown in Table 1. The analysis of total costs showed that the highest costs in the Clinical group were related to medications, followed by fees, materials and exams. In the stent- group, higher costs were associated with the use of materials, followed by fees, procedures and use of medications. In the stent+ group, the higher costs were related to the use of materials, followed by procedures, fees and medications. Finally, in the CABG group, the higher costs were associated with the use of materials, followed by procedures, fees and medications. The results of the analysis of the mean costs per procedure, segmented by group, are shown in Table 2. The median costs among the four groups were compared using the Kruskal-Wallis method, which showed a p-value < 0.001, rejecting the hypothesis of equality between the costs. A post‑hoc test was used to perform the pairwise comparison, as shown in Table 3. The comparison analysis of the median costs of treatment, in the period between 1/2010 and 6/2012, indicated that the difference was not significant when comparing the Clinical group with stent- group and in the comparison between the stent+ group and CABG group. All other comparisons showed statistically significant differences. The representativeness of the types of cost in the four analyzed groups is shown in Figure 1. The chart analysis shows that the stent-, stent+ and CABG groups had higher cost with materials and procedures (representing > 50% of the total cost of each group), while in the Clinical group this cost is only 18%. The Clinical group showed that most of the costs are related to medications and fees (58%), which was expected, as the cost is basically restricted to the use of medications and consultations. The results of the analysis of hospital stay of the four groups and the mean cost per day of hospitalization are shown in Table 4. Patients in the Clinical group showed a minimum hospital stay of two days and a maximum of 35 days. In the stent+ patients group, the hospital stay varied from one day to a maximum of 515 days. Patients in the stent- group had a maximum length of stay of 80 days, while in the CABG group patients showed a variation in hospital stay from four to 50 days. To test the normality of the data related to the length of stay, exploratory analysis was performed through a QQ Plot graphic, and non-adherence to a normal distribution was confirmed by the Shapiro-Wilk test (p < 0.001). Therefore, it was decided to analyze the data by non-parametric methods. Thus, when comparing the mean length of hospital stay, the mean costs among the four groups were compared using the Kruskal‑Wallis method, which showed a p-value < 0.001, rejecting the hypothesis of equality between lengths of hospitalization. A post-hoc test was used to perform the pairwise comparison, as shown in Table 5. Regarding the median hospitalization time, only the comparison of the Clinical group versus the stent- group was not significant. All other comparisons showed significant results. These results can be confirmed graphically in Figure 2, where the confidence interval of the difference between mean lengths of hospitalization crosses the vertical axis of the graph only for the comparison between Clinical and stent- groups. Discussion An analysis was performed of the data related to medical claims of Supplementary Health System patients with ACS, clinically treated without intervention, patients undergoing angioplasty with or without stenting and patients undergoing CABG. The patients that were only clinically treated were considered the control group in this analysis. Arq Bras Cardiol. 2015; 105(4):339-344 340 Teich et al. Economic evaluation of acute coronary syndrome Original Article Table 1 – Total cost of hospital treatment by type of cost Type of cost Clinical Food stent- stent+ CABG R$ 8,735.28 R$ 62,470.20 R$ 205,822.95 R$ 39,885.35 Examination R$ 122,649.76 R$ 559,699.66 R$ 4,374,932.76 R$ 574,814.36 Medical Gases R$ 72,369.09 R$ 198,039.56 R$ 848,664.42 R$ 217,487.94 R$ 897,14 R$ 1,125.15 R$ 10,062.67 R$ 1,823.80 Hygiene/Cosmetics Fees R$ 62,786.31 R$ 131,953.21 R$ 1,425,054.16 R$ 276,275.32 Materials R$ 196,965.06 R$ 2,139,035.25 R$ 55,820,543.70 R$ 2,629,796.09 Medications R$ 357,560.41 R$ 961,490.33 R$ 4,855,775.35 R$ 971,924.45 Procedures R$ 16,969.35 R$ 1,101,482.66 R$ 13,435,554.79 R$ 2,219,036.26 Taxes R$ 311,558.95 R$ 1,210,965.32 R$ 8,724,484.12 R$ 1,654,359.39 Others Total R$ 0,00 R$ 841,11 R$ 3.696,23 R$ 104,40 R$ 1,150,491.35 R$ 6,367,102.45 R$89,704,591.15 R$ 8,585,507.36 stent- stent+ CABG CABG: Coronary artery bypass surgery. Table 2 – Mean cost per procedure by type of cost Type of cost Food Clinical R$ 138.66 R$ 300.34 R$ 85.69 R$ 188.14 Examination R$ 1,946.82 R$ 2,690.86 R$ 1,821.37 R$ 2,711.39 Medical Gases R$ 1,148.72 R$ 952.11 R$ 353.32 R$ 1,025.89 R$ 14.24 R$ 5.41 R$ 4.19 R$ 8.60 Hygiene/Cosmetics R$ 996.61 R$ 634.39 R$ 593.28 R$ 1,303.19 Materials Fees R$ 3,126.43 R$ 10,283.82 R$ 23,239.19 R$ 12,404.70 Medications R$ 5,675.56 R$ 4,622.55 R$ 2,021.56 R$ 4,584.55 Procedures R$ 269.35 R$ 5,295.59 R$ 5,593.49 R$ 10,467.15 Taxes R$ 4,945.38 R$ 5,821.95 R$ 3,632.17 R$ 7,803.58 Others R$ 0.00 R$ 4.05 R$ 1.53 R$ 0.49 R$ 18,261.77 R$ 30,611.07 R$ 37,345.79 R$ 40,497.68 stent+ stent- CABG S NS S S NS Total CABG: Coronary artery bypass surgery. Table 3 – Cost comparison between groups Clinical Clinical stent+ stentCABG S: Significant; NS: Non-significant; CABG: Coronary artery bypass surgery. 341 Arq Bras Cardiol. 2015; 105(4):339-344 S Teich et al. Economic evaluation of acute coronary syndrome Original Article 100% 90% Food 80% Examination Cytopathological analysis 70% Exame Genética 60% Medical gases 50% Hygiene/Cosmetics 40% Fees 30% Materials 20% Medicamentos 10% Procedures 0% Taxes Clinical Stent- Stent+ CABG Figure 1 – Percentage of average costs by type of cost and analyzed group; CABG: Coronary artery bypass surgery. Table 4 – Mean length of stay and mean cost of hospitalization Admission Clinical stent- stent+ CABG Mean (DP) 9.19 days (6,7) 7.61 days (8.1) 619 days* (12) 15.20 days* (7.3) 8 days 6 days 5 days 14 days Median Mode Mean cost - Admission day 5 days 2 days 2 days 14 days R$ 1,987.03 R$ 4,024.72 R$ 6,033.40 R$ 2,663.82 stent+ stent- CABG S NS S S S * Significant difference compared to the Clinical group; CABG: Coronary artery bypass surgery. Table 5 – Length of stay comparison between groups Clinical Clinical stent+ stentCABG S S: significant; NS: non-significant; CABG: Coronary artery bypass surgery. An important finding of this analysis is related to the fact that the mean cost results did not show a statistically significant difference between the clinically treated group and the group submitted to angioplasty without stenting, as well as between the group treated by CABG and the group submitted to angioplasty with stenting. This finding suggests that patients treated with angioplasty without stenting and those submitted only to clinical treatment have similar treatment costs, which can be explained by the lower complexity of angioplasty, often performed on an outpatient basis and with shorter hospital length of stay. Patients undergoing CABG and those submitted to angioplasty with stent implantation showed similar costs between them and higher costs when compared to less complex procedures (angioplasty without stent and clinical treatment), representing significant expenditures for the treatment of patients with ACS. Arq Bras Cardiol. 2015; 105(4):339-344 342 Teich et al. Economic evaluation of acute coronary syndrome Original Article CABG - Clinical Stent- - Clinical Stent+ - Clinical Stent- - CABG Stent+ - CABG Stent+ - Stent- -10 -5 0 5 Figure 2 – Mean length of stay difference and 95%CI; CABG: coronary artery bypass surgery. A retrospective study carried out in France, involving 154 patients with ACS and submitted to angioplasty with stent implantation in 2005, concluded that the costs involved in performing this procedure have a financial impact for hospitals8. Another study carried out in Brazil measured direct and indirect costs related to the treatment of ACS, from the perspectives of the Unified Health System (SUS) and Supplementary Health System. The study considered the historical series of hospitalizations in SUS between 1999 and 2010 and the expected number of hospitalizations for 2011 projected by a linear extrapolation of the historical series and concluded that the estimated direct cost associated with ACS in 2011, from the SUS perspective, is approximately 0.77% of the total SUS budget, and from the SHS perspective, this estimate would come to R$ 515.138.6179. Studies like this demonstrate the importance of following these patients, the pharmacological treatment and lifestyle changes that can contribute to preserving the health of patients and prevention of complications, in order to prevent patients from undergoing complex treatments that may excessively burden the health care system. A limitation of the present study is the lack of a reliable national registry of cases of cardiovascular diseases and 343 Arq Bras Cardiol. 2015; 105(4):339-344 hence, the scarcity of supplementary medical data and other health care providers, as this study used data from health insurance companies linked to the Orizon© company. Conclusions In the present study it was observed that the clinical treatment and angioplasty without stenting procedure, associated with the use of antiplatelet agents, are less onerous for the SHS compared to major procedures such as angioplasty with stenting and CABG, as, due to the high degree of complexity, these procedures had higher associated costs and therefore should be considered as relevant costs to the health system. Author contributions Conception and design of the research:Teich V, Piha T, Fahham L, Squiassi HB, Paloni EM, Araújo DV, Miranda P. Acquisition of data:Piha T, Paloni EM. Analysis and interpretation of the data: Teich V, Piha T, Fahham L, Squiassi HB, Araújo DV, Miranda P. Statistical analysis: Fahham L. Obtaining financing: Teich V, Piha T, Miranda P. Writing of the manuscript:Squiassi HB. Critical revision of the manuscript for intellectual content: Teich V, Piha T, Fahham L, Paloni EM, Araújo DV, Miranda P. Teich et al. Economic evaluation of acute coronary syndrome Original Article Potential Conflict of Interest Sources of Funding Drs. Tony Piha and Paulo Miranda are employees of AstraZeneca Brazil. Vanessa Teich, Lucas Fahham, Haline Bianca Squiassi are employees of Medinsight, company that received funding from AstraZeneca to perform the analysis and preparation of the article. This study was funded by Astrazeneca do Brasil. Study Association This study is not associated with any thesis or dissertation work. References 1. Polanczyk CA, Ribeiro JP. Coronary artery disease in Brazil: contemporary management and future perspectives. Heart. 2009;95(11):870-6. 2. Souza e Silva NA. Saúde cardiovascular na era tecnológica. Arq Bras Cardiol. 2004;83(6):453-5. 3. Grech ED, Ramsdale DR. Acute coronary syndrome: unstable angina and non-ST segment elevation myocardial infarction. BMJ. 2003;326(7401):1259-61. 4. Ministério da Saúde. Protocolo Clínico Síndromes Coronarianas Agudas. Brasília; 2011. [Acesso em 2013 jn 21]. Disponível em: http://portal.saude. gov.br/portal/arquivos/pdf/protocolo_clinico_sindromes_coronarianas_ agudas.pdf 5. 6. Pesaro AE, Campos PC, Katz M, Corrêa TD, Knobel E. Síndromes coronarianas agudas: tratamento e estratificação de risco. Rev Bras Ter Intensiva. 2008;20(2):197-204. 7. R Core Team (2014). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.Rproject.org/. 8. Nidegger D, Metz D, Vacter C, Tassan-Mangina S, Deschildre A, Gawron M, et al. Financial impact of coronary stenting in emergency for acute coronary syndromes. Arch Cardiovasc Dis. 2009;102(5):409-18. 9. Teich V, Araujo DV. Estimativa de custo da síndrome coronariana aguda no Brasil. Rev Bras Cardiol. 2011;24(2):85-94. Polanczyk CA, Prado K, Borges MS, Ribeiro JP. Acute myocardial infarction in the thrombolytic era: high mortality in elderly patients. Rev Assoc Med Bras. 1993;39(2):65-72. Arq Bras Cardiol. 2015; 105(4):339-344 344 Back to the Cover Original Article The Benefits of Prone SPECT Myocardial Perfusion Imaging in Reducing Both Artifact Defects and Patient Radiation Exposure Maria Stathaki, Sophia Koukouraki, Emmanouela Papadaki, Angeliki Tsaroucha, Nikolaos Karkavitsas Department of Nuclear Medicine, University Hospital of Heraklion, Crete – Greece Abstract Background: Prone imaging has been demonstrated to minimize diaphragmatic and breast tissue attenuation. Objectives: To determine the role of prone imaging on the reduction of unnecessary rest perfusion studies and coronary angiographies performed, thus decreasing investigation time and radiation exposure. Methods: We examined 139 patients, 120 with an inferior wall and 19 with an anterior wall perfusion defect that might represented attenuation artifact. Post-stress images were acquired in both the supine and prone position. Coronary angiography was used as the “gold standard” for evaluating coronary artery patency. The study was terminated and rest imaging was obviated in the presence of complete improvement of the defect in the prone position. Quantitative interpretation was performed. Results were compared with clinical data and coronary angiographic findings. Results: Prone acquisition correctly revealed defect improvement in 89 patients (89/120) with inferior wall and 12 patients (12/19) with anterior wall attenuation artifact. Quantitative analysis demonstrated statistically significant difference in the mean summed stress scores (SSS) of supine and mean SSS of prone studies in patients with disappearing inferior wall defect in the prone position and patent right coronary artery (true negative results). The mean difference between SSS in supine and in prone position was higher with disappearing than with remaining defects. Conclusion: Technetium-99m (Tc-99m) tetrofosmin myocardial perfusion imaging with the patient in the prone position overcomes soft tissue attenuation; moreover it provides an inexpensive, accurate approach to limit the number of unnecessary rest perfusion studies and coronary angiographies performed. (Arq Bras Cardiol. 2015; 105(4):345-352) Keywords: Prone Position; Myocardial Perfusion; Radioactive Emission; Technetium (Tc-99m) Tetrofosmin; SPECT instead of Tomography emission-computed single-photon. Introduction Myocardial perfusion imaging has become an effective clinical tool for diagnosing coronary artery disease (CAD), risk stratifying of patients after infarction, assessing myocardial viability and planning therapy1,2 and is usually performed with the patient in the supine position3,4. It is, however, recognized that the diaphragmatic attenuation of the inferior wall and the breast attenuation of the anterior wall in females, has an impact on the test specificity1,3-5. Planar acquisition, prone imaging, ECG gating and image quantitation constitute commonly used approaches to overcome soft tissue attenuation. Although direct approaches for attenuation correction have been commercially available, they are quite expensive and possibly not provided to all nuclear medicine departments1,6. Mailing Address: Maria Stathaki • University Hospital of Heraklion, Stavrakia, Voutes. Postal Code 71306, Heraklion Crete – Greece E-mail: [email protected] Manuscript received July 20, 2014; revised manuscript January 15, 2015; accepted January 19, 2015. DOI: 10.5935/abc.20150122 345 Prone imaging has been reported to improve inferior wall attenuation artifact by producing an anterior shifting of the heart and lowering of the diaphragm and subdiaphragmatic organs 4,5. Normal prone scans in patients with inferior wall defects in the supine images are associated with low cardiac event rates, similar to that of patients with normal supine‑only studies4,7,8. The main pitfall of this imaging approach is that sternal and rib attenuation may create an anterior or anteroseptal wall defect1,4. In addition, the technique seems to be less suitable for reducing attenuation from the breast tissue9,10. Although stress studies have traditionally been followed by several hour-rest delayed images, the normal stress-only approach is recently preferred8, as it is less time-consuming , reduces radiation exposure and has an excellent short-term prognosis 4,6,8. In the presence of an inferior wall perfusion defect in the stress-supine study, positional change (prone imaging) is a low cost, effective and clinically validated technique to overcome diaphragmatic attenuation artifacts 5,7. The purpose of this study was initially to confirm the impact of the supine and prone approaches on attenuation artifacts. Additionally, we investigated its role in reducing subsequent rest imaging and unnecessary referrals to Stathaki et al. Prone imaging in myocardial perfusion SPECT Original Article coronary arteriography, aiming to decrease investigation and hospital waiting time, patient discomfort and also radiation exposure. Methods Study population We examined 139 patients, 120 with an inferior wall and 19 with an anterior wall perfusion defect. The clinical characteristics of the patients are shown in Table 1. Post‑stress images were acquired in both the supine and prone position. Coronary angiography was used as the “gold standard” for identifying coronary vessels patency. In many instances, scintigraphy was performed within 6 months of coronary angiography so as to evaluate the success of revascularization and/or to determine the hemodynamic significance of coronary stenosis, the adequacy of collateral circulation and the risk stratification of known CAD. In some cases myocardial perfusion imaging was followed by coronary angiography, in order to determine coronary artery narrowing of a scintigraphically-demonstrated ischemia and/or to evaluate patients with inexplicable chest pain. In all cases, the time interval between coronary angiography and scintigraphy was limited to no more than 6 months. The aforementioned criteria defined the size of our sample. The clinical indications for myocardial perfusion imaging are shown in Table 2. There was no case of dominant left circumflex artery (LCx), which could also be relevant to inferior wall defects. Scintigraphic imaging Technetium-99m 1,2-bis [di-(2-ethoxyethyl) phosphino] ethane ([Tc-99m] tetrofosmin) one day stress-rest protocol was used. All patients had fasted for at least 4 hours and were previously advised to discontinue b-blockers, calcium-channel blockers, nitrates and avoid taking caffeine‑containing products for 24 hours before the radionuclide study. Exercise stress testing was preferred, using a modified Bruce protocol. In the presence of exercise limitations or contraindications, pharmacological stress with adenosine was used. Tc-99m tetrofosmin (370‑555 MBq) was administrated intravenously 1 min prior to peak exercise or 3 min into the adenosine infusion. Stress images were acquired first in the supine and second in the prone position, starting 15-30 min after exercise and 30-45 min after adenosine. A dual-headed, large-field-of view gamma camera (Philips, Forte Jetstream AZ) with a low-energy, high resolution collimator was used. The same acquisition settings and reconstruction parameters were used for both the supine and prone image acquisitions. In the presence of a disappearing defect in the prone position, rest imaging was omitted. Otherwise, 2 hours after the stress test, Tc-99m tetrofosmin (740-925 MBq) was infused intravenously and rest acquisition in the supine position was initiated 45‑60 min after the injection. Attenuation or scatter correction was not available and cine testing was not applied. Table 1 – Patients’ Characteristics Parameter Value Number of patients 139 Age (years) Sex (male : female) 65.8 ± 11.6 114 (82%):25 (18%) Perfusion defect location Inferior wall 120 (86.4%) Anterior wall 19 (13.6%) Hypertension 72 (51.7%) Diabetes 33 (23.7%) Hypercholesterolemia 58 (41.7%) Smoking 68 (48.9%) Family history of CAD 51 (36.6%) History of MI 8 (5.7%) History of revascularization 60 (43.1%) Adenosine stress 17 (12.2%) Data are shown as mean ± SD or number (%). CAD: Coronary artery disease, MI: Myocardial infarction Image analysis The supine defects were classified as remaining or disappearing in the prone position. The wall defect improvement with positional change had to be complete to be considered as disappearing. New apparent anterior-anteroseptal defects in the prone position were attributed to sternal or rib attenuation artifact and did not alter the classification. Processing and quantitative visual interpretation was performed using a 20-segment model 4,11. Scintigrams were evaluated by observers with more than 15 years’ experience in nuclear cardiology. In case of difference in observers’ scores, there was agreement following discussion. The 5-point scoring system was used: 0 = normal; 1 = equivocal; 2 = moderate reduction of uptake; 3 = severe reduction of uptake; and 4 = no detectable tracer uptake. Based on the number and severity of segments with scores ≥ 2, the observers defined the study results as normal, probably normal, equivocal, probably abnormal or definitely abnormal4,11. To further define the results as normal or abnormal, the summed stress score (SSS) was calculated by adding the scores of the 20 segments of the stress Tc-99m tetrofosmin images4,11. SSS < 4 were considered normal, 4 to 8 mildly abnormal and >8 moderate to severely abnormal. The SSS had to be < 4 and the final scan interpretation had to be normal or probably normal, as any other case was considered abnormal4. Moreover, the SSS difference (SSS in supine image minus SSS in prone image) was calculated for each patient. Then the mean value of SSS difference for each defect group (disappearing or remaining defect group) was calculated. When rest imaging was done, segments were scored as well. Results were compared with clinical data and coronary angiography findings. Arq Bras Cardiol. 2015; 105(4):345-352 346 Stathaki et al. Prone imaging in myocardial perfusion SPECT Original Article Table 2 – Clinical indications for myocardial perfusion imaging Inferior wall defect Anterior wall defect Diagnosis 41 8 Prognosis 24 4 Therapeutic control 45 3 Preoperative evaluation 10 4 Statistical analysis The paired sample t-test was used to assess the statistical significance between the mean SSS derived from supine and prone studies. The mean SSS difference between the disappearing and remaining defect groups were compared using the independent samples t-test. The software program used for the statistical analysis was the SPSS statistics 19.0. A significance level of 0.01 was used. The normality of the data was tested by using the Shapiro-Wilk test, which showed the data followed a normal distribution. Results Inferior wall artifacts were seen in 114 male and in 6 female patients. In the present study, 94 of 120 patients with an inferior defect in the supine position (78.3%) showed normal prone interpretation (disappearing defect) and no further scintigraphy study was performed. The finding was attributed to diaphragmatic attenuation (Figure 1). Coronary angiography showed a patent right coronary artery (RCA) in 89 (74.2%) of 94 patients (true negative) and significant stenosis of the RCA in 5 (4.2%) of 94 patients (false negative). Among the study population, 26 of 120 patients (21.6%) showed abnormal prone interpretation (remaining defect) and the rest study was performed. In 19 (15.8%) of 26 patients, RCA stenosis was angiographically confirmed and the rest study disclosed evidence of transient ischemia or prior infarction (true positive). Of the remaining 7 patients (5.8%), the angiography showed normal RCA (false positive). The rest study demonstrated reversible defect in 4 of them, resulting in insufficient differentiation between ischemia and attenuation artifact. A fixed inferior wall defect was shown in the remaining 3 patients. Based on the patient’s clinical data and our experience, these findings were finally attributed to diaphragmatic attenuation. Among all 120 patients studied, an apparently new anterior-anteroseptal defect was observed in 8 patients (6.7%) in the prone position. This was attributed to sternal or rib attenuation, considering the angiographically confirmed normal patency of the corresponding coronary artery. Moreover, prone imaging tended to improve the specificity (92.7%) of detecting CAD in the inferior wall, without a significant reduction in sensitivity (79.2%). Considering our data, 6 of 120 patients with an inferior wall defect in the supine position had prior infarction. Scintigraphy showed a “remaining” defect in the prone 347 Arq Bras Cardiol. 2015; 105(4):345-352 position in 4 of them (true positive). This finding was expected due to history of inferior wall infarction. In one female patient with prior inferior infarction, an unexpected prone normal interpretation was observed (false negative). Finally, one patient with anterior wall infarction showed perfusion defect improvement with positional change (true negative). In patients with normal prone interpretation (disappearing defect) and angiographically confirmed patent RCA, the mean SSS of supine and prone studies were 9.35 ± 2.32 and 2.07 ± 1.28, respectively with the difference between them being statistically significant (p: 0.00). The mean SSS in patients with abnormal prone interpretation (remaining defect) and severely stenotic RCA were 11.74 ± 3.05 for the supine versus 10.95 ± 2.65 for the prone studies and the difference was marginally non-significant (p: 0.012). The statistical analysis is shown in Table 3. The mean SSS difference of the abnormal supine - normal prone and abnormal supine - abnormal prone scans was 7.28 ± 2.65 and 0.85 ± 1.19 respectively, with a significant difference (p: 0.00). Patients with inferior wall perfusion defect that had supine and prone acquisitions were more frequently males. Quantitative analysis did not change the scintigraphic results of visual interpretation and provided more accuracy. Performing the statistical analysis in women with an anterior wall defect was not feasible, due to the limited number of patients. Prone acquisition showed normal anterior wall activity in 12 of 19 patients (63.1%) and rest imaging was not performed. The finding was correctly attributed to breast attenuation (Figure 2). The normal patency of coronary vessels was angiographically confirmed. Two patients (10.5%) showed a defect that persisted despite positional change and the rest study was performed. Both had a history of anterior wall infarction. In spite of normal coronary angiograms and no history of CAD, 4 patients (21%) showed remaining defects (false positive). Moreover, one patient (5.2%) with total occlusion of the first diagonal branch showed prone normal tracer uptake (false negative). Exercise on a treadmill was performed in 122 out of the 139 patients and achieved at least 85% of the maximum predicted heart rate (52 maximal and 70 sub-maximal stress tests). Pharmacological stress was performed with adenosine infusion in 17 patients. Positive exercise stress test suggestive of ischemia was observed in 29 patients. Scintigraphy showed reversible and fixed perfusion defects in 19 and in 2 patients respectively. In the remaining 8, normal perfusion imaging was detected. Fifteen patients with reversible perfusion defects had angiographically confirmed coronary artery stenosis, while 4 patients had a history of revascularization. Both cases with fixed defects had prior infarction, while angiography revealed borderline stenosis. Four patients with normal perfusion imaging had coronary artery stenosis, 3 had history of revascularization and one patient was highly suspected of cardiac syndrome X. Negative exercise stress test was observed in 93 patients. Myocardial imaging showed normal perfusion in 86 and abnormal in 7 cases. Observers diagnosed reversible and fixed defects in 3 and 4 cases respectively. One patient with reversible defect had angiographically confirmed stenosis, while the angiography showed normal vessel patency in the remaining 2; therefore, Stathaki et al. Prone imaging in myocardial perfusion SPECT Original Article Figure 1 – A 65-year old man with normal findings on coronary arteriography: an inferior wall defect in the supine position (arrow) that disappears with positional change (arrowhead), attributed to diaphragmatic attenuation artifact. Table 3 – Data of the statistical analysis in the comparison of supine versus prone study Summed Stress Score Supine Prone p Value Disappearing defect by prone SPECT 9.35 ± 2.32 2.07 ± 1.28 0.00 Remaining defect by prone SPECT 11.77 ± 3.05 10.95 ± 2.65 0.012 Figure 2 – A 75-year old woman with no obstructive coronary artery disease: an anterior wall perfusion defect (arrow) that improves completely when changing from supine to prone (arrowhead). The defect was considered breast tissue attenuation artifact. the finding was most likely attributed to attenuation artifact. Two patients with fixed defects had prior myocardial infarction, 1 had a history of revascularization and 1 was scheduled for angioplasty because of severe stenosis of the left anterior descending artery (LAD). Discussion The present study confirms that prone imaging enhances the specificity and reduces artifact inferior wall abnormalities associated with supine-only study 3-5,9, leading to more appropriate clinical decisions and shortening the hospital waiting period and patient discomfort5,7,12. Most importantly, rest myocardial perfusion study can be safely excluded in patients with an inferior wall “disappearing” defect by prone SPECT. This provides an excellent approach to limit radiation exposure by avoiding additional radiotracer infusion. Soft tissue attenuation artifacts constitute a major shortcoming of myocardial perfusion imaging. Various techniques to improve specificity have been evaluated1, but to date there has been no clear definition of which is the best one13,14. It is generally accepted that attenuation artifacts are less frequent with Tc‑99m tracers than with thallium-201 (Tl-201)15. Prone imaging yields more accurate scintigraphic interpretations without any additional cost, it is inexpensive and it does not deliver any extra radiation to the patient6. It is associated with increased inferior and septal wall counts, less patient motion, patient discomfort and cardiac drift12,16-18. However, it is less suitable for females with large breasts and obese patients2,19. ECG-gating Arq Bras Cardiol. 2015; 105(4):345-352 348 Stathaki et al. Prone imaging in myocardial perfusion SPECT Original Article improves specificity of inferior wall disease detection and it additionally provides functional information6,16. The presence of normal wall motion in a fixed perfusion defect is usually consistent with attenuation artifact; however, small scars or nontransmural injuries may display this same imaging pattern1. Nevertheless, some authors believe that ECG-gating is the most practical method in routine investigations20. Direct attenuation correction systems are commercially available1. Although these systems tend to decrease the rate of equivocal interpretations to a greater extent than prone imaging, they require high-cost hardware and software products1,5,6,21. The routine change of supine to prone imaging is a controversial matter, given the occasionally seen artifactual anterior‑anteroseptal wall prone defect19,22,23. This finding is presumably attributed to sternal and/or rib attenuation1,4 In the present study, this pitfall was observed in 8 out of the 120 patients (6.7%) The majority feels that prone should be considered only when imaging in the supine position raises the question of true inferior wall perfusion defect or artifact abnormality4,19,22. The use of combined supine and prone quantitative imaging in overcoming diaphragmatic and/or breast attenuation artifacts has been evaluated before. Data from several researchers have shown significantly increased specificity without compromising sensitivity for the diagnosis of CAD 3,4,24. This is in agreement with the results of our study, where a sensitivity of 79.2% and a specificity of 92.7% were shown. Katayama et al. have similarly demonstrated that prone stress Tl-201 study tends to improve the specificity of detecting coronary disease in the inferior wall. On the other hand, they showed that sensitivity is reduced when compared to stress-rest supine images25. In our study population, rest acquisition was omitted in patients with defects on supine SPECT that disappear on prone imaging. However, few research groups performed stress and rest scans in all cases4,9,10,18.19. They all pointed out the excellent usefulness of combined supine and prone acquisitions on attenuation artifacts, which was also seen in our study. Segall and Davis have demonstrated that specificity for RCA was dramatically better (90% versus 66%) when patients were submitted to prone image acquisition compared to supine. Furthermore, the overall effect on the detection of CAD was an improved accuracy and higher specificity (82% versus 59%) without significant loss of sensitivity (75% versus 79%)9. In addition, Hayer et al concluded that patients with inferior wall defect in the supine position that was not present in the prone image had similar low risk of cardiac events, when compared with those that had normal supine only studies4. Recently Nishiyama et al, assessed the feasibility of combined imaging using a novel ultrafast cadmium zinc telluride (CZT) camera. They concluded that the combined supine and prone CZT SPECT yields significant gains in specificity and accuracy, whereas acquisition time is reduced by up to one fifth26. False negative and false positive results of prone imaging were seen in 4.2% and 5.8% of our study population, respectively. The development of coronary collateral 349 Arq Bras Cardiol. 2015; 105(4):345-352 circulation could be a possible explanation for the false negative results. Thus, positional change may not always be sufficient to differentiate attenuation artifacts from CAD6. Although some authors believe that prone imaging is associated with increased camera-to-chest wall distance and lower total myocardial counts when compared to supine position2,19, in this work prone image quality was very satisfactory. This is in agreement with a recent study by Gutstein et al. which showed that prone and supine imaging is associated with comparable good image quality in the non-obese population, even though half-time acquisition has been used27. Anterior wall defects are most common in women. Although some believe that positional change mainly contributes to the disappearance rate of diaphragmatic attenuation9,10, it is a confirmed knowledge that combined supine and prone approach improve specificity and normalcy rates in women24. Although our study was limited to 19 patients only, 63.1% of the anterior wall defects disappeared in the prone image and subsequently, the rest perfusion study was properly obviated. Anterior wall defects in the supine acquisition that were absent with positional change tended to represent breast attenuation artifacts. A number of strategies have been used to minimize dose in cardiac nuclear imaging. According to the “ALARA” philosophy, one should strive to keep radiation exposure As Low As Reasonably Achievable28. One enticing strategy is the use of Tc-99m agents and stress-first or stress-only protocols 28. It seems that prone imaging provides an alternative imaging approach to reduce patient’s radiation exposure. Based on our study, prone acquisition correctly disclosed disappearing defects in 89 out of 120 patients with reduced uptake in the inferior wall and in 12 out of 19 women with reduced uptake in the anterior wall. The findings were considered to be diaphragmatic and breast tissue attenuation artifacts, respectively. Hence, prone SPECT imaging offers the possibility of avoiding the additional radiotracer infusion in an unnecessary rest study. This tends to reduce radiation dose by a factor of 429,30, whilst providing similar prognostic information to normal rest-stress perfusion study8,29. Moreover, it saves time for both patients and busy departments, thus allowing additional nuclear medicine studies to be performed29. Recently, a research group compared the inter-observer agreement between two experienced readers using supine alone versus combined supine/prone imaging. They showed improved inter-observer correlation and diagnostic agreement, by eliminating common artifacts, such as inferior wall attenuation, patient’s motion and interfering external activity. This will likely result in more uniform and standard care, which in addition to improvement in accuracy, will lead to fewer unnecessary additional tests30. Ceylan Gunay et al have recently reported that an unnecessary rest Tc-99m methoxyisobutylisonitrile myocardial perfusion scintigraphy could be prevented in patients with complete disappearing inferior wall defect at stress prone imaging7. Similar to our results, they indicated that in patients with true defects, perfusion quantification Stathaki et al. Prone imaging in myocardial perfusion SPECT Original Article was irrelevant to imaging position, as SSS of supine and prone stress studies were not different. This is of utmost importance, regarding the improvement of specificity, true positive rate and reliability of scintigraphic study. Considering our data, there were 7 patients with an inferior wall and one patient with an anterior wall disappearing prone defect that underwent coronary angiography within a month after perfusion scintigraphy. They were highly suspected of having coronary artery stenosis because of their symptoms and risk factors. Angiograms showed no stenotic CAD. It seems that prone imaging might have an additional role in preventing unnecessary coronary angiograms and furthermore minimize radiation exposure, especially in low-risk patients. Recently, Worden et al. showed that patients with perfusion abnormalities during stress supine imaging that resolved during prone imaging are at low risk for cardiac death or myocardial infarction at medium-term follow up. Given that they seldom require invasive coronary angiography, broader application of prone imaging could lead to reduced exposure to the risks and expenses of unnecessary invasive procedures31. Limitations of the study There are some limitations to the present study. The analysis is limited to the stress images of 120 patients only. Although rest imaging was performed in the presence of a remaining defect in the prone position and segments were scored as well, this was acquired only in the supine position. The study population was selected from a single center. Our results were related to supine and prone quantitative imaging without using gated assessment of wall motion or wall thickening. We investigated a mixed gender population regarding inferior wall perfusion defects, without performing any feasibility investigation. Although our data regarding female patients with an anterior wall defect are encouraging, the study sample is quite small and further trials are required on this issue. Here, we only present the preliminary results of an ongoing study. Conclusion The addition of prone position to stress supine myocardial scintigraphy decreases the false positive rates and leads to more accurate results. Furthermore, it increases specificity without compromising sensitivity for the diagnosis of CAD. It has a key benefit of reducing the number of unnecessary rest studies performed, whilst minimizing radiation exposure, investigation time and costs. Moreover, it could possibly be a useful and practical method of obviating unnecessary referrals to coronary angiograms, especially in low-risk patients. There were no external funding sources for this study. Acknowledgments We thank Dr. Panagiotis Stratakis for statistical assistance. Author contributions Conception and design of the research: Stathaki M, Karkavitsas N. Acquisition of data: Stathaki M, Koukouraki S, Papadaki E, Tsaroucha A. Analysis and interpretation of the data: Stathaki M, Koukouraki S, Papadaki E, Tsaroucha A. Statistical analysis: Stathaki M. Writing of the manuscript: Stathaki M, Papadaki E. Critical revision of the manuscript for intellectual content: Stathaki M, Koukouraki S. Supervision / as the major investigador: Stathaki M, Koukouraki S, Karkavitsas N. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. 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Prone imaging in myocardial perfusion SPECT Original Article Arq Bras Cardiol. 2015; 105(4):345-352 352 Back to the Cover Original Article Palliative Senning in the Treatment of Congenital Heart Disease with Severe Pulmonary Hypertension Juliano Gomes Penha, Leina Zorzanelli, Antonio Augusto Barbosa-Lopes, Edimar Atik, Leonardo Augusto Miana, Carla Tanamati, Luiz Fernando Caneo, Nana Miura, Vera Demarchi Aiello, Marcelo Biscegli Jatene Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, SP – Brazil Abstract Background: Transposition of the great arteries (TGA) is the most common cyanotic cardiopathy, with an incidence ranging between 0.2 and 0.4 per 1000 live births. Many patients not treated in the first few months of life may progress with severe pulmonary vascular disease. Treatment of these patients may include palliative surgery to redirect the flow at the atrial level. Objective: Report our institutional experience with the palliative Senning procedure in children diagnosed with TGA and double outlet right ventricle with severe pulmonary vascular disease, and to evaluate the early and late clinical progression of the palliative Senning procedure. Method: Retrospective study based on the evaluation of medical records in the period of 1991 to 2014. Only patients without an indication for definitive surgical treatment of the cardiopathy due to elevated pulmonary pressure were included. Results: After one year of follow-up there was a mean increase in arterial oxygen saturation from 62.1% to 92.5% and a mean decrease in hematocrit from 49.4% to 36.3%. Lung histological analysis was feasible in 16 patients. In 8 patients, pulmonary biopsy grades 3 and 4 were evidenced. Conclusion: The palliative Senning procedure improved arterial oxygen saturation, reduced polycythemia, and provided a better quality of life for patients with TGA with ventricular septal defect, severe pulmonary hypertension, and poor prognosis. (Arq Bras Cardiol. 2015; 105(4):353-361) Keywords: Heart Defects, Congenital; Pulmonary Hypertension; Child; Transposition of the Great Vessels/surgery. Introduction Congenital cardiopathies are the most frequent inborn defects in newborns, representing about 1% of the cases. The transposition of the great arteries (TGA) is the most common cyanotic cardiopathy, with an incidence ranging from 0.2 to 0.4 per 1000 live births1,2. The first proposal for physiologic correction of TGA at the atrial level was described by Albert in 1954. In 1958, Ake Senning performed with success the proposal suggested by Albert, performing the correction at the atrial level using autogenous atrial tissue to construct intracardiac baffles. The use of flaps made of a prosthetic material for intra-atrial correction was first proposed and performed by Mustard in 1964. However, the occurrence of systemic ventricular dysfunction and a high prevalence of arrhythmias as late morbidity factors placed this technique out of use and replaced it with a more physiologic technique, the Jatene procedure3. Mailing address: Juliano Gomes Penha • Av. Dr. Enéas de Carvalho Aguiar 44, bloco 2, sala 5, Jardim Paulista. Postal Code 05403-900, São Paulo, SP – Brazil E-mail: [email protected] Manuscript received December 09, 2014; revised manuscript May 14, 2015; accepted May 18, 2015. DOI: 10.5935/abc.20150097 353 In 1972, Lindesmith et al4 reported for the first time a series of patients with TGA and ventricular septal defect (VSD) with severe pulmonary vascular obstructive disease who underwent a palliative surgery to redirect the flow at the atrial level. The Mustard surgery was the proposed procedure to redirect the pulmonary and systemic venous drainage, maintaining the VSD open. The VSD is maintained open in these patients because its closure is associated with early and late prohibitive mortality, as previously described4. From then on, the indications for palliative surgery were widened to include other complex congenital lesions with VSD and pulmonary hypertension (PH)5. The present study aims to report the results of palliative surgical treatment in patients with complex congenital heart disease with PH due to an important intracardiac shunt which was not surgically treated within the period considered safe. It also aims at evaluating the early and late clinical progression with the palliative Senning procedure in this group of patients with contraindication to total surgical correction of the cardiopathy. Methods The study included patients with a diagnosis of TGA with VSD and Taussig-Bing double-outlet right ventricle (DORV), aged up to 11 years, seen by the Pediatric Cardiology and Pediatric Cardiac Surgery teams at Instituto do Coração, Penha et al. Palliative Senning in severe PH Original Article Hospital das Clínicas of the School of Medicine at USP (InCor-HCFMUSP). This was a retrospective study based on the evaluation of medical records between 1991 to 2014. Only patients without indication of definitive surgical treatment of the cardiopathy due to suprasystemic pulmonary pressure were part of the analysis. Patients with a diagnosis of TGA and Taussig-Bing DORV with favorable pulmonary pressure were not included in this study. The data collected included age and weight at the time of the surgery, preoperative diagnosis, preoperative functional status, palliative procedures prior to the main surgical procedure, type of surgical procedure performed, preoperative hemodynamic status, early and late morbidity including any cardiovascular or pulmonary event and reoperations, late functional status, analysis of lung biopsies, and survival. The statistical analysis was descriptive. (A software was not required since the calculations were performed manually.) As for the surgical procedure, all patients underwent median sternotomy and opening of the pericardium. The anatomy was verified with careful initial inspection. Following that, an extensive dissection and release of the superior and inferior venae cavae was performed, with the dissection also including the groove between the left and right atria. Pockets were created in the aorta and venae cavae with prolene suture, heparin was infused, and direct cannulation of the aorta and venae cavae was performed. Care was taken to cannulate the venae cavae as distal as possible to facilitate the surgical maneuvers inside the atria. Before full heparinization, a fragment of the lung was removed for histological analysis. This was generally performed with wedge resection of the right upper lobe with the lung inflated. The biopsy was feasible in 16 patients. We used the studies of Heath and Edwards6 and Rabinovitch et al7 as the criteria for the histological classification of the lung fragments (Table 1). After full heparinization and cannulation, cardiopulmonary bypass (CPB) was initiated. The ascending aorta was clamped, and the St. Thomas' solution was used for cardioplegia. The cardioplegic solution was initially infused at a rate of 20 mL/kg, and then maintained at 10 mL/kg every 20 to 30 minutes. The target temperature was 28oC in patients not undergoing total circulatory arrest (TCA) and 20°C in those undergoing TCA. The right atrium was opened with an incision parallel to the interatrial groove, positioned at a distance of about 0.5 to 1 cm from the caval drainage into the right atrium. The atrial septal defect (ASD), the anatomical relations of the tricuspid and mitral valves, and the caval drainage were analyzed. A wide enlargement of the ASD towards the superior and inferior venae cavae was performed and a bovine pericardium patch was sutured covering and isolating the pulmonary veins, leaving the two atrioventricular valves and venae cavae in the same cavity. After that, a cava baffle was constructed by suturing the edge of the lateral wall of the right atriotomy, directing the flow from the venae cavae to the mitral valve. This procedure allows the caval drainage to be directed to the left ventricle which is connected to the pulmonary trunk. An incision was then performed in the left atrium anteriorly to the right pulmonary veins, exposing the left atrium along with the pulmonary veins. After that, the right edge of the left atriotomy was sutured to the left edge of the right atriotomy. With this procedure, the left atrium and pulmonary veins were connected to the tricuspid valve and right ventricle, which is related to the aorta. The VSD was maintained open (Figures 1, 2, 3 and 4). After redirecting the flow from the atria, the patient was warmed up. Maneuvers were carried out to remove the air from the cavities and for weaning from CPB. The use of modified ultrafiltration became routine after 2011, and intraoperative transesophageal echocardiography was only feasible in children weighing more than 3 kg due to an incompatibility of the probe used in our institution for children weighing less than that. Death in the initial postoperative period was defined as any death occurring within the first 30 days after the surgical procedure or during the same hospitalization. Results From November 1991 to April 2011, a total of 21 patients with a diagnosis of TGA with VSD or Taussig-Bing DORV and severe pulmonary vascular disease were referred to palliative surgical treatment after other types of treatment were precluded. (The last surgery was performed in 2011, but patients were followed up until 2014. This fact results in two different dates in the Results and in the Methods sections). The age of the patients at the time of the surgery ranged from 1 to 130 months (mean 24.6 months and median 16 months), and 30% were aged 12 months or less. Among the 21 patients, 11 were male. The weight of the patients ranged from 2.8 to 30 kg (mean 8.3 kg and median 7.1 kg). Preoperative functional evaluation according to the New York Heart Association (NYHA) was feasible in 18 patients, and most (83%) were classified as functional class III or IV. The main anatomic diagnoses were TGA with VSD in 17 patients (81%), and Taussig-Bing DORV in 4 patients (19%). Smaller associated defects are shown in Table 2. Table 1 – Lung biopsy histological classification Classification of Rabinovitch et al. Classification of Heath and Edwards Grade A: early muscularization of the distal arteries; Grade B: hypertrophy of the arterial wall; Grade C: grade B changes associated with increased proportion of the number of alveoli and arteries. Grade 1: isolated hypertrophy of the media; Grade 2: fibrointimal proliferation; Grade 3: total occlusion of the lumen by fibrosis; Grade 4: plexiform lesions; Grade 5: hypertrophy of muscular arteries, cavernous lesions,angiomatoid lesions; Grade 6: necrotizing arteritis. Arq Bras Cardiol. 2015; 105(4):353-361 354 Penha et al. Palliative Senning in severe PH Original Article Figure 1 – Place of the incision in the right atrium, maintaining a safety margin between the venae cavae and the pulmonary veins. Figure 2 – Atrial septal sutures or bovine pericardium and isolation of the pulmonary veins which will be directed to the tricuspid valve and to the aorta. The Rashkind procedure was performed in 13 of the 21 patients before the surgery, 11 of which had TGA with VSD. One patient in the DORV group who had aortic coarctation had previously undergone isthmoplasty and pulmonary artery banding at the age of 20 days. Cardiac catheterization was performed prior to the surgery in all cases. Pulmonary vascular resistance (PVR) with inhaled 100% oxygen ranged from 3.2 to 14 U.m2 (mean 8.1 U.m2 and median 7.7 U.m2). The PVR of 3.2 U.m2 was found in a patient with systolic pulmonary artery pressure (SPAP) of 94 mmHg and no response to the oxygen test. Preoperative 355 Arq Bras Cardiol. 2015; 105(4):353-361 SPAPs ranged from 41 to 130 mmHg (mean 77.8 mmHg and median 75 mmHg). Oxygen saturation and hematocrit ranged from 40% to 80% (mean 62.1% and median 67%) and 40% to 65% (mean 49.2% and median 50%), respectively. Length of circulatory assistance ranged between 65 and 170 minutes (mean 113.6 minutes and median 108 minutes). Length of aortic clamping ranged between 50 and 95 minutes (mean 72.5 minutes and median 78.5 minutes). In three patients, TCA with selective cerebral perfusion through the brachiocephalic trunk and deep hypothermia (20°C) were performed, with a mean duration of 52 minutes. Penha et al. Palliative Senning in severe PH Original Article Figure 3 – Cava baffle and direction of the venous blood flow to the mitral valve. Opening of the left atrium above the right pulmonary veins. Figure 4 – Suture of the edge of the right atrium in place of the opening of the left atrium with redirection of the arterial blood flow to the tricuspid valve. The initial mortality rate was 47% (10 patients). The causes of death were low output in 6 patients, sepsis in 2 patients, and pulmonary hypertensive crisis in the 2 remaining patients. The mean total duration of hospitalization was 15 days (range 1 to 43 days), with a mean duration of hospitalization of 19.1 days in patients discharged from the hospital. Postoperative comorbidities not resulting in death were pulmonary hypertensive crisis (which improved with nitric oxide), pneumonia, acute renal failure (ARF), chylothorax with ligation of the thoracic duct, pulmonary congestion, total atrioventricular block (TAVB), and junctional rhythm (Table 3). Assessments performed 1 year after hospital discharge showed a mean increase in arterial oxygen saturation from 62.1% to 92.5%, and a mean reduction in hematocrit from 49.4% to 36.3%. Lung histological analysis was feasible in 16 patients and was performed with the classifications of Heath and Edwards6, and Rabinovitch et al7. In 8 patients, grades 3 and 4 pulmonary biopsies were evidenced. Of 10 biopsies in which the classification of Rabinovitch et al7 was used, 4 Arq Bras Cardiol. 2015; 105(4):353-361 356 Penha et al. Palliative Senning in severe PH Original Article Table 2 – Associated defects TGA with VSD 17 Taussig-Bing DORV 4 Coronary anomaly 6 Coronary anomaly 2 Single left coronary ostium 5 Single left coronary ostium 1 Right coronary artery arising from the circumflex artery 1 Right coronary artery arising from the circumflex artery 1 Situs inversus totalis 1 VSD > 5mm 4 Patent ductus arteriosus 2 Aortic coarctation 1 VSD > 5 mm 10 Pulmonary valve infundibular stenosis 3 Patent ductus arteriosus 5 TGA: Transposition of the great arteries; VSD: Ventricular septal defect; DORV: Double-outlet right ventricle. were grade B and 6 were grade C (Table 4). All patients with grades 3 and 4 biopsies were older than 16 months and had a mean pulmonary artery pressure above 45 mmHg. Mean follow-up of the 11 survivors was 6.4 years with a maximum of 19 years. Five patients continue to follow up at our institution while 5 other patients are currently following up in other centers closer to their homes (Manaus, Fortaleza, Brasília, and Salvador). There was 1 case of sudden death at home due to an unknown cause 18 months after hospital discharge. Functional assessment according to the NYHA was feasible in 10 of the 11 survivors. Functional class improved in all patients (5 class I and 5 class II). Ten had a sinus rhythm, and 1 had a junctional rhythm. None of the patients required definitive pacemaker implantation during follow-up. PH crisis 6 Pulmonary congestion 4 ARF 2 Chylothorax 2 Pneumonia 1 TAVB 1 Junctional rhythm 1 PH: Pulmonary hypertension; ARF: Acute renal failure; TAVB: Total atrioventricular block However, we unfortunately still see complex congenital cardiopathies diagnosed late, often when signs and symptoms of severe PH are already manifesting, hindering the total correction of the anomaly. With a lack of reference centers in congenital cardiopathies in Brazil for establishment of early diagnosis and treatment, there are still patients with PH without access to an ideal and definitive surgical treatment. These patients present clinically with cyanosis, and most are NYHA functional class IV and unable to undergo definitive correction due to elevated levels of pulmonary pressure and vascular resistance. Some centers are trying and testing pharmacological treatment with sildenafil in these patients. However, the high cost of this treatment, lack of standardization by the Unified Health System (Sistema Único de Saúde, SUS) and use by only a few institutions provide no scientific evidence to justify its widespread use in this type of patient. (Regarding pharmacological treatment, sildenafil was only approved by the FDA for the treatment of PH patients in 2005, and even then, only for adult patients. Only 1 patient underwent surgery after this date, in 2011. This patient was on sildenafil on his last follow-up in 2014. There was no preoperative pharmacological preparation or postoperative pharmacological treatment intended for PH patients operated on with this technique in the 1990s, the period in which 17 of the 21 surgeries were performed. Only tests with nitric oxide and 100% oxygen during diagnostic catheterization and inhaled nitric oxide after surgery were available. The technique was proposed due to lack of other forms of preoperative care and postoperative treatment.) Progression of PH occurs particularly in patients with large left-right shunts. It is worth noting that the structural changes in the pulmonary circulation are histologically similar to those seen in other forms of primary PH1. The presence of large intracardiac communication and ductus arteriosus accelerate the progression of the pulmonary vascular disease8. Considering that there is no current evidence of treatment for patients in the pediatric age group with severe PH and the fact that the guidelines are empirically based on experts recommendations1, the palliative Senning procedure should be considered in patients with late diagnosis, when severe pulmonary vascular disease is already established. Echocardiographic evaluations were performed during follow-up. The ventricular function remained preserved in all patients. One patient presented cava baffle stenosis and 5 presented tricuspid valve insufficiency (3 of moderate degree and 2 of severe degree). Discussion Most patients currently diagnosed with TGA with VSD and Taussig-Bing DORV do not progress to pulmonary vascular disease because total surgical correction is performed early, soon after establishment of the diagnosis, which often occurs before birth due to the increasingly frequent use of fetal echocardiography. 357 Table 3 – Non-fatal postoperative comorbidities Arq Bras Cardiol. 2015; 105(4):353-361 Penha et al. Palliative Senning in severe PH Original Article Table 4 – Correlation between histology, hemodynamics, and age Patient Age (months) SPAP (mmHg) Classification of Heath and Edwards Classification of Rabinovitch et al. 1 16 80 4 C 2 18 88 1 B C 3 3 94 2 4 73 130 3 5 23 75 2 C 6 8 107 2 C 7 130 89 3 8 11 41 2 9 21 53 4 10 33 67 11 1 12 14 PVR (U.m2) C 5 3 C 9.6 90 1 B 48 2 B C 6.6 13 11 59 2 14 23 55 4 6.8 15 8 66 3 8.6 16 38 45 4 SPAP: Systolic pulmonary artery pressure; PVR: Pulmonary vascular resistance. Historically, operations at the atrial level were the first truly effective surgical procedures in the treatment of TGA9. The technique proposed by Mustard was the procedure of choice for correction of simple TGA from 1965 to 19823. However, a 1982 survey conducted in several institutions showed a high incidence of complications caused by the synthetic flaps used in the procedure10,11. Since the Senning procedure is only performed with autogenous tissues, it has allowed most patients to reach adulthood, with a survival rate of 88% after 20 years and with a late mortality of 9.4% according to Roubertie et al12. It should be noted that arterial correction is still the treatment of choice in the neonatal period in patients with a diagnosis of TGA with or without VSD. These patients are operated on with the technique successfully performed for the first time by Jatene in 197513. After the decade of 1980, this became the surgery of choice by most centers specialized in congenital cardiopathies11. Patients with an intracardiac shunt with increased PVR are unable to be promptly referred to surgical correction of the anomaly, and in many centers are treated with pulmonary vasodilators prior to the surgery. It was previously believed that the early correction of the heart defect would result in regression of the pulmonary vascular abnormalities6, regardless of the degree of arterial remodeling14. However, wait for the regression of pulmonary lesions only with surgical repair is not recommended, wherein the combination of pharmacological treatment (sildenafil and/or bosentan) has been used in the management of these patients, even in the absence of widespread evidence-based recommendation for this type of approach1,15. Cardiac catheterization is essential to define treatment in patients with PH. Tests with inhaled 100% oxygen and/or nitric oxide are important in defining management. The definition of severe PH is often arbitrary. A PVR of 10 to 12 U.m2 or greater is generally considered severe. The presence of advanced grades in the Heath and Edwards histological classification is often considered irreversible 6. In patients aged 1 to 2 years presenting reduced PVR with inhaled 100% oxygen, the Senning procedure with VSD closure may be considered. However, in patients with an inadequate response to inhaled 100% oxygen, the procedure of choice would be the palliative Senning procedure5. Hemodynamic studies have shown that almost all patients above the age of 1 year with a diagnosis of TGA and large VSD have a significant increase in PVR. Fourteen of the 21 patients operated on at InCor-HCFMUSP were older than 1 year. In contrast, the increase in PVR was a rare finding in older children with TGA and intact ventricular septum8. Newfeld et al8 have shown that patients with pulmonary pressure of 50 mmHg or greater and pulmonary biopsies grade 4 or greater were older than 1 year. In contrast, all patients with pulmonary pressure of 50 mmHg or greater with a pulmonary biopsy grade below 4 were younger than 1 year of age8. In this study, all patients with a grade 4 biopsy were older than 1 year, and of the 6 patients younger than 1 year at the time of the surgery, 4 presented a grade 2, 1 a grade 1, and 1 a grade 3 biopsy. For the decision of treatment type, age is an important factor in view of the complications associated with longer exposure of the pulmonary parenchyma in cardiopathies with hyperflow. The development of severe pulmonary vascular disease remains one of the major concerns in patients with TGA, and its occurrence is often considered a contraindication for surgical correction. Histological studies have shown that a Arq Bras Cardiol. 2015; 105(4):353-361 358 Penha et al. Palliative Senning in severe PH Original Article rapid progression of the pulmonary vascular disease may occur in TGA patients, particularly in those with non-restrictive VSD8. Ferencz16 reported early and severe hypertensive changes in biopsies of pulmonary arteries in 106 TGA patients. He noted that the lung lesions increased in severity with the increase in VSD size16. Many patients older than 1 year with a diagnosis of TGA with VSD and mean pulmonary pressure of 50 mmHg or greater have established pulmonary vascular disease grade 4 on Heath and Edwards' classification8. Of the patients operated on at InCor, 66% had a non-restrictive VSD, and 6 had patent ductus arteriosus causing hemodynamic repercussion. According to the classic work of Heath et al17, when specific histological changes emerge on the pulmonary vasculature of patients with TGA with large communications, PH will not regress until the defect is corrected. These authors also reported that a pulmonary biopsy grade 4 or greater is usually indicative of irreversible pulmonary vascular disease and that the pulmonary pressure levels were unlikely to decrease unless surgical treatment was performed. Pulmonary vascular disease of advanced grade (above 3) also increased significantly the risk associated with surgery and death due to low output, which occurred in the immediate postoperative period17. Even after surgical correction, PH may still progress along with the disease. Microscopic studies of these patients' lungs showed biopsies grade 4 or greater in the majority of the cases18. In an attempt to contain the advance of the PH or improve the arterial oxygen saturation, palliative procedures are a therapeutic option. In 1950, Blalock and Hanlon published a procedure that allowed mixing of the pulmonary and systemic circulations with the establishment of an interatrial communication. This was the first palliative procedure to allow survival of patients with TGA and restrictive intracardiac communications. The Rashkind technique has now replaced the previous procedure with enlargement of the foramen ovale with a balloon catheter11. Pulmonary artery banding has also been advocated to protect the lungs against the development of pulmonary vascular disease in patients with TGA and VSD, particularly in those younger than 6 months. A persistent large ductus arteriosus should also be treated. In patients with large septal defects, treatment of the ductus arteriosus, pulmonary artery banding, or corrective surgery with closure of the VSD should be performed up to the age of 6 months to prevent progressive pulmonary vascular disease8. There are currently four indications for the Senning procedure. The first is in children with isolated TGA presenting after the neonatal period, in which the left ventricle would already be misadjusted and unable to support the systemic circulation with the Jatene procedure. The second is as a palliative method in patients with a pulmonary vascular disease associated with VSD. The third indication is for patients with corrected TGA. In this case, both the venous and arterial switch are required to create a concordant ventricle (double switch). The fourth is in the presence of rare isolated ventricular inversion. In this situation, there is an atrioventricular discordance with a ventriculoarterial concordance11. Burkhart et al5 have shown in a study with 28 patients, operated on at the Mayo Clinic in Rochester and at the Hospital for Sick Children in Toronto, that there was a 23% increase in oxygen saturation, a significant decrease in 359 Arq Bras Cardiol. 2015; 105(4):353-361 hematocrit, and improvement in NYHA functional class III and IV to I and II after atrial palliative surgery in patients with severe PH. The Mustard procedure was performed in 25 patients and the Senning procedure in 35. These improvements were also found in all patients operated on with the Senning procedure in our study, with a mean 12.9 points decrease in hematocrit, 30.4 points increase in pulse oximetry, and improvement in functional class. Humes et al19 also found a significant decrease in hemoglobin levels and increase in mean oxygen saturation from 64% to 85% after 9 years of follow-up19. In a series of 132 Senning cases with 20 years of follow‑up, Roubertie et al12 showed a 5.3% mortality within the first 30 thirty days and a 9.6% late mortality. Senning reported that 6% of the patients died due to systemic ventricular failure after 10 years of progression, and Cochrane et al20 reported this occurrence in 10% of the patients after 7 years. Right ventricular dysfunction is a well-known late complication of the Senning procedure and is described in almost all studies. The rate of right ventricular dysfunction may be as high as 48% in simple TGAs and 61% in complex TGAs at 15 years of follow-up12. It is worth noting that in previous studies the patients had normal pulmonary pressures. Mortality due to ventricular failure occurred within 30 days of follow-up in our series, accounting for 6 of the 10 deaths. Of the 21 patients who were operated on, 11 were discharged from the hospital, and 1 died at home due to an unknown cause after 18 months. Greater rates of sudden death have been reported in patients undergoing the Mustard procedure when compared with those undergoing the Senning procedure9. Rhythm disturbances are the most common causes of morbidity in the first few days after surgery. Junctional rhythm is present in 56% and TAVB in 6% of the operated patients. The late follow-up showed that 65% progressed with brief episodes of junctional rhythm and 38% with sinus bradycardia3. Rhythm abnormalities occurred in only 2 patients in our series. One patient presented transient TAVB that soon improved and returned to sinus rhythm, and another patient presented junctional rhythm. Arrhythmias may be explained by reentrant mechanisms caused by suture lines in the atrium, whereas sinus node dysfunction may occur due to direct injury of the node or its artery8. Some late complications may be observed, many related to technical aspects of the surgical correction such as obstruction of the superior vena cava in 10% of the cases, obstruction of the inferior vena cava in 2%, interatrial leaks, obstruction of the pulmonary veins, atrial arrhythmias (sinus node dysfunction), right ventricular dysfunction, and tricuspid insufficiency21, this last probably due to annular dilatation as a consequence of right ventricular dysfunction9. Baffle stenosis or leak was the main complication in 5% of the patients operated on in Toronto, and also the most frequent reason for reoperation22. During follow‑up in our study, we found 1 case of cava baffle stenosis and 5 cases of tricuspid valve dysfunction. Reoperations are related to systemic venous or pulmonary venous obstruction3. Sarkar et al23 found a lower incidence of reoperation for intra-atrial baffle abnormalities in patients operated with the Senning procedure. They occurred in 12% of the 226 survivors undergoing the Mustard procedure and in 2% of the 132 survivors undergoing the Senning procedure23. Penha et al. Palliative Senning in severe PH Original Article The palliative Senning procedure aims at improving the quality of life in critical patients unable to undergo another surgical treatment or improve with pharmacological therapy, since high levels of pulmonary pressure increase the risk of premature mortality and worsen the quality of life of the few survivors. The group of patients included in this study had elevated early mortality with low output as the main cause. The hypoxemia in these patients, who survive in a regimen of overload both in the systemic right ventricle as well as in the pulmonary left ventricle, aggravate the function of the ventricles. This has also been reported by Burkhart et al5 who found low output as the main cause of early mortality in 5 of the 6 deaths within the first 30 days5. Low output was also the leading cause in our series, accounting for 6 of the 10 initial deaths. However, the survival rate found in our study after 19 years of follow-up was superior: 52.3% versus 46.4%. The fact that 7 of the 10 deaths occurred more than 20 years ago may be associated with the few therapeutic resources existing at that time. The use of nitric oxide as postoperative treatment was not feasible in all patients in the initial series due to the absence of this resource in our institution in the early 1990s. Lack of improved postoperative support, which contrasts to the support currently available, may have influenced the early mortality in the first operated patients. Conclusion The palliative Senning procedure improved arterial oxygen saturation, reduced polycythemia, and provided a better quality of life to patients with TGA and VSD or Taussig-Bing DORV who had severe PH, were considered inoperable, and had a poor prognosis. Our study also showed that pulmonary lesions of more advanced grades are predominant in patients who were operated on after the age of 12 months. This confirms the need for surgical treatment as early as possible. Author contributions Conception and design of the research: Penha JG, Zorzanelli L, Aiello VD; Acquisition of data: Penha JG, Zorzanelli L; Analysis and interpretation of the data: Penha JG, Zorzanelli L, Barbosa-Lopes AA, Atik E, Tanamati C, Miana LA, Caneo LF, Aiello VD, Jatene MB; Statistical analysis: Penha JG; Writing of the manuscript: Penha JG, Zorzanelli L, Atik E, Tanamati C, Miura N, Jatene MB; Critical revision of the manuscript for intellectual content: Zorzanelli L, BarbosaLopes AA, Miana LA, Caneo LF, Aiello VD, Miura N, Jatene MB. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Study Association This study is not associated with any thesis or dissertation work. References 1. Galié N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, et al. Bonsetan therapy in patients with Eisenmenger syndrome. A multicenter, double blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48-54. 9. Hörer J, Karl E, Theodoratou G, Scheiber C, Cleuziou J, Prodan Z, et al. Incidence and results of reoperations following the Senning operation: 27 years of follow-up in 314 patients at a single center. Eur J Cardiothorac Surg. 2008;33(6):1061-7. 2. Wa r n e s C A . Tr a n s p o s i t i o n o f t h e g r e a t a r t e r i e s . C i r c u l a t i o n . 2006;114(24):2699-709. 10. Cobanoglu A, Abbruzzese PA, Freimanis I, Garcia CE, Grunkemeier G, Starr A. Pericardial baffle complications following the Mustard operation: age-related incidence and ease of management. J Thorac Cardiovasc Surg. 1984;87(3):371-8. 3. Reddy V, Sharma S, Cobanoglu A. 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Palliative transposition of venous return: long-term follow-up. J Thorac Cardiovasc Surg. 1988;96(3):364-7. 20. Cochrane AD, Karl TR, Mee RB. Staged conversion to arterial switch for late failure of the systemic right ventricle. Ann Thorac Surg. 1993;56(4):854-62. 361 Arq Bras Cardiol. 2015; 105(4):353-361 21. Jatene IB, Jatene MB. Transposição das Grandes Artérias. In: Croti U, Mattos SS, Pinto VC, Aiello VD. Cardiologia e cirurgia cardiovascular pediátrica. São Paulo: Ed. Roca; 2008. p. 355-76. 22. Wells WJ, Blackstone E. Intermediate outcome after Mustard and Senning procedures: a study by the Congenital Heart Surgeons Society. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2000;3:186-97. 23. Sarkar D, Bull C, Yates R, Wright D, Cullen S, Gewillig M, et al. Comparison of long-term outcomes of atrial repair of simple transposition with implications for a late arterial switch strategy. Circulation. 1999;100(19 Suppl):II176-81. Back to the Cover Original Article Anxiety, Depression, and General Psychological Distress in Patients with Coronary Slow Flow Mehmet Baran Karataş1, Ebru Şahan2, Kazım Serhan Özcan3, Yiğit Çanga4, Barış Güngör1, Tolga Onuk1, Göktürk İpek1, Yasin Çakıllı1, Emre Arugaslan1, Osman Bolca1 Siyami Ersek Thoracic and Cardiovascular Surgery Center, Training and Research Hospital Department of Cardiology1, Haydarpaşa Numune Training and Research Hospital Department of Psychiatry2, Derince Training and Research Hospital Department of Cardiology3, Kartal Yavuz Selim Hospital Department of Cardiology4 Abstract Background: The relationship between psychiatric illness and heart disease has been frequently discussed in the literature. The aim of the present study was to investigate the relationship between anxiety, depression and overall psychological distress, and coronary slow flow (CSF). Methods: In total, 44 patients with CSF and a control group of 50 patients with normal coronary arteries (NCA) were prospectively recruited. Clinical data, admission laboratory parameters, and echocardiographic and angiographic characteristics were recorded. Symptom Checklist 90 Revised (SCL-90-R), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) scales were administered to each patient. Results: The groups were comparable with respect to age, sex, and atherosclerotic risk factors. In the CSF group, BAI score, BDI score, and general symptom index were significantly higher than controls (13 [18.7] vs. 7.5 [7], p = 0.01; 11 [14.7] vs. 6.5 [7], p = 0.01; 1.76 [0.81] vs. 1.1[0.24], p = 0.01; respectively). Patients with CSF in more than one vessel had the highest test scores. In univariate correlation analysis, mean thrombolysis in myocardial infarction (TIMI) frame counts were positively correlated with BAI (r = 0.56, p = 0.01), BDI (r = 0.47, p = 0.01), and general symptom index (r = 0.65, p = 0.01). The psychiatric tests were not correlated with risk factors for atherosclerosis. Conclusion: Our study revealed higher rates of depression, anxiety, and overall psychological distress in patients with CSF. This conclusion warrants further studies. (Arq Bras Cardiol. 2015; 105(4):362-370) Keywords: Coronary Circulation; Depression; Anxiety Disorders; Stress, Psychological; Coronary Artery Disease / psychology. Introduction The effect of psychiatric disorders on the incidence and progression of cardiovascular diseases has been investigated in previous studies1. Concomitant depression is associated with an increased risk of cardiac morbidity and mortality after an acute myocardial infarction (MI) and coronary revascularization procedures2,3. Coronary slow flow (CSF) is a relatively common angiographic phenomenon that is characterized by slow progression of a contrast agent through the coronary arteries in the absence of any stenosis 4. Functional and morphological abnormalities in the microvasculature, endothelial dysfunction, raised inflammatory markers, occult atherosclerosis, and anatomical factors of epicardial Mailing Address: Barış Güngör • Siyami Ersek Training and Research Hospital, Tibbiye Caddesi, N° 13, Postal Code 34668, Kadiköy/Istanbul, Turkey. E-mail: [email protected] Manuscript received January 24, 2015; manuscript revised May 28, 2015; accepted June 01, 2015. DOI: 10.5935/abc.20150092 362 arteries have all been implicated in the pathogenesis of CSF5. However, little is known about the relationship between CSF and psychiatric disorders. Thus, in this study, we aimed to investigate the correlation of CSF with anxiety, depression, and general psychiatric status. Methods Study Protocol We prospectively enrolled 44 consecutive patients with CSF who had undergone diagnostic coronary angiography (CAG) between January 2014 and March 2014 in Siyami Ersek Training and Research Hospital. The control group consisted of 50 consecutive patients with normal coronary arteries who had undergone CAG between January 2014 and March 2014. Indications of coronary angiographies were determined with positive results of myocardial ischemia in noninvasive myocardial imaging and typical angina pectoris. All patients were assessed for demographic features, cardiovascular risk factors, laboratory parameters, and medications. The local ethics committee approved the study protocol and written informed consent was obtained from the study participants according to the Declaration of Helsinki. Karataş et al. Psychiatric scales and coronary slow flow Original Article Exclusion criteria included the following: refusal to participate in the study, known coronary artery disease (CAD), acute coronary syndrome, left ventricular (LV) dysfunction (defined as LV ejection fraction [LVEF] < 50%), severe valvular heart disease, rhythm other than sinus, end-stage renal or hepatic dysfunction, severe chronic obstructive pulmonary disease, systemic diseases, subjects receiving medical treatment for any type of psychiatric disorder, insufficient cooperation, presence of coronary artery stenosis > 20%, or any type of congenital coronary abnormality (such as myocardial bridging and coronary fistulas). Hypertension (HT) was defined as the use of antihypertensive drugs or initial blood pressure over 140/90 mmHg . Diabetes mellitus (DM) was defined as the use of antidiabetic drugs or fasting plasma glucose levels of > 126 mg/dL. Hyperlipidemia was defined as total serum cholesterol levels > 240 mg/dL. Smoking status was defined as current tobacco use. Body mass index (BMI) was calculated by dividing weight into the square of height. Venous blood samples were taken from the antecubital vein and collected in calcium EDTA tubes, and were then studied by an auto-analyser (Cell-dyn 3700 Abbott, USA) on the day of CAG. Transthoracic echocardiography (Vivid 3 system, General Electric, made in Norway) was performed prior to CAG to detect LV functions and valvular heart disease. LVEF was measured using the modified Simpson method. Coronary angiography and documentation of coronary slow flow Selective CAG was performed by the femoral approach using the Judkins technique. Angiographic images were obtained by the Simens Axiom 792 Axa Angiographic System. Multiple views were obtained with visualization of the left anterior descending (LAD) and left circumflex coronary arteries in at least four projections, and the right coronary artery in at least two projections. CAGs were recorded at 15 frames per second and recorded on compact discs in DICOM format. Angiograms were interpreted by two cardiologists and thrombolysis in myocardial infarction (TIMI) frame counts (TFC) were calculated for each coronary artery6. TFC were defined as the number of cine frames required for the contrast agent to reach standardized distal coronary landmarks as described by Gibson et al6. TFC for the left anterior descending artery were divided by 1.7 to obtain the corrected TFC (cTFC). Since the most frequently standardized filming rate is 30 frames per second, the TFCs were multiplied by 2. The subjects with a TFC greater than two standard deviations (SD) above the normal range were considered to have CSF6. Total TFC was defined as the sum of TFC in three major epicardial vessels. Mean TFC was calculated by dividing the total TFC by 3. Beck Anxiety Inventory (BAI). The SCL-90-R is a revised version of the original SCL-90 (Derogatis et al.) scale, which is a psychiatric self-report inventory screening for general psychiatric symptomatology. This inventory focuses on nine dimensions: somatization, anxiety, obsessive-compulsive, depression, interpersonal sensitivity, psychoticism, paranoid ideation, hostility, and phobic anxiety7. Each of 90 items is scored on a five-point Likert scale from 0 (not at all) to 4 (extremely) according to the rate of occurence of each symptom over the last week. Global Severity Index (GSI) is a quantitative indicator concerning the respondent’s current level of psychological distress and is calculated by summing the scores of nine dimensions and additional items, then dividing by the total number of responses. The realibility and validity of the Turkish version of SCL-90 has been analyzed by Dağ et al8. The severity of depression was assessed using BDI, which is a 21 item self-report scale developed by Beck et al9. Items in the scale are rated from 0 to 3 in increasing order of severity. Item scores are totaled and can range from 0 to 63. Higher scores correlate with more severe depression. The pathologic cut-off value for the BDI score was determined to be 17 in the Turkish population, which reflects moderate and severe depressive states10,11. The validity and accuracy of the BDI in the Turkish population have been studied by Hisli et al12. Anxiety is measured using the 21-item self-reported BAI13. Each item is scored from 0 to 3 according to severity. Item scores are totaled and higher scores indicate higher anxiety levels. The pathologic cut-off value for the BAI score was determined to be 16 in the Turkish population; scores above this value reflect moderate to severe anxiety states10,11. The validity and realibility of the Turkish version of the BAI have been studied by Ulusoy et al14. Statistical Analyses All data is presented as a mean ± SD for variables with normal distribution or a median [interquantile range] for variables with non-normal distribution. Categorical variables are reported as numbers and percentages. Continuous variables were checked for the normal distribution assumption using Kolmogorov‑Smirnov statistics. Categorical variables were tested by Pearson’s χ2 test and Fisher’s Exact Test. Differences between patients and control subjects were evaluated using the Mann–Whitney U test or the Student t-test, when appropriate. The relation between numerical variables was identified using Pearson or Spearman’s rho test. Multivariate linear regression analysis was performed to investigate the independent correlates of mean TFC. p-values were two sided and values < 0.05 were considered statistically significant. All statistical studies were carried out using Statistical Package for Social Sciences software (SPSS 16.0 for Windows, SPSS Inc., Chicago, Illinois). Psychological tests Results Psychological interviews were performed by a psychiatrist blinded to the CAG results. Subjects who met the inclusion criteria for the study completed the following psychological symptoms scales: Symptom Checklist 90 Revised (SCL‑90-R), Beck Depression Inventory (BDI), and Demographic, clinical, laboratory, echocardiographic, and angiographic characteristics of the 44 patients with CSF and 50 control subjects were summarized in Table 1. The two groups were similar in terms of age, sex, DM, HT, hyperlipidemia, alcohol consumption, smoking status, Arq Bras Cardiol. 2015; 105(4):362-370 363 Karataş et al. Psychiatric scales and coronary slow flow Original Article Table 1 – Demographic, clinical, echocardiographic, laboratory, and demographic characteristics of the study population Characteristics Control Group (n = 50) Slow flow group (n = 44) p value Age, years 53.8 ± 7.8 53.1 ± 10.4 0.73 Male, n (%) 27 (54) 29 (66) 0.24 HT, n (%) 24 (48) 20 (45) 0.80 Hyperlipiemia, n (%) 19 (38) 16 (36) 0.87 Diabetes, n (%) 9 (18) 8 (18) 0.98 Smoking, n (%) 27 (54) 20 (45) 0.41 Alcohol, n (%) 7 (14) 5 (11) 0.70 3 (6) 4 (9) 0.57 Medications ASA, n (%) Beta Blocker, n (%) 3 (6) 2 (5) 0.76 ACEI, n (%) 6 (12) 5 (11) 0.92 ARB, n (%) 9 (18) 5 (11) 0.37 Calcium Channel Blocker, n (%) 7 (14) 6 (14) 0.95 Statin, n (%) 17 (34) 13 (30) 0.66 OAD, n (%) 6 (12) 5 (11) 0.92 Insulin, n (%) 5 (10) 6 (14) 0.58 Diuretic, n (%) 12 (24) 8 (18) 0.49 Education level Primary school, n(%) 23 (46) 25 (57) High school, n(%) 20 (40) 13 (29) University, n(%) 7 (14) 6 (14) 0.55 Montly income Low, n(%) 27 (54) 25 (57) Intermediate, n(%) 20 (40) 17 (39) High, n(%) BMI Heart rate (bpm) 3 (6) 2 (4) 25.6 ± 2.2 30.1 ± 6.4 0.93 0.01 78 ± 8 76 ± 7 0.11 Systolic BP (mmHg) 117 ± 12 119 ± 13 0.85 LDL cholesterol (mg/dL) 108 ± 27 110 ± 31 0.87 Fasting plasma glucose (mg/dL) 100 ± 32 103 ± 35 0.71 60 ± 9 59 ± 8 0.61 1 vessel , n(%) - 24 (54) - > 1 vessel , n(%) - 20 (45) - LAD 18.9 ± 1.1 27.7 ± 8.2 0.01 LCx 19.1 ± 1.7 24.5 ± 6.3 0.01 RCA 18.5 ± 1.3 24.9 ± 7.2 0.01 LV ejection fraction (%) Total number of vessels with CSF TIMI frame counts HT: Hypertension; ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; ASA: Acetylsalicylic acid; BMI: Body mass index; CSF: Coronary slow flow; BP: Blood pressure; LAD: Left anterior descending; LCx: Left circumflex; LDL: Low-density lipoprotein; LV: Left ventricular; n: Number; OAD: Oral antidiabetic; RCA: Right coronary artery; TIMI: Thrombolysis in myocardial infarction. 364 Arq Bras Cardiol. 2015; 105(4):362-370 Karataş et al. Psychiatric scales and coronary slow flow Original Article medications, heart rate, systolic blood pressure, low-density lipoprotein (LDL) cholesterol, and fasting plasma glucose levels. In addition, there was no significant difference in terms of monthly income and educational levels between the two groups (p = 0.93 and p = 0.55, respectively). TIMI frame counts were significantly higher in patients with CSF than those in controls (p = 0.01). In 24 (54%) of the cases, CSF was observed in one vessel, and in 20 (46%) of the cases, more than one vessel had CSF. A comparison of psychiatric test results between the two groups is summarized in Table 2. In the CSF group, the BAI score was significantly higher than in controls (13 [18.7] vs 7.5 [7], p = 0.01). Twenty patients in the CSF group had a BAI score ≥ 16, which was significantly higher than the control group (8 cases) (p = 0.01). When the BDI test scores were compared between the two groups, subjects in the CSF group had significantly higher scores than those in control group (11 [14.7] vs. 6.5 [7], p = 0.01). The frequency of subjects with a BDI score ≥ 17 was higher in the CSF group (32% vs. 2%, p = 0.01). In addition, the median general symptoms index score was significantly higher in the CSF group (1.76 [0.81] vs 1.1[0.24], p = 0.01). In univariate correlation analysis, mean TIMI scores were positively correlated with BAI (r = 0.56, p = 0.01), as were BDI scores (r = 0.47, p = 0.01) and the general symptom index (r = 0.65, p = 0.01); however, they were not correlated with age, educational level, monthly income, glucose, or LDL levels (Table 3). In addition, BMI was significantly correlated with mean TFC (r = 0.28, p = 0.01) but was not correlated with BAI (r = 0.16, p = 0.11), BDI (r = 0.08, p = 0.78), or GSI (r = 0.15, p = 0.18). To investigate the independent determinants of mean TFC, we performed a multivariate linear regression analysis using a model adjusted for age, gender, and BMI. Results indicated that BMI (standardized β coefficient = 0.221; p = 0.01), BAI (standardized β coefficient = 0.546; p = 0.01), BDI (standardized β coefficient = 0.444; p = 0.01), and GSI (standardized β coefficient = 0.607; p = 0.01) were independently correlated with mean TFC. No correlation with age or gender was observed. Correlation and subgroup analyses were performed to investigate the correlation of BAI, BDI, and GSI with atherosclerosis risk factors. In these analyses, BAI was not significantly correlated with age (r=0.09, p = 0.54), fasting glucose levels (r = −0.05, p = 0.64), LDL (r = −0.14, p = 0.19), or systolic blood pressure (r = 0.07, p = 0.72). BDI was not significantly correlated with age (r = 0.08, p = 0.41), fasting glucose levels (r = −0.11, p = 0.31), LDL (r = −0.14, p = 0.11), or systolic blood pressure (r = 0.17, p = 0.09). GSI was not significantly correlated with age (r = 0.03, p = 0.79), fasting glucose levels (r = −0.06, p = 0.65), LDL (r = −0.12, p = 0.26) or systolic blood pressure (r = 0.12, p = 0.24). In subgroup analysis, BAI, BDI, and GSI were not significantly different when compared between females and males (10 [14.9] vs. 8 [9.7], p = 0.26; 9 [13] vs. 8.5 [9.5], p = 0.18; 1.12 [0.92] vs. 1.38 [0.67], p = 0.46, respectively). In addition, BAI, BDI, and GSI were not significantly different between smokers and non-smokers (8 [10] vs. 10 [12], p = 0.21; 9 [8] vs. 9 [12], p = 0.49; 1.35 [0.57] vs. 1.21 [0.89], p = 0.57, respectively). In total, 28 study participants (30%) had BAI scores ≥ 16 (Table 4). In these patients, total TFC and mean TFC were significantly higher (75.2 ± 17.5 vs. 62.4 ± 9.6, p = 0.01 and 25.1 ± 5.8 vs. 20.8 ± 3.2, p = 0.01, respectively). Age, gender, HT, DM, hyperlipidemia, smoking, alcohol consumption, educational status, monthly income, BMI, systolic blood pressure, fasting glucose, LDL cholesterol, and LVEF were similar among patients with BAI score < 16 and BAI score ≥ 16. A comparison of study parameters in subgroups of patients classified as BDI score < 17 and ≥ 17 is depicted in Table 5. Overall, 76 patients (81%) had a BDI score < 17, whereas 18 patients (19%) had BDI scores ≥ 17. In both groups, age, gender, HT, DM, hyperlipidemia, smoking, alcohol, educational status, monthly income, BMI, systolic blood pressure, fasting glucose, LDL cholesterol, and LVEF were similar. Total TFC and mean TFC were significantly higher in subjects with a BDI score ≥ 17 than in those with a BDI score < 17. (78 ± 19 vs 63 ± 10; 25.9 ± 6.5 vs 21.1 ± 3.4, p = 0.01, respectively). In a subgroup analysis of the 44 patients with CSF patients, those with CSF in more than one vessel had significantly higher BAI, BDI, and GSI scores than those with CSF restricted to one vessel (26 [16] vs. 8 [7.2], p = 0.01; 17 [14] vs 6 [1.1], p = 0.01; 2.1 [0.7] vs 1.4 [0.6], p = 0.01, respectively). In univariate correlation analysis, the number of vessels with CSF was positively correlated with BAI (r = 0.66, p = 0.01), BDI (r = 0.61, p = 0.01), and GSI (r = 0.59, p = 0.01). Table 2 – Comparison of psychiatric tests results between CNF and CSF patients Characteristics CNF (n = 50) CSF (n = 44) p value 7.5 [7] 13 [18.7] 0.01 < 16, n (%) 42 (84) 24 (55) 0.01 ≥ 16, n (%) 8 (16) 20 (45) 0.01 6.5 [7] 11 [14.7] 0.03 < 17, n (%) 46 (92) 30 (68) 0.01 4 (8) 14 (32) 0.01 1.1 [0.24] 1.76 [0.81] 0.01 BAI BDI ≥ 17, n (%) General Symptoms Index BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; CNF: Coronary normal flow; CSF: Coronary slow flow. Arq Bras Cardiol. 2015; 105(4):362-370 365 Karataş et al. Psychiatric scales and coronary slow flow Original Article Table 3 – Univariate correlation analysis of mean TIMI frame counts with study parameters Characteristics Mean TIMI frame count BAI r = 0.56; p = 0.01 BDI r = 0.47; p = 0.01 General Symptoms Index r = 0.65; p = 0.01 Age r = 0.09; p = 0.36 BMI r = 0.28; p = 0.01 Education level r = −0.15; p = 0.15 Montly income r = 0.08; p = 0.44 LDL r = 0.02; p = 0.88 Glucose r = 0.05; p = 0.67 EF r = 0.09; p = 0.92 BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; BMI: Body mass index; LDL: Low-density lipoprotein; EF: Ejection fraction; TIMI: Thrombolysis in myocardial infarction. Table 4 – Comparison of study parameters in patients with BAI score < 16 and ≥ 16 Characteristics BAI < 16 (n = 66) BAI ≥ 16 (n = 28) p value Age 53 ± 8.7 54.7 ± 9.8 0.42 Female Gender, n (%) 23 (35) 15 (53) 0.06 HT, n (%) 32 (48) 12 (43) 0.82 Hyperlipiemia, n (%) 23 (35) 12 (43) 0.48 Diabetes, n (%) 14 (21) 3 (11) 0.38 Smoking, n (%) 36 (54) 11 (39) 0.36 Alcohol, n (%) 10 (15) 3 (11) 0.75 Primary school, n(%) 31 (52) 19 (68) High school, n(%) 27 (41) 6 (21) University, n(%) 8 (12) 3 (11) < 1500 TL, n (%) 36 (54) 16 (57) 1500-3000 TL, n (%) 26 (39) 11 (39) 4 (6) 1 (3) BMI 27 ± 3.4 29.3 ± 7.7 0.07 Systolic BP (mmHg) 116 ± 10 118 ± 12 0.46 LDL cholesterol (mg/dL) 110 ± 28 113 ± 30 0.35 Glucose (mg/dL) 95 ± 33 103 ± 34 0.33 Education level 0.11 Montly income >3000 TL, n (%) EF (%) 0.88 62 ± 4 59 ± 6 0.15 Mean TIMI FC 20.8 ± 3.2 25.1 ± 5.8 0.01 Total TIMI FC 62.4 ± 9.6 75.2 ± 17.5 0.01 BAI: Beck Anxiety Inventory; HT: Hypertension; BMI: Body mass index; BP: Blood pressure; EF: Ejection fraction; LDL: Low-density lipoprotein; TIMI FC: Thrombolysis in miyocardial infarction frame count; TL: Turkish Liras. 366 Arq Bras Cardiol. 2015; 105(4):362-370 Karataş et al. Psychiatric scales and coronary slow flow Original Article Table 5 – Comparison of study parameters in patients with BDI score < 17 and ≥ 17 Characteristics BDI < 17 (n = 76) BDI ≥ 17 (n = 18) p value Age, years 53 ± 9.3 55.3 ± 8.2 0.36 Female gender, n (%) 28 (37) 10 (55) 0.15 HT, n (%) 37 (49) 7 (39) 0.60 Hyperlipiemia, n (%) 29 (38) 6 (33) 0.79 Diabetes, n (%) 13 (17) 4 (22) 0.73 Smoking, n (%) 41 (54) 6 (33) 0.19 Alcohol, n (%) 11 (14) 2 (11) 0.71 Primary school, n (%) 40 (53) 10 (55) High school, n (%) 27 (35) 6 (33) University, n (%) 9 (12) 2 (11) < 1500 TL, n (%) 41 (54) 11 (61) 1500-3000 TL, n (%) 31 (41) 6 (33) Education level 0.97 Montly income > 3000 TL, n (%) BMI 0.84 4 (5) 1 (5) 27 ± 5.4 28.7 ± 4.1 0.36 Systolic BP (mmHg) 116 ± 12 120 ± 11 0.21 LDL cholesterol (mg/dL) 110 ± 29 101 ± 27 0.23 Glucose (mg/dL) 100 ± 32 106 ± 42 0.47 62 ± 4 59 ± 5 0.14 Mean TIMI 21.1 ± 3.4 25.9 ± 6.5 0.01 Total TIMI 63 ± 10 78 ± 19 0.01 EF (%) BDI: Beck Depression Inventory; HT: Hypertension; BP: Blood pressure; LDL: Low-density lipoprotein; TIMI: Trombolysis in myocardial infarction; TL:Turkish Liras; BMI: Body mass index; EF: Ejection fraction. Discussion Results of the present study indicate that patients with CSF had significantly increased levels of depression, anxiety, and overall psychological distress compared with patients having CNF. The INTERHEART study is the largest trial conducted to date to investigate the correlation between stress and heart disease. This trial included 11,119 patients with MI from 52 countries. In this study, perceived stress and depression were shown to be important risk factors, which together accounted for 32.5% of the population with attributable risk for CAD. These findings suggest that these variables together were as important as smoking and more important than DM15. In a previous study, every 5-point increase in BDI score was associated with a 25%–30% increase in the risk of abnormal CAG findings or definitive CAD10. Furthermore, Shiozaki et al. demonstrated that depression emerging during the year after experiencing a MI is significantly associated with subsequent cardiovascular events in a 2.9-year follow-up for male patients16. The prevalence of depression in the Turkish population is estimated to beabout 10%–20% 17. Prior studies have estimated the prevalence of depression ranging from 20% to 40% in patients with CAD and have found that the presence of depression is associated with increased risk for adverse events18. In our study, 32% of patients with CSF were found to have major depressive disorder documented with a BDI score ≥ 17. Consistent with our results, Durmaz et al. have reported higher depression rates among patients with CSF (50% vs. 8%)19. Their study examined 90 patients and used the Hamilton Rating Scale (HAMD) to measure depression19. A total of 94 patients were included in our study but a different scale for depression (BDI) was used. The pathophysiological mechanism between psychological distress and cardiovascular events has not been fully elucidated. Some of the proposed mechanisms are as follows: high sympathetic tone; increased cortisol and catecholamine; endothelial dysfunction; abnormal platelet activation, including enhanced platelet reactivity and release of platelet products (such as platelet factor 4 and b-thromboglobulin); augmented release of inflammatory markers; decreased heart rate variability; accelerated atherogenesis; and poor adherence10,11. We did not observe any correlation between level of anxiety or depression and atherosclerotic risk factors, which is similar to a prior report by Zafar et al20 Furthermore, no relationship between educational or monthly income (socioeconomic) status and depression or anxiety have been established. Arq Bras Cardiol. 2015; 105(4):362-370 367 Karataş et al. Psychiatric scales and coronary slow flow Original Article Compared with the extensive literature on depression in patients with CAD, relatively few studies have examined the role of anxiety. Some studies have reported anxiety symptoms to be predictive of subsequent cardiac events, mortality, and in-hospital complications in patients with CAD, whereas others have found no association21-23. Martens et al24 have found that participants with baseline generalized anxiety disorder (GAD) had a greater rate of subsequent cardiovascular events than did participants without GAD. Vural et al10 found significant correlation between CAD and BAI scores. Todaro et al25 reported the lifetime prevalence of anxiety disorders to be 45.3% in patients with CAD. In addition, Durmaz et al19 investigated the relationship between anxiety and CSF. Unlike the other studies in the literature, their study utilized State-Trait Anxiety Inventory (STAI) for anxiety. They found that STAI scores were significantly higher in the CSF group. However, their study did not include a known cut-off value for anxiety; therefore, whether a difference was observed between the two groups in terms of the number of people with anxiety is unknown. As a result, no percentage was provided for anxiety19. Our present study utilized the BAI scale to identify anxious people according to the cut-off value and found that 45.4% of patients with CSF had anxiety disorder; this was significantly higher than the control group. Previous studies have shown that obese and overweight people are more likely to experience anxiety and depression than those who are of normal weight26. However, comparison of the frequency of psychiatric disorders between overweight and obese people are controversial in the literature. In our study population, CNF patients were overweight, whereas patients with CSF were obese according to the mean BMI levels. As we did not intend to investigate correlation of obesity with psychiatric tests, our data may not be suitable to draw conclusions regarding obesity and psychiatric disorders; however, in our study, BMI was not correlated with BAI, BDI, and GSI scores. GSI, which can be used as a summary of the SCL-90-R test, is designed to measure overall psychological distress. In our study, the GSI of patients CSF was 1.76, whereas the GSI of those subjects in the control group was 1.1 (p = 0.01), indicating that patients with CSF exhibit more psychological distress than those with normal coronary blood flow. Therefore, our study is the first study in the literature to use the SCL-90-R scale in patients with CSF. 368 Arq Bras Cardiol. 2015; 105(4):362-370 Our study also found that patients with CSF in more than one coronary vessel had higher BAI, BDI, and GSI scores, which indicates the positive correlation between these scores and the extent and severity of CSF. Our study is the first study in the literature to report this correlation. Limitations This study has several limitations that deserve mention. This is a single center, cross-sectional prospective study with relatively small sample size. In addition, we could not report the correlation of the study parameters with long-term outcomes in the study population. Conclusions Although we could not draw a causal relationship, we observed higher levels of depression, anxiety, and overall psychological distress in patients with CSF. Further studies are needed to confirm our results and the importance of these findings in long-term outcomes and prognosis of patients with CSF. Author contributions Conception and design of the research: Karataş MB, Bolca O; Acquisition of data: Şahan E, Çakıllı Y, Arugaslan E; Analysis and interpretation of the data: Karataş MB, Şahan E, Güngör B, İpek G, Çakıllı Y, Bolca O; Statistical analysis: Güngör B, İpek G; Writing of the manuscript: Özcan KS, Çanga Y, Arugaslan E; Critical revision of the manuscript for intellectual content: Karataş MB, Özcan KS, Çanga Y, Güngör B. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Study Association This study is not associated with any thesis or dissertation work. Karataş et al. Psychiatric scales and coronary slow flow Original Article References 1. Bunker SJ, Colquhoun DM, Esler MD, Hickie IB, Hunt D, Jelinek VM, et al. “Stress” and coronary heart disease:psychosocial risk factors. Med J Aust. 2003;178(6):2726. 2. Barth J, Schumacher M, HerrmannLinger C. 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Arq Bras Cardiol. 2015; 105(4):362-370 369 Karataş et al. Psychiatric scales and coronary slow flow Original Article 370 Arq Bras Cardiol. 2015; 105(4):362-370 Back to the Cover Original Article Mortality from Cardiovascular Diseases in the Elderly: Comparative Analysis of Two Five-year Periods Grasiela Piuvezam, Wilton Rodrigues Medeiros, Andressa Vellasco Costa, Felipe Fonseca Emerenciano, Renata Cristina Santos, Danilo Silveira Seabra Universidade Federal do Rio Grande do Norte, Natal, RN – Brazil Abstract Background: Cardiovascular diseases are the leading cause of death in Brazil. The better understanding of the spatial and temporal distribution of mortality from cardiovascular diseases in the Brazilian elderly population is essential to support more appropriate health actions for each region of the country. Objective: To describe and to compare geospatially the rates of mortality from cardiovascular disease in elderly individuals living in Brazil by gender in two 5-year periods: 1996 to 2000 and 2006 to 2010. Methods: This is an ecological study, for which rates of mortality were obtained from DATASUS and the population rates from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística). An average mortality rate for cardiovascular disease in elderly by gender was calculated for each period. The spatial autocorrelation was evaluated by TerraView 4.2.0 through global Moran index and the formation of clusters by the index of local Moran-LISA. Results: There was an increase, in the second 5-year period, in the mortality rates in the Northeast and North regions, parallel to a decrease in the South, South-East and Midwest regions. Moreover, there was the formation of clusters with high mortality rates in the second period in Roraima among females, and in Ceará, Pernambuco and Roraima among males. Conclusion: The increase in mortality rates in the North and Northeast regions is probably related to the changing profile of mortality and improvement in the quality of information, a result of the increase in surveillance and health care measures in these regions. (Arq Bras Cardiol. 2015; 105(4):371-380) Keywords: Cardiovascular Diseases / mortality; Cardiovascular Diseases / epidemiology; Comparative Study; Aged. Introduction Noncommunicable diseases (NCD), according to the worldwide trend of recent decades, currently determine the majority of causes of death in Brazil, changing the profile of diseases that occur in the population, being higher than mortality rates from infectious and parasitic diseases1. In the country, the NCD in 2007 accounted for 72% of causes of death and affected more individuals that belong to vulnerable groups, such as the elderly2. Over the past decade, cardiovascular diseases (CVD) accounted for 50% of the mortality of all the NCD3. According to data from the Ministry of Health, NCD corresponded to the first cause of death in Brazil and accounted in 2008 for 40.8% of deaths of individuals aged 60 or older4. Mailing Address: Andressa Vellasco Brito Costa • Universidade Federal do Rio Grande do Norte. Rua Joana D’Arc, 1.780, Candelária. Postal Code 59065-620, Natal, RN – Brazil E-mail: [email protected] Manuscript received December 22, 2014; revised manuscript May 04, 2015; accepted May 06, 2015 DOI: 10.5935/abc.20150096 371 Although CVD are the leading cause of death in Brazil, few studies have addressed the spatial and temporal distribution of mortality caused by them, especially regarding the elderly age group. Mortality from CVD is a phenomenon that has different risk factors, from behavioral and social factors to genetic ones and, therefore, one can infer that their distribution can be shown in different ways, as the context in which different population groups are inserted is variable. In this sense, it can be observed that the territory configurations, as well as the process of urbanization, have a direct impact on the way several population groups deal with this group of diseases5. From this perspective, this study aimed to describe the geographical distribution of mortality from CVD in the elderly population in Brazil by gender, in the five-year period of 1996 to 2000 and from 2006 to 2010, and compare them in both periods. The search for a better understanding of the spatial and temporal distribution of these rates is critical for planning evidence-based sustainable public policies. This set of information can contribute to a better control and prevention of CVD, as it supports the achievement of more targeted actions for each country region, aiming thereby to reduce health inequalities. Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Methods This was an ecological study, of which the area analysis units were the Brazilian states, which constitute 27 elements in the total sample. Data considered in the study are covered by the five-year periods of 1996-2000 and 2006-2010. The study population was a group of elderly residents in Brazil who died from CVD in the analyzed period. For inclusion in the study, it was considered an elderly any individual aged ≥ 60 years6. Data were obtained from the Data Processing Department of the Unified Health System (DATASUS), from the mortality information system (SIM). These data are grouped by SIM through the records of its legal instrument collection, the death certificate (DC). This information is available on the Internet for free consultation as data amassed by municipalities, that is, they were not individually and nominally collected. In this sense, there is no possibility of physical or moral damage from the individual's and community’s perspective, as the principles contained in Resolution 466 of 12 December 2012 were followed. Therefore, this article did not require approval by the Ethics Committee of Universidade Federal do Rio Grande do Norte (CEP-UFRN). The outcome variables were the adjusted mortality rate from cardiovascular diseases (MRCD) in female elderly (MRCDf) and male (MRCDm) for each state. MRCD is calculated by the ratio of the number of elderly deaths from CVD by gender in Brazil in the assessed period and the elderly population in Brazil in the same period, by gender and per thousand inhabitants. It is appropriate to clarify that the present investigation was based on the rate adjusted by the year 2003 population (corresponding to half of the study period five-year periods of 1996-2000 and 2006-2010), as well as by age groups detailed by five-year intervals, from 60 years to 80 years and older, according to the standardization established by DATASUS. We chose to perform, simultaneously, the comparison of mortality rates from III-defined causes (IDC) in both periods, to better demonstrate the information qualification process during the assessed period. Thus, a similar methodology was used to obtain adjusted rates of mortality from IDC in male and female elderly individuals. Therefore, for comparative analysis, data were selected for two five-year periods, the first from 1996 to 2000, and the second from 2006 to 2010. The necessary population data to calculate the MRCD for each municipality were obtained from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística - IBGE), available in DATASUS site. The TabWin software was used for data tabulation and calculation of mortality rates. The analysis of this coefficient in two different five-year periods allowed this study to assess changes in the epidemiology of mortality from CVD in Brazil, focusing on their geospatial characteristics. This rate was calculated for each year of the two assessed five-year periods. Then, for each five-year period, using arithmetic mean, we obtained the mean mortality rate from cardiovascular diseases (MMRCD) per thousand individuals for each state of Brazil. This MMRCD was then distributed spatially to carry out exploratory and geostatistical analysis. The IBGE cartographic shape was used in the study, which was obtained from its site. Initially, thematic maps were built for the two five-year periods, a phase that consisted in the exploratory analysis of spatial data. Their production was carried out using the SIG TerraView 4.2.0. program, in which the distribution amount was divided into five ranges for the legend, through the "equal step" division for the second five-year period, which was the basis for the first period distribution. At this point, the gray scale was chosen for visual comparison. At the time when the legend was created, which was carried out using a color gradient, the darker color represented the group of municipalities with the worse situations. The spatial autocorrelation was calculated using the free Software TerraView 4.2.0 through the global Moran index for the MMRCD distribution in both analyzed periods. The value of the global Moran index ranges from -1 to 1. Values close to zero indicate lack of spatial autocorrelation; positive values indicate positive spatial autocorrelation; and negative values indicate negative autocorrelation. Subsequently, the standard analysis of the spatial distribution and the possible cluster formation was performed. For this, we used the local index of Moran‑LISA, in order to map the intensity of clusters, considering a p value < 0.05 as statistically significant. The representative map of this situation is the Moran Map. Results The overall population of elderly individuals in Brazil varied by 17.24% in the first analyzed five-year period, totaling 14,536,029 in 2000. Regarding the period between 2006 and 2010, there was a 30.57% increase in the elderly population, i.e., in the end of the last year of the second five-year period, there were 20,590,599 Brazilians aged 60 and older in absolute numbers. In relative terms, 7.86% of the population of the country was elderly in 1996 and, after 15 years, this number increased to 10.79%. Regarding the elderly population divided by gender, there was an increase between 1996 and 2010 of 38.22% for males and 41.03% for females. In the period of 1996-2000, there were 4,629,638 deaths in Brazil, of which 53.8% occurred in individuals aged 60 and older. In the years 2006-2010, 5,396,557 records of deaths were released by SIM, with 60.5% being related to elderly individuals. Converting this analysis to the causes related to Chapter IX - Circulatory Disorders of the International Classification of Diseases and Health-Related Problems (ICD-10)7, it is possible to see that such diseases accounted for 27.51% of deaths in the general population and 37.42% among the elderly, in the first five-year period. For the second period, these numbers were respectively 29.19% and 37.17%. Arq Bras Cardiol. 2015; 105(4):371-380 372 Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Regarding the eight leading causes of death, Graph 1 shows the proportional mortality of the elderly, by gender, in both studied periods. In both genders, in the first five‑year period, the three main causes of death corresponded to diseases of the circulatory system in the first place, IDC in the second, and neoplasms in the third; in the second five‑year period, the top three were: diseases of the circulatory system, cancer and respiratory diseases. Regarding the categories of most prevalent cause of CVD in Brazil, it can be observed that in the first five years, more than 50% were caused by the following conditions: acute myocardial infarction (21.18%), CVA (19.50 %), heart failure (13.43%) and chronic ischemic heart disease (6.09%). In the second five-year period, it was observed that the most prevalent were: acute myocardial infarction, with 22.05%; hemorrhagic or ischemic CVA, with 15.86%; heart failure, with 9.64% and primary hypertension, with 6.64%. A XX XVIII XI X IX IV II I 5 0 10 15 20 Proportional Mortality Causes (%) 2006-2010 25 30 35 40 45 Proportional Mortality Causes (%) 1996-2000 B XX XVIII XI X IX IV II I 0 5 10 15 Proportional Mortality Causes (%) 2006-2010 20 25 30 35 40 Proportional Mortality Causes (%) 1996-2000 Graph 1 – (A) Proportional mortality among female elderly in Brazil, divided by cause of death in five-year periods, from 1996 to 2000 and 2006 to 2010. (B) Proportional mortality among male elderly in Brazil, divided by cause of death in five-year periods, from 1996 to 2000 and 2006 2010. Chapter I: infectious and parasitic diseases; Chapter II: neoplasms; Chapter IV: endocrine, nutritional and metabolic diseases; Chapter IX: circulatory system diseases; Chapter X: respiratory diseases; Chapter XI: digestive diseases; Chapter XVIII: poorly-defined causes; Chapter XX: External causes. Source: Department of Informatics of the Unified Health System (DATASUS) / Ministry of Health. 373 Arq Bras Cardiol. 2015; 105(4):371-380 Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Table 1 shows the distribution of MMRCD in the elderly, per thousand inhabitants, by gender, in the Brazilian states in the period from 1996 to 2000 and from 2006 to 2010. The highest rates in the first five year period was concentrated in the South and Southeast states. The lowest value found in Brazil was observed in the state of Maranhão (4.24% for females and 5.32% for males), in the Northeast, and the highest in the state of Paraná (19.78% for females and 23.07% for males), in the South. In the period 2006-2010, the lowest rate was found in the state of Amapá (6.02% for females and 8.72% for men) and the highest in the state of Santa Catarina, for elderly women (21,92%) and Mato Grosso do Sul, for males (16.47%). A significant decrease was observed regarding results found in the South, Southeast and Midwest regions. In contrast, the North and Northeast regions showed significant increase in their rates, with emphasis on the states of Piauí, Paraíba, Maranhão and Tocantins, for both genders. The analysis concerning the distribution of MMRCDf and MMRCDm in the Brazilian states is shown in Figure 1. The results were obtained from the mean rate of deaths from cardiovascular diseases in the elderly, in the periods 1996‑2000 and 2006-2010, and the significance test for the global Moran's index, under the null hypothesis of absence of spatial autocorrelation. It was observed that the global Moran’s index for the first five years was 0.225048 for females and 0.209145 for males, with p = 0.09 and 0.16, respectively. In the second five-year period, the value was 0.0887927, with p = 0.21 for elderly women and 0.0842536 and p = 0.21 for men older than 60 years. In order to support the results obtained by the aforementioned analysis, the characterization of deaths in the elderly was performed using an analogous methodology, by gender and Brazilian Federation unit, Table 1 – Distribution by gender of the mean mortality rate from cardiovascular disease (MMRCD) in the elderly, per thousand inhabitants, in the Brazilian states in the periods 1996-2000 and 2006-2010 Federation Unit First 5-year period (A) Second 5-year period (B) Delta (B-A) Female Male Female Male Female Male Rondônia 13.56 14.15 11.75 13.12 -1.81 -1.03 Acre 8.31 9.32 9.58 11.96 1.27 2.64 Amazonas 8.02 8.94 7.90 9.86 -0.12 0.92 Roraima 11.03 15.87 9.49 12.72 -1.54 -3.15 Pará 8.69 9.46 8.74 10.72 0.04 1.26 Amapá 9.76 12.97 6.02 8.72 -3.73 -4.25 Tocantins 8.33 9.56 13.04 14.54 4.71 4.98 Maranhão 4.24 5.32 9.84 13.54 5.60 8.22 Piauí 6.59 8.43 14.68 17.83 8.09 9.39 Ceará 8.19 9.31 11.04 13.61 2.85 4.30 Rio Grande do Norte 7.44 8.69 9.99 12.67 2.55 3.98 Paraíba 5.43 6.00 11.99 14.00 6.56 8.00 Pernambuco 12.67 14.42 13.51 15.35 0.84 0.93 Alagoas 9.04 10.47 12.71 15.32 3.68 4.85 Sergipe 7.96 8.58 11.96 13.32 4.01 4.74 Bahia 8.10 9.01 8.73 10.03 0.63 1.02 Minas Gerais 13.76 16.25 9.84 12.03 -3.93 -4.21 Espírito Santo 13.63 17.46 12.50 15.89 -1.13 -1.58 Rio de Janeiro 17.14 22.27 11.36 15.77 -5.78 -6.50 São Paulo 18.00 22.00 11.51 14.96 -6.49 -7.04 Paraná 19.78 23.07 12.46 15.45 -7.32 -7.61 Santa Catarina 16.36 19.41 21.92 13.50 5.57 -5.91 Rio Grande do Sul 17.56 19.45 11.88 14.64 -5.69 -4.81 Mato Grosso do Sul 16.19 19.26 12.67 16.47 -3.52 -2.79 Mato Grosso 14.80 16.44 11.66 14.30 -3.14 -2.14 Goiás 14.41 15.54 11.31 12.99 -3.10 -2.55 Distrito Federal 17.25 21.35 9.63 14.29 -7.62 -7.05 Source: Mortality Information System (SIM). Department of Informatics of the Brazilian Unified Health System (DATASUS)/Ministry of Health, 2015. Arq Bras Cardiol. 2015; 105(4):371-380 374 Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Back to the Cover Original Article Figure 1 – Thematic maps of the mean mortality rate from cardiovascular diseases (MMRCD) per thousand inhabitants in each Brazilian state and gender in the periods from 1996 to 2000 and from 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics the Unified Health System (DATASUS)/ Ministry of Health, 2015. 375 classified as ill‑defined causes (IDC) (Chapter XVIII of ICD 10). The global Moran’s index values found for elderly women and men, in the first five-year period were, respectively: 0.388822 (p = 0.01) and 0.335994 (p = 0.04). For the second five-year period, the values were 0.06128 (p = 0.38) and -0.00415266 (p = 44). Distribution of deaths from IDC can be seen in Figure 2. Therefore, in the first five-year period, in relation to the outcome variables, clusters were formed in the states of Ceará and Pernambuco for the female gender and in Rio Grande do Norte, Ceará and Pernambuco for the male gender. In the second five-year period, the autocorrelation was observed in the states of Roraima, for the group of elderly women, and Roraima, Ceará and Pernambuco, in relation to males. To create the maps depicted in Figure 3, we used the interpretation capabilities of the Moran Map, which allows the visualization of the statistically significant spatial autocorrelation areas 8 and identify the location of homogeneous regions consisting of states with spatial association, regarding MMRCDf and MMRCDm. Thus, the Federation units were classified according to their location in relation to the Moran scatter plot quadrants: the quadrants 1 (high-high) and 2 (low-low) indicate areas with positive spatial association, i.e., the values were similar to those shown for neighboring states; quadrant 3 (high-low) and 4 (low-high) showed that the results did not follow the global trend and therefore had a negative spatial association, as there were neighbors that had discordant values8. It is noteworthy the fact that for the spatial autocorrelation analysis performed for deaths classified as IDC, as seen in Figure 4, the methods described for the MMRCDf and MMRCDm variables were used. Therefore, clusters were formed, in the first five-year period, in Ceará and Pernambuco for both genders. In the second five-year period, the autocorrelation was observed in the states of Roraima, Acre, Rondonia, Goias and Minas Gerais for the elderly females, and Roraima, Acre, Goias and Minas Gerais for males. Arq Bras Cardiol. 2015; 105(4):371-380 Discussion Based on the results, it was observed that in the first five‑year period, the highest MRCD were mainly concentrated Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Figure 2 – Thematic maps of the mean rate of mortality from ill-defined causes (IDC) per thousand inhabitants for each Brazilian state and by gender in the periods from 1996 to 2000 and from 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics of the Unified Health System (DATASUS) / Ministry of Health, 2015. in the South and Southeast regions. In the second five-year period, there was a considerable increase in the rates observed in the Northeast, as well as a decrease in the rates in the South and Southeast regions. There was also a slight increase in mortality rates in the North region. The emergence of a cluster in the states of Rio Grande do Norte, Ceará and Pernambuco, as seen in the Moran Map for both genders, in the period 1996-2000, allowed the identification of a positive spatial association of MMRCD, indicating the similarity of this rate between those states and their neighbors. Thus, a homogeneous area in the Northeast was observed, characterized by high levels of MMRCD that appeared in the second five-year period. The literature shows that mortality statistics, as shown in this study, are the most often used to obtain health status information of a population and to plan necessary actions for health promotion. However, it is of utmost importance to also discuss the proportion of deaths attributed to IDC, as it constitutes one of the indicators used to assess the quality of that information and the correct trend of the mortality analysis9. At the stratification of deaths in the elderly population in Brazil for the period of 1996-2000, the causes identified as ill-defined encompassed the second overall position, with a total of 17.64% of notifications. For the second five-year period, there was substantial improvement, relocating mortality from undetermined causes to the fourth position (8.10%). Therefore, the lowest proportion of notifications from Chapter XVIII of ICD-10 (CMD) indicates more accurate statistics on mortality10. In the country, the highest number deaths from ill-defined causes concentrated in the age group older than 60 years; that is, regarding the data for 2005, 67.2% of deaths from IDC corresponded to this population group. One explanation for the high proportion of deaths from IDC is the difficulty in establishing the underlying cause of death in the elderly. This is probably due to the presence of multiple diseases in the elderly and the influence of age on the clinical expression of signs and symptoms for the correct diagnosis of the underlying cause of death11. In this sense, the data obtained in the first five years for the analysis carried out on deaths from IDC in the elderly corroborate the above statements, as they show statistically significant results (p < 0.05). Arq Bras Cardiol. 2015; 105(4):371-380 376 Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Figure 3 – Moran Map (significant) of spatial autocorrelation of the variable mean mortality rate from cardiovascular disease by gender, per thousand individuals for each state in Brazil, in the periods 1996-2000, and 2006 to 2010. Natal (RN), Brazil, 2015. CVD: cardiovascular disease; Source: Department of Informatics of the Unified Health System (DATASUS) / Ministry of Health, 2015. One question to be assessed is the increased prevalence of CVD in the North and Northeast states during the study period. This fact was possibly related to the information production qualification, both regarding the collection and sending of data to the health management central level. Studies have shown that over the past three decades, advances in health information systems used in Brazil were supported by the development of computer technology and the training of Health Secretariat employees12,13. The mortality information is compiled from SIM of the Ministry of Health, which was designed in 1975 and initially covered only some Brazilian states, which already held the collection of this information12. Another milestone related to the development of the mentioned information system was the creation of the current design of the DO, along the development of a new computerized application, which was first used in 199914. The information on mortality is obtained from the SIM of the Ministry of Health, designed in 1975 and that initially covered only a few Brazilian states, which already performed this information collection12. Another milestone related to 377 Arq Bras Cardiol. 2015; 105(4):371-380 the development of the aforementioned information system was the creation of the current design of the DC, along with the development of a new computer application, which was first used in 199914. In 2004, the Health Surveillance Secretariat of the Ministry of Health included the program Percentage Reduction of Death from Ill-defined Causes in the Multi‑Year Plan 2004-2008 and the "Investigation of the cause of death” form was standardized. This program included the data provided by medical or health professionals, or those obtained from medical records and the results of additional tests, to also ensure a more accurate recording of information on the causes of death15. In addition to this investigation, in March 2008, the Ministry of Health launched a project to implement the verbal autopsy in the country as a method to investigate deaths from IDC, so that its analysis would allow the physician to identify the sequence of events that led to the death. Several international studies using verbal autopsy methodology also observed changes in the structure of causes of death, decrease in IDC and identification of external Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Figure 4 – Moran Map (significant) of spatial autocorrelation of the mean mortality rate from ill-defined causes (IDC) by gender, per thousand individuals for each state in Brazil, in the periods 1996-2000, and 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics of the Unified Health System (DATASUS) / Ministry of Health, 2015. causes, with the most frequent diseases being allocated in the chapter of circulatory diseases and external causes - results that are similar to those observed in this study16. This phenomenon is called the "paradox of information", which is characterized by the relocation of deaths from IDC to other chapters of ICD-10. That is, the variation in the proportion of death notifications from IDC can modify the temporal series of mortality rates for certain groups of causes17. In this regard, the absolute increase in the number of deaths from diseases of the circulatory system is closely associated to the decrease in notifications originating from Chapter XVIII. Another factor to be considered is the significant increase in mortality from CVD among the elderly in the North and Northeast states of the country, a trend less intense in the South, Southeast and Midwest regions, where the increases were discreet. Such regional variation is influenced by the fact that primary and secondary prevention would be more appropriate in more developed regions, with better control of risk factors for CVD, such as smoking, dyslipidemia, diabetes and systemic hypertension9. In a study carried out between 2000 and 2009 in Brazil, it was clear that the coverage provided by the family health strategy was associated with a reduction in MRCD (acute myocardial infarction and CVA). However, it is noteworthy that this study evaluated 1,662 of the 5,507 Brazilian municipalities and used as an exclusion criterion the municipalities with high mortality rates from IDC. Therefore, their results are valid for municipalities where the quality of information is better18,19. Another relevant aspect is related to the distribution of medical professionals registered in the Regional Councils of Medicine in their physician per thousand inhabitant ratio. In this regard, the North and Northeast regions have the lowest proportions, 0.98% and 1.19%, respectively, below the national average, which is 1.95%20. That is, the North and Northeast regions have higher limitation regarding health services provided to the population, a fact that also corroborates the increase in MRCD in the study. Regarding the aspects related to the epidemiological transition, it is possible to estimate that, in general, it occurs together with socioeconomic transformations and, therefore, it shows major demographic differences 21. Arq Bras Cardiol. 2015; 105(4):371-380 378 Piuvezam et al. Mortality from Cardiovascular Diseases in the Elderly Original Article Hence, the majority of published studies provide evidence of the association between social inequalities and morbimortality. Brazil is the tenth most unequal country in the world in terms of income distribution; even though changes in the economy have resulted in improvements in this regard, they do not seem to have been able to reduce mortality inequalities. Hence, important differences persist in the distribution of morbidity and mortality, both between different Brazilian states and within the same state22. It is worth mentioning that this study has as limiting factor the use of data collected by a Federation state, which can conceal the heterogeneous distribution of deaths and, therefore, mask relevant intrastate differences. Furthermore, the use of secondary data record is subject to several data recording errors and underreporting. Another limitation is due to the "ecological fallacy" in which, due to the effects of data aggregation and scale, the results found for a population cannot be repeated at the individual level. In this study, the mortality analysis was based only on the cause of death and there was no analysis of multiple causes; thus, there may be an underestimation of cardiovascular mortality, especially among the elderly, which may have several comorbidities. Conclusion Based on the analyses, it was observed that the proportion of mortality from circulatory system diseases in the elderly, in the 2006-2010 period, decreased significantly in the South, Southeast and Midwest states, and showed a considerable increase in the North and Northeast regions. These results are consistent with geographical clusters obtained in the aforementioned period, during which spatial autocorrelation was observed between the states of Rio Grande do Norte, Ceará, Pernambuco and Roraima. These findings can be explained by the information qualification, reallocation of deaths from ill-defined causes and improved health care. Added to these, other issues were also evaluated, such as changes in the socioeconomic situation of the country, mainly regarding the phase of epidemiological transition in which Brazil currently is, with decreased morbidity and mortality from infectious and parasitic diseases, and increase in the number of deaths due to chronic non-communicable diseases and external injuries. Effective planning of health promotion actions originates from the knowledge of a population’s health status, based on mortality statistics. The quality of information on the causes of death is, therefore, essential. The search for a better understanding of the spatial and temporal distribution of these rates is critical for the planning of evidence-based sustainable public policies. Therefore, the study may contribute to better control and prevention of cardiovascular disease, as it supports the achievement of more targeted actions for the different regions of the country, thus aiming to reduce health inequalities. The study was carried out with the authors’ own resources and also received a scientific initiation research grant (PIBIC) from Pró-Reitoria de Pesquisa da Universidade Federal do Rio Grande do Norte (PROPESQ-UFRN). Author contributions Conception and design of the research and Critical revision of the manuscript for intellectual content: Piuvezam G, Medeiros WR; Acquisition of data, Analysis and interpretation of the data and Statistical analysis: Costa AV, Emerenciano FF, Seabra DS; Obtaining financing: Piuvezam G; Writing of the manuscript: Piuvezam G, Medeiros WR, Costa AV, Emerenciano FF, Seabra DS. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding This study was partially funded by Bolsa de pesquisa de Iniciação Científica (PIBIC) da Pró-reitoria de Pesquisa da Universidade Federal do Rio Grande do Norte (PROPESQ-UFRN). Study Association This study is not associated with any thesis or dissertation work. References 1. Malta DC, Cezario AC, Moura L. A construção da vigilância e prevenção das doenças crônicas não transmissíveis no contexto do Sistema Único de Saúde. Epidemiol Serv Saúde. 2006;15(3):47-65. 5. Mansur AP, Favarato D. Mortalidade por doenças cardiovasculares no Brasil e na região metropolitana de São Paulo: atualização 2011. Arq Bras Cardiol. 2012;99(2):755-61. 2. Schmidt MI, Duncan BB, Azevedo e Silva G, Menezes AM, Monteiro CA, Barreto SM, et al. Chronic non-communicable diseases in Brazil: burden and current challenges. Lancet. 2011;377(9781):1949-61. 6. Brasil. Senado Federal. Lei nº 10.741 de 1 de outubro de 2003. Dispõe sobre o Estatuto do Idoso e dá outras providências. Brasília; 2003. 3. 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Uso da autópsia verbal na investigação de óbitos com causa mal definida em Minas Gerais, Brasil. Cad Saúde Pública. 2010;26(6):1221-33. 17. Teixeira CL, Klein CH, Bloch KV, Coeli CM. Reclassificação dos grupos de causas prováveis dos óbitos de causas mal definidas, com base nas Autorizações de Internação Hospitalar no Sistema Único de Saúde, Estado do Rio de Janeiro, Brasil. Cad Saúde Pública. 2006;22(6):1315‑24. 18. Rasella D, Harhay MO, Pamponet ML, Aquino R, Barreto ML. Impact of primary health care on mortality from heart and cerebrovascular diseases in Brazil: a nationwide analysis of longitudinal data. BMJ. 2014;349:g4014. 19. Rasella D, Aquino R, Barreto Ml. Impact of the Family Health Program on the quality of vital information and reduction of child unattended deaths in Brazil: an ecological longitudinal study. BMC Public Health. 2010;10:380. 20. São Paulo. Conselho Regional de Medicina do Estado de São Paulo (CREMESP). Conselho Federal de Medicina. Demografia médica no Brasil: dados gerais e descrições de desigualdades. São Paulo; 2011. 21. Schramm JM, Oliveira AF, Leite IC, Valente JG, Gadelha AM, Portela MC, et al. Transição epidemiológica e o estudo de carga de doença no Brasil. Ciênc Saúde Colet. 2004;9(4):897-908. 22. Cruz AS, Vieira-da-Silva SM, Costa MC, Paim JS. Evolution of inequalities in mortality in Salvador, Bahia State, Brazil, 1991/2006. Cad Saúde Pública. 2011; 27 (2):S176-84. Arq Bras Cardiol. 2015; 105(4):371-380 380 Back to the Cover Original Article Sex-Specific Equations to Estimate Maximum Oxygen Uptake in Cycle Ergometry Christina G. de Souza e Silva e Claudio Gil S. Araújo Programa de Pós-Graduação em Cardiologia - Universidade Federal do Rio de Janeiro; Instituto do Coração Edson Saad - Universidade Federal do Rio de Janeiro; Clínica de Medicina do Exercício - CLINIMEX, Rio de Janeiro, RJ – Brazil Abstract Background: Aerobic fitness, assessed by measuring VO2max in maximum cardiopulmonary exercise testing (CPX) or by estimating VO2max through the use of equations in exercise testing, is a predictor of mortality. However, the error resulting from this estimate in a given individual can be high, affecting clinical decisions. Objective: To determine the error of estimate of VO2max in cycle ergometry in a population attending clinical exercise testing laboratories, and to propose sex-specific equations to minimize that error. Methods: This study assessed 1715 adults (18 to 91 years, 68% men) undertaking maximum CPX in a lower limbs cycle ergometer (LLCE) with ramp protocol. The percentage error (E%) between measured VO2max and that estimated from the modified ACSM equation (Lang et al. MSSE, 1992) was calculated. Then, estimation equations were developed: 1) for all the population tested (C-GENERAL); and 2) separately by sex (C-MEN and C-WOMEN). Results: Measured VO2max was higher in men than in WOMEN: -29.4 ± 10.5 and 24.2 ± 9.2 mL.(kg.min)-1 (p < 0.01). The equations for estimating VO2max [in mL.(kg.min)-1] were: C-GENERAL = [final workload (W)/body weight (kg)] x 10.483 + 7; C-MEN = [final workload (W)/body weight (kg)] x 10.791 + 7; and C-WOMEN = [final workload (W)/body weight (kg)] x 9.820 + 7. The E% for MEN was: -3.4 ± 13.4% (modified ACSM); 1.2 ± 13.2% (C-GENERAL); and -0.9 ± 13.4% (C-MEN) (p < 0.01). For WOMEN: -14.7 ± 17.4% (modified ACSM); -6.3 ± 16.5% (C-GENERAL); and -1.7 ± 16.2% (C-WOMEN) (p < 0.01). Conclusion: The error of estimate of VO2max by use of sex-specific equations was reduced, but not eliminated, in exercise tests on LLCE. (Arq Bras Cardiol. 2015; 105(4):381-389) Keywords: Breathing Exercise / utilization; Physical Exertion; Oxygen Consumption; Cardiopulmonary Exercise Testing; Demographic Data; Ergometry. Introduction Aerobic fitness is an independent predictor of mortality1-3 and provides relevant diagnostic and prognostic information4-8. It is non-invasively assessed by measuring maximum oxygen uptake (VO2max) during exercise testing, in which expired gases are collected and analyzed. This procedure is called maximum cardiopulmonary exercise testing (CPX)9,10. Although available at several clinical exercise testing laboratories, VO2max measurement requires professional training11 and specific equipment, and increases the time for test performance, hindering the wider use of CPX. When CPX cannot be performed, VO 2max can be estimated by use of equations based on duration12 or intensity Mailing Address: Claudio Gil Soares de Araújo • Clínica de Medicina do Exercício – CLINIMEX. Rua Siqueira Campos, 93/101, Copacabana. Postal Code 22071-030, Rio de Janeiro, RJ – Brazil E-mail: [email protected], [email protected] Manuscript received January 29, 2015; revised manuscript May 04, 2015; accepted May 06, 2015. DOI: 10.5935/abc.20150089 381 at peak exertion13,14. By applying these equations to groups of individuals, the association between estimated and measured VO2max values tends to be good. However, the margin of error of estimate (EE) for a given subject can be large, greater than 15%15. Errors of such magnitude are rarely accepted in other biological variables, and exceed those observed in laboratory tests or in clinical and anthropometric measurements (height and weight). Considering that small variations in VO2max can lead to important differences in clinical management or sports training guidance16, such errors can be challenging, requiring some effort to minimize them. Theoretically, the mechanical efficiency in performing a certain motor gesture is expressed by the ratio between the work generated and the oxygen consumed in its performance17. That efficiency varies between individuals and depends on age, sex, clinical condition and physical fitness. Most equations available for estimating VO2max, however, do not consider those possible relationships, which might contribute to errors in VO 2max estimate. For example, considering anthropometric, physiological and biomechanical differences, as well as sports performance, the influence of sex on the EE of VO2max is worth assessing. The objectives of this study were: a) to determine the EE of VO2max in cycle ergometry for a population undergoing de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article CPX at a clinical exercise testing laboratory; and b) to propose sex-specific equations aimed at reducing the EE of aerobic capacity in cycle ergometry. Body weight was measured with a Cardiomed scale, Welmy model, with 0.1-kg resolution. Height was measured with a Sanny stadiometer with 0.1-cm resolution. Methods Maximum cardiopulmonary exercise testing Sample This study reviewed data of patients voluntarily submitted to CPX between January 2008 and June 2014 at a private clinical exercise testing laboratory. Patients simultaneously meeting the following inclusion criteria were selected: a) no previous assessment at the private clinical exercise testing laboratory; b) age ≥ 18 years; and c) maximum CPX performed on a lower limbs cycle ergometer (LLCE) (Inbrasport CG-04, Inbrasport, Brazil). During that period, 3874 assessments were performed and, after applying the inclusion criteria, 1715 individuals (1172 men) were included (Figure 1). In addition, 200 individuals subsequently undergoing CPX and meeting the inclusion criteria were used to validate the equations developed. Ethical considerations All patients provided written informed consent before undergoing CPX. The retrospective analysis of data was approved by the Committee on Ethics and Research of the institution. Clinical assessment and body weight and height measurements Before performing CPX, clinical history was taken, with emphasis on regularly used medications and cardiovascular risk factors, and physical examination was undertaken. Body weight and height of all individuals were measured. The prescribed medications were not suspended before CPX. The CPX was conducted in a specific room, with temperature ranging from 21°C to 24°C, and relative air humidity between 40% and 60%. The test was performed according to an individualized ramp protocol, aimed at 8-12-minute duration, on an LLCE, according to the Brazilian Society of Cardiology guidelines18, in the presence of a qualified physician, at a laboratory properly equipped to manage occasional clinical events. Only four physicians performed all the tests, following a routine of well-defined procedures, especially regarding the stimulus to reach truly maximum exertion. The height of the saddle was individually adjusted to provide both an almost complete knee extension at the lowest pedal position, and a lower‑hip 90-degree flexion at the highest pedal position. The pedaling frequency was kept between 65 and 75 rotations per minute. During CPX, the individuals were monitored with a digital electrocardiograph (ErgoPC Elite, versions 3.2.1.5 or 3.3.4.3 or 3.3.6.2, Micromed, Brazil), and heart rate (HR) was measured on the ECG recording (leads CC5 or CM5) at the end of each minute. Expired gases were collected by use of a Prevent pneumotacograph (MedGraphics, USA) coupled to a mouthpiece, with concomitant nasal occlusion. The expired gases were measured and analyzed by using a VO2000 metabolic analyzer (MedGraphics, USA), daily calibrated before the first assessment and whenever necessary. The mean results of the expired gases were read every 10 seconds, and consolidated at every minute. The highest VO2 value obtained at a certain point of the CPX was considered the VO2max. Blood pressure was measured every minute on the right arm by using a manual sphygmomanometer. Figure 1 – Flowchart of study sample selection. Arq Bras Cardiol. 2015; 105(4):381-389 382 de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article The maximum intensity of the exercise, which is more easily assessed by using CPX – presence of anaerobic threshold and U-pattern curves of ventilatory equivalents -, was confirmed by maximum voluntary exhaustion (score 10 in the Borg scale ranging from 0 to 1019) represented by the incapacity to continue pedaling at the previously established frequency despite strong verbal encouragement. As already reported in a previous study20, the characterization of CPX as maximum was also confirmed by the impression of the physician in charge, and recorded on the CPX description. It is worth noting that CPX was neither interrupted nor considered maximum based exclusively on HR. Equations to predict VO2max and maximum HR The predicted values of VO2max for each patient, as a mere reference for comparison with the actually measured VO2max values, were obtained based on specific equations for men [60 – 0.55 x age (years)] and women [48 – 0.37 x age (years)]21. The predicted values of maximum HR were obtained from the equation 208 – 0.7 x age22, for patients of both sexes. Equations to estimate VO2max To assess the EE of VO2max, VO2max was initially estimated based on the modified American College of Sports Medicine (ACSM) equation14, in which VO2max is adjusted for body weight [mL.(kg.min)-1] as follows: (W x 11.4 + 260 + body weight x 3.5)/weight. In that equation, W is the maximum workload in watts, body weight is expressed in kg, and the constant 260 mL.min-1 represents the oxygen volume in mL and corresponds to the necessary energetic expenditure to pedal without any additional resistance [approximately 3.5 mL.(kg.min)-1 x mean body weight of the individuals studied by Lang et al.]14. In addition, the last term in that equation corresponds to the energetic expenditure at rest. Following that line of thought, and in accordance with that adopted by the ACSM23, in our study, we subtracted 7 mL.(kg .min) -1 from the VO 2 max value measured [corresponding to 3.5 mL.(kg.min) -1 of VO2 at rest and 3.5 mL.(kg.min)-1 of VO2 expended to pedal without any load]. The result obtained was divided by the ratio between workloads (watts) and body weight (kg), originating the constant “k” for each participant. From the mean value of the constant “k”, we obtained the multiplying factor values of the workloads (watts)/body weight (kg) ratio for the equations for the general sample, men and women, respectively: a) general equation to estimate VO2max (equation C-GENERAL); b) specific equation to estimate VO2max in the male sex (equation C-MEN); and c) specific equation to estimate VO2max in the female sex (equation C-WOMEN). Error of estimate of VO2max The magnitude of the EE of VO 2max expressed as a function of body weight was assessed based on the calculation of: 1) the difference between the measured and estimated values: (measured VO2max – estimated VO2max) in mL.(kg.min)-1; and the percentage error (E%): [(measured VO2max - estimated VO2max)/measured VO2max] x 100. 383 Arq Bras Cardiol. 2015; 105(4):381-389 The measured VO2max was obtained by collecting and analyzing expired gases, as previously detailed. A negative EE or E% value thus means that the estimated VO2max was higher than the measured VO2max, that is, the value calculated by using the equation overestimated the value measured. Statistical analysis The results were expressed as mean and standard deviation or as percentage, depending on the nature of the variable. The demographic characteristics and CPX results were compared between men and women by using non-paired t test or chi-square test. The ER and E% of the equations, when appropriate, were compared by using paired t test or ANOVA, when the comparison was performed between three or more groups. The measured VO2max value and that estimated based on the three equations of the study – C-GENERAL, C-MEN and C-WOMEN – were compared and analyzed by using linear regression and intraclass correlation. The statistical analyses were performed with the programs Prism 6 (GraphPad, USA) and SPSS 16 (SPSS, USA), adopting 5% as the significance level. Results Demographic and clinical characteristics of the sample The sample was mostly formed by men (68.3%), with age ranging from 18 to 91 years, and 23.2% had a body mass index (BMI) ≥ 30 kg.m-2. Tables 1 and 2 show other demographic and clinical data, as well as the prevalence of some risk factors for coronary artery disease, major morbidities and medications regularly used. CPX data The mean duration of CPX was 10 ± 2 minutes. The mean maximum HR for the set of individuals was 159 ± 25 bpm, corresponding to 92% of that predicted, being higher in patients not on beta-blockers (166 ± 20 bpm) (p < 0.01). Men achieved final workloads higher than women (172 ± 70 vs 111 ± 45 watts; p < 0.01), as well as greater VO2max values [29.4 ± 10.5 vs 24.2 ± 9.2 mL.(kg.min)-1; p < 0.01]. In the sample studied, the measured VO2max tended to be slightly lower than that predicted based on age and sex, corresponding to 96% and 82% of the value predicted by using the equations of Jones et al.21 for men and women, respectively. Table 3 shows the major CPX results. Estimated VO2max values Regarding estimated VO2max, the values obtained by using the modified ACSM equation were 29.8 ± 9.8 and 26.9 ± 8.9 mL.(kg.min)-1 for men and women, respectively, showing that the equation tends to overestimate VO2max. Both ER and E% differed between sexes (p < 0.01), with values of -0.4 ± 3.2 mL.(kg.min)-1 and -3.4 ± 13.4% for men, and -2.7 ± 3.5 mL.(kg.min)-1 and -14.7 ± 17.4% for women, respectively. de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article Table 1 – Major demographic and morphofunctional characteristics of the sample (n = 1715)* Demographic characteristics Men 1172 (68.3%) Women 543 (31.7%) Age (years) 53 ± 15 51 ± 15 BMI (kg.m-2) 27.9 ± 4.2 25.3 ± 4.9 Weight (kg) 85.9 ± 14.8 66.9 ± 12.8 Height (cm) 175.3 ± 6.9 162.6 ± 6.5 Predicted VO2max [mL.(kg.min) )] -1 Predicted maximum HR (bpm) 30.7 ± 8.1 29.3 ± 5.5 170.7 ± 10.3 172.6 ± 10.5 BMI: Body mass index; HR: Heart rate. *Values expressed as mean ± standard deviation. Table 2 – Major clinical characteristics of the sample and regularly used medications (n = 1715)* Men (n = 1172) Women (n = 543) Morbidities Systemic arterial hypertension 428 (36.5%) 114 (21.0%) Dyslipidemia 496 (42.6%) 140 (25.8%) Obesity 193 (16.5%) 61 (11.2%) Diabetes mellitus 113 (9.6%) 29 (5.3%) Coronary artery disease 249 (21.2%) 39 (7.2%) Acute myocardial infarction 125 (10.7%) 18 (3.3%) Myocardial revascularization 96 (8.2%) 10 (1.8%) 302 (25.8%) 91 (16.8%) Calcium channel blocker 109 (9.3%) 37 (6.8%) ACEI 125 (10.7%) 19 (3.5%) ARB 340 (29.0%) 113 (20.8%) Diuretic 186 (15.9%) 68 (12.5%) Use of medications Beta-blocker Vasodilator 82 (7.0%) 14 (2.6%) Lipid-lowering 531 (45.3%) 151 (27.8%) Antiplatelet 387 (33.0%) 82 (15.1%) 71 (6.1%) 25 (4.6%) Antiarrhythmic ARB: Angiotensin-receptor blocker; ACEI: Angiotensin-converting-enzyme inhibitor. * Values expressed as N(%). Table 3 – Major results of cardiopulmonary exercise test (n = 1715)* Variable Duration (min) Maximum HR (bpm) Men (n = 1172) Women (n = 543) 10 ± 2 9±3 158 ± 26 161 ± 24 - with beta-blocker 135 ± 25 133 ± 24 - without beta-blocker 166 ± 21 167 ± 20 172 ± 70 111 ± 45 29.4 ± 10.5 24.2 ± 9.2 Maximum workload (watts) Measured VO2max [mL.(kg.min) )] -1 HR: Heart rate. *Values expressed as mean ± standard deviation. Arq Bras Cardiol. 2015; 105(4):381-389 384 de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article C-GENERAL equation Determining the specific equation for the sample studied, with no distinction between sexes and with the same variables of the modified ACSM equation, the following C-GENERAL equation was obtained: (final workload/body weight x 10.483 + 7, where 7, as previously explained, corresponds to a simplification of the last two terms of that equation [the addition of oxygen uptake at rest (3.5 mL.(kg.min)-1 and an identical oxygen uptake value to pedal with no resistance]. Applying the C-GENERAL equation, the estimated VO2max values obtained were 28.3 ± 8.9 mL.(kg.min)-1 and 24.9 ± 7.9 mL.(kg .min) -1 for men and women, respectively. Although EE and E% values remained similar in men [1.1 ± 3.3 mL.(kg .min) -1 and 1.2 ± 13.2%, respectively], a significant reduction in the EE of VO2max was observed in women [-0.7 ± 3.5 mL.(kg.min)-1], and E% was -6.3 ± 16.5% (p < 0.01). C-MEN and C-WOMEN equations Then the following sex-specific equations, C-MEN and C-WOMEN were obtained: (final workload/body weight) x 10.791 + 7 and (final workload/body weight) x 9.820 + 7, respectively. Using these equations, the estimated VO2max values were 28.9 ± 9.2 mL.(kg.min)-1 and 23.7 ± 7.4 mL.(kg.min)-1 for men and women, respectively. Errors of estimate were reduced in both sexes, but more expressively for women. For men, EE and E% were 0.5 ± 3.2 mL.(kg.min)-1 and -0.9 ± 13.4% (p < 0.01), respectively, while for women, they were reduced to 0.5 ± 3.6 mL.(kg.min)-1 and only -1.7 ± 16.2% (p < 0.01), respectively (Figure 2). Figure 3 shows the standard EE and the association between the estimated and measured VO2max values for the general sample and for men and women, analyzed separately. It is worth noting the high intraclass correlation coefficients, with their respective confidence intervals (CI) obtained: C-GENERAL, 0.9703 (95%CI: 0.9674 - 0.9730); C-MEN, 0.9725 (95%CI: 0.9691 - 0.9755), and C-WOMEN, 0.9680 (95%CI: 0.9621 - 0.9729). The visual inspection of the distributions allowed characterizing the linear regressions as homoscedastic. Based on the application of the equations developed in the present study, the following EE and E% were obtained in the validation sample: C-GENERAL (n = 200) 0.5 ± 2.5 mL.(kg.min)-1 and 0.7 ± 9.1%; C-MEN (n = 135) 0.5 ± 2.5 mL.(kg.min)-1 and 1.0 ± 8.6%; and C-WOMEN (n = 65) 0.5 ± 2.0 mL.(kg.min)-1 and 0.5 ± 8.5%, respectively. Discussion The CPX is the most appropriate test to assess aerobic capacity. However, the use of the exercise test with neither collection nor analysis of expired gases is very common among us, even though accompanied by a significant margin of error15. Therefore, it is important to develop specific equations to reduce that EE in exercise tests performed at hospitals and clinics. Although previous studies with that same objective have been conducted24-27, the use of small samples hinders the extrapolation of the results found. For example, Lang et al.14 and Latin et al.28 have used the ACSM equation to estimate VO2max13 for 60 men and 60 women, respectively, and have Figure 2 – Percentage errors obtained from the comparison between measured VO2max and estimated VO2max by using the modified ACSM equations, and the C-GENERAL, C-MEN e C-WOMEN equations. 385 Arq Bras Cardiol. 2015; 105(4):381-389 de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article Figure 3 – Correlation between measured VO2max values and those estimated by using the equations: a) C-GENERAL, b) C-MEN and c) C-WOMEN. SEE: Standard error of estimate; ric: Intraclass correlation coefficient. Arq Bras Cardiol. 2015; 105(4):381-389 386 de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article found lower estimated VO2max values than the measured ones, for both sexes. On the other hand, Greiwe et al.29, applying that same equation to 15 men and 15 women with similar clinical profiles, have obtained overestimated VO2max values. In addition, the introduction by Lang et al. 14 of the factor 260 mL.min -1, which corresponds to the energetic expenditure of pedaling without additional resistance, has produced estimated results more similar to measured VO 2 max results in their sample. In our study, however, the use of that modified ACSM equation maintained significant errors in the comparison between estimated and measured values. The discrepancy in the results described suggests significant errors when the equations are developed based on small samples. In addition, the difference in EE between men and women using the same equation suggests that sex‑specific equations should be developed. Storer et al. 30 have developed three equations of to estimate VO2max using the variables workload, body weight and age: one general for both sexes; one specific for men; and one specific for women. Those authors have reported a significant increase in the coefficient of determination when the variable ‘sex’ was added to the linear regression model used to create the equations. However, when applied to 77 men and 30 women of the Brazilian population31, a trend to overestimate VO2max was observed in men, evidencing the need to develop specific equations for each population. Recently, Almeida et al. have conducted an important study with a large sample of Brazilians (3119 individuals), aimed at developing an equation to predict VO2max for treadmill exercise tests, based on age, sex, BMI and physical activity level. However, it is worth noting that, despite the importance of having VO2max reference data from equations developed for the Brazilian population, this does not contemplate the EE of VO2max when expired gases are not collected and analyzed during exercise testing. While the predicted VO2max is obtained based on pre‑test clinical variables, such as age and sex, the estimated VO2max is calculated based on variables obtained during exercise testing, such as workload and test duration. To the best of our knowledge, there is no study on the Brazilian population with a large sample (more than 1000 cases) developing specific equations to estimate VO 2max in exercise tests performed on a LLCE. 32 In reality, sample size and representability are extremely relevant. Neder et al. 33 have observed that individuals typically selected to participate in studies did not represent those most commonly referred for exercise testing, which could lead to selection biases. Thus, in our study, we chose not to exclude obese patients, individuals with cardiovascular or pulmonary diseases and/or individuals on regular use of medications that could influence the physiological responses to exercise, to guarantee a sample representing the individuals most commonly referred to clinical exercise testing laboratories. It is worth noting that despite that varied clinical profile, the VO2max predicted for age was relatively close to that actually measured, especially 387 Arq Bras Cardiol. 2015; 105(4):381-389 in men. Comparing the data obtained in our study with those reported by Herdy and Uhlendorf34 in the Brazilian Southern region, the VO2max values measured in men were similar to the reference values for sedentary individuals aged 55 to 64 years [30.0 ± 6.3 mL.(kg.min)-1] or active individuals aged 65 to 74 years [30.0 ± 6.1 mL.(kg.min)-1]. The VO 2max values found for women were similar to the reference values of sedentary individuals aged 55 to 64 years [23.9 ± 4.2 mL.(kg.min)-1]34. The most probable reason for that slight discrepancy is due to the fact that the study by Herdy and Uhlendorf34 used CPX on a treadmill, which might explain the tendency towards higher values for the same age group. The strong points of our study are as follows: 1) to our knowledge, no other Brazilian study assessing equations for VO2max estimation was based on such a large number of individuals (over 1000); 2) the cycle ergometers and gas analyzers were periodically calibrated according to the specifications of their manufacturers; and 3) all original information of test reports was available in the digital format (data bank) and carefully reviewed to exclude those incomplete. This study has limitations. All tests were performed following the ramp protocol. Thus, one cannot know if the equations for VO2max estimate here presented can be applied to exercise tests performed following other protocols. Other factors, such as age, adiposity level, recent pattern or history of regular physical training, and use of certain medications, might contribute to the EE by influencing mechanical efficiency. This was a preliminary study to assess the influence of sex on the EE of VO2max. Other variables are being assessed, as already reported. Subsequent statistical analyses, such as multivariate regression, using the variables that evidenced influence on EE of VO2max can lead to the development of one single equation for VO2max estimate capable of effectively reducing EE. Briefly, the present study contributed to current knowledge by proposing equations derived from a large sample of Brazilian adults, with clinical characteristics and profiles similar to those usually observed at clinical exercise testing laboratories. The equations are specific to the male and female sexes, thus contributing to reduce EE when VO2max measurement is not available. Conclusion Our study identified that the use of foreign equations (modified ACSM) induced an important EE when applied to a typical population of clinical exercise testing laboratories in Brazil. Thus, an equation was developed – C-GENERAL –, partially reducing EE. However, an analysis separated by sex identified the need to develop specific equations – C-MEN and C-WOMEN – that could further reduce, but not eliminate, EE. Thus, more accurate alternatives to VO2max estimate in exercise tests of lower limbs are presented to places with no condition to effectively perform CPX to measure VO2max. de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article Author contributions Sources of Funding Conception and design of the research, Analysis and interpretation of the data, Statistical analysis, Writing of the manuscript and Critical revision of the manuscript for intellectual content: de Souza e Silva CG, Araújo CGS; Acquisition of data: Araújo CGS. This study was partially funded by CNPq and FAPERJ. Potential Conflict of Interest Study Association This article is part of the MSc thesis submitted by Christina G. de Souza e Silva, from Instituto do Coração Edson Saad Universidade Federal do Rio de Janeiro. No potential conflict of interest relevant to this article was reported. References 1. Barry VW, Baruth M, Beets MW, Durstine JL, Liu J, Blair SN. 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Eur Heart J. 2012;33(23):2917-27. 12. Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J. 1973;85(4):546-62. 13. American College of Sports Medicine. (ACSM). Guidelines for graded exercise testing and training. 3rd ed. Philadelphia: Lea & Febiger; 1986. p. 162-3. 25. Grant S, Corbett K, Amjad AM, Wilson J, Aitchison T. A comparison of methods of predicting maximum oxygen uptake. Br J Sports Med. 1995;29(3):147-52. 26. Harrison MH, Bruce DL, Brown GA, Cochrane LA. A comparison of some indirect methods for predicting maximal oxygen uptake. Aviat Space Environ Med. 1980;51(10):1128-33. 27. Peterson MJ, Pieper CF, Morey MC. Accuracy of VO2(max) prediction equations in older adults. Med Sci Sports Exerc. 2003;35(1):145-9. 28. Latin RW, Berg KE. The accuracy of the ACSM and a new cycle ergometry equation for young women. Med Sci Sports Exerc. 1994;26(5):642-6. 29. Greiwe JS, Kaminsky LA, Whaley MH, Dwyer GB. Evaluation of the ACSM submaximal ergometer test for estimating VO2max. Med Sci Sports Exerc. 1995;27(9):1315-20. Arq Bras Cardiol. 2015; 105(4):381-389 388 de Souza e Silva and Araújo Estimation of VO2max in cycle ergometry Original Article 30. Storer TW, Davis JA, Caiozzo VJ. Accurate prediction of VO2max in cycle ergometry. Med Sci Sports Exerc. 1990;22(5):704-12. 31. Magrani P, Pompeu FA. Equations for predicting aerobic power (VO2) of young Brazilian adults. Arq Bras Cardiol. 2010;94(6):763-70. 32. Almeida AE, Stefani CM, Nascimento JA, Almeida NM, Santos AC, Ribeiro JP, et al. An equation for the prediction of oxygen consumption in a Brazilian population. Arq Bras Cardiol. 2014;103(4):299-307. 389 Arq Bras Cardiol. 2015; 105(4):381-389 33. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs A, et al. Prediction of metabolic and cardiopulmonary responses to maximum cycle ergometry: a randomised study. Eur Respir J. 1999;14(6):1304-13. 34. Herdy AH, Uhlendorf D. Reference values for cardiopulmonary exercise testing for sedentary and active men and women. Arq Bras Cardiol. 2011;96(1):54-9. Back to the Cover Original Article A Novel Algorithm to Quantify Coronary Remodeling Using Inferred Normal Dimensions Breno A. A. Falcão1, João Luiz A. A. Falcão1, Gustavo R. Morais1, Rafael C. Silva1, Augusto C. Lopes2, Paulo R. Soares1, José Mariani Jr1, Roberto Kalil-Filho1, Elazer R. Edelman2,3, Pedro A. Lemos1 Departamento de Cardiologia Intervencionista, Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo1, São Paulo, SP - Brazil; Institute of Medical Engineering and Science, Massachusetts Institute of Technology2, Cambridge; Divisão Cardiovascular, Departamento de Medicina, Brigham and Womens Hospital, Harvard Medical School3, Boston, MA - USA Abstract Background: Vascular remodeling, the dynamic dimensional change in face of stress, can assume different directions as well as magnitudes in atherosclerotic disease. Classical measurements rely on reference to segments at a distance, risking inappropriate comparison between dislike vessel portions. Objective: to explore a new method for quantifying vessel remodeling, based on the comparison between a given target segment and its inferred normal dimensions. Methods: Geometric parameters and plaque composition were determined in 67 patients using three-vessel intravascular ultrasound with virtual histology (IVUS-VH). Coronary vessel remodeling at cross-section (n = 27.639) and lesion (n = 618) levels was assessed using classical metrics and a novel analytic algorithm based on the fractional vessel remodeling index (FVRI), which quantifies the total change in arterial wall dimensions related to the estimated normal dimension of the vessel. A prediction model was built to estimate the normal dimension of the vessel for calculation of FVRI. Results: According to the new algorithm, “Ectatic” remodeling pattern was least common, “Complete compensatory” remodeling was present in approximately half of the instances, and “Negative” and “Incomplete compensatory” remodeling types were detected in the remaining. Compared to a traditional diagnostic scheme, FVRI-based classification seemed to better discriminate plaque composition by IVUS-VH. Conclusions: Quantitative assessment of coronary remodeling using target segment dimensions offers a promising approach to evaluate the vessel response to plaque growth/regression. (Arq Bras Cardiol. 2015; 105(4):390-398) Keywords: Coronary Artery Diseases; Vascular Remodeling; Atherosclerosis / physiopathology; Neovascularization, Pathologic; Ultrasonography. Introduction Coronary artery remodeling, the geometric change in artery dimensions, evolves with the ebb and flow of the atherosclerotic process. Arterial remodeling encompasses a wide spectrum of presentations, ranging from expansive to constrictive remodeling 1,2. In the former, coronary vessel dimensions increase as plaque accumulates, while in the latter there is relative contraction of the vessel wall and impingement on the lumen. There might be a limit to expansive effects, which eventually stabilize or decompensate to luminal encroachment1. It is therefore evident that the pattern and extent of arterial remodeling Mailing Address: Breno de Alencar Araripe Falcão • Rua Oscar Freire, 1753 Apt. 41b, Pinheiros. Postal Code 05409-011, São Paulo, SP – Brazil E-mail: [email protected]; [email protected] Manuscript received January 17, 2014; revised manuscript April 10, 2015; accepted April 13, 2015. DOI: 10.5935/abc.20150098 390 play an important role in ultimately determining the effect of the atherosclerotic disease on luminal dimensions3-5. Several methods have been described to characterize and quantify vessel remodeling in patients with coronary artery disease, mostly using intravascular ultrasound (IVUS) imaging. In cross-sectional studies, the evaluation of coronary remodeling is frequently described as a simple comparison between the most diseased portion and nearby reference segments 6,7. However, reference vessel segments are not perfect surrogates for normality8. In sequential studies a region of interest is examined at baseline and compared with the same matched portion during follow‑up9. This approach, however, only captures the changes in plaque and vessel dimensions over time, regardless of the degree of atherosclerosis and remodeling at baseline, which may have a marked influence on the outcomes thereafter. The classification of remodeling varies substantially as a function of definition10, and no consensus exists for a universal definition of remodeling11. In theory, the ideal method to measure vessel remodeling would evaluate the diseased coronary segment compared to the same region before the Falcão et al. Novel algorithm for vessel remodeling Original Article existence of the atherosclerotic plaque. Obviously, such a normality comparator cannot be directly assessed in practice. We hypothesized, however, that the native normal vessel size could be inferred for any given coronary segment to create a more appropriate baseline for determination of remodeling. The present study explored a new method to quantify vessel remodeling, based on the comparison between any target segment with its assumed normal dimensions. Methods FVRI = EEM areaACTUAL EEM areaPREDICTED + plaque area Where, EEM areaACTUAL is the real EEM area measured in the cross‑section, EEM areaPREDICTED is the hypothetical dimension of the vessel before the formation of the atherosclerotic plaque (estimated according to the methodology described below), and Plaque area is the current plaque plus media area measured. Study Design and Patient Population This prospective, single-arm survey enrolled 67 patients scheduled to undergo coronary angioplasty. During the procedure, before any coronary intervention, all patients were examined with three-vessel coronary IVUS to evaluate coronary geometric parameters. The study was approved by the institutional review board and signed written informed consent was obtained from every patient. IVUS Procedure and Image Segmentation Intracoronary nitroglycerin (100-200 µg) was injected before imaging acquisition. Intravascular ultrasound imaging of the left main trunk and of the proximal portions (40-80 mm) of the three coronary arteries was obtained using a 20 MHz electronic solid-state catheter (Eagle Eye Gold catheter and Vision Gold System console, Volcano Corporation, Rancho Cordova-CA, USA) during automatic pullback at 0.5 mm/s (R100 pullback device, Volcano Corporation, Rancho Cordova-CA, USA). Two experienced analysts, blinded to clinical data, performed all offline analyses using dedicated software (pcVH 2.2, Volcano Corporation, Rancho Cordova-CA, USA). The external elastic lamina and lumen contours were traced semi-automatically in every acquired IVUS frame to obtain the following grey-scale IVUS parameters: lumen area, elastic external membrane area (EEM area), plaque + media area (EEM area minus lumen area) and plaque burden (plaque + media area divided by the EEM area, multiplied by 100). In addition to the geometric vessel information, radiofrequency analysis of the IVUS signal backscatter, the so-called virtual histology (IVUS‑VH), was used to characterize plaque composition into four components: fibrous, fibrolipidic, necrotic core, and dense calcium. The absolute area and percent contribution of each component were computed for all frames. To verify data accuracy, interobserver reproducibility analyses were performed in 1,000 randomly selected coronary frames of ten patients. The Pearson correlation coefficient for EEM area, lumen area, and plaque + media area were 0.98, 0.95, and 0.93, respectively. For the calculation of the EEM area PREDICTED , we hypothesized that the original coronary lumen is maintained in the initial phases of the atherosclerotic process. Therefore, all cross-sections with an IVUS plaque burden < 20% were assumed to have normal lumen dimensions. As EEM and lumen areas are coincident on IVUS in the absence of plaque, the estimation of the EEM areaPREDICTED was based on the lumen size of cross-sections with absent or trivial plaque (i.e. plaque burden < 20%)12. Those cross-sections were analyzed to derive a predictive model for the normal luminal area (i.e. the EEM areaORIGINAL) using the following arbitrarily chosen constitutional and anatomical parameters: body surface area, coronary dominance, coronary territory, and the distance in millimeters from the coronary ostium. A final multivariable linear model was built using a bootstrap technique with 5000 replicated samples, with a final prediction equation obtained from the bootstrapped B-coefficients13. For the sake of keeping the prediction within the limits of clinically relevant coronary vessels, and because of the sample size, the analysis was restricted to frames with luminal areas between 3.1 mm2 and 19.6 mm2 (i.e. average vessel diameter between 2.0 mm and 5.0 mm). Interpretation of FVRI An FVRI close to a unit, in face of significant plaque, indicates compensatory vessel enlargement resulting in complete accommodation for plaque growth (Figure 1). The cutoff of one standard deviation of FVRI at plaque level was arbitrarily chosen for the FVRI range (between 0.83 and 1.17) to signal “complete compensatory” remodeling. Conversely, an FVRI > 1.17 indicates a disproportionally larger vessel increase compared to the plaque load, denoting "ectatic” remodeling. Finally, an FVRI < 0.83 implies that plaque accumulation was not totally compensated, and there is absolute shrinkage of the vessel (i.e. current EEM is smaller than the hypothetical vessel size) or insufficient vessel enlargement to counterbalance plaque growth. Per Cross-Section & Lesion Remodeling Analysis Calculation of the Novel Fractional Vessel Remodeling Index The FVRI was calculated at the cross-sectional frame level, together with the classification of the remodeling pattern according to the FVRI-based algorithm. The fractional vessel remodeling index (FVRI) was conceived to quantify the total change in arterial wall dimensions related to the atherosclerotic plaque load, and was calculated as: For the lesion level, a coronary lesion was defined as any sequence of three consecutive frames with a plaque burden > 40%14. Within each lesion, the frame with the minimal Arq Bras Cardiol. 2015; 105(4):390-398 391 Falcão et al. Novel algorithm for vessel remodeling Original Article “Negative” remodeling FVRI = 0.72 Luminal area = 9 mm2 2 Plaque area = 4 mm 2 EEM area = 13 mm ↓ EEM FVRI < 0.83 “Incomplete compensatory” remodeling FVRI = 0.71 2 Luminal area = 8 mm2 Plaque area = 7 mm 2 EEM area = 15 mm ↑ EEM NORMAL VESSEL Luminal area = 14 mm2 EEM area = 14 mm2 “Complete compensatory” remodeling FVRI = 1.00 2 Luminal area = 14 mm 2 Plaque area = 7 mm EEM area = 21 mm2 0.83 ≤ FVRI ≤ 1.17 FVRI > 1.17 “Ectatic” remodeling FVRI = 1.19 2 Luminal area = 18 mm 2 Plaque area = 7 mm EEM area = 25 mm2 Figure 1 – Possible remodeling outcomes of a normal coronary vessel after the occurrence of atherosclerotic plaque. The figure shows the remodeling patterns classified according to the algorithm based on the fractional vessel remodeling index (FVRI). The numeric values are only illustrative. EEM: External elastic membrane. lumen area was chosen as the representative cross-section for the assessment of the lesion remodeling pattern, which was classified according to two methods: the FVRI-based algorithm and the classical remodeling index, calculated as the ratio of EEM area of plaque and reference vessel. In this classic case, EEM plaque area was measured at the in-plaque cross-section with the smallest lumen area, and the reference EEM area was the average EEM area of the proximal and distal references. ANOVA one‑way testing. Univariable association between continuous variables was assessed by the Pearson correlation method. Categorical variables were expressed by their count and proportions. Statistical significance was set at p < 0.05 and all tests were bicaudal. The regression modelling to estimate the normal vessel size and the calculation of the derived parameters were detailed above. Statistical analyses were performed using SPSS version 21.0 (IBM Corporation). The proximal and distal references were specified as the frames with a plaque burden ≤40% adjacent to the respective plaque edges. Only lesions for which both distal and proximal references were available were considered for analysis. Results As recently proposed14, the plaques were categorized based on the classical remodeling index into "negative remodeling” (classical index < 0.88), "intermediate remodeling" (classical index 0.88 – 1.00) or "positive remodeling" (classical index > 1.00). Statistical Considerations This is an exploratory study for which no formal sample size calculation was performed. A total study population of approximately 65 patients was arbitrarily set to permit, for illustrative purposes, demonstrating a significant linear correlation with an r-coefficient of 0.4 between two continuous variables, considering a two-tailed alpha value of 0.05 and a one-tailed beta value of 0.115. Continuous variables were expressed as mean ± standard deviation and median (interquartile range) and compared by 392 Arq Bras Cardiol. 2015; 105(4):390-398 Baseline clinical characteristics of the 67 patients (Table 1) display classic demographics of patients presenting for cardiac catheterization and coronary angioplasty. On average, 3.8 ± 1.0 arteries were imaged per patient (total number of coronary arteries = 255): 25% left main, 26% left anterior descending artery, 24% circumflex artery, 22% right coronary artery, 3% others. Overall, 31,159 IVUS cross-sections along a total length of 9,579.8 mm (142.9 ± 22.3 mm per patient) were analyzed. For all frames, lumen area was 8.2 ± 4.0 mm2, EEM area was 14.2 ± 5.7 mm2, plaque area was 6.0 ± 3.5 mm2, and percent plaque burden was 41.6 ± 16.5% of the arterial section. A total of 3,520 cross-sections (11.3%) had no or only mild atherosclerotic plaques (i.e. percent plaque burden < 20%), which were computed for the calculation of the EEM areaPREDICTED. The overall characteristics of the bootstrapped prediction model to estimate the EEM areaPREDICTED (Table 2) Falcão et al. Novel algorithm for vessel remodeling Original Article demonstrated that all preselected variables remained significant in the final multivariable model. The estimated and the actual vessel areas in cross-sections with absent or trivial plaques (plaque burden < 20%) correlated well (p < 0.001; adjusted R2 = 0.46) (Figure 2). Vessel Remodeling at Cross-Section Level For cross-sections with established plaques (i.e. plaque burden ≥ 20%), the average FVRI was 0.86 ± 0.21 (median 0.84; interquartile range 0.71 – 0.98). Overall, 43% of frames had FVRI between 0.83 and 1.17 ("complete compensatory" remodeling). For the remaining cross‑sections, 8.6% had FVRI > 1.17 ("ectatic" remodeling) and, in 48.4%, the FVRI was < 0.83. From these, 38.7% (18.7% of the total) exhibited reduction in EEM area ("negative" remodeling), while 61.3% (29.6% of the total) had insufficient increment in EEM area ("incomplete compensatory" remodeling) (Figure 3). The level of FVRI was influenced by the degree of the atherosclerotic load. FVRI was negatively related to increasing plaque burden (Figure 4); cross-sections with a percent Table 1 – Baseline Characteristics plaque burden < 20% had an average FVRI of 0.99, which progressively decreased to a mean FVRI of 0.71 in frames with plaque burden > 60%. Vessel Remodeling at Lesion Level The analysis included 618 lesions (mean length 7.7 ± 11.2 mm). In-lesion, lumen area was 6.0 ± 3.1 mm2, EEM area was 13.4 ± 5.4 mm2, and percent plaque burden was 55.0 ± 11.3%. For the mean reference segments, lumen area was 8.9 ± 3.5 mm2, EEM area was 14.0 ± 5.4 mm2, and percent plaque burden was 36.2 ± 3.2%. Overall, the in-lesion FVRI was 0.77 ± 0.17 (median 0.77; interquartile range 0.64 – 0.88). When classified according to the FVRI-based algorithm, lesions had complete compensatory remodeling in 35.1%, ectatic remodeling in 1.3%, negative remodeling in 22.3%, and incomplete compensatory remodeling in 41.3% (Figure 3). The classical remodeling index for the lesions was 0.96 ± 0.16 (median 0.99; interquartile range 0.90 – 1.04). The remodeling categories according to the classical index were: negative remodeling 22%, intermediate remodeling 34.6%, and positive remodeling 43.4%. The FVRI-based algorithm and the classical remodeling index had a low agreement for the remodeling classification of the lesions, with an overall concordance of only 38.1%: negative/negative in 8.3%, complete compensatory/positive in 17%, and incomplete compensatory/intermediate in 12.8% (Table 3). Nevertheless, there was a significant trend towards increasing FVRI values from negative to positive remodeling categories according to the classical index groups (Table 3). Age, years 58.9 ± 9.2 Male gender 44 (66%) Weight, kg 72.0 ± 11.6 Height, cm 161.6 ± 7.9 Body mass index, cm/kg2 27.6 ± 4.0 Waist circumference, cm 97.4 + 11.1 Acute coronary syndrome 30 (45%) Multivessel coronary disease 46 (69%) Diabetes mellitus 28 (42%) Hypertension 56 (84%) Current smoking 14 (21%) Metabolic syndrome 30 (45%) Total cholesterol 165.0 ± 39.8 LDL cholesterol 99.9 ± 35.4 HDL cholesterol 36.5 ± 10.3 Triglycerides 143.2 ± 72.1 Impact of Vessel Remodeling on Plaque Composition Numbers are counts (percentages) or mean ± standard deviation. The two diagnostic schemes of remodeling classification at plaque level (FVRI or classical remodeling index) were further analyzed for their diagnostic ability in identifying plaque tissue composition. The FVRI-based classification seemed to better discriminate plaque composition: FVRI remodeling classes significantly differed in their plaque composition profile, for all tissue types (fibrous, fibrolipidic, necrolipidic, and calcific) (Figure 5). Conversely, remodeling types by classical remodeling index were not significantly different in relation to their fibrous and necrolipidic components (Figure 5). Table 2 – Final prediction model* to estimate the original external elastic membrane area (EEM areaPREDICTED) Variable Β-coefficient (95% confidence interval) p-value Constant 12.20 (11.07 – 13.33) < 0.001 Dominance pattern -1.14 (-1.46 – -0.82) < 0.001 Coronary vessel -1.73 (-1.80 – -1.66) < 0.001 Distance from the coronary ostium (in mm) † -1.28 (-1.39 – -1.18) < 0.001 2.60 (1.99 – 3.20) < 0.001 Body surface area (in m2) *Adjusted R2 = 0.46; † Logarithmic transformation. Arq Bras Cardiol. 2015; 105(4):390-398 393 Falcão et al. Novel algorithm for vessel remodeling Original Article Figure 2 – Scatter correlation graph between estimated normal external elastic membrane area (EEM areaPREDICTED) and the actual lumen area in cross-sections with absent or trivial plaque (plaque burden < 20%). Discussion Classic quantitative techniques to evaluate coronary remodeling compare vessel size to "normal" adjacent segments, but do so with no standard for distance from the predicate site or precision in "normality". We now describe a new method of assessing coronary vessel remodeling that replaces arbitrary reference vessels with a quantitative approach derived from the estimation of the original normal vessel size. The proposed analytic algorithm, based on the novel FVRI, compares the current vessel to its inferred native state, allowing to measure and classify the remodeling pattern in any point of the coronary tree, providing a numeric assessment of arterial expansion or shrinkage related to coronary atherosclerosis. The proposed method permitted a frame-by-frame, as well as a per-lesion, analysis of the remodeling pattern. To the best of our knowledge, this is the first description of an approach to assess remodeling at individual cross-section level. The FVRI adds precision and physiologic insight to the remodeling classification, distinguishing vascular responses where plaque is associated with absolute vessel shrinkage from those where plaque growth leads to different degrees of vessel accommodation. In our test population, complete vessel adaptation to plaque accumulation occurred in approximately half of the instances, at both the cross‑section and plaque levels. Moreover, partial vessel 394 Arq Bras Cardiol. 2015; 105(4):390-398 adaptation to atherosclerosis or negative vessel remodeling (i.e. vessel shrinkage) was often detected, although vessel ectasia was infrequent. In line with previous studies12,16, the present findings indicate that the adaptive vessel enlargement to plaque growth is progressively lost as plaque load increases, beginning as early as plaque burden ~20%, but with a more marked failure in the accommodation in larger plaque burdens. Similar results were seen in a recent cross-sectional substudy from the PROSPECT trial, where compensatory remodeling was also shown to decrease with increasing plaque loads12. These results challenge the common concept that lumen dimensions are maintained intact until 40-50% plaque burden occurs9. A number of different approaches have been proposed to measure coronary remodeling in the lesion level10,14. Commonly, vessel remodeling is assessed by comparing the vessel size at target segment with the dimensions of adjacent “normal” references7. In sequential studies, current guidelines propose the simple change in target vessel size to assess remodeling17. Other sequential studies have suggested a classification of remodeling based on the ratio between vessel size and plaque variation18. This method, however, is unable to provide quantitative information regarding the magnitude of the remodeling response and is not applicable to segments with minimal or no plaque change (due to Falcão et al. Novel algorithm for vessel remodeling Original Article Cross-section (n = 27,639) Negative 18.7% Incomplete compensatory 29.6% Ectatic 8.6% Complete compensatory 43% Lesion (n = 618) Incomplete compensatory 41.4% Negative 22.3% Ectatic 1.3% Complete compensatory 35.1% Figure 3 – Per cross-section (frames with plaque burden ≥ 20%) and per lesion types of vascular remodeling classified according to the algorithm based on fractional vessel remodeling index (FVRI). division by a null or very low denominator). Use of FVRI reduces some of the caveats of previous methods and may be a viable alternative to quantify remodeling in cross-sectional as well as sequential studies. A recent study, using alternative cutoff values for the classical remodeling index, showed that "positive" and "negative" remodeling were associated with similar outcomes, and both were worse than "intermediate remodeling"14. One could hypothesize that the similarly poorer outcomes for the two opposite types of remodeling, to some extent, might have been related to limitations in measurement and categorization of the remodeling pattern. Indeed, the classical definitions of remodeling as positive, negative, or intermediate are adequate descriptors in only ~40% of cases, as compared to the FVRI-based algorithm. The authors of the previous work reasoned that the impact of remodeling on outcomes could be explained by differences in plaque composition14. In line with that, in our series, plaques with classical positive remodeling had more fibrolipidic tissue, while classical negative remodeling was associated with an increase in the calcific component. However, there were no significant differences among the classical remodeling categories in terms of their fibrous and necrotic components. Conversely, the FVRI-based assessment seemed to be more discriminative for the composition of the underlying plaque than the classical approach, with FVRI remodeling types significantly associated with varying profiles for all IVUS-VH plaque components. Altogether, FRVI appears to stratify coronary remodeling into four, instead of three, physiologically meaningful patterns with markedly different plaque composition. Whether these findings will be translated to the addition of clinical value by FVRI assessment remains open for future investigations. Arq Bras Cardiol. 2015; 105(4):390-398 395 Falcão et al. Novel algorithm for vessel remodeling Original Article Fractional vessel remodeling index 1.0 p < 0.001 0.8 0.6 0.99 0.4 0.96 0.94 0.87 0.80 0.71 0.2 0 < 20 20-30 30-40 40-50 50-60 Percent plaque burden > 60 Figure 4 – Average fractional vessel remodeling index in relation to percent plaque burden (error bars are one standard error of the mean). Table 3 – Comparative classification of the lesion remodeling patterns according to FVRI-based algorithm or classical remodeling index (n = 618 lesions) Classical remodeling Mean FVRI* Mean classical remodeling index* Negative Intermediate Positive 0.70 ± 0.16 0.79 ± 0.18 0.80 ± 0.16 51 (8.3) 49 (7.9) 38 (6.1) 0.90 ± 0.16 FVRI-based remodeling class Negative Incomplete compensatory 57 (9.2) 79 (12.8) 119 (19.3) 0.97 ± 0.18 Complete compensatory 28 (4.5) 84 (13.6) 105 (17.0) 0.99 ± 0.11 Ectatic 0 (0.0) 2 (0.3) 6 (1.0) 1.09 ± 0.15 Numbers are mean ± standard deviation or counts (percentages relative to total number of lesions); FVRI: Fractional vessel remodeling index; *p < 0.001 for all. Our analyses suggest that the estimation of the original normal lumen and vessel size in any point of the coronary tree - a crucial step to calculate FVRI - is feasible and easily obtained. Nevertheless, due to the relatively small sample size of the present study and the intrinsic statistical limitations of any prediction modeling of multiple interdependent parameters, future studies are warranted to further refine and validate the estimation of normal vessel dimensions. It must be highlighted, however, that our study does not aim at validating the proposed method, but has the main objective of describing the theoretical concept of the FVRI‑based algorithm for remodeling assessment and providing initial exploratory results of the new score. Conclusion The FVRI provides a quantitative assessment of coronary vessel remodeling, independent of nearby references, and 396 Arq Bras Cardiol. 2015; 105(4):390-398 offers a promising approach to evaluate the vessel response to plaque growth/regression. Author contributions Conception and design of the research: Falcão BAA, Falcão JLAA, Morais GR, Edelman ER, Lemos PA; Acquisition of data: Falcão BAA, Falcão JLAA, Morais GR, Silva RC, Lopes AC, Soares PR, Mariani Jr J, Lemos PA; Analysis and interpretation of the data and Critical revision of the manuscript for intellectual content: Falcão BAA, Falcão JLAA, Morais GR, Silva RC, Lopes AC, Soares PR, Mariani Jr J, Kalil-Filho R, Edelman ER, Lemos PA; Statistical analysis: Falcão BAA, Falcão JLAA, Morais GR, Silva RC, Lemos PA; Obtaining financing: Falcão BAA, Falcão JLAA, Lemos PA; Writing of the manuscript: Falcão BAA, Lopes AC, Edelman ER, Lemos PA. Falcão et al. Novel algorithm for vessel remodeling Original Article Classical remodeling index 60 FVRI algorithm p = 0.2 60 Fibrous component 40 (%) 20 61.2 63.5 63.0 p = 0.019 61.6 62.4 70.1 p < 0.001 20 15 12.1 15.0 14.8 10 5 12.9 11.8 17.3 16.6 0 0 p = 0.13 15 Necro-lipidic component 10 (%) 5 p = 0.019 20 15 17.7 15.3 16.0 0 12 10 Calcific 8 component 6 (%) 4 2 0 65.0 0 15 Fibro-lipidic component 10 (%) 5 20 40 20 0 20 p = 0.024 80 10 5 17.4 16.4 14.7 10.3 0 p = 0.001 p = 0.004 10 8 10.7 Negative 6 7.7 Intermediate 7.3 Positive 4 9.2 9.1 2 0 Negative 6.6 Incomplete Complete compensatory compensatory 4.0 Ectatic Figure 5 – Plaque composition in vascular remodeling types according to fractional vessel remodeling index or classical remodeling index (FVRI) (n = 618 plaques). Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Study Association This article is part of the thesis of Doctoral submitted by Breno de Alencar Araripe Falcão, from Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo. Sources of Funding This study was partially funded by FAPESP. References 1. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316(22):1371-5. 2. Nishioka T, Luo H, Eigler NL, Berglund H, Kim CJ, Siegel RJ. Contribution of inadequate compensatory enlargement to development of human coronary artery stenosis: an in vivo intravascular ultrasound study. J Am Coll Cardiol. 1996;27(7):1571-6. 3. Berry C, Noble S, Ibrahim R, Gregoire J, Levesque S, L’Allier PL, et al. Remodeling is a more important determinant of lumen size than atheroma burden in left main coronary artery disease. Am Heart J. 2010;160(1):188-194. 4. Puri R, Wolski K, Uno K, Kataoka Y, King KL, Crowe TD, et al. Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events. JACC Cardiovasc Interv. 2013;6:29-35. Arq Bras Cardiol. 2015; 105(4):390-398 397 Falcão et al. Novel algorithm for vessel remodeling Original Article 5. Kang SJ, Kim WJ, Yun SC, Park DW, Lee SW, Kim YH, et al. Vascular remodeling at both branch ostia in bifurcation disease assessed by intravascular ultrasound. Catheter Cardiovasc Interv. 2013;81(7):1150-5. 12. Inaba S, Mintz GS, Shimizu T, Weisz G, Mehran R, Marso SP, et al. Compensatory enlargement of the left main coronary artery: insights from the PROSPECT study. Coron Artery Dis. 2014;25(2):98-103. 6. Mintz GS, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses: an intravascular ultrasound study. Circulation. 1997;95(7):1791-8. 13. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15(4):361-87. 7. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes : an intravascular ultrasound study. Circulation. 2000;101(6):598603. 14. Inaba S, Mintz GS, Farhat NZ, Fajadet J, Dudek D, Marzocchi A, et al. Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT. JACC Cardiovasc Imaging. 2014;7(1):70-8. 8. Mintz GS, Painter JA, Pichard AD, Kent KM, Satler LF, Popma JJ, et al. Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J Am Coll Cardiol. 1995;25(7):1479-85. 9. Schoenhagen P, Ziada KM, Vince DG, Nissen SE, Tuzcu EM. Arterial remodeling and coronary artery disease: the concept of “dilated” versus “obstructive” coronary atherosclerosis. J Am Coll Cardiol. 2001;38(2):297-306. 10. Hibi K, Ward MR, Honda Y, Suzuki T, Jeremias A, Okura H, et al. Impact of different definitions on the interpretation of coronary remodeling determined by intravascular ultrasound. Catheter Cardiovasc Interv. 2005;65(2):233-9. 11. von Birgelen C, Hartmann M, Mintz GS, Bose D, Eggebrecht H, Neumann T, et al. Remodeling index compared to actual vascular remodeling in atherosclerotic left main coronary arteries as assessed with long-term (> or =12 months) serial intravascular ultrasound. J Am Coll Cardiol. 2006;47(7):1363-8. 398 Arq Bras Cardiol. 2015; 105(4):390-398 15. Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calculation for linear and logistic regression. Stat Med. 1998;17(14):1623-34. 16. von Birgelen C, Airiian SG, Mintz GS, van der Giessen WJ, Foley DP, Roelandt JR, et al. Variations of remodeling in response to left main atherosclerosis assessed with intravascular ultrasound in vivo. Am J Cardiol. 1997;80(11):1408-13. 17. Mintz GS, Garcia-Garcia HM, Nicholls SJ, Weissman NJ, Bruining N, Crowe T, et al. Clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound regression/ progression studies. EuroIntervention. 2011;6(9):1123-30, 9. 18. Sipahi I, Tuzcu EM, Schoenhagen P, Nicholls SJ, Crowe T, Kapadia S, et al. Static and serial assessments of coronary arterial remodeling are discordant: an intravascular ultrasound análise from the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Am Heart J. 2006;152(3):544-50. Back to the Cover Original Article Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy Eduardo Arrais Rocha1, Francisca Tatiana Moreira Pereira2, José Sebastião Abreu2, José Wellington O. Lima3, Marcelo de Paula Martins Monteiro2, Almino Cavalcante Rocha Neto2, Camilla Viana Arrais Goés1, Ana Gardênia P. Farias2, Carlos Roberto Martins Rodrigues Sobrinho2, Ana Rosa Pinto Quidute2, Maurício Ibrahim Scanavacca1 Instituto do Coração (InCor) – Universidade de São Paulo1, São Paulo, SP; Hospital Universitário – Universidade Federal do Ceará2, CE; Departamento de Saúde Pública – Universidade Estadual do Ceará3, Fortaleza CE – Brazil Abstract Background: 30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes. Objective: This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx) at different stages of cardiac resynchronization therapy (CRT). Methods: Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional class (FC) III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were assessed by using Cox regression and Kaplan–Meier curves. Results: The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to implantation, right ventricular dysfunction (RVD), ejection fraction < 25% and use of high doses of diuretics (HDD) increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD, HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and 12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping. Conclusion: We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated for CRT. (Arq Bras Cardiol. 2015; 105(4):399-409) Keywords: Heart Transplantation / mortality; Heart Failure / physiopathology; Cardiac Resynchronization Therapy; Follow-Up Studies; Pacemaker, Artificial. Introduction The main international guidelines strongly recommend (class I) cardiac resynchronization therapy (CRT) for patients with congestive heart failure (CHF) and New York Heart Association (NYHA) functional class (FC) II or III or ambulatory class IV when they have intraventricular conduction disturbances and ejection fraction (EF) ≤ 35% while undergoing optimal medical therapy1. However, 30%–40% of CRT cases do not achieve favorable outcomes, which means that these patients undergo surgery with high risks and costs but with no clinical, hemodynamic, or survival benefits2. Thus, multifactorial indexes or scores Mailing Address: Eduardo Arrais Rocha • Universidade Federal do Ceará. Av. Padre Antônio Tomás, 3535 / 1301, Cocó. Postal Code 60192-120, Fortaleza, CE – Brazil E-mail: [email protected], [email protected] Manuscript received March 15, 2015; reviewed manuscript May 05, 2015; accepted May 06, 2015. DOI: 10.5935/abc.20150093 399 need to be developed to more accurately identify survival predictors and treatment responders3,4. Such indexes should involve variables related to mortality reduction, with high rates of sensitivity and specificity. This work aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx) at different stages of CRT. Methods This prospective observational study evaluated 116 patients with multisite pacemakers implanted consecutively in a tertiary university hospital between January 2008 and March 2013 (Table 1), who had NYHA FC III or ambulatory FC IV (ambulatory outpatients who were taking oral medications), EF ≤ 35%, QRS ≥ 120 ms (left bundle branch block [LBBB] and right bundle branch block [RBBB] with divisional block or pacemaker rhythm), and optimized treatment. The exclusion criteria were severe comorbidities, previous indication for pacemaker implantation, hospitalization for NYHA FC IV heart failure, primary valvular disease, and incomplete data. Rocha et al. Development of predictive models in CRT Original Article Table 1 – Baseline characteristics and comparison of the results of some variables during the assessment periods Variables Patients Age (years) Sex (male) Time 1 Time 2 P Value Time 3 p Value* 116 114 - 92 - 64.8 ± 11.1 - - - - 69.8% - - - - 25.8 ± 4.1 - - - - Beta-blockers 88.7% 89.2% - 91.8% ACE-inhibitors 97.4% 96% Furosemide ≥ 80mg/day 31.9% 17% - - - Dilated cardiomyopathy 59.4% - - - - Ischemic cardiomyopathy 29.3% - - - - Chagas disease 11.2% - - - - BMI Atrial fibrillation 95.9% 12% - - - - CRT-D 54.2% - - - - LBBB 71.55% - - - - 140 < 0.001 - - RBBB with divisional block 12% Pacemaker 16.3% Posterolateral vein 45.4% Anterolateral veins 52.5% Prior QRS width (ms) 160 Number of hospitalizations due to CHF 108 24 < 0.001 16 0.79* Ejection fraction (median) 29% 33% < 0.001 35% 0.03* LVDD (mm) 70 66 < 0.001 65 0.73* Systolic BP (mm Hg) 115 119.6 < 0.001 121.8 0.84* Diastolic BP (mm Hg) 70 80 0.07 70 0.34* FC IIl (NYHA) 68.1% 8.7% < 0.001 12% 0.07* FC IV (NYHA) 31.9% 6.1% DD < 0.001 7.6% 0.07* < 0.001 - 0.06* DD Grade I 34.6% 59.2% - 63.2% - DD Grade II 23.7% 27.1% - 13.9% - DD Grade III 29.7% 8.7% - 16.4% - DD Grade IV 11.8% 4.8% - 5.0% 0.009* - - 0.008 - No MR MR 3.4% 5.3% - 15.3% Mild MR 50.4% 66.0% - 56.0% - Moderate MR 30.4% 18.7% - 18.6% - Severe MR 15.6% 9.8% - 9.8% - RV dysfunction 20.9% 17% 0.62 12% 0.5* 1.1 1.1 - 1.2 - Creatinine (mg/dL) Time 1, preimplantation; time 2, 1 year; time 3, 2 years. *Analysis of time 3 in relation to time 2; QRS width, ejection fraction, left ventricular diastolic diameter and blood pressure were variables without normal distribution (median values); BMI: Body mass index; ACE: Angiotensin-converting enzyme; CRT-D: Cardioverter-defibrillator with biventricular pacing; LBBB: Left bundle branch block; RBBB: Right bundle branch block; CHF: Congestive heart failure; LVDD: Left ventricular diastolic diameter; BP: Blood pressure; FC: Functional class (NYHA); DD: Diastolic dysfunction; MR: Mitral regurgitation; RV: Right ventricle. Arq Bras Cardiol. 2015; 105(4):399-409 400 Rocha et al. Development of predictive models in CRT Original Article Of the 147 patients who underwent implantation during the study period, only 116 were included in the study for the following reasons: 4 had an EF >35%, 3 had total atrioventricular block, 2 had primary valvular heart disease, 2 had pacemaker infection, 7 had incomplete data, 4 had loss of capture in the left ventricle electrode, 2 did not undergo complete follow-up, 1 had severe comorbidity, 5 were hospitalized for class IV CHF at the time of inclusion, and 1 died of premature respiratory infection. The electrodes of the right ventricle were positioned preferentially in the apical region (84%). The models used in 92, 12, 10, and 2 patients were from St. Jude Medical, Biotronik, Medtronic, and Guidant, respectively. Patients with concomitant indication for an implantable cardioverter-defibrillator (CRT-D group) (54% of the 116 patients) were also included in this study. This indication was for primary prevention in 47 patients and for secondary prevention in 16 patients. Assessments were performed in the preimplantation period (first analysis), at 1 year after implantation (second analysis), and at 2 years after implantation (third analysis) according to a fixed protocol. We analyzed 12 clinical, 8 electrocardiographic, and 7 echocardiographic variables. The clinical variables were age, sex, body mass index, cardiac cachexia, FC, etiology of cardiomyopathy, cardiac vein where the electrode was positioned in the left ventricle, serum creatinine level, systolic and diastolic blood pressures, use of high-dose loop diuretics (≥ 80 mg/day of furosemide), and hospitalization due to heart failure. The electrocardiographic variables were: atrial fibrillation; LBBB or RBBB; previous cardiac pacemaker; 1st-degree atrioventricular block; QRS duration; QRS narrowing after implantation; R wave in the V1 lead in patients with LBBB; and QRS axis in the frontal plane after implantation. The echocardiographic variables were: left ventricular (LV) diastolic and systolic diameters; EF computed using Simpson’s method; degree of diastolic dysfunction (DD) from I to IV; degree of mitral regurgitation from I to III; right ventricular dysfunction (RVD); and dyssynchrony. A 12-lead surface electrocardiogram was recorded at the speed of 25 mm/s and amplitude of 10 mm/mV. The longest duration of the QRS measured in one of the leads of the frontal or horizontal plane, which was the lead with the highest value and thus allowed for better evaluation, was taken into account. Cardiac mortality was defined for deaths of end-stage CHF or for sudden death. Echocardiographic parameters The echocardiographic guidelines for the analysis of various echocardiographic parameters were followed, as well as the guidelines for dyssynchrony for the analysis of such parameters5, 6. Three experienced physicians performed the echocardiographic examinations, 72% of which were performed by the same specialist. The examinations were performed using the GE Vivid 7 Ultrasound System (GE Healthcare, Fairfield, CT, USA). The systolic function analysis of the cardiac chambers was performed using Simpson’s method in the two-dimensional mode. Ventricular diameters were obtained on M-mode 401 Arq Bras Cardiol. 2015; 105(4):399-409 echocardiography, according to the standard guideline5. Right ventricular function was analyzed qualitatively, differentiated between the presence and absence of any degree of dysfunction5. Diastolic dysfunction analysis was conducted by assessing mitral flow (at rest and after a Valsalva maneuver), tissue Doppler images, and flow propagation speed on color M-mode. Results were used to classify DD into four grades (0, absent; I, mild; II, moderate; III, accentuated or with restrictive dysfunction; and IV, severe or with irreversible restrictive dysfunction)7. The degree of mitral regurgitation was assessed as the percentage of the left atrium filling using color Doppler echocardiography. The percentage was less than 20% in mild reflux, and between 20% and 40% in moderate reflux; values above these percentages indicated severe reflux5. In this practical context, the Coanda effect was interpreted as a moderate reflux when restricted to the atrial sidewall and accentuated when it stretched through the upper pole of the left atrium. All patients provided informed consent, and the ethics committee of the hospital approved the study, whose protocol conforms to the ethical guidelines of the declaration of Helsinki. Statistical analysis The categorical variables were presented as frequencies and percentages, whereas the continuous variables were presented as means and standard deviations, or medians. The categorical variables were compared using the McNemar, Stuart–Maxwell, or chi-square test. The Student t test was used to compare the distribution of approximately normal, continuous variables, and the Wilcoxon/Mann–Whitney U test was used for the comparisons of continuous variables without normal distribution. Distributions were considered significantly different if p < 0.05. The univariate relationship between the clinical, electrocardiographic, and echocardiographic variables and the combined endpoint of cardiac mortality and Tx was evaluated by using the Kaplan–Meier survival curve, log-rank test, and Cox regression analysis. Some continuous variables were assessed to determine a cutoff value. Cox multiple regression models were developed in the following analysis times to assess the independent contribution of each of the significant variables in the Cox univariate model: preimplantation (time 1), first year after CRT (time 2), and second year after CRT (time 3). Variables with p < 10% were considered potential confounders. Each of the variables was included in the multivariate model according to hazard descending order and was excluded when p ≥ 5%. After obtaining the final model, the previously excluded variables were included again in the model and tested individually using the same criteria. We conducted logistic regression analyses by using hazard8 as an independent variable to measure risk, and cardiac death/ Tx as the dependent variable. The accuracy of the models was tested with the receiver-operating characteristic (ROC) curve, along with its sensitivity and specificity. Models were prepared Rocha et al. Development of predictive models in CRT Original Article by dividing the hazard scores into risk categories according to the number of variables present and classified as low (class A), medium (class B), and high risk (class C). Kaplan–Meier survival curves were elaborated individually for the independent variables and risk classes, and compared using the log-rank test. For the proposed models, all the variables were tested for compliance with the proportional hazards assumptions by performing the Schoenfeld test and a visual analysis of the Schoenfeld residuals against the time of deaths or censorship. For each model, the effect of each observation on the estimated parameters was analyzed. To achieve this, after the deletion of an observation, the model was estimated again and the new estimates were compared to the previous ones. Values should not change much or the model may be too sensitive to a particular observation. To obtain the bootstrap confidence intervals, the original data were sampled 10,000 times to obtain 10,000 pseudo-samples of size 60. Then, for each pseudo-sample, the hazard ratios of the three models were estimated. These estimated hazard rates were sorted, and the 95% confidence interval was reported. The data were analyzed by using Stata/SE version 12.1 (StataCorp LP, College Station, TX, USA) and the “R” software (2014 –“R”: A language and environment for statistical computing . R Foundation for Statistical Computing, Vienna, Austria). Results During the study, 29 deaths were recorded, representing a total mortality rate of 25% during the follow-up period of 34.09 ± 17.9 months. Cardiac mortality/Tx accounted for 16.3% (19 patients) of the cases. Six patients underwent Tx during the study period, 5 for refractory CHF and 1 for recurrent arrhythmic storm. Three Tx patients died prematurely due to disease severity at the time of Tx. No sudden death occurred in the CRT-D group, but sudden death occurred in 3 patients in the CRT-P (pacemaker without defibrillator) group. In the CRT-D group, 6 patients with fast ventricular tachycardia or fibrillation were treated with effective shock. The baseline characteristics of the patients and the comparison of the results of the variables during the assessment period are shown in Table 1. No significant statistical evidence showed that the assumption of proportional hazards was violated. The effect of each observation on the estimated parameters for each model was analyzed. The data obtained do not suggest influential observations. Bootstrapping confidence intervals for a 95% level of significance were obtained and confirmed the statistical significance of the estimated hazard ratios. These results did not reject the adjustment of the model with the proposed variables (Table 2). Analysis of the variables at time 1 (preimplantation) Of the 27 variables analyzed during the first study period (preimplantation), 13 were significant in the Cox univariate regression model. In the Cox multivariate model, RVD, Table 2 – Bootstrap 95% confidence intervals and formal test for the proportional hazards assumption Model 1 Covariate CI EF (1.7142; 14.2053) RVD (1.8754; 16.6939) HDD (2.2563; 18.7021) Model 2 CHF (2.1747; 11.4814) RVD (3.0642; 10.6684) HDD (4.0963; 18.3712) Model 3 FC (3.5177; 37.5661) RVD (6.0592; 46.8405) Model 1 Covariate ρ χ2 p value EF 0,073 0,08099 0,776 RVD 0,124 0,28512 0,593 HDD -0,012 0,00259 0,939 0,33714 0,953 Global Model 2 ICC 0,3713 1,785 0,182 RVD 0,1089 0,223 0,637 HDD -0,0934 0,167 0,683 1,905 0,592 Global Model 3 FC -0,110 0,118 0,732 RVD 0,125 0,162 0,687 0,254 0,881 Global CI: Confidence interval; EF: Ejection fraction; RVD: Right ventricular dysfunction; CHF: Hospitalization due to congestive heart failure; HDD: High doses of diuretic (furosemide ≥ 80 mg/day); FC: Functional class (NYHA) III/IV compared with I/II. EF <25%, and use of high-dose diuretics (HDD) were independently associated with increased cardiac mortality/Tx, with hazard ratios of 3.9, 4.8, and 5.9, respectively (Table 3). Significant variables in the multivariate model were also significant in the Kaplan–Meier model when compared using the log-rank test. The analysis of the model by using the ROC curve showed an area under the curve (AUC) of 0.81, with a sensitivity of 61.1%, a specificity of 89.5%, and an accuracy of 84.6% (Figure 1). From the combinations of these variables, we developed a model with three classes as follows: class A (low risk for cardiac death/Tx) was the absence of the variables or the presence of only one of the significant variables in the Arq Bras Cardiol. 2015; 105(4):399-409 402 Rocha et al. Development of predictive models in CRT Original Article Table 3 – Analysis by the Cox model with respect to cardiac mortality/Tx at time 1 (preimplantation) Variable HR 95% CI p HR Univariate 95% CI p Multivariate Hospitalization ≥ 1 9.23 1.23-69.21 0.031 RV dysfunction 5.01 1.97-12.76 0.001 FC III / IV 4.87 1.85-12.83 0.001 Chagas Disease 4.73 1.77-12.63 0.002 EF < 25 % 4.43 1.77-11.05 Diuretic ↑ 3.89 1.56-9.72 SBP < 100 mmHg 3.38 1.35-8.46 0.009 Creatinine > 1.1 2.85 1.06-7.67 0.038 LVDD > 80 mm 2.68 1.00-7.15 0.048 DBP < 60 mmHg 2.63 1.02-6.75 0.044 ACE inhibitors 4.34 0.98-19.17 0.052 MR grade II 2.50 0.89-7.41 0.08 MR grade III 2.80 0.87-9.43 0.08 3.95 1.45-10.74 0.007 0.001 4.85 1.71-13.73 0.003 0.004 5.97 2.15-16.53 0.001 HR: Hazard ratio (hazard ratio in the Cox model); CI: Confidence interval, P: Level of statistical significance; Diuretic ↑: ≥ 80mg of furosemide; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; FC III / IV: Percentage of functional class (FC) III over FC IV; Hospitalization ≥ 1: one or more hospitalizations due to congestive heart failure (CHF); RV: Right ventricular; EF: Ejection fraction; LVDD: Left ventricular diastolic diameter; ACE: Angiotensin-converting enzyme; MR: Mitral regurgitation. multivariate analysis, implying a 30-month cardiac event‑free rate of 93%. The combination of two (class B) and three variables (class C) resulted in 30-month cardiac event-free rates of 61% and 0%, respectively. Analysis of the variables at time 2 (first year after CRT) During time 2 (first year after CTR), 13 variables were significant in the Cox univariate regression model. In the Cox multivariate model, RVD, use of HDD, and hospitalization due to CHF were independently related to increased cardiac mortality/Tx rate, with hazard ratios of 3.5, 5.3, and 12.5, respectively. The significant variables in the multivariate model were also significant in the Kaplan–Meier model, when compared by using the log-rank test. The analysis of the model by using the ROC curve showed an AUC of 0.910, with a sensitivity of 76.4%, a specificity of 96.3%, and an accuracy of 93% (Figure 2). From the combinations of these variables, we were able to construct a model with three classes (Table 4). Class A means low risk of cardiac death/Tx, composed by the absence or presence of only one of the significant variables in the multivariate analysis, resulting in a 30-month cardiac event‑free rate of 98%. The combination of two (class B) and three variables (class C) resulted in 30-month cardiac event-free rates of 65% and 0%, respectively (Figure 2). Analysis of the variables at time 3 (second year after CRT) Hospitalizations due to CHF, use of HDD, FC, DD, RVD, EF < 30%, Chagas disease, and systolic blood pressure < 110 mmHg were significant in the univariate Cox regression model in the second year after CRT. 403 Arq Bras Cardiol. 2015; 105(4):399-409 In the multivariate Cox model, RVD and FC III/IV were independently related to increased cardiac mortality/ Tx rate, with hazard ratios of 7.7 and 12.0, respectively. The significant variables in the multivariate model were also separately significant in the Kaplan–Meier model when compared using the log-rank test (p < 0.001). The analysis of the model using the ROC curve showed an AUC of 0.789, with a sensitivity of 40%, a specificity of 98.4%, and an accuracy of 90.5% (Figure 3). From the combination of these variables, we were able to construct a model with three classes. Class A means low risk of cardiac death/Tx, composed by the absence of the two significant variables in the multivariate analysis, implying a 30-month cardiac event-free rate of 97.5%. The presence of the combination of two (class B) and three variables (class C) resulted in 30-month cardiac event-free rates of 83.1% and 38.5%, respectively. Discussion In the present study, we developed three predictive models for the risk of cardiac death and Tx at different stages of CRT. To our knowledge, this is the first study to sequentially and prospectively analyze predictive variables in the same population and at different stages of development (at preimplantation, in the first year after CRT, and in the second year after CRT) and to develop risk models for cardiac death/ Tx. The models identified simple variables that, when present, were associated with a high risk for cardiac death/Tx. The total mortality rate was 25% (29/116) at 34 ± 17 months. In the CARE-HF study9, the mortality was 30% in the group without intervention, compared with 20% in the group with Rocha et al. Development of predictive models in CRT Original Article Figure 1 – Kaplan-Meier survival curve of the variables with independent value in the multivariate Cox analysis, compared by using the log-rank test, with the construction of the ROC curve, an area under the curve (AUC) of 0.81, sensitivity of 61%, specificity of 89%, and accuracy of 84%. At the bottom right, risk model, being a low risk of cardiac mortality/Tx the absence of the three variables, furosemide> 80 mg/day, right ventricular dysfunction, and ejection fraction (EF) < 25% or presence of one of them. Arq Bras Cardiol. 2015; 105(4):399-409 404 Rocha et al. Development of predictive models in CRT Original Article Figure 2 – Kaplan-Meier curve of the variable hospitalization due to congestive heart failure (CHF), which, associated with right ventricular dysfunction and use of high doses of diuretics, formed the predictive model of cardiac death/Tx at time 2 (1st year). The absence of the three variables or the presence of only one (low risk) indicates an event‑free rate in 30 months of 98%. At the top right, the ROC curve with an area under the curve (AUC) of 0.91, sensitivity of 76.4%, specificity of 96.3%, and accuracy of 93%. CRT, during a 29.4-month follow-up. In the COMPANION study10, the mortality rate was 21% (131/617) in the CRT group, compared with 25% (77/308) in the control group, during a 24-month follow-up. Therefore, our total mortality data are within the range described by large-scale studies. In our study, we analyzed the combined endpoints of cardiac mortality and Tx, aiming at identifying more-specific variables related to CRT results11. 405 right ventricle as an independent predictor of mortality. Therefore, patients with RVD should not be excluded from the indication for CRT, although they represent a subgroup at higher risk of cardiac death or Tx after CRT22. The importance of the right ventricle in CRT has been demonstrated in other recent studies, but not in the elaboration of risk models for different evolution stages23,24. Several studies have evaluated predictors of response or death in different populations and with different response criteria, and the results were inconsistent. However, several publications identified the following predictors of response: dilated cardiomyopathy12, QRS width13, QRS narrowing14, presence of dyssynchrony15, female sex16, type of bundle branch block 17, LV diameter 18, the aortic velocity time integral13, and DD19. Thirteen patients (11.2%) had Chagas disease, 5 of whom had RVD. Chagas cardiomyopathy was related to increased mortality in the survival curve, similar to another study that related it with worse outcome25. In the multivariate analysis, Chagas disease did not remain as an independent variable, probably because 41% of the patients had RVD, a variable that was significant at all the analysis times. Therefore, the relevance of RVD was not exclusively related to Chagas disease, as 19 patients had RVD due to other etiologies. The patients with RVD (20.9% of the group) had worse evolution in all the analysis times. However, we noticed that 6 patients with good outcomes had regression of the alterations in the right ventricle. The study by Praus et al20 showed that the regression of the right ventricle occurred later (15 months), whereas Leong et al 21 identified the A preimplantation EF < 25% identified a subgroup with the highest risk for cardiac death. Linde et al26, in a subanalysis of the REVERSE study, have shown that a basal EF < 30%, compared with values between 30% and 40%, was positively related to survival. Meanwhile, Kronborg et al27 showed that a basal EF < 22.5% determined an increased mortality after CRT. Arq Bras Cardiol. 2015; 105(4):399-409 Rocha et al. Development of predictive models in CRT Original Article Table 4 – Predictive scores of cardiac mortality and transplantation in cardiac resynchronization therapy Score at time 1 (preimplantation) Variable Hazard N Scores Class Risk None 1.0 45 0 A1 Low RVD 3.9 8 3 A2 Low EF 4.8 14 4 A2 Low Diuretic ↑ 5.9 17 5 A2 Low RVD + EF 19.1 5 7 B Intermediate RVD + Diuretic ↑ 23.6 4 8 B Intermediate EF + Diuretic ↑ 29.0 6 9 B Intermediate RVD + EF + Diuretic ↑ 114.0 5 12 C High Hazard N Scores Class Risk None 1.0 62 0 A Low RVD 3.5 7 2 A Low Diuretic ↑ 5.3 12 3 A Low Hospitalization 12.5 3 5 A Low RVD + Diuretic ↑ 18.7 2 6* B Intermediate RVD + Hospitalization 44.0 2 7 B Intermediate Diuretic ↑ + Hospitalization 66.3 6 8 B Intermediate RVD + Hospitalization + Diuretic ↑ 234.0 6 10 C High Hazard N Scores Class Risk None 1.0 55 0 A Low FC III/IV 7.7 10 8 B Intermediate RVD 12.1 4 13 B Intermediate RVD + FC III/IV 94.5 5 21 C High Score at time 2 (1st year) Variable Score at time 3 (2nd year) Variable RVD: Right ventricular dysfunction; EF: Ejection fraction lower than 25%; diuretic ↑: use of ≥ 80 mg of furosemide; FC: Functional class (NYHA); Hospitalization: ≥ 1 hospitalization due to congestive heart failure. Class A: Low risk category, Class B: Intermediate risk and Class C: High risk. The hazard was used as an independent variable in the logistic regression model for the preparation of the score. The score was obtained by the hazard ratio of the variable divided by the highest value. * one unit was added to maintain the hazard proportion. N: Number of patients. The hospitalizations for heart failure proved to be an independent variable in relation to the prediction of cardiac mortality/Tx in the first year after CRT. The study represents, to our knowledge, the first time this variable was included as independent in the analysis of mortality risk in the first year after CRT and not as part of the outcome combined with death. Hospitalization due to CHF is a well-defined risk factor for cardiomyopathy, with a reduction in the incidence of these events after CRT demonstrated in several studies9,10. Another easily obtainable clinical variable that showed significant value in the preimplantation period and first year after CRT was the use of high-dose loop diuretics (furosemide ≥ 80 mg/day). Van Boven et al28 reported an association between chronic non-use of diuretics and response to CRT. Meanwhile, Cleland et al29 observed that the use of HDD was related to a worse prognosis only in the univariate analysis. We believe that the description of this variable as an independent value of cardiac death in two periods of the CRT analysis in our study is an original observation. A clinical prediction rule to identify patients at heightened risk for early demise after CRT has been recently elaborated30, including the following four independent variables: LV end‑diastolic diameter (LVEDD) > 65 mm, non-LBBB morphology, creatinine level > 1.5, and non-use of beta‑blockers. In our study, LVEDD and creatinine level were significant only in the univariate analyses. Hospitalization due to CHF, use of HDD, and RVD, some independent variables in our work, were not included in the previous study. Arq Bras Cardiol. 2015; 105(4):399-409 406 Rocha et al. Development of predictive models in CRT Original Article Figure 3 – A: ROC curve of the model at time 3 (2nd year), with the variables right ventricle (RV) dysfunction and functional class (FC) III and IV compared with I and II, with an area under the curve (AUC) of 0.789, sensitivity of 40%, specificity of 98.4% and accuracy of 90.5%. B: Kaplan-Meier curve showing that the absence of the variables RV dysfunction and FC III / IV (Class A - low risk) indicates an event-free rate of 97.5% at 30 months. We achieved a significant improvement in the specificity of the predictive models of mortality or response after CRT, reaching 96% in the first year after CTR and 98% in the second year after CRT, when compared with the specificity of 22%–70% of previously described models in relation to total and cardiac mortality. These results are in accordance with the target outcomes of CRT in the treatment of patients with severe illnesses, with high costs and risks in the procedure31. The models used in this study showed good accuracy, ranging from 84.6% to 93%, and can be used in three different stages of CRT, which is another original contribution of our work. At the usual significance levels, the model was validated internally and did not reveal lack of adjustment or exaggerated sensitivity to the data. We believe that the study contributes to and advances the search for better criteria for prognostic evaluation, with the composition of simple multifactorial indexes and with the inclusion of easily obtainable variables that are used in clinical practice. The models will be useful in the selection, monitoring, and counseling of patients indicated for CRT. 407 Arq Bras Cardiol. 2015; 105(4):399-409 Study limitations Analyses of intraobserver and interobserver variabilities of echocardiographic and electrocardiographic parameters were not performed. The patients did not undergo optimization of the atrioventricular interval after surgery. The models created were not validated externally, although they were validated internally. This study is also limited by the small number of patients, the large number of excluded patients, and the fact that it was conducted at a single center. The RV function was analyzed qualitatively due to the absence of correlation between the RV measures and the prognosis at the beginning of the study. These results must be considered within the study population, who had 59.4% of dilated cardiomyopathy, 11.2% of Chagas cardiomyopathy, 12% of patients with RBBB and 16.3% of patients with prior cardiac pacemaker. Future larger prospective studies will help validate the important variables related to cardiac death or Tx after CRT. Rocha et al. Development of predictive models in CRT Original Article Conclusion We developed predictive models of cardiac death or Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring, and counseling of patients indicated for CRT. Acknowledgments We are grateful to Professor José Wellington O. Lima, Luis Gustavo Bastos Pinho, and Juvêncio Santos Nobre for the statistical advice and Dr. Italo Martins by the local coordination of Ph.D. Author contributions Conception and design of the research: Rocha EA, Pereira FTM, Abreu JS, Lima JWO, Rocha Neto AC, Farias AGP, Sobrinho CRMR, Scanavacca MI; Acquisition of data: Rocha EA, Pereira FTM, Abreu JS, Monteiro MPM, Goés CVA, Farias AGP; Analysis and interpretation of the data: Rocha EA, Pereira FTM, Abreu JS, Lima JWO, Monteiro MPM, Rocha Neto AC; Statistical analysis: Rocha EA, Lima JWO, Quidute ARP; Obtaining financing: Rocha EA; Writing of the manuscript: Rocha EA, Abreu JS, Rocha Neto AC, Quidute ARP, Sobrinho CRMR, Scanavacca MI. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding This study was funded by CAPES and FUNCAP. Study Association This article is part of the thesis of Doctoral submitted by Eduardo Arrais Rocha, from Universidade de São Paulo e Universidade Federal do Ceará. References 1. Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Estes NA 3rd, et al. ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60(14):1297-313. 10. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-50. 2. Saxon LA, Ellenbogen KA. Resynchronization therapy for the treatment of heart failure. Circulation. 2003;108(9):1044-8. 11. Carson P, Anand I, O’Connor C, Jaski B, Steinberg J, Lwin A, et al. Mode of death in advanced heart failure: the Comparison of Medical, Pacing, and Defibrillation Therapies in Heart Failure (COMPANION) Trial. J Am Coll Cardiol. 2005;46(12):2329-34. Erratum in: J Am Coll Cardiol. 2008;51(22):2197. 3. Achilli A, Peraldo C, Sassara M, Orazi S, Bianchi S, Laurenzi F, et al; SCART Study Investigators. Prediction of response to cardiac resynchronization therapy: the selection of candidates for CRT (SCART) study. Pacing Clin Electrophysiol. 2006;29 Suppl 2:S11-9. 4. Foley PW, Leyva F, Frenneaux MP. What is treatment success in cardiac resynchronization therapy? Europace 2009;11 Suppl 5:v58-65. 12. Mangiavacchi M, Gasparini M, Faletra F, Klersy C, Morenghi E, Galimberti P, et al. Clinical predictors of marked improvement in left ventricular performance after cardiac resynchronization therapy in patients with chronic heart failure. Am Heart J. 2006;151(2):477.e1-477. 5. 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Predictors of a positive response to biventricular pacing in patients with severe heart failure and ventricular conduction delay. Pacing Clin Electrophysiol. 2007;30(8):970-5. 7. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr. 2009;10(2):165-93. 8. Boidol J, Średniawa B, Kowalski O, Szulik M, Mazurek M, Sokal A, et al; Triple-Site Versus Standard Cardiac Resynchronisation Trial (TRUST CRT) Investigators. Many response criteria are poor predictors of outcomes after cardiac resynchronization therapy: validation using data from the randomized trial. Europace. 2013;15(6):835-44. 9. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-49. 15. Shen X, Nair CK, Aronow WS, Holmberg MJ, Reddy M, Anand K, et al. A new baseline scoring system may help to predict response to cardiac resynchronization therapy. Arch Med Sci. 2011;7(4):627-33. 16. Verhaert D, Grimm RA, Puntawangkoon C, Wolski K, De S, Wilkoff BL, et al. Long-term reverse remodeling with cardiac resynchronization therapy: results of extended echocardiographic follow-up. J Am Coll Cardiol. 2010;55(17):1788-95. 17. Martinelli Filho M, Baggio Júnior JM, Nishioka SA, Pedrosa A, Torres GG, Escarião A, et al. Cardiac resynchronization in long-term follow up: analysis of clinical response predictors. Relampa. 2006;19(1):45-52. 18. Gradaus R, Stuckenborg V, Loher A, Kobe J, Reinke F, Gunia S, et al. Diastolic filling pattern and left ventricular diameter predict response and prognosis after cardiac resynchronisation therapy. Heart. 2008;94(8):1026-31. Arq Bras Cardiol. 2015; 105(4):399-409 408 Rocha et al. Development of predictive models in CRT Original Article 19. Kandala J, Altman RK, Park MY, Singh JP. Clinical, laboratory, and pacing predictors of CRT response. J Cardiovasc Transl Res. 2012;5(2):196-212. 20. Pr aus R , H am an L , Tauchm an M, Pud i l R , B laha V, Par i zek P. Echocardiographic changes after cardiac resynchronisation therapy. Kardiol Pol. 2012;70(12):1250-7. 21. Leong DP, Hoke U, Delgado V, Auger D, Witkowski T, Thijssen J, et al. Right ventricular function and survival following cardiac resynchronisation therapy. Heart. 2013;99(10):722-8. 22. Nunes Mdo C, Rocha MO, Ribeiro AL, Colosimo EA, Rezende RA, Carmo GA, et al. Right ventricular dysfunction is an independent predictor of survival in patients with dilated chronic Chagas’ cardiomyopathy. Int J Cardiol. 2008;127(3):372-9. 23. Ogunyankin KO, Puthumana JJ. Effect of cardiac resynchronization therapy on right ventricular function. Curr Opin Cardiol. 2010;25(5):464-8. 24. Aksoy H, Okutucu S, Aytemir K, Kaya EB, Tulumen E, Evranos B, et al. Improvement in right ventricular systolic function after cardiac resynchronization therapy correlates with left ventricular reverse remodeling. Pacing Clin Electrophysiol. 2011;34(2):200-7. 25. Freitas HF, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a Brazilian hospital-based cohort of 1220 outpatients with heart failure: role of Chagas’ heart disease. Int J Cardiol. 2005;102(2):239-47. 26. Linde C, Daubert C, Abraham WT, St John Sutton M, Ghio S, Hassager C, et al; REsynchronization reVErses Remodeling in Systolic left vEntricular 409 Arq Bras Cardiol. 2015; 105(4):399-409 dysfunction (REVERSE) Study Group. Impact of ejection fraction on the clinical response to cardiac resynchronization therapy in mil heart failure. Circ Heart Fail. 2013;6(6):1180-9. 27. Kronborg MB, Mortensen PT, Kirkfeldt RE, Nielsen JC. Very long term followup of cardiac resynchronization therapy: clinical outcome and predictors of mortality. Eur J Heart Fail. 2008;10(8):796-801. 28. Van Boven N, Bogaard K, Ruiter J, Kimman G, Theuns D, Kardys I, et al. Functional response to cardiac resynchronization therapy is associated with improved clinical outcome and absence of appropriate shocks. J Cardiovasc Electrophysiol. 2013;24(3):316-22. 29. Cleland J, Freemantle N, Ghio S, Fruhwald F, Shankar A, Marijanowski M, et al. Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response a report from the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial. J Am Coll Cardiol. 2008;52(6):438-45. 30. Rickard J, Cheng A, Spragg D, Cantillon D, Baranowski B, Varma N, et al. A clinical prediction rule to identify patients at heightened risk for early demise following cardiac resynchronization therapy. J Cardiovasc Electrophysiol. 2014;25(3):278-82. 31. Van Rees JB, de Bie MK, Thijssen J, Borleffs CJ, Schalij MJ, van Erven L. Implantation-related complications of implantable cardioverterdefibrillators and cardiac resynchronization therapy devices: a systematic review of randomized clinical trials. J Am Coll Cardiol. 2011;58(10):995-1000. Back to the Cover Original Article Changes in Medical Management after Coronary CT Angiography Vânia Mairi Naue, Gabriel Camargo, Letícia Roberto Sabioni, Ronaldo de Souza Leão Lima, Maria Eduarda Derenne, Andréa Rocha de Lorenzo, Monica Di Calafiori Freire, Clério Francisco Azevedo Filho, Elmiro Santos Resende, Ilan Gottlieb CDPI - Clínica de Diagnóstico por Imagem Abstract Introduction: Coronary computed tomography angiography (CCTA) allows for non-invasive coronary artery disease (CAD) phenotyping. There are still some uncertainties regarding the impact this knowledge has on the clinical care of patients. Objective: To determine whether CAD phenotyping by CCTA influences clinical decision making by the prescription of cardiovascular drugs and their impact on non-LDL cholesterol (NLDLC) levels. Methods: We analysed consecutive patients from 2008 to 2011 submitted to CCTA without previous diagnosis of CAD that had two serial measures of NLDLC, one up to 3 months before CCTA and the second from 3 to 6 months after. Results: A total of 97 patients were included, of which 69% were men, mean age 64 ± 12 years. CCTA revealed that 18 (18%) patients had no CAD, 38 (39%) had non-obstructive (< 50%) lesions and 41 (42%) had at least one obstructive ≥ 50% lesion. NLDLC was similar at baseline between the grups (138 ± 52 mg/dL vs. 135 ± 42 mg/dL vs. 131 ± 44 mg/dL, respectively, p = 0.32). We found significative reduction in NLDLC among patients with obstrctive lesions (-18%, p = 0.001). We also found a positive relationship between clinical treatment intensification with aspirin and cholesterol reducing drugs and the severity of CAD. Conclusions: Our data suggest that CCTA results were used for cardiovascular clinical treatment titration, with especial intensification seen in patients with obstructive ≥50% CAD. (Arq Bras Cardiol. 2015; 105(4):410-417) Keywords: Coronary Artery Disease; Diagnostic Imaging; Atherosclerosis/physiopathology; Therapeutics. Introduction Cardiovascular clinical treatment titration in patients without prior diagnosis of coronary artery disease (CAD) is based on patient cardiovascular risk estimated by clinical variables, being generally indicated in patients classified as high risk1. Coronary computed tomography angiography (CCTA) is generally used with high accuracy2 for obstructive CAD diagnosis and, as it allows three-dimensional evaluation of the wall vessel, it also provides non-obstructive CAD visualization, showing good correlation with intravascular ultrasound3. The main therapeutic intervention used in patients with atherosclerosis, as a means of primary prevention of ischemic events, are cholesterol-lowering drugs (CLD)4. However, the number needed to treat (NNT) varies according to the studied population and low cardiovascular risk patients benefit less than those at high cardiovascular risk. However, the potential for adverse effects remains similar1,5,6. According to the variation Mailing Address: Vania Mairi Naue • Rua H, 53, Parque Dez. Postal Code 69050-230, Manaus, AM – Brasil E-mail: [email protected], [email protected] Manuscript received August 23, 2014; revised manuscript May 06, 2015; accepted May 06, 2015. DOI: 10.5935/abc.20150088 410 of baseline risk, the NNT may vary from 24 to 549 treated patients, for the reduction of an event5. Studies show that approximately 20% to 30% of asymptomatic patients considered at low cardiovascular risk (event rate less than 10% in ten years) have atherosclerosis in the coronary computed tomography angiography (CCTA)7,8 and it is known that these findings are associated with increased incidence of cardiovascular events, independently from and in addition to the clinical risk factors9,10. However, it is still uncertain how doctors use the results of CCTA in the clinical treatment titration of their patients. This study aimed to evaluate the changes in both the prescription and plasma cholesterol levels in the short term, after a CCTA assessment in patients with no prior diagnosis of CAD, according to the severity of CAD found at the examination. Methods A retrospective and analytical cohort was analyzed, and the project was approved by the Research Ethics Committee of HUCFF/FM/UFRJ, under protocol number 27341114.7.0000.5257. All patients (123) submitted to CCTA between the years 2008 and 2011 in a cardiac imaging laboratory in Rio de Janeiro, with no prior diagnosis of CAD (i.e. without Naue et al. Impact of Coronary CT angiography on clinical treatment Original Article myocardial revascularization history or AMI and no previous CCTA) and had cholesterol measurement recorded at two different times: one up to three months before the CCTA (index measurement), followed by a second sample taken from three to six months after the CCTA (follow-up measurement) were included in this analysis. This period was chosen due to the homogeneity of image acquisition protocols used at that time. In this institution, a physician from the team performs an interview with the patient prior to the examination, in which information such as anthropometric data, indication for the examination, risk factors, current medications and previous examinations is recorded. Access to the existing clinic database was requested for this study. The analyzed items were: gender, age, CCTA indication (asymptomatic, typical pain, atypical pain or dyspnea), risk factors (hypertension, diabetes, dyslipidemia, sedentary lifestyle, smoking and family history), medications being used in the index consultation and at the second consultation, such as antiplatelet drugs and CLD and the cholesterol levels both at the index and the second consultations. CLD were defined as any drug of the statins or fibrates classes. Patients whose medical records did not provide the necessary data for this analysis, such as current medication or present risk factors were excluded from the analysis. Additionally patients whose imaging tests had inadequate quality for analysis in three or more coronary segments were also excluded. The primary outcome of this study was non-LDL cholesterol (NLDLC) reduction after assessment by CCTA in the pre-specified period (three to six months). The NLDLC was considered as the sum of VLDL cholesterol and LDL cholesterol. It was decided to restrict the follow‑up to such short period in order to minimize the influence of factors rather than the CCTA outcome on therapeutic decision‑making. As a secondary outcome, the change in medications prescription after the CCTA outcome. was assessed. CCTA images were acquired using 256-channel devices (BrillianceTIC, Philips Healthcare®, Cleveland, Ohio) or one of the two 64-channel scanners (Brilliance64, Philips Healthcare®, Cleveland, Ohio, SomatomSensation 64, Siemens Healthcare®, Erlangen). For CCTA acquisition, venous and oral beta-blockers were used aiming to reduce HR to less than 60 bpm. Isosorbide dinitrate, 0.4 mg, sublingually was also administered to all patients without contraindications, 3 to 5 minutes prior to image acquisition. Image analysis was performed by a single expert that had broad experience with the method. The coronary plaques were defined as the presence of image with soft tissue density ≥ 1 mm2 compatible with coronary atheromatosis, whereas the degree of luminal stenosis was defined as the ratio between the smallest luminal diameter at the lesion and the reference diameter closest to the lesion. Patients were classified according to the highest degree of coronary stenosis found, considering: I - no plaque; II - non‑obstructive plaques only (< 50% in stenosis); III - at least one obstructive plaque (≥ 50% in stenosis). To measure the cholesterol-lowering effects, a positive CCTA was considered the one with any evidence of coronary atherosclerosis. Statistical analysis The following software programs were used for data processing: SPSS version 19.0 and Microsoft Excel 2000© (9.0.2812). To calculate sample size, we considered a difference of 30% in LDL cholesterol between patients with positive (estimated at 30% of the sample) and negative CCTA (70% of the sample). The estimated “n” was 90 patients for an alpha error of 0.05 and beta of 0.25. Quantitative data showed normal distribution through the Kolmogorov-Smirnov test with a significance level of 5%. Continuous variables were expressed as mean ± standard deviation and were compared using paired and unpaired Student’s t test, as appropriate. Categorical variables were expressed as amounts and proportions and were compared using the Chi-square and Fisher tests, when appropriate. p values < 0.05 were considered significant. Patients were divided into three groups: without CAD, non-obstructive CAD (< 50% in stenosis) and obstructive CAD (≥ 50% in stenosis). Statistical analysis was carried out for each group separately and the two periods were compared by paired-t test. Results Of a total of 123 patients that had two cholesterol measurements recorded in the proposed time period, 24 were excluded due to incomplete filling out of medical records and two due to poor quality of the images, resulting in 97 patients included in the analysis, of which 67 (69%) were men. The mean age was 64 ± 12 years. Nineteen percent had no risk factor; 15% had only one risk factor; 35% had two or three risk factors; and 31% had four or more risk factors for CAD. CCTA was performed to assess pain with angina characteristics in 10% of patients; atypical pain in 16%; dyspnea or decreased functional capacity of 23%; and 51% of patients were asymptomatic. The clinical characteristics are described in Table 1. CCTA was normal in 18 (18%) patients, showed no obstructive CAD < 50% in 38 (39%) patients and obstructive CAD ≥ 50% in 42 (43%) patients. Cholesterol levels NLDLC significantly decreased from 136 ± 44 mg/dL in the first to 117 ± 38 mg/dL in the follow-up visit (p = 0.007), a 14% decrease in the average of the general population (Chart 1). Between the index and the follow-up visit, the variation in NLDLC in the group with negative CCTA was 4% (137 ± 53 mg/dL to 132 ± 39 mg/dL, p = 0.7), in the group with non‑obstructive CCTA was 10% (135 ± 42 mg/dL to 121 ± 39 mg/dL, p = 0.07) and the in group in which CCTA showed obstructive lesions was 18% (130 ± 44 mg/dL to 107 ± 36 mg/dL, p = 0.001). There was no significant difference in NLDLC values between the different groups of CCTA in the index visit (p = 0.3). Arq Bras Cardiol. 2015; 105(4):410-417 411 Naue et al. Impact of Coronary CT angiography on clinical treatment Original Article Table 1 – Population characteristics of individuals submitted to CCTA Variables Age (years) 64.2 ± 12 Gender Male 67(69) Female 30(31) Hypertension 57(58) Risk Factors DM 23(24) DLP 57(58) Family history 35(36) Smoking 13(13) Sedentary life style 17(17) Without pain 50 (51) Indications of CCTA Typical angina 10(10) Atypical angina 16(16) Dyspnea and exercise intolerance 11(11) DM: Diabetes mellitus; DLP: Dyslipidemia; CCTA: Coronary computed tomography angiography. Chart 1 – Difference of NLDLC levels pre and post-CCTA when divided into categories according to CAD severity (without CAD, lesions < 50% and lesions ≥ 50%). CAD: Coronary artery disease; NLDLC: Non-LDL cholesterol. 412 Arq Bras Cardiol. 2015; 105(4):410-417 Naue et al. Impact of Coronary CT angiography on clinical treatment Original Article Of the 42 individuals that had lesions ≥ 50% in stenosis, 32 (76%) showed LDL values < 100 mg/dL at the second visit (Chart 2). This study allowed to evaluate, in the real world and in the short term, the impact of CCTA results on drug therapy, evaluating trends in cholesterol levels and the use of medications shortly after the CCTA results. Medication use The analysis of this impact on clinical therapy is relevant, as the benefit of antiplatelet agents and CLD is directly associated with the patient’s cardiovascular risk. It has been demonstrated that in an asymptomatic population with zero calcium score, the NNT with aspirin is approximately two thousand individuals to prevent one major cardiovascular event, while the number needed to harm (NNH) is 442 individuals, demonstrating a much greater risk in the prescription of aspirin than its benefits15. A cost-effectiveness analysis showed that the aspirin is only cost-effective in men with clinical risk in ten years greater than 10% and in women when the risk is > 15%16. In our study, aspirin was started in 5% of patients after a completely normal CCTA result, which probably would not be indicated, considering that the annual risk is < 0.1% of combined coronary events9,16,17. Conversely, we observed that 22% of patients with positive CCTA (obstructive or not) in our study started aspirin therapy. Considering only the 64 (65%) patients that did not use the CLD in the index visit, 28 (43%) started using them after CCTA, when the latter showed at least one coronary segment with lesion (obstructive or not) versus 2 (3%) patients with normal CCTA (p < 0.05). Considering only the 34 patients that used CLD in the index visit, 8 (23%) had negative CCTA (of which 3 discontinued use of CLD) and 5 had at least one coronary segment with lesion (obstructive or not) and discontinued these drugs. Chart 3 illustrates the dynamics between treatment with CLD and CCTA results. Aspirin use was started after the normal CCTA result in 2 (11%) patients and in 17 (21%) patients with positive CCTA (Chart 4). Importantly, 15 (36%) patients with obstructive lesions were not using any antiplatelet agents on the second visit. The combined use of aspirin and CLD was started at 0%, 2% and 19% of patients with negative CCTA, with non-obstructive lesions and lesions ≥ 50%, respectively (p = 0.004), and only one of the two drugs alone in 18%, 24% and 38% respectively (p = 0.006). Discussion CAD phenotyping by CCTA has a relevant prognostic impact and improves risk classification for cardiovascular events when compared to the classic risk factors11-14. The proportion of patients that initiated therapy with CLD has increased significantly as the severity of CAD increased (normal CCTA = 12%; non-obstructive CAD = 24%; CAD ≥ 50% = 43%), demonstrating that in the real world there is an agreement between therapy intensity and the severity of CAD lesions. There was no reduction in NLDLC in patients with normal CCTA, which occurred in patients with obstructive lesions ≥ 50%. There was a NLDLC decrease trend Chart 2 – Changes in the decrease of total cholesterol levels, its fractions and triglycerides, pre and post-CCTA. NLDLC: Non-LDL cholesterol; HDL: High-density lipoprotein; NHDL: Non-high-density lipoprotein; LDL: Low-density lipoprotein; VLDL: Very low-density lipoprotein. Arq Bras Cardiol. 2015; 105(4):410-417 413 Naue et al. Impact of Coronary CT angiography on clinical treatment Original Article Chart 3 – Changes in therapy with cholesterol-lowering drugs, according to CAD severity, demonstrated by CCTA (without CAD, lesions < 50% and lesions ≥ 50%). CAD: Coronary artery disease; CLD: Chodesterol lowering drugs. Chart 4 – Aspirin prescription as primary preventive therapy, pre and post-CCTA. CAD: Coronary artery disease; ASA: Aspirim. 414 Arq Bras Cardiol. 2015; 105(4):410-417 Naue et al. Impact of Coronary CT angiography on clinical treatment Original Article in patients with non-obstructive lesions, and these data are corroborated by other studies 9,15,18,19. Among the 42 patients with obstructive CAD ≥ 50%, 12 (29%) maintained the prescription of statin and/or aspirin and 24 (57%) started the use of the two drugs or added one of the two to previous therapy, after the CCTA result, corroborating the results of other published studies19-23. A meta-analysis24 involving 170,000 patients showed that a 1-mmol/L decrease in LDL cholesterol was able to reduce the risk of cardiovascular events by 20%. We observed in this study that 28 (29%) showed LDL decrease > 1 mmol/L, which implies a reduction of cardiovascular risk in this group. The reduction in all lipid fractions, except HDL, demonstrates not only the potent LDL-lowering effect of the CLD, as well as reductions more related to changes in dietary habits, as demonstrated by the reduction in triglycerides 1,4,19. Of all patients considered at high risk by CCTA (lesion ≥ 50%), 32 (76%) reached the LDL target < 100 mg/dL. This result contrasts with the data collected by Vacanti et al.25in a Brazilian population, in which it was found that only 30% of patients had LDL values within the Guideline’s targets. The stratification of cardiovascular risk made by visualization of coronary atherosclerosis has previously demonstrated to have greater impact on medication adherence and change in clinical management than the risk stratification by clinical scores20,21,26-29. The results of this study indirectly corroborate that, showing patients with higher atherosclerotic disease severity have higher reduction in cholesterol levels. Hulten et al.26 recently addressed the impact of CCTA findings on drug therapy in a study that evaluated 2,839 patients with a mean follow-up of 3.6 years, and found that after the CCTA examination there was an increase in the prescription of aspirin even in the group without CAD (10‑46% vs. 17%-72% vs. 25%-89%, p = 0.001). This study also found statin prescription intensification after the CCTA results. After the CCTA results, 36% of patients without CAD were using CLD and 18% had been prescribed therapy intensification; in patients with non-obstructive lesions < 50%, 72% were using CLD and in 42%, prescription intensified occurred; in patients with lesions > 50% in stenosis, of the total 90% in use of statin, there was an intensification of 63%. Among the assessed patients, two of them are especially illustrative for the analysis of the results. The first one, aged 54, had fatigue on moderate exertion, hypertension and did not use statins or aspirin. He had NLDLC of 201 mg/dL in the index visit. The CCTA disclosed 50% -70% lesion in the middle third of the Anterior Descending Artery (ADA). In the follow-up assessment, the patient was using aspirin and CLD and the NLDLC had decreased to 140 mg/dL. The second patient, aged 66 years, had atypical chest pain, diabetes, dyslipidemia, was hypertensive and sedentary, was using aspirin and CLD in the index visit had a NLDLC of 120 mg/dL. The CCTA disclosed a 50% -70% lesion in the proximal third of the ADA. At the second assessment, the NLDLC had decreased to 100 mg/dL with medication maintenance. The two patients were at high risk for cardiovascular events, but in the second case, there was not so marked decrease in NLDLC values, probably because the patient was already undergoing medical treatment and the medication was only optimized after CCTA the result. Study limitations Some limitations should be considered in our study, which was observational and retrospective, performed at a single diagnostic imaging center, with two CTs of different manufacturers, with a relatively small sample. Because we selected patients with two sequential cholesterol measurements, there may have been some selection bias, preferably excluding patients that had not started treatment with CLD and therefore had no clinical need to collect a new blood sample for lipid level measurement. Therefore, the results are more relevant for the analysis of factors involved in the prescription of antiplatelet agents and CLD than for the lack of their indication. Conclusions The severity of CAD positively correlated with the decrease in cholesterol levels and more frequent prescription of antiplatelet agents and CLD. These data suggest that the CCTA result can influence drug treatment approach in the short term in the real world. Author contributions Conception and design of the research: Camargo G, Derenne MR, Resende ES, Gottlieb I; Acquisition of data: Naue VM, Freire MDC, Sabioni LR; Analysis and interpretation of the data: Naue VM, Camargo G, de Lorenzo AR, Lima RSL, Gottlieb I; Statistical analysis: Azevedo Filho CF, Gottlieb I; Writing of the manuscript: Naue VM, Camargo G, Gottlieb I; Critical revision of the manuscript for intellectual content: Gottlieb I. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. 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Impact of Coronary CT angiography on clinical treatment Original Article Arq Bras Cardiol. 2015; 105(4):410-417 417 Back to the Cover Review Article A Systematic Review on Sleep Duration and Dyslipidemia in Adolescents: Understanding Inconsistencies Gabriela de Azevedo Abreu, Laura Augusta Barufaldi, Katia Vergetti Bloch, Moyses Szklo Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ – Brazil Introduction Although many questions about the role of sleep remain unanswered, it is known that sleep is not only a physiological function, but also performs an important role in promoting growth, maturation and general health of children and adolescents1, contributing significantly to cognitive, emotional functions and school performance2. Currently, there is a tendency for the young population to have irregular sleeping hours, with differences in bed and wake-up times between weekdays and weekends, especially as they get older2-4. There is a growing interest about the impact of sleep and its disorders on regulation of inflammatory processes and morbidities, particularly in the context of metabolic and cardiovascular diseases (CVD) and their complications1. In children and adolescents, cross-sectional 5-7 and prospective8,9 studies have shown an association between overweight or obesity and few hours of sleep. In adults, there is evidence supporting this association, as well as correlations with insulin resistance, diabetes and cardiovascular diseases10-15. Few hours of sleep can also play a role in the etiology of a key risk factor to CVD, dyslipidemia12,14,15. Physiologically, sleep reduction is associated with hormonal alterations that may promote the development of an atherogenic lipid profile, including increase of cortisol and ghrelin and reduction of leptin levels, in addition to sympathovagal responses16-18. In order to obtain more information about the association between lipid metabolism alterations and sleep duration specifically in adolescents, we have performed a systematic review of the literature. Methods This systematic review was based on the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‑analyses (PRISMA) statement19. The search was performed in the electronic databases Medline via Pubmed20 Lilacs21, Web of Science22, Scopus23 and Adolec 24. Keywords Sleep; Dyslipidemias; Adolescent; Review. Mailing Address: Gabriela de Azevedo Abreu • Universidade Federal do Rio de Janeiro Avenida Horácio Macedo, S/N – Cidade Universitária. Postal Code 21941-598, Rio de Janeiro, RJ, Brasil, Rio de Janeiro, RJ – Brazil E-mail: [email protected] Manuscript received January 18, 2015; revised manuscript June 29, 2015; accepted July 01, 2015. DOI: 10.5935/abc.20150121 418 Selection of the descriptors used in the review process was made through MeSH (Pubmed’s Medical Subject Headings). The search was performed in English, using three concept blocks: the first with terms related to sleep (sleep); the second with terms related to adolescence (adoles*, teen*, student*, youth, young); and the third with terms related to lipids (lipid*, lipemia*, cholesterol, HDL, LDL, triglyceride*, lipoprotein*, hypercholesterolemia*, hypercholesteremia*, dyslipidemia*, dyslipoproteinemia*, hyperlipidemia*, hyperlipemia*, “high density lipoprotein cholesterol”, “low density lipoprotein cholesterol”). The Boolean operator “OR” was used for the combination of the descriptors within each block and the Boolean operator “AND” was used to combine the blocks amongst themselves. The truncation of terms was applied when necessary. No search limits were used for date, language, study design or sample size. The search was carried out in August 2014, contemplating articles published up to that date. Table 1 shows the search strategy used in each database. Criteria for article inclusion in the systematic review were as follows: (a) studies on adolescents older than 10 years old; (b) studies that evaluated the association between sleep duration in hours and any lipid marker; (c) original research article. Articles evaluating any kind of sleep-related disorder, review studies, and experimental studies with animals were excluded. It was decided not to include theses, dissertations, and monographs. We reviewed the bibliographic references of reviews, systematic reviews, and meta-analyses that were found in the databases. The articles were selected by two epidemiologists (GAA and LAB), initially based on title reading and then on abstract reading. Of the selected abstracts, the full articles were reviewed. In case of disagreement between the two reviewers with regard to the inclusion criteria, the title, and the abstract or the full article was maintained to be further evaluated. In case of disagreement with regard to the inclusion criteria, a third person was consulted. Data from included articles were extracted independently, in duplicate (GAA and LAB), using a standard form. After extraction, data were compared and discussed. We extracted information about authorship, publication date, study place, population study, type of study, methods of sleep duration measurement and lipid profile assessment, sleep duration in hours, lipid markers, measure of association used to evaluate the correlation between hours of sleep and lipid profile, and variables used for adjustment of regression models. We used an adaptation of the Newcastle-Ottawa (NOS) Quality Assessment Scale for Case-Control and Cohort Studies25, from the Ottawa Hospital Research Institute, to assess the quality of the longitudinal study included in this review. We also used the same scale adapted by Flynn et al26 to assess the quality of cross-sectional studies. Abreu et al. Sleep hours and lipid profile in adolescents Review Article Table 1 – Search strategy used for each database Pubmed (sleep*[Title/Abstract] AND (adoles* OR teen* OR student* OR youth OR young[Title/Abstract]) AND (lipid* OR lipemia* OR cholesterol OR HDL OR LDL OR VLDL OR triglyceride* OR lipoprotein* OR hypercholesterolemia* OR hypercholesteremia* OR dyslipidemia* OR dyslipoproteinemia* OR hyperlipidemia* OR hyperlipemia* OR "high density lipoprotein cholesterol" OR "low density lipoprotein cholesterol"[Title/Abstract])) Lilacs sleep$ and (adoles$ OR teen$ OR student$ OR youth OR young) and (lipid$ OR lipemia$ OR cholesterol OR HDL OR LDL OR VLDL OR triglyceride$ OR lipoprotein$ OR hypercholesterolemia$ OR hypercholesteremia$ OR dyslipidemia$ OR dyslipoproteinemia$ OR hyperlipidemia$ OR hyperlipemia$ OR "high density lipoprotein cholesterol" OR "low density lipoprotein cholesterol") Adolec sleep$ [Words] and adoles$ OR teen$ OR student$ OR youth OR young [Words] and lipid$ OR lipemia$ OR cholesterol OR HDL OR LDL OR VLDL OR triglyceride$ OR lipoprotein$ OR hypercholesterolemia$ OR hypercholesteremia$ OR dyslipidemia$ OR dyslipoproteinemia$ OR hyperlipidemia$ OR hyperlipemia$ OR "high density lipoprotein cholesterol" OR "low density lipoprotein cholesterol" [Words] Web of Science (Topic(sleep*) AND Topic(adoles* OR teen* OR student* OR youth OR young) AND Topic(lipid* OR lipemia* OR cholesterol OR hdl OR ldl OR vldl OR triglyceride* OR lipoprotein* OR hypercholesterolemia* OR hypercholesteremia* OR dyslipidemia* OR dyslipoproteinemia* OR hyperlipidemia* OR hyperlipemia* OR "high density lipoprotein cholesterol" OR "low density lipoprotein cholesterol")) Scopus (TITLE-ABS-KEY(sleep*) AND TITLE-ABS-KEY(adoles* OR teen* OR student* OR youth OR young) AND TITLE-ABS-KEY(lipid* OR lipemia* OR cholesterol OR HDL OR LDL OR VLDL OR triglyceride* OR lipoprotein* OR hypercholesterolemia* OR hypercholesteremia* OR dyslipidemia* OR dyslipoproteinemia* OR hyperlipidemia* OR hyperlipemia* OR "high density lipoprotein cholesterol" OR "low density lipoprotein cholesterol")) Due to the great amount of methodological heterogeneity observed between the assessed studies, a narrative approach to synthesize the results of studies included in the present systematic review was considered a better strategy. Results The flowchart showing the selection process is shown in Figure 1. By the end of the evaluation process, of the 859 articles chosen after the removal of duplicates, 25 were submitted to full evaluation. Seven articles met the inclusion criteria at the end of the process. Table 2 shows the relevant characteristics of the selected studies. Of the seven studies included, only one27 is longitudinal. The other six studies are cross-sectional. Five of the 7 studies27-31 included students. Sample sizes varied considerably, from 699 in the study by Rey-López et al30 to 14,267 adolescents in the study by Gangwisch et al27. All studies used questionnaires to obtain hours of sleep. The variable “sleep duration” was used as continuous in three studies27,29,30; whereas the other studies used different categories to classify sleep duration. To obtain the lipid profiles, five studies collected venous blood28,30-33, one collected capillary blood29, and another used self-reported information27. Five studies measured total cholesterol28-32 and HDL-cholesterol28-30,32,33, four measured triglycerides28,30,31,33, and two evaluated LDL-cholesterol28,31. Almost all studies controlled for gender27,28,30,33 and age27,28,30-33; waist perimeter was adjusted for in two28,29, physical activity in four27,30,31,33, Tanner stage in two28,32, maternal level of education in two31,32, socioeconomic status in two30,31, body mass index (BMI) in one28, and caloric intake in one33. The methodological quality assessment of the seven included studies is shown in Table 3. Only two cross-sectional studies28,31 obtained four points out of six in the bias risk evaluation. The longitudinal study showed a moderate risk of bias27. Table 4 shows the main results of the associations found and the control variables each study used. Considering the seven studies included, only in three an association was found between hours of sleep and lipid profile27,28,33. Two studies found that shorter sleep duration was associated with a worse lipid profile (total cholesterol and LDL-cholesterol)27,28, and the results of the third one33 showed that long sleep duration was associated with high triglyceride levels. The other four studies29-32 did not find any association. In four studies 27,29,31,33 the odds ratio was reported, whereas the other studies reported28,30,32 β coefficients from regression analysis. Discussion The present systematic review showed lack of consistent evidence regarding the association between sleep duration and lipid profile in adolescents. Few studies were found and some had methodological limitations. There was great heterogeneity regarding the classification and type of analysis of sleep duration and lipid metabolism markers, which probably contributed to the inconsistency of the observed results. Concerning heterogeneity between studies, this systematic review included studies that evaluated the outcome using different methods (self-reported27, capillary blood sample29, venous blood sample28,30-33) or with different interval duration between the measure of exposition and the outcome32. Gangwisch et al 27 did not exclude adolescents with dyslipidemia at baseline, thus, the incidence of dyslipidemia in adolescents could not be ascertained. Moreover, as the outcome established was self-reported, and the diagnosis of dyslipidemia depends on access to medical care, a bias may have occurred if adolescents from different socioeconomic status have different sleep habits. Arq Bras Cardiol. 2015; 105(4):418-425 419 Abreu et al. Sleep hours and lipid profile in adolescents Review Article Figure 1 – Flowchart of article selection. All studies included in this systematic review obtained information about sleep duration based on questionnaires, a method frequently used in sleep research because of its easy application and low cost. However, the validity of the information obtained through questionnaires is of concern, particularly when the tools have not been submitted to a validation process. Adolescents may report only socially desirable sleeping and waking up hours 34. Although all studies used questionnaires, sleep duration evaluation was also heterogeneous: one study asked the parents about the adolescent´s sleep duration31, one used pre-defined categories of bedtime and waking-up time32, while the others asked about sleep duration in an open question27-30,33. Actigraphy – based on monitoring of activities – has been established as a valid and reliable method to evaluate sleep-wake patterns in children, adolescents and adults35,36. Objective methods for hours of sleep quantification in a population-based study are difficult to use, particularly in studies with relatively large samples. Kong et al28 used actigraphy in only about 7% of their study sample (138 out of 2,053) and demonstrated a reasonable agreement between actigraphy and adolescents’ self-reports (intra-class correlation coefficient = 0.72, CI 95%: 0.61-0.80). In the studies included in this review, duration of sleep was measured in two different ways, as a continuous27,29,30 or categorical variable28,31-33. The lack of consensus about the best 420 Arq Bras Cardiol. 2015; 105(4):418-425 cut-off point to define short sleep duration makes it difficult to compare different studies, which would become easier if sleep duration were used as a continuous variable. The present systematic review included a longitudinal study with important limitations and the cross-sectional studies showed associations in different directions. It was not possible to evaluate publication bias, due to the small number of studies identified. In summary, it is still uncertain whether there is an association between hours of sleep and lipid profile in adolescents. Heterogeneity regarding the way sleep hours were classified and analyzed, as well as the use of different lipids analytes may have contributed for the inconsistency of findings. More studies should be conducted on this issue to clarify the nature of this association and the involved biological mechanisms. These future studies must be longitudinal, use sleep duration as a continuous variable and consider the role of potential confounders or effect modifiers. Care must be taken to avoid over-adjustment, including variables that can be intermediary in the association between sleep duration and dyslipidemia such as BMI and food consumption. Because of its strong association with cardiovascular disease in adults, it is important to identify and modify factors that are associated with lipid profile15 in adolescents. If short sleep duration is responsible for an unfavorable lipid profile, interventions that improve the quality and duration of sleep may contribute to decrease long-term cardiovascular risk. Abreu et al. Sleep hours and lipid profile in adolescents Review Article Table 2 – Main characteristics of the selected studies Reference/ Country Gangwisch et al.27, 2010/ United States Study design/ Collection date Study population Longitudinal Students, with national representativeness n = 14,257 Wave I: 1994-95 Wave II: 1996 Wave III 2001-02 48.7% male Age 11-21 years boys ≅ 15.8 years old girls ≅ 15.9 years old Method for obtaining hours of sleep Questionnaire Exposure classification (hours of sleep) Method for lipid profile evaluation Outcome (alterations of lipids) Continuous Questionnaire/ “Has any doctor ever (between the 1st and the 3rd wave) said you have high cholesterol?” Dichotomous variable Yes/No Blood collection (TC, TG, HDL, LDL cholesterol) Hypercholesterolemia Comparison of extreme quintiles TC ≥ 5.2 mmol/L LDL ≥ 2.6 mmol/L HDL <1.0 mmol/L TG ≥ 1.7 mmol/L Questionnaire7 Kong et al28, 2011/ Hong Kong Cross-sectional/ February 2007 – April 2008 Students* n = 1,274 12-20 years old† Actigraphy in sub-sample (n = 138) Student n = 3,372 Narang et al , 2012/ Canada 29 Cross-sectional/ 2009-2010 Continuous ≅ 14.6 years old‡ Questionnaire37,38 48.9% male Azadbakht et al31, 2013/ Iran Cross-sectional Data from CASPIAN III// Students n = 5,528 General population n = 1,481 Berentzen et al32, 2014/ Netherlands Cross-sectional 49% male Rey-López et al30, 2014/ Greece, Germany, Belgium, France, Hungary, Italy, Sweden, Austria, Spain Cross-sectional/ 2006-2007 Lee et al, 2014/ Republic of Korea33 Cross-sectional/ 2007-2008 Students n = 699 52% male General population n = 1,187 53% male <6.5h: 20% 6.5-8h: 40% >8h: 20% Quartiles ≅ 14.69 (2.45) years old boys Capillary blood collection without fasting (TC and HDL cholesterol) TC Borderline: 4.4-5.1 mmol/L: High: ≥ 5.2 mmol/L Non-HDL-cholesterol§ Borderline: > 3.10 to 3.75 mmol/L High: > 3.75 mmol/L Questionnaire < 5h 5 to 8h > 8h Blood collection (TC, TG and LDL) Abnormal serum lipids were defined as TC, LDL-C and or TG higher than the level corresponding to the age and gender-specific 95th percentile39 Mean age at completion of the questionnaire 11.4 (± 0.3) years Mean age at the moment of medical examination 12.7 (± 0.4) years Questionnaire 7.5–9.5 h 10–10.5 h (ref. cat.) 11–12.5 h Blood collection (TC and HDL cholesterol) Continuous variable (mM) ≅ 14.8 years old Questionnaire Continuous variable Blood collection (TG, TC and HDL cholesterol) Continuous variable (mg/dL) ≅ 15 years old Questionnaire ≤ 5h 6-7h 8-9h (ref. cat.) ≥ 10h Blood collection (TG and HDL cholesterol) Continuous variable (mg/dL) ≅ 14.7 (2.38) years old girls LDL: Low-density lipoprotein; HDL: High-density lipoprotein; TC: Total cholesterol; TG: Triglycerides; BMI: Body mass index. number of adolescents evaluated; total number of individuals evaluated in the study is 2,053, including children and adolescents; † does not provide average age data or distribution by gender only for the adolescents’ group; ‡ does not provide age group; § non-HDL cholesterol corresponds to total cholesterol minus HDL cholesterol; //CASPIAN III – Childhood and Adolescence Surveillance and Prevention of Adult Non-communicable disease. * Arq Bras Cardiol. 2015; 105(4):418-425 421 Abreu et al. Sleep hours and lipid profile in adolescents Review Article Table 3 – Evaluation of the risk of bias of the studies included Kong et al , 2011/ Hong Kong Narang et al29, 2012/ Canada Azadbakht et al31, 2013/ Iran Berentzen et al32, 2014/ Netherlands Rey-López et al30, 2014/ Greece, Germany, Belgium, France, Hungary, Italy, Sweden, Austria, Spain Sample representativeness 0 0 1 0 0 1 0 Definition of presenting condition 1 1 1 1 1 1 0 Evaluation of exposure 1 0 0 0 0 0 0 Evaluation of outcome 2 1 2 2 2 2 0 Nonresponse rate 0 0 0 0 0 0 0 Representativeness of the exposed cohort 0 0 0 0 0 0 1 Demonstration that outcome of interest was not present at start of study 0 0 0 0 0 0 0 Comparability of cohorts 0 0 0 0 0 0 1 Assessment of outcome 0 0 0 0 0 0 0 Was follow-up long enough for outcomes to occur 0 0 0 0 0 0 1 Adequacy of follow up of cohorts 0 0 0 0 0 0 1 4/6 2/6 4/6 3/6 3/6 3/6 4/9 28 Study Total Lee et al33, 2014/ Republic of Korea Gangwisch et al27, 2010/ United States Cross-sectional studies (maximum 6 points) Sample representativeness: yes (1); no (0); not informed (0) Definition of presenting condition: classification based on two or more lipid markers (1); on only one lipid marker (0) Evaluation of Exposure (hours of sleep): combination of questionnaire with another evaluation method (1); only questionnaire (0) Evaluation of Outcome (lipid profile): venous blood (2); capillary blood (1); self-referred (0) Nonresponse rate: non-respondents described (1); non-described (0) Cohort studies (maximum 9 points) Evaluation of Exposure (hours of sleep): combination of questionnaire with another evaluation method (1); only questionnaire (0) Evaluation of Outcome (lipid profile): venous blood (2); capillary blood (1); self-reported (0) Representativeness of the exposed cohort (representative of the average): adequately addressed (1); not adequately addressed ⁄ not reported (0) Demonstration that outcome of interest was not present at start of study: adequately addressed (1); not adequately addressed ⁄ not reported (0) Comparability of cohorts on the basis of the design or analysis: adequately addressed (1); not adequately addressed ⁄ not reported (0) Assessment of outcome (independent blind assessment or record linkage): adequately addressed (1); not adequately addressed ⁄ not reported (0) Was follow-up long enough for outcomes to occur: adequately addressed (1); not adequately addressed ⁄ not reported (0) Adequacy of follow up of cohorts (complete follow up or subjects lost to follow up unlikely to introduce bias): adequately addressed (1); not adequately addressed ⁄ not reported (0) 422 Arq Bras Cardiol. 2015; 105(4):418-425 Abreu et al. Sleep hours and lipid profile in adolescents Review Article Table 4 – Main results of the studies included in the review Total Male Female Control variables investigated OR (CI 95%) Each hour: 0.87 (0.79-0.96) OR (CI 95%) Each hour: 0.91 (0.79‑1.05) OR (CI 95%) Each hour: 0.85 (0.75‑0.96) Age/ gender/ race/ ethnic group/ alcohol/ smoke/ physical activity/ inactivity/ stress/ body weight β* = -0.160 (p-value = 0.023) --- --- Age/ sex/ BMI/ waist perimeter/ Tanner stages (2-3 and 4-5) --- OR (CI 95%) <5h = 1 5–8h = 4.00 (0.54–29.94) > 8h = 5.63 (0.76–41.56) OR (CI 95%) < 5h = 1 5–8h = 1.07 (0.31–3.73) >8h = 1.14 (0.33–3.85) Age/ socioeconomic status/ parents’ level of education/ family history of chronic disease/ sedentary lifestyle/ BMI --- β (CI 95%) 7.5–9.5 h = -0.15 (-0.35; 0.04) 10–10.5 h = 1 11–12.5 h = -0.06 (-0.17; 0.05) β (CI 95%) 7.5–9.5 h = -0.01 (-0.22; 0.21) 10–10.5 h = 1 11–12.5 h = -0.06 (-0.16; 0.05) Age at completion of the questionnaire/ age at medical examination/ height/ maternal level of education/ puberty and screen time β* = -0.122 (p-value = 0.042) --- --- --- OR (95%CI) <5h=1 5–8 h = 1.04 (0.30-3.61) >8 h = 0.97 (0.28–3.30) OR (95%CI) <5h=1 5–8 h = 1.36 (0.26–5.05) >8 h = 0.76 (0.20–2.89) β* = -0.056 (p-value = 0.061) --- --- --- β (95% CI) 7.5–9.5 h = 0.03 (-0.07; 0.12) 10–10.5 h = 1 11–12.5 h = 0.02 (-0.04; 0.07) β(95% CI) 7.5–9.5 h = 0.07 (-0.03; 0.17) 10–10.5 h = 1 11–12.5 h = <0.01 (-0.05; 0.05) OR (95%CI) ≤ 5 h = 0.79 (0.40 - 1.53) 6-7 h = 0.86 (0.50 - 1.49) 8-9 h = 1 ≥ 10 h = 1.03 (0.44 - 2.40) --- --- β* = 0.060 (p = 0.115) --- --- Azadbakht et al31, 2013 --- OR (95%CI) <5h=1 5–8 h = 1.09 (0.41–2.92) > 8 h = 1.16 (0.44–3.09) OR (95%CI) <5h=1 5–8 h = 0.53 (0.22–1.30) > 8 h = 0.53 (0.22–1.30) Rey-López et al30, 2014 β (95%CI) School days: 0.26 (-2.57; 3.09) Weekends: 0.69 (-1.50; 2.88) --- --- Age/ gender/ socioeconomic status/ physical activity OR (95%CI) ≤ 5 h= 1.05 (0.55 - 2.00) 6-7 h= 1.20 (0.79 - 1.83) 8-9 h= 1 ≥ 10 h = 2.17 (1.14 - 4.13) --- --- Age/ gender/ household income/ caloric intake/ physical activity Total cholesterol Gangwisch et al27, 2010 Kong et al28, 2011 Azadbakht et al31, 2013 Berentzen et al32, 2014 LDL cholesterol Kong et al28, 2011 Azadbakht et al , 2013 31 HDL cholesterol Kong et al28, 201 Berentzen et al31, 2014 Lee et al33, 2014 TG Kong et al28, 2011 Lee et al , 2014 33 Arq Bras Cardiol. 2015; 105(4):418-425 423 Abreu et al. Sleep hours and lipid profile in adolescents Review Article Continuation Non-HDL† Narang et al29, 2012 OR (95%CI) Each hour 1.03 (0.93-1.13) First quartile (reference) x last quartile 0.92 (0.70-1.22) --- --- β (95%CI) School days: -0.001 (-0.05; 0.05) Weekends: 0.009 (-0.03; 0.05) --- --- --- β(95% CI) 7.5–9.5 h = -0.22 (-0.51; 0.08) 10–10.5 h = 1 11–12.5 h = -0.14 (-0.31; 0.02) β(95% CI) 7.5–9.5 h = -0.18 (-0.44; 0.08) 10–10.5 h = 1 11–12.5 h = -0.04 (-0.17; 0.09) Waist perimeter/nutrition/physical activity/sex/ family history of premature cardiovascular disease in first degree relatives/sleep disturbance score TC/HDL-c Rey-López et al30, 2014 Berentzen et al31, 2014 OR: OPdds ratio; CI: Confidence interval; SD: Standard deviation; LDL: Low-density lipoprotein; HDL: Gigh-density lipoprotein; TC: Total cholesterol; TG: Triglycerides; BMI: Body mass index; PR: Prevalence ratio. * β regression coefficient of the multiple regression model to compare groups with the largest and smallest (reference) quintile of the lipid variables in relation to hours of sleep (group with 20% of individual with shorter sleep duration vs. group with 20% of individual with longer sleep duration.); † non-HDL cholesterol corresponds to total cholesterol minus HDL cholesterol. Acknowledgments We would like to thank Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) for providing a doctoral fellowship to GAA (process nº E26/100.332/2013). KVB (process nº 303594/2009-8) and MS process nº 302877/2009-6) were partially supported by CNPq. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Author contributions Conception and design of the research, Analysis and interpretation of the data and Critical revision of the manuscript for intellectual content: Abreu GA, Barufaldi LA, Bloch KV, Szklo M; Acquisition of data: Abreu GA, Barufaldi LA; Writing of the manuscript: Abreu GA. Study Association This article is part of the thesis of Doctoral submitted by Gabriela de Azevedo Abreu, from Universidade Federal do Rio de Janeiro. References 1. Kim J, Hakim F, Kheirandish-Gozal L, Gozal D. 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Arq Bras Cardiol. 2015; 105(4):418-425 425 Back to the Cover Viewpoint Patient Management with Metallic Valve Prosthesis during Pregnancy and Postpartum Period Juliane Dantas Seabra Garcez, Vitor Emer Egypto Rosa, Antonio Sergio de Santis Andrade Lopes, Tarso Augusto Duenhas Accorsi, João Ricardo Cordeiro Fernandes, Pablo Maria Pomerantzeff, Walkiria Samuel Avila, Flavio Tarasoutchi Instituto do Coração – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo – USP, São Paulo, SP – Brazil Abstract Prosthetic thrombosis is a rare complication, but it has high mortality and morbidity. Young women of childbearing age that have prosthetic heart valves are at increased risk of thrombosis during pregnancy due to changes in coagulation factors. Anticoagulation with adequate control and frequent follow-up if pregnancy occurs must be performed in order to prevent complications related to anticoagulant use. Surgery remains the treatment of choice for prosthetic heart valve thrombosis in most clinical conditions. Patients with metallic prosthetic valves have an estimated 5% risk of thrombosis during pregnancy and maternal mortality of 1.5% related to the event. Anticoagulation with vitamin K antagonists during pregnancy is related to varying degrees of complications at each stage of the pregnancy and postpartum periods. Warfarin sodium crosses the placental barrier and when used in the first trimester of pregnancy is a teratogenic agent, causing 1-3% of malformations characterized by fetal warfarin syndrome and also constitutes a major cause of miscarriage in 10-30% of cases. In the third trimester and at delivery, the use of warfarin is associated with maternal and neonatal bleeding in approximately 5 to 15% of cases, respectively. On the other hand, inadequate anticoagulation, including the suspension of the oral anticoagulants aiming at fetal protection, carries a maternal risk of about 25% of metallic prosthesis thrombosis, particularly in the mitral valve. This fact is also due to the state of maternal hypercoagulability with activation of coagulation factors V, VI, VII, IX, X, platelet activity and fibrinogen synthesis, and decrease in protein S levels. The Registry of Pregnancy and Cardiac Disease (ROPAC), assessing 212 pregnant women with metal prosthesis, showed that prosthesis thrombosis occurred in 10 (4.7%) patients and maternal hemorrhage in 23.1%, concluding that only 58% of patients with metallic prosthesis had a complication-free pregnancy1-7. Keywords Heart Valve Prosthesis; Thrombosis; Anticoagulants / therapeutic use; Pregnancy; Mortality; Abortion, Spontaneous. Mailing Address: Flavio Tarasoutchi • Instituto do Coração do Hospital das Clínicas da FMUSP. Avenida Doutor Enéas de Carvalho Aguiar, 44, Cerqueira Cesar. Postal Code 05403-900, São Paulo, SP – Brazil E-mail: [email protected] Manuscript received March 24, 2015; revised manuscript August 19, 2015; accepted August 27, 2015. DOI: 10.5935/abc.20150130 426 There are controversies about the best anticoagulation regimen during pregnancy, childbirth and postpartum of women with metallic valve prosthesis. There are no guidelines about the best single or combined treatment option considering the presumed risk of thrombosis, because there is no evidence regarding maternal effectiveness while taking fetal protection into account. Current recommendations, based on the literature, have been the replacement of warfarin sodium in the first trimester of pregnancy by low-molecular weight heparin (LMWH) until the 12 th week of pregnancy. After this gestational age, warfarin is reintroduced until the 36th week of gestation and then replaced again by LMWH 24 hours before delivery8. The target INR (International Normalized Ratio) during pregnancy should be 2.5 to 3.5 (mean 3.0) when it is mitral prosthesis, and 2.0 to 3.0 when it is aortic prosthesis, values that give the highest maternal protection rates (5.7% risk of death or thromboembolism) compared with heparine8. Published review of pregnant women with prosthetic outcomes showed that warfarin provides better protection than heparin as prophylaxis of thromboembolic events in women with metal prostheses, but with greater risk of embryopathy9. However, a retrospective, observational study with 3 anticoagulation regimens: enoxaparin before 6 weeks of pregnancy, between 6‑12 weeks or oral anticoagulants throughout the pregnancy, showed that with the use of enoxaparin, thromboembolic complications were seen in 14.9% and most of them were related to subtherapeutic doses, verified through the measurement of anti-factor Xa 10 . The anticoagulation regimen at subtherapeutic levels is the main cause of valve thrombosis, being found in up to 93% of cases, regardless of the regimen used11,12. The risk of thrombosis is probably lower if the anticoagulant dose is appropriate and varies according to the type and position of the metal valve, also taking into consideration the patient’s risk factors. Data from the literature1,8,9, warn about the inefficiency of using subcutaneous unfractionated heparin (UFH) in preventing metal prosthetic valve thrombosis during pregnancy, due to difficulties in attaining effective anticoagulation, its control and patient adherence to the drug. However, in services that choose this alternative, it is recommended that UFH be initiated at high doses (17,500-20,000 IU 2xday/subcutaneously) and controlled by activated partial prothrombin time (aPTT), which should be twice the control value, remembering that response to heparin is modified by the physiological state of maternal hypercoagulability. When the LMWH is selected, the dose Seabra Garcez et al. Metal prosthesis during pregnancy and postpartum period Viewpoint should be administered every 12 hours, subcutaneously, based on the control of the anti-factor Xa between 0.8‑1.2 U/ml, which should be determined after 4-6h of use. Factors that should be taken into account in deciding the best anticoagulant therapy include: patient preferences, expertise of the attending physician and availability of medication level monitoring11-14 (Table 1). The European Society of Cardiology contraindicates the use of ASA in addition to anticoagulation in patients with prosthetic valves, as there is no data in the literature demonstrating its benefit and safety13. On the other hand, the latest guideline of American Heart Association/American College of Cardiology suggests adding 75-110 mg/day of ASA to the anticoagulation regimen to all patients with metal valves and in patients with biological valves, anticoagulation should be prescribed in the first 3 months and after that maintain ASA at a dose of 75-100 mg/day indefinitely. The addition of aspirin reduces the incidence of embolic phenomena, cardiovascular death and stroke and the Brazilian Society of Cardiology suggests its association in patients with high thromboembolic risk (old prosthesis model in the mitral position, atrial fibrillation, more than one metal prosthesis)6,15. The use of new anticoagulants (direct thrombin inhibitors and Factor Xa oral inhibitors) is formally contraindicated in patients with metallic prosthetic valve. In the postpartum period, LMWH should be used with Anti‑factor Xa control and subsequent interruption after reaching 3.0 INR with warfarin. During this period, valve thrombosis should be suspected when patients develop progressive dyspnea, pulmonary edema, syncope, symptoms of low cardiac output or hemodynamic instability, after excluding tachyarrhythmias as the cause, especially in patients with inadequate anticoagulation. Additionally, an auscultatory finding that suggests valve thrombosis is the cessation or muffling of the clicking sound when the prosthesis closes. Transesophageal echocardiography seems to be the most sensitive method to confirm the diagnosis16. The treatment of thrombosis during the puerperal period should be the one proposed for patients with prosthetic valve out of the pregnancy and postpartum period, taking into consideration their clinical condition, thrombus size and location of the affected prosthesis. Surgery is the treatment of choice and should preferably be indicated in patients with NYHA functional class III and IV dyspnea, with no surgical contraindication, left prosthesis thrombosis, thrombus ≥ 10 mm or thrombus area > 0.8 cm 2 6,17. The disadvantage of surgery is due to high perioperative mortality (between 5%-18%) closely associated with functional class, which is the main predictor. Patients in functional classes I to III (NYHA) have 4-7% mortality, while those in FC IV have 17.5% and 31.3%. However, compared to thrombolysis, surgery has the highest success rates (81% vs. 70.9%)18,19. The use of thrombolytic should be considered in: critical patients at high risk of death if submitted to surgery in places where there is no surgical team available or tricuspid or pulmonary valve thrombosis20. Thrombolysis has a systemic embolization risk of 5-19 %, major bleeding 5-8%, recurrence 15-31% and mortality from 6 to 12.5%. Success rates vary from 64 to 89%, with a high chance of being effective if the thrombus has presumably existed for less than 14 days12,19,21,22. In case of partial success, or residual thrombus, the patient should be referred to surgery after 24 hours of thrombolytic infusion withdrawal. In this scenario, surgery should be considered an urgency or emergency case, depending on the patient’s clinical condition, with high mortality rates. This reinforces the importance of choosing the initial therapy for patients with valve thrombosis, to minimize risks of re-interventions and increase the full resolution rate19. Patient monitoring with transesophageal echocardiography should be performed during the procedure. The recommended doses of thrombolytic agents are: streptokinase 1,500,000 IU in 60 min without UFH and Alteplase (rtPA) 10mg in bolus + 90 mg in 90 minutes with UFH20. Recently, a thrombolytic protocol with low-dose and slow infusion (rtPA 25 mg intravenous infusion in 6 hours, repeating at 24 h and, if necessary, up to 6x reaching the maximum dose of 150 mg, without bolus or use of concomitant heparin) in pregnant women with prosthetic thrombosis, showed effective thrombolysis with no maternal deaths and fetal mortality around 20%, a better result than the commonly used strategies11. However, the author compares it with old studies, and perhaps this difference could be less with the improvement in surgical techniques. Therefore, we can not infer that thrombolysis is better than the surgical strategy in pregnant women. Table 1 – Anticoagulation in pregnant patient Time Up to 6-12th week 12th up to 36th week After 36th week up to delivery Puerperium Medication Control LMWH 1.0 mg/kg SC 12/12h UFH 17.500 to 20.000 IU SC 2x/day Anti-factor Xa: 0.8-1.2 U/mL aPTT 2x higher than control Warfarin 5 mg 1x/day orally LMWH 1.0 mg/kg SC 12/12h INR between 2.0 and 3.0 if aortic prosthesis and between 2.5 and 3.5 if mitral valve prosthesis Anti-factor Xa: 0.8-1.2 U/mL LMWH 1.0 mg/kg SC 12/12h UFH 17,500 to 20,000 IU SC 2x/day Anti-factor Xa: 0.8-1.2 U/mL aPTT 2x higher than control LMWH 1.0 mg/kg SC 12/12h Reach target INR after introduction of warfarin 5 mg 1x/day orally Anti-factor Xa: 0.8-1.2 U/mL INR between 2.0 and 3.0 if aortic prosthesis and between 2.5 and 3.5 if mitral valve prosthesis LMWH: Low molecular weight heparin; SC: Subcutaneous; UFH: Unfractionated heparin; IU: International units. INR: International normalized ratio. Arq Bras Cardiol. 2015; 105(4):426-429 427 Seabra Garcez et al. Metal prosthesis during pregnancy and postpartum period Viewpoint After surgery or thrombolysis, the patients should be anticoagulated. The US Guidelines advises INR: 3-4 for prostheses in the aortic position and INR: 3.5-4.5 with the addition of aspirin in the mitral position. On the other hand, the European guideline recommends anticoagulation according to the prosthesis thrombogenicity and risk factors for thromboembolic events of the patient (mitral or tricuspid valve, previous thromboembolism, atrial fibrillation, mitral stenosis, ventricular dysfunction EF < 35%), with INR ranging from: 2.5 - 3.5 for low-risk, INR: 3.0 - 4.0 for high risk regardless of prosthesis position6,20. Considering the abovementioned facts, we highlight the importance of warning women of childbearing age that have prosthetic heart valves of the risks during pregnancy, establishing anticoagulation with adequate control and frequent monitoring if pregnancy occurs, preferably at centers of excellence in valvular heart disease, in order to prevent complications related to the use of anticoagulants such as embryopathies, miscarriage, bleeding and prosthesis thrombosis 23. The treatment should be individualized depending on the patient’s clinical condition, according to the our algorithm proposed by our team (Figure 1). Author contributions Conception and design of the research: Seabra Garcez JDS, Rosa VEE, Lopes ASSA, Accorsi TAD, Fernandes JRC, Pomerantzeff PM, Avila WS, Tarasoutchi F; Writing of the manuscript: Seabra Garcez JDS, Rosa VEE, Lopes ASSA, Accorsi TAD, Fernandes JRC, Pomerantzeff PM, Avila WS, Tarasoutchi F; Critical revision of the manuscript for intellectual content: Seabra Garcez JDS, Rosa VEE, Lopes ASSA, Accorsi TAD, Fernandes JRC, Pomerantzeff PM, Avila WS, Tarasoutchi F. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Study Association This study is not associated with any thesis or dissertation work. Figure 1 – Algorithm proposed for the treatment of prosthetic heart valve thrombosis in pregnant and postpartum women. FC: Functional class the New York Heart Association (NYHA) 428 Arq Bras Cardiol. 2015; 105(4):426-429 Seabra Garcez et al. Metal prosthesis during pregnancy and postpartum period Viewpoint References 1. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH; American College of Chest Physicians. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e576S-600S. 2. Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve prostheses. Br Heart J. 1994;71:196-201. 3. Casais P, Rolandi F. Prosthetic valve thrombosis in pregnancy: a promising treatment for a rare and mostly preventable complication. Circulation. 2013;128(5):481-2. 4. Elkayam U, Bitar F. Valvular heart disease and pregnancy: part II: prosthetic valves. J Am Coll Cardiol. 2005;46(3):403-10. 5. Katz M, Tarasoutchi F, Grinberg M. [Thrombolytic therapy in prosthetic valve thrombosis]. Arq Bras Cardiol. 2005;85(1):76-8. 6. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(22):e57-185. Erratum in: J Am Coll Cardiol. 2014;63(22):2489. 7. Van Hagen IM, Roos-Hesselink JW, Ruys TP, Merz WM, Goland S, Gabriel H, et al; ROPAC Investigators and the EURObservational Research Programme (EORP) Team. Pregnancy in women with a mechanical heart valve: data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). Circulation. 2015;132(2):132-42. 8. Tarasoutchi F, Montera MW, Grinberg M, Piñeiro DJ, Sánchez CR, Bacelar AC, et al. [Brazilian Guidelines for Valve Disease - SBC 2011 / I Guideline Inter-American Valve Disease - 2011 SIAC]. Arq Bras Cardiol. 2011;97(5 Suppl 1):1-67. 9. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160(2):191-6. 10. McLintock C, McCowan LM, North RA. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valve treated with enoxaparin. BJOG. 2009;116(12):1585-92. 11. Özkan M, Çakal B, Karakoyun S, Gürsoy OM, Çevik C, Kalçık M, et al. Thrombolytic therapy for the treatment of prosthetic heart valve thrombosis in pregnancy with low-dose, slow infusion of tissue-type plasminogen activator. Circulation. 2013;128(5):532-40. 12. Ramos AI, Ramos RF, Togna DJ, Arnoni AS, Staico R, Galo MM, et al. Fibrinolytic therapy for thrombosis in cardiac valvular prosthesis short and long term results. Arq Bras Cardiol. 2003;81(4):393-8, 387-92. 13. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart JM, et al; European Society of Gynecology (ESG); Association for European Paediatric Cardiology (AEPC); German Society for Gender Medicine (DGesGM); ESC Committee for Practice Guidelines. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(24):3147-97. 14. McLintock C. Anticoagulant choices in pregnant women with mechanical heart valves: balancing maternal and fetal risks – the difference the dose makes. Thromb Res. 2013;131 Suppl 1:S8-10. 15. Sociedade Brasileira de Cardiologia. [Guidelines for pregnancy in the woman with heart disease]. Arq Bras Cardiol. 2009;93(6 supl.1):e110-e78. 16. Parro A Jr, Carramona ML, Amaral CA, Jacob JL, Nicolau JC. Bioprosthetic mitral valve thrombosis. Importance of transesophageal echocardiography in the diagnosis and follow-up after treatment. Arq Bras Cardiol. 2004;82(4):346-59. 17. Tong AT, Roudaut R, Ozkan M, Sagie A, Shahid MS, Pontes Júnior SC, et al; Prosthetic Valve Thrombolysis-Role of Transesophageal Echocardiography (PRO-TEE) Registry Investigators. Transesophageal echocardiography improves risk assessment of thrombolysis of prosthetic valve thrombosis: results of the International PRO-TEE registry. J Am Coll Cardiol. 2004;43(1):77-84. 18. Roudaut R, Lafitte S, Roudaut MF, Reant P, Pillois X, Durrieu-Jaïs C, et al. Management of prosthetic heart valve obstruction: fibrinolysis versus surgery. Early results and long-term follow-up in a single-centre study of 263 cases. Arch Cardiovasc Dis. 2009;102(4):269-77. 19. Huang G, Schaff HV, Sundt TM, Rahimtoola SH. Treatment of obstructive thrombosed prosthetic heart valve. J Am Coll Cardiol. 2013;62(19):1731-6. 20. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33(19):2451-96. 21. Cáceres-Lóriga FM, Pérez-López H, Morlans-Hernández K, FacundoSánchez H, Santos-Gracia J, Valiente-Mustelier J, et al. Thrombolysis as first choice therapy in prosthetic heart valve thrombosis: a study of 68 patients. J Thromb Thrombolysis. 2006;21(2):185-90. 22. Bonou M, Lampropoulos K, Barbetseas J. Prosthetic heart valve obstruction: thrombolysis or surgical treatment? Eur Heart J Acute Cardiovasc Care. 2012;1(2):122-7. 23. Avila WS, Grinberg M. [Anticoagulation, pregnancy and cardiopathy. A triad, three dominions and five moments]. Arq Bras Cardiol. 2005;84(1):44-8. Arq Bras Cardiol. 2015; 105(4):426-429 429 Back to the Cover Anatomopathological Session Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to Restrictive Cardiomyopathy Sumaia Mustafa1, Alice Tatsuko Yamada1, Fabio Mitsuo Lima2, Valdemir Melechco Carvalho2, Vera Demarchi Aiello1, Jussara Bianchi Castelli1 Instituto do Coração (InCor) HC-FMUSP1; Grupo Fleury Medicina e Saúde2, São Paulo, SP – Brasil JAP, a 79-year-old male and retired metalworker, born in Várzea Alegre (Ceará, Brazil) and residing in São Paulo was admitted to the hospital in October 2013 due to decompensated heart failure. The patient was referred 1 year before to InCor with a history of progressive dyspnea triggered by less than ordinary activities, lower-extremity edema, and abdominal enlargement. He sought medical care due to the abdominal enlargement, which was diagnosed as an ascites. He denied chest pain, hospitalization due to myocardial infarction or stroke, hypertension, dyslipidemia, and diabetes. The patient was a previous smoker and had stopped smoking at the age of 37 years. He was also an alcoholic and reported drinking alcohol for the last time 1 year before. He was referred to InCor for treatment of heart failure. An echocardiogram revealed an increased thickness in the septum (17 mm) and free left ventricular wall (15 mm), and a left ventricular ejection fraction of 26%. The patient reported daily use of enalapril 10 mg, spironolactone 25 mg, furosemide 80 mg, omeprazole 40 mg, and ferrous sulfate (40 mg Fe) three tablets. On March 12, 2013, his physical examination showed a weight of 55 kg, height of 1.75 m, body mass index (BMI) of 18 kg/m², heart rate of 60 bpm, blood pressure of 90 X 50 mm Hg, and the presence of a hepatojugular reflux. There were no signs of jugular venous hypertension, and the pulmonary and cardiac auscultations were normal. He had ascites, and his liver was palpable 5 cm below the right costal margin. Peripheral pulses were palpable, and a ++/4+ edema was observed. An ECG (February 23, 2012) had shown a sinus rhythm, heart rate of 52 bpm, PR interval of 192 ms, QRS duration of 106 ms, indirect signs of right atrial overload (wide variability in QRS amplitude between V1 and V2), and left A chest x-ray showed cardiomegaly. Laboratory tests performed on April 20, 2012, had shown the following results: hemoglobin 13.1 g/dL, hematocrit 40%, mean corpuscular volume (MCV) 87 fL, leukocytes 9,230/mm³ (banded neutrophils 1%, segmented neutrophils 35%, eosinophils 20%, basophils 1%, lymphocytes 33%, and monocytes 10%), platelets 222,000 /mm³, cholesterol 207 mg/dL, HDL-cholesterol 54 mg/dL, LDL‑cholesterol 138 mg/dL, triglycerides 77 mg/dL, creatine phosphokinase (CPK) 77 U/L, blood glucose 88 mg/dL, urea 80 mg/dL, creatinine 1.2 mg/dL (glomerular filtration rate ≥ 60 mL/min/1.73 m²), sodium 131 mEq/L, potassium 6.3 mEq/L, aspartate aminotransferase (AST) 22 U/L, alanine aminotransferase (ALT) 34 U/L, uric acid 6.3 mg/dL, TSH 1.24 µUI/mL, free T4 1.36 ng/dL, prostate‑specific antigen (PSA) 1.24 ng/mL. On urinalysis, urine specific gravity was 1.007, pH 5.5, the sediment was normal, and there were no abnormal elements. A new echocardiographic assessment on April 20, 2012, had shown an aortic diameter of 32 mm, left atrium of 52 mm, septal and posterior left ventricular wall thickness of 15 mm, diastolic/systolic left ventricular diameters of 46/40 mm, and left ventricular ejection fraction of 28%. Both ventricles had diffuse and marked hypokinesia. The valves were normal and the pulmonary artery systolic pressure was estimated at 32 mmHg (Figure 2). A 24-hour electrocardiographic (Holter) monitoring on April 19, 2012, showed a baseline sinus rhythm with a lowest rate of 46 bpm and greatest rate of 97 bpm; 48 isolated, polymorphic, and paired ventricular extrasystoles; 137 atrial extrasystoles; and an episode of atrial tachycardia over three beats with a frequency of 98 bpm. There were no atrioventricular or intraventricular blocks interfering with the conduction of the stimulus. The patient was transferred from the pacemaker clinic to the general cardiopathy clinic. Keywords Heart Failure; Cardiomyopathy, Restrictive; Ascites; Cardiomegaly; Heart Arrest. Editor da Seção: Alfredo José Mansur ([email protected]) Editores Associados: Desidério Favarato ([email protected]) Vera Demarchi Aiello ([email protected]) Mailing Address: Vera Demarchi Aiello • Avenida Dr. Enéas de Carvalho Aguiar, 44, subsolo, bloco I, Cerqueira César. Postal Code 05403-000, São Paulo, SP – Brazil E-mail: [email protected], [email protected] DOI: 10.5935/abc.20150135 430 atrial overload (prolonged and notched P waves), low QRS voltage in the frontal plane with an indeterminate axis, an electrically inactive area in the anteroseptal region and secondary changes in ventricular repolarization (Figure 1). During a clinic appointment on January 22, 2013, the patient was asymptomatic and reported the use of enalapril 10 mg, spironolactone 25 mg, furosemide 60 mg, and carvedilol 12.5 mg. His physical examination was normal. The main diagnostic hypotheses were hypertrophic or restrictive cardiomyopathy. A testicular ultrasound (September 09, 2013) was normal, except for cystic formations in the right inguinal canal. An abdominal ultrasonography (September 10, 2013) showed substantial ascites and hepatic cysts with internal septations, and no signs of portal hypertension. Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 1 – ECG: sinus bradycardia, low-voltage QRS complexes in the frontal plane, indirect signs of right atrial overload (small QRS complexes in V1 and wide QRS complexes in V2), left atrial overload, electrically inactive area in the anteroseptal region. Figure 2 – Echocardiogram - a) Four-chamber view: marked enlargement of the left and right atria; b) parasternal long-axis view: enlarged left atrium, left ventricular wall thickening, normal cavity. After presenting an increase in dyspnea with the development of paroxysmal nocturnal dyspnea, worsening ascites and lower-extremity edema, and paresthesia on hands and feet, the patient was admitted to the hospital. On physical examination (October 19, 2013) he was oriented and eupneic, with a heart rate of 69 bpm, blood pressure of 80 X 60 mmHg, a normal pulmonary auscultation, cardiac auscultation with arrhythmia and no murmurs, substantial ascites, and edema and hyperemia of the lower extremities. A chest x-ray (October 21, 2013) showed cardiomegaly and interstitial lung infiltrates; the lateral incidence showed the right ventricle markedly enlarged (Figures 3 and 4). On ECG, the patient presented atrial flutter with variable atrioventricular block, indirect signs of right atrial overload (Peñaloza-Tranchesi sign), heart rate of 61 bpm, low QRS voltage in the frontal plane, intraventricular conduction impairment, left ventricular overload, and secondary changes in ventricular repolarization (Figure 5). Laboratory tests on October 19, 2013, showed the following results: hemoglobin 13.5 g/dL, hematocrit 42%, leukocytes 7,230/mm³ (neutrophils 66%, eosinophils 12%, lymphocytes 13%, monocytes 9%), platelets 232,000 /mm³, urea 193 mg/dL, creatinine 2.03 m/dL (glomerular filtration rate of 34 mL/min/1,73 m²), sodium 133 mEq/L, potassium Arq Bras Cardiol. 2015; 105(4):430-439 431 Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 3 – Chest x-ray (October 21, 2013), posteroanterior (PA) view: pulmonary interstitial infiltrates and cardiomegaly. Figure 4 – Chest x-ray (October 21, 2013) in lateral view: right ventricle markedly enlarged. 3.9 mEq/L, C-reactive protein (CRP) 18.1 mg/L, vitamin B12 360 pg/mL, folic acid 8.35 ng/mL, total bilirubin 0.75 mg/dL, direct bilirubin 0.37 mg/dL, AST 24 U/L, ALT 16 U/L, gammaglutamyl transferase (gamma GT) 241 U/L, alkaline phosphatase 166 U/L, iron 71 µg/dL, ferritin 62.9 ng/mL, prothrombin time (PT, INR) 0.95, activated partial thromboplastin time (aPTT, rel) 0.95, ionic calcium 1.09 mmol/L, chloride 89 mEq/L, and arterial lactate 15 mg/dL. Urinalysis showed urine specific gravity of 1.020, pH 5.5, proteinuria 0.25 g/L, epithelial cells 432 Arq Bras Cardiol. 2015; 105(4):430-439 4,000/mL, leukocytes 2,000/mL, erythrocytes 3,000/mL, and hyaline casts 27,250/mL. Another echocardiogram performed on October 21, 2013, showed a left atrial diameter of 56 mm, septal thickness of 18 mm, posterior wall thickness of 13 mm, left ventricle (diastole/systole) with 46/40 mm, left ventricular ejection fraction of 28%, pulmonary artery systolic pressure estimated at 45 mmHg, marked left ventricular and moderate right ventricular dysfunction, and moderate tricuspid insufficiency. Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 5 – ECG: Atrial flutter, impaired intraventricular conduction, left ventricular overload. An ultrasound of the kidneys and urinary tract (October 24, 2013) showed that the left kidney measured 9.6 cm, and the right kidney measured 9 cm and had simple cortical cysts. Serum protein electrophoresis was normal, and a urinary electrophoresis did not detect proteins. Measurement of serum beta 2-microglobulin was 7 mg/mL (limit for individuals above the age of 60 years = 2.6 mg/mL). A biopsy of the cheek mucosa (October 23, 2013) showed deposits of amyloid substance in the deep chorion and in the adjacent adipose tissue. Stool microscopy (October 25, 2013) was positive for Blastocystis hominis and Entamoeba coli. A paracentesis drained 3,500 mL of a yellowish fluid with normal cellularity. During hospitalization, the patient received daily intravenous furosemide 60 mg, carvedilol 25 mg, hydrochlorothiazide 100 mg, hydralazine 75 mg, isosorbide 80 mg, aspirin 100 mg, spironolactone 25 mg, and enoxaparin 40 mg. The patient also received oxacillin 2 g/day for 7 days initially, and later vancomycin, meropenem and teicoplanin, and piperacillin/tazobactam. A new chest x-ray (November 08, 2013) showed cardiomegaly and an interstitial pulmonary infiltrate suggestive of pulmonary congestion (Figure 6). During a new paracentesis (November 11, 2013), the aspirated fluid was bloody, and the patient presented hypotension and decreased consciousness, progressing to cardiac arrest with pulseless electrical activity, which was reverted. This was followed by ventricular tachycardia, cardioverted with 200 J. New tests (November 11, 2013 - morning) showed the following results: hemoglobin 11.9 g/dL, hematocrit 36%, leukocytes 7,780/mm³ (neutrophils 83%, eosinophils 2%, lymphocytes 9%, and monocytes 6%), platelets 188,000 /mm³, urea 301 mg/dL, creatinine 4.14 mg/dL, sodium 125 mEq/L, potassium 4.4 mEq/L, CRP 97.06 mg/L. On venous blood gas analysis, pH was 7.33, bicarbonate 19.9 mmol/L, and base excess (-) 5.4 mmol/L. Additional tests performed on the same day (November 11, 2013 – 5:44 pm) showed hemoglobin of 6.3 g/dL, sodium of 123 mEq/L, potassium of 5.4 mEq/L, venous lactate of 93 mg/dL, PT (INR) of 3.2 and aPTT (rel) of 1.98. Later during the day, the patient progressed with shock refractory to high doses of dobutamine (20 µg/kg/min ) and norepinephrine (1.2 µg/kg/min), followed by cardiac arrest with pulseless electrical activity that recovered but was followed by a new irreversible cardiac arrest with pulseless electrical activity during intra-aortic balloon placement (November 11, 2013 – 6:30 pm). Clinical Aspects The patient JAB, a 79-year-old previous smoker and alcoholic man residing in São Paulo, attended an outpatient clinic at InCor due to heart failure which worsened progressively since 2012, requiring hospitalization for treatment. Heart failure is a systemic and complex clinical syndrome, defined as a cardiac dysfunction that causes the blood supply to be insufficient to meet tissular metabolic demands, in the presence of a normal venous return, or which only meets the demands with high filling pressure1. Prevalence studies estimate that 23 million individuals worldwide have heart failure and that 2 million new cases are diagnosed annually. According to DATASUS information, Brazil has about 2 million individuals with heart failure and 240,000 new cases diagnosed annually2. The main causes of heart failure are hypertension, coronary artery disease, Chagas disease, cardiomyopathies, endocrinopathies, toxins, and drugs, among others 1 . The cardinal manifestations of heart failure are dyspnea and fatigue, and may include exercise intolerance, fluid retention, and pulmonary and systemic congestion3. The patient in this case presented with progressive dyspnea triggered by less than Arq Bras Cardiol. 2015; 105(4):430-439 433 Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 6 – Chest x-ray (November 08, 2013): pulmonary interstitial infiltrates suggestive of pulmonary congestion and cardiomegaly. ordinary activities, lower-extremity edema, and ascites, which characterized him as class III according to the New York Heart Association (NYHA) classification. On complementary tests, the echocardiogram showed marked left ventricular hypertrophy with some degree of asymmetry, and reduced ejection fraction. Cardiac hypertrophy is often associated with hypertension or hypertrophic cardiomyopathy, but both present with normal or increased ECG voltage. Therefore, the findings of ventricular hypertrophy associated with decreased ECG voltage in the absence of pericardial effusion are exclusive of infiltrative cardiomyopathies, a group of cardiac disorders within the restrictive cardiomyopathies4. Restrictive cardiomyopathy may occur with a wide variety of systemic diseases. Some restrictive cardiomyopathies are rare in clinical practice and may present initially with heart failure. This type of cardiomyopathy is characterized by filling restriction, with reduced diastolic volume in one or both ventricles, normal or close to normal systolic function, and ventricular wall thickening. It may be idiopathic or associated with other diseases, such as amyloidosis, endomyocardial disease with or without eosinophilia, sarcoidosis, and hemochromatosis, among others5. In this case, the presence of amyloid deposits in the cheek mucosa biopsy indicated a diagnosis of amyloidosis, and the increase in serum beta-2 microglobulin reflected a worse prognosis5. Amyloidosis is characterized by deposits of amyloid protein in different organs and tissues. These deposits may be responsible for different types of clinical presentation, with a spectrum that ranges from lack of symptoms to sequential organic dysfunction culminating with death6. Cardiac amyloidosis is caused by amyloid deposits around cardiac fibers, and can be identified by a left ventricular wall 434 Arq Bras Cardiol. 2015; 105(4):430-439 thickening exceeding 12 mm in the absence of hypertension with at least one of the following characteristics: conduction disorder and low voltage complexes on the ECG, restrictive cardiomyopathy, low cardiac output, isolate atrial involvement (as commonly seen in elderly individuals) or diffuse involvement affecting the ventricles. In the latter situation, it can cause heart failure with a poor prognosis4,7. Our patient, who was not hypertensive, presented low voltage complexes on the ECG, which were more prominent in the frontal plane, an electrically inactive area in the anteroseptal region, and diffuse changes in ventricular repolarization. This pattern can be found in some diseases in addition to infiltrative cardiomyopathies, such as decompensated hypothyroidism, pericardial effusion, chronic obstructive pulmonary disease, and obesity. Other electrocardiographic information, such as the pattern of infarction, can be found with or without obstructive coronary atherosclerotic disease by deposition of substances in the microcirculation and small intramyocardial arteries8. Amyloidosis may be classified as primary, secondary, or hereditary. Primary amyloidosis, in which AL is the primarily involved protein, may be further subdivided into idiopathic (localized forms) or associated with multiple myeloma or other plasma cell dyscrasias (systemic forms)9. Multiple myeloma is a neoplastic disorder of plasma cells that affects individuals with an average age of 70 years at diagnosis. Some characteristics of the patient in this case could suggest multiple myeloma: age, male gender, renal failure, and cylindruria. However, other important clinical parameters were absent, such as hypercalcemia, anemia, and bone disease. Also, the Bence-Jones protein, which is present in up to 75% of the cases, was not detected on urinary electrophoresis10. Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session The secondary type of amyloidosis results from deposits of AA protein and frequently arises as a complication of infectious or inflammatory processes, such as rheumatoid arthritis (the most common cause), tuberculosis, systemic lupus erythematosus, inflammatory bowel disease, syphilis, or even neoplastic diseases. Pro-inflammatory cytokines, which are present in these disorders, stimulate the hepatic production of serum A amyloid11. Finally, the hereditary type of the disease has an autosomal dominant transmission and may involve several types of amyloid proteins, such as the AA protein in some groups of patients with familial Mediterranean fever, and the ATTR protein (derived from the transthyretin or prealbumin) in familial amyloid polyneuropathy12. As for the treatment, measures to control symptoms related to diastolic heart failure, such as volume control, should be implemented. Diuretics and vasodilators should be administered with caution since the cardiac output in these patients is greatly dependent on increased venous pressures. Specific treatment should be directed to the etiology of the amyloidosis13. After an evaluation in the clinic on January, 2013, the patient received medications that are proven to modify the rates of hospitalization and mortality in heart failure with reduced ejection fraction (beta-blockers, angiotensinconverting enzyme inhibitors, aldosterone antagonist), and symptom-relieving agents (diuretics)14. The patient was receiving enalapril 10 mg, spironolactone 25 mg, furosemide 60 mg, and carvedilol 12.5 mg. After 8 months, due to the decompensated heart failure and hypotension, the patient returned to the emergency room and required hospitalization. The use of conventional therapy for heart failure often worsens the progression of amyloidosis. Therefore, cardiac amyloidosis should be suspected when the patient’s clinical condition worsens in response to conventional treatment, particularly in individuals older than 50 years. The therapy is exclusively symptomatic and should not include digitalis, beta-blockers, angiotensin-converting enzyme inhibitors, or calcium channel antagonists, since some studies have shown an increased sensitivity to these drugs which can lead to hypotension and intensification of conduction disorders15. Therefore, the decompensation of the patient’s heart failure with deterioration of the ascites culminated in two paracenteses, with the last paracentesis probably accompanied by a puncture accident due to the appearance of bloody fluid, decrease in red blood count, and hypovolemic shock associated with cardiogenic shock, culminating in a mixed refractory shock and cardiac arrest with pulseless electrical activity (Dr. Sumaia Mustafa, Dr. Alice Tatsuko Yamada). Diagnostic hypotheses: 1. Heart failure due to restrictive cardiomyopathy (probably cardiac amyloidosis associated with multiple myeloma); 2. Decompensated heart failure; 3. Cause of death: mixed shock (hypovolemic + cardiogenic) with cardiac arrest with pulseless electrical activity (Dr. Sumaia Mustafa, Dr. Alice Tatsuko Yamada). Autopsy The heart weighed 680 g and was increased in volume due to moderate cavity dilation and wall thickening in all four chambers (Figure 7). The myocardium had an increased consistency. The endocardium of the atria, in particular, was finely granular and brown-yellowish in appearance. There were no significant changes in the valves, and the coronary arteries were armed without significant obstruction of their lumen. Histological examination of the myocardium showed extracellular deposits of amorphous and eosinophilic material promoting atrophy of the contractile cells. These deposits stained positive with Congo red when observed under polarized light (Figures 8 and 9). This same material was present in the interstitium of the cheek mucosa evaluated by biopsy (Figure 10) according to data from the clinical history. Deposits were also observed in the tunica media of muscular arteries in both lungs (Figure 11) and in the renal hilum. Bone marrow histological examination showed hypercellularity of moderate degree for the patient's age, and no signs of monoclonal proliferation. Immunohistochemical reactions for immunoglobulin kappa and lambda light chains were inconclusive, and CD138 labeling showed no proliferation of plasma cells. Autopsy findings included a 4-cm hepatic cyst in the right lobe lined with flat cells without atypia, and retention cysts in the right kidney. The right adrenal weighed 44 g and was increased in volume and completely calcified. The histological examination showed only calcification and was inconclusive for the possibility of prior malignancy. There was a voluminous serosanguinous ascites and a serous pericardial effusion. We found no visceral or abdominal vessel injury resulting from the paracentesis and the amount of bloody material in the ascitic fluid was small. Histologically, there were signs of congestive heart failure in the lungs and liver (Dr. Vera Demarchi Aiello). Diagnoses: Cardiovascular amyloidosis; Congestive heart failure; Calcified nodule in the right adrenal gland (Dr. Vera Demarchi Aiello). Mass spectrometry Mass spectrometry gathers all qualities to establish an unequivocal diagnosis of amyloidosis since it has a high sensitivity and ability to identify the proteins through sequencing16. Therefore, we adopted an approach based on shotgun proteomics to identify the amyloid deposits in the sample. Sections of heart tissue containing amyloid deposits (confirmed by staining with Congo red) fixed in formalin and embedded in paraffin were dissected and the proteins were then extracted with Liquid Tissue® MS Protein Prep Kit (Expression Pathology) according to the manufacturer's protocol. After digestion with trypsin, the resulting peptides were analyzed by high-resolution liquid chromatography-mass spectrometry using the mass spectrometer Q-Exactive (Thermo Arq Bras Cardiol. 2015; 105(4):430-439 435 Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 7 – Gross Section of the heart base showing biatrial enlargement and thickening of the cardiac walls. Note the granular aspect of the right atrial endocardium (area demarcated with an ellipse). Figure 8 – Photomicrography of the ventricular myocardium showing atrophic cardiomyocytes due to deposits of amorphous eosinophilic material in the interstitium. Hematoxylin and eosin staining (20x objective magnification). Fisher Scientific). The acquisitions of spectral data were carried out using the DDA (date dependent analysis) mode with a selection of the 10 most abundant ions for sequencing by HCD (Higher-energy collisional dissociation). The data were processed with the software MaxQuant. The proteomic analysis was performed in triplicate. The processed data generated lists of proteins representing the protein content of the sample. In total, 25 possible 436 Arq Bras Cardiol. 2015; 105(4):430-439 amyloid proteins were investigated in these lists in order to determine the identity of the deposited substance. There were 15 peptides belonging to transthyretin that together covered 76.2% of the full sequence of the protein. To confirm the result, we also evaluated the abundance of different peptides present in the sample. Among the 25 most abundant peptides, three belonged to transthyretin (ALGISPFHEHAEVVFTANDSGPR, TSESGELHGLTTEEEFVEGIYK, and GSPAINVAVHVFR). The others were assigned to actin, Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 9 – Photomicrography of myocardial tissue obtained under polarized light. Note the greenish material that corresponds to amyloid substance stained by Congo red (5x objective magnification). Figure 10 – Biopsy of the cheek mucosa performed approximately 1 month before death. Note that the mucosal chorion reacts positively to Congo red (photomicrography obtained under conventional microscopy with a 10x objective magnification). myosin, desmin, and myoglobin, confirming the identity of the amyloid protein (Dr. Fabio Mitsuo Lima and Dr. Valdemir Melechco Carvalho- Fleury Group). Conclusion Cardiovascular amyloidosis due to deposition of transthyretin (Dr. Vera Demarchi Aiello, Dr. Jussara Bianchi Castelli, Dr. Fabio Mitsuo Lima and Dr. Valdemir Melechco Carvalho). Comments: This case demonstrates how important it is in amyloidosis to investigate the deposited substance. Amyloidosis is a generic name to describe a group of diseases characterized by extracellular deposits of different substances in different organs. These substances are fibrillar proteins that become insoluble with changes in their spatial conformation. More than 20 types of proteins have been described in these deposits16. From an anatomopathological perspective, the deposits can be characterized by immunohistochemical reactions, but with Arq Bras Cardiol. 2015; 105(4):430-439 437 Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session Figure 11 – Photomicrography of a peripheral muscular pulmonary artery showing areas of positivity for deposits of amyloid in the arterial wall (Congo red staining photographed under conventional microscopy, 5x objective magnification). some restrictions as described below. The cardiovascular system is most often affected by the AL protein (deposits of light-chain immunoglobulin), senile, and familial forms17,18. The pathologist may identify neoplastic proliferation of plasmocytes producing the deposited immunoglobulins by bone marrow examination labeled for these cells. In tissue preparations, the pathologist may demonstrate by immunohistochemistry if the deposited substance is one of these immunoglobulins. Some authors recommend a biopsy of other organs before the endomyocardial biopsy to confirm the diagnosis and identify the type of amyloid19. In this case, immunohistochemical labeling was not helpful in establishing the diagnosis, because it was inconclusive to the type of protein deposited. Although there are reports in the literature of identification of transthyretin in tissues by immunohistochemical 438 Arq Bras Cardiol. 2015; 105(4):430-439 reactions, this was not possible in this case. However, with mass spectrometry analysis, we identified that the deposited protein was transthyretin, which is usually present in senile and familial forms of amyloidosis. In this patient, the familial form was less likely due to the exclusive involvement of heart and blood vessels. However, only a genetic research and evaluation of other members of the family could exclude it completely. Another point that deserves discussion in this case is the laboratory report of high levels of immunoglobulin E. We could assume that this referred to the deposited protein, but the diagnostic methods performed to complement the autopsy revealed that this was not the case. Dr. Vera Demarchi Aiello and Dr. Jussara Bianchi Castelli (Pathology Laboratory, InCor, FMUSP). Mustafa et al Congestive heart failure due to restrictive cardiomyopathy Anatomopathological Session References 1. Bocchi EA, Marcondes-Braga FG, Ayub-Ferreira SM, Rohde LE, 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. 11. Ohdama S, Akagawa S, Matsubara O, Yoshizawa Y. Primary diffuse alveolar septal amyloidosis with multiple cysts anda calcification. Eur Respir J. 1996;9(7):1569-71. 2. 12. Rahman JE, Helou EF, Geizer-Bell R, Thompson RE, Kuo C, Rodriguez ER, et al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-5. Nogueira PR, Rassi S, Corrêa Kde S. Epidemiological, clinical e therapeutic profile of heart failure in a tertiary hospital. Arq Bras Cardiol. 2010;95(3):392-8. 3. Yancy CW, Jessuo M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/ AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Pratice Guidelines. Circulation. 2013;128(16):e240-327. 4. Hassan W, Al-Sergani H, Mourad W, Tabbas R. Amyloid heart disease: new frontiesanda insights in pathophysiology, diagnosis, and management. Tex Heart Inst. J. 2005;32(2):178-84. 5. Report of WHO/ISFC task force on the definition and classification of cardiomyopathies. Br Heart J. 1980;44(6):672-3. 6. Lachmann HJ, Hawkins PN. Amyloidosis and the lung. Chron Respir Dis. 2006;3(4):203-14. 7. 8. Dubrey SM, Cha K, Simms RW, Skinner M, Falk RH. Eletrocardiography and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol. 1996;77(4):313-5. Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med. 1997;336(4):267-76. 9. Khan MF, Falk RH. Amyloidosis. Postgrad Med J. 2001;77(913):686-93. 10. Pa l u m b o A , A n d e r s o n K . M u l t i p l e m y e l o m a . N E n g l J M e d . 2011;364(11):1046-60. 13. Salemi V, Fernandes F, Nastari L, Mady C. Cardiomiopatias restritivas. In: Mesquita ET, Lagoeiro AJ, Mesquita JE. Insuficiencia cardíaca com fração de ejeção normal. São Paulo: Atheneu; 2009. p. 197-211. 14. Sacks CA, MD, Jarcho JA, Curfman GD. Paradigm shifts in heart-failure therapy: a timeline. N Engl J Med. 2014;371(11):989-91. 15. Somaio Neto F, Silva CJ, Domingues JS, Assis RP, Borges RS, Prado SP, et al. The importance of accuracy of clinical examination in the diagnosis of cardiac amyloidosis. Case report. Rev Bras Clin Med. 2009;7:198-201. 16. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd, Dogan A. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114(24):4957-9. 17. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart: assessment, diagnosis, and referral. Heart. 2011;97(1):75-84. 18. Diagnosis and management of the cardiac amyloidoses. Circulation. 2005;112(13):2047-60. 19. Fine NM, Arruda-Olson AM, Dispenzieri A, Zeldenrust SR, Gertz MA, Kyle RA, et al. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac amyloidosis. Am J Cardiol. 2014;113(10):1723-7. Arq Bras Cardiol. 2015; 105(4):430-439 439 Back to the Cover Case Report Percutaneous Treatment of Mitral Paraprosthetic Regurgitation: an Alternative to Surgery Roney Orismar Sampaio, Alessandra Gomes de Oliveira, George Barreto Miranda, Pedro Alves Lemos Neto, Marcelo Luiz Campos Vieira, Flávio Tarasoutchi Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, SP – Brazil Introduction Paraprosthetic regurgitation occurs in approximately 7%–17% of patients undergoing mitral valve replacement and 2%–10% of patients undergoing aortic valve replacement1,2. Typically, this regurgitation is discrete and does imply major clinical complications; however, when it is moderate or severe, the consequences can be serious, leading to heart failure and/or hemolysis3,4. It is estimated that approximately 1%–5% of cases develop to more clinically severe conditions1,4. The main causes of paraprosthetic regurgitation are calcification of the valvular annulus, infection, suture technique, and size and shape of the prosthesis1,5. Usually, surgical treatment is considered as the first treatment option for symptomatic patients4. In 1992, however, an alternative treatment via percutaneous occlusion of the paravalvular orifice was proposed for cases in which the patient faces high risk from surgical treatment6-8. Case Report A 70-year-old male patient received a mechanical mitral prosthesis implant in 2002 during his fourth heart surgery. At that time, the patient presented multiple postoperative complications: septic shock requiring high doses of vasoactive medications, acute renal failure and atrial fibrillation, and prolonged hospitalization. After this period, the patient made good progress and had no limitations on daily activities, until 3 years previously, when he began to experience recurrent hematuria due to intravascular hemolysis. The patient was clinically followed until June 2012, when the hemolysis markedly worsened, in association with heart failure up to functional class III [New York Heart Association (NYHA)]. On physical examination, there was a regurgitant systolic murmur +++/4 in the mitral area and crackle at the base of the lungs. Keywords Mitral Valve / surgery; Heart Valve Prosthesis Implantation; Prosthesis-Related Infections / complications; Heart Failure; Hemolysis; Atrioventricular Block. Mailing Address: Roney Orismar Sampaio • Rua Comandante Garcia d’Avila, 412, Morumbi. Postal Code 05654040, São Paulo, SP – Brazil E-mail: [email protected]; [email protected] Manuscript received May 06, 2014; revised manuscript September 24, 2014; accepted September 30, 2014. DOI: 10.5935/abc.20150115 440 Laboratory examinations showed the following: lactate dehydrogenase (LDH) 3256 U/L [reference value (RV): 85‑227 U/L], haptoglobin 0.2 g/L (RV: 0.3–2.0 g/L), hemoglobin (Hb) 7.3 g/dL (RV: 13.0–18.0 g/dL), hematocrit (Hct) 22% (RV: 40.0-52.0%), and hemoglobinuria. Two‑dimensional transesophageal echocardiography demonstrated the mechanical prosthesis with normal mobility for its elements as well as moderate/significant periprosthetic regurgitation (Figures 1A and B) associated with maximum LA–LV diastolic gradient estimated at 13 mmHg (average, 4 mmHg). The valve area was estimated at 3.2 cm2. Because of the difficulty in accurately determining the size of the regurgitant orifice and subsequently choosing the best occlusion device, we performed three-dimensional transesophageal echocardiography. This technique identified both anterior and posterior periprosthetic insufficiency: anterior gap of 22 mm along the long axis and posterior gap of approximately 12 mm (Figure 1C). Because of the risk of many postoperative complications (as in 2002) and the high surgical risk associated with a fifth heart surgery, in a joint decision along with the patient and family, we opted for percutaneous treatment. Treatment Two percutaneous devices, “Duct Occluder 8 mm × 6” and “5 mm VSD,” were implanted, with a significant reduction in postimplant regurgitation (there was a decrease of approximately 70% in the anterior orifice) (Figure 2). A second 3D echocardiography (Figure 1D) was performed 45 days after the procedure and demonstrated good positioning of the occlusion devices and minimum residual paraprosthetic reflux. Six months after the procedure, the patient presented with a second-degree atrioventricular block, Mobitz II, and two episodes of presyncope; a DDD pacemaker was implanted. The patient improved to functional class I (NYHA). Physical examination at this time showed a slight systolic murmur of mitral regurgitation (+/4) and improved laboratory results (LDH 728 U/L, Hb 10.5 g/dL, Hct 32.3%). Discussion Paraprosthetic reflux is a significant complication of valve replacement surgery. Percutaneous closure of a paraprosthetic orifice is now considered a safe procedure, providing an alternative to surgery in patients with a high surgical risk. However, there are still few reports of percutaneous intervention in patients with paraprosthetic regurgitation. In 2006, Pate et al.9 published a study of 10 patients who were not candidates for surgery and underwent percutaneous closure of mitral paravalvular leak; this author Sampaio et al. Percutaneous treatment of paraprosthetic regurgitation Case Report (A) 2D transesophageal echocardiogram (B) 2D TE, preoperative (TE), preoperative (C) 3D TE, preoperative (D) 3D TE, postoperative Figure 1 – (A) Two-dimensional transesophageal echocardiogram (2D-TEE). (A) Preoperative 2D-TEE (B and C); (C) preoperative 3D-TEE; (D) post-operative 3D-TEE A B Image from hemodynamics laboratory showing catheter positioned in the paraprosthetic orifice before its release Image from hemodynamics laboratory showing the device in place Figure 2 – (A) Hemodynamics laboratory image of the catheter in the paraprosthetic orifice before deployment. (B) Hemodynamics laboratory image of the deployed device. Arq Bras Cardiol. 2015; 105(4):440-442 441 Sampaio et al. Percutaneous treatment of paraprosthetic regurgitation Case Report noted a 70% success rate for this procedure, associated with clinical improvement. However, four patients required a second intervention. In 2011, Sorajja et al.10 published a study of 115 patients who underwent the percutaneous procedure, with technical success in 77% of cases and clinical improvement in 67%. The total number of complications 30 days after the procedure was 8.7%: death in two cases (1.7%), stroke in three cases (2.6%), vascular complications in one case (0.9%), hemothorax in four cases (3.5%), and emergency surgery in one case (0.9%). In addition, in 2011, Ruiz et al.8 showed that in retrospective analysis of 43 patients, procedural success was observed in 86% of cases and clinical improvement was observed in 77%. In this present case, 6 months after percutaneous treatment, the patient developed atrioventricular block and required a pacemaker. After an extensive review of the literature, we found no reports of second-degree atrioventricular block as a late complication of percutaneous closure of the paraprosthetic mitral valve orifice1. Even in the aortic position, where it may be more common considering the anatomy of the conduction system, there are no reports of this complication. The risk of this event (late implant pacemaker for AVB) seems to have been random, particularly in closing the paraprosthetic mitral orifice; however, it cannot be ruled out. Nevertheless, the fact the pacemaker was implanted 6 months after the procedure is also relevant, which in our view leaves it unclear whether a possible complication exists and is yet to be described. Therefore, this event should be noted and followed in the literature. Therefore, we conclude that a percutaneous procedure to correct paraprosthetic regurgitation is feasible in patients with a high surgical risk and has a significant clinical impact. Author contributions Conception and design of the research: Sampaio RO, Oliveira AG, Lemos Neto PA. Acquisition of data: Sampaio RO, Oliveira AG, Lemos Neto PA, Vieira MLC. Analysis and interpretation of the data: Sampaio RO, Miranda GB, Lemos Neto PA, Vieira MLC. Writing of the manuscript: Sampaio RO, Oliveira AG, Miranda GB, Lemos Neto PA, Tarasoutchi F. Critical revision of the manuscript for intellectual content: Sampaio RO, Tarasoutchi F. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Study Association This study is not associated with any thesis or dissertation work. References 1. Kliger C, Eiros R, Isasti G, Einhorn B, Jelnin V, Cohen H, et al. Review of surgical prosthetic paravalvular leaks: diagnosis and catheter-based closure. Eur Heart J. 2013;34(9):638-49. 6. Hourihan M, Perry SB, Mandell VS, Keane JF, Rome JJ, Bittl JA, et al Transcatheter umbrella closure of valvular and paravalvar leaks. J Am Coll Cardiol. 1992;20(6):1371-7. 2. Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian C, Rahimtoola SH. Outcomes 15 years after valve replacement with mechanical versus a bioprostetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol. 2000;36 (4):1152-8. 7. Ruiz CE, Cohen H, Del Valle-Fernandes R, Jelnin V, Perk G, Kronzon I. Closure of prosthetic paravalvular leaks: a long way to go. Eur Heart J Suppl. 2010;12(Suppl E):E52-62. 3. Kim MS, Casserly IP, Garcia JA, Klein AJ, Salcedo EE, Carroll JD. Percutaneous transcatheter closure of prosthetic mitral paravalvar leaks: are we there yet? JACC Cardiovasc Interv. 2009;2(2):81-90. 4. Buellesfeld L, Meier B. Treatment of paravalvular leaks through interventional techniques. Multimed Man Cardiothorac Surg. 2011;2011(924):mmc ts.2010.004895. 5. Sampaio RO, Silva FC Jr, Oliveira IS, Padovesi CM, Soares JA, Silva WM, et al. Evolução pós-operatória de pacientes com refluxo protético valvar. Arq Bras Cardiol. 2009;93(3):283-9. 442 Arq Bras Cardiol. 2015; 105(4):440-442 8. Ruiz CE, Jelin V, Kronzon I, Dudy Y, Del Valle-Fernandez R, Einhorn BN, et al. Clinical outcomes in patients undergoing percutaneous closure of periprosthetic paravalvular leaks. J Am Coll Cardiol. 2011;58(21):2210-7. 9. Pate GE, Al Zubaidi A, Chandavimol M, Thompson CR, Munt BI, Webb JG. Percutaneous closure of prosthetic paravalvular leaks: case series and review. Catheter Cardiovasc Interv. 2006;68(4):528-33. 10. Sorajja P, Cabalka AK, Hagler DJ, Rihal CS. Percutaneous repair of paravalvular prosthetic regurgitation: acute and 30-day outcome in 115 patients. Circ Cardiovasc Interv. 2011;4(4):314-21. Back to the Cover Image Persistent Left Superior Vena Cava in Permanent Pacemaker Implantation Jerson Hernando Quitián1,2, José Julian Carvajal1,2, Mariana Soto1,2, Guillermo Mora1,2,3 Hospital Universitario Fundación Santa Fe de Bogotá1; Universidad de los Andes2; Universidad Nacional de Colombia3, Bogotá – Colombia This was an 84-year-old male patient, with worsening functional class from NYHA III/IV to IV/IV and palpitations. No syncope. Physical examination revealed bradycardia, the rest was uneventful. Electrocardiogram showed Mobitz II atrioventricular block. Patient was scheduled for permanent pacemaker implantation. tricuspid valve. Subsequently, the guide was withdrawn 3 cm. The guide withdrawal, without moving the electrode, is associated with the passage of the electrode through the tricuspid valve. The electrode was advanced and finally the active fixation mechanism was deployed1. Subclavian vein access was performed via direct puncture. The guide wire was advanced, entered the subclavian vein and descended parallel to the spine without crossing over to the right side. Subsequently, the guide wire traversed the coronary sinus and ended in the right atrium. Persistent left superior vena cava was diagnosed. During fluoroscopic observation, another feature that aids in the diagnosis is left paravertebral shadow above the aortic bow. The electrode was initially introduced with a straight guide reaching into the right atrium (RA). Afterwards, the straight guide was replaced by a conventional J guide and the electrode was pushed towards the anterolateral wall of the RA. The electrode tip was thus lying against the Author contributions Keywords Heart Defects, Congenital; Vena Cava, Superior; Pacemaker, Artificial. Mailing Address: Mariana Soto • Hospital Universitario Fundación Santa Fe de Bogotá. Calle 94A 16-76, Chico. Postal Code NA, Bogota, Bogota – Colombia E-mail: [email protected] Manuscript received February 10, 2015; revised manuscript March 06, 2015; accepted March 17, 2015. DOI: 10.5935/abc.20150116 443 Conception and design of the research, Acquisition of data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Quitián JH, Carvajal JJ, Soto M, Mora G Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. Study Association This study is not associated with any thesis or dissertation work. Quitián et al. Persistent left superior vena cava in device implantation Image Reference 1. Mora G. A Novel method of placing right ventricular leads in patients with persistent left superior vena cava using a conventional J Stylet. Indian Pacing Electrophysiol J. 2014;14(2):65–74. Arq Bras Cardiol. 2015; 105(4):443-444 444 Back to the Cover Erratum January 2015 Issue, vol. 104 (1), pages 32-44 The original article “Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System” published in the January 2015 issue of the Brazilian Archives of Cardiology [Arq Bras Cardiol. 2015; 104 (1): 32-44], was published in the Portuguese version as “Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System”. A correction was made in the Portuguese version. DOI: 10.5935/abc.20150138 445