Análise da função miocárdica sistólica e diastólica na cirrose hepática

Francisco Pedro Morais Dias de Almeida Sampaio Análise da função miocárdica sistólica e diastólica na cirrose hepática Dissertação de candidatura ao grau de Doutor apresentada à Faculdade de Medicina da Universidade do Porto Porto, 2014 Artigo 48º, § 3º - “A Faculdade não responde pelas doutrinas expendidas na dissertação.” Regulamento da Faculdade de Medicina da Universidade do Porto Decreto-Lei n.º 19337 de 29 de Janeiro de 1931 3 JÚRI DA PROVA DE DOUTORAMENTO Presidente: Reitor da Universidade do Porto Vogais: Doutor Fausto José da Conceição Alexandre Pinto Professor Catedrático Convidado da Faculdade de Medicina da Universidade de Lisboa Doutora Ana Maria Gomes de Almeida Professora Associada da Faculdade de Medicina da Universidade de Lisboa Doutor Joaquim Adelino Correia Ferreira Leite Moreira Professor Catedrático da Faculdade de Medicina da Universidade do Porto Doutor Paulo Miguel Bettencourt Sardinha Pontes Fernando Professor Catedrático Convidado da Faculdade de Medicina da Universidade do Porto Orientador da Tese Doutor Luís Filipe Vilela Pereira de Macedo Professor Associado Convidado da Faculdade de Medicina da Universidade do Porto Doutora Maria Júlia Pires Maciel Barbosa Professora Auxiliar da Faculdade de Medicina da Universidade do Porto 5 Corpo Catedrático da Faculdade de Medicina da Universidade do Porto Professores Catedráticos Efectivos Doutor Manuel Alberto Coimbra Sobrinho Simões Doutora Maria Amélia Duarte Ferreira Doutor José Agostinho Marques Lopes Doutor Patrício Manuel Vieira Araújo Soares Silva Doutor Daniel Filipe Lima Moura Doutor Alberto Manuel Barros da Silva Doutor José Manuel Lopes Teixeira Amarante Doutor José Henrique Dias Pinto de Barros Doutora Maria Fátima Machado Henriques Carneiro Doutora Isabel Maria Amorim Pereira Ramos Doutora Deolinda Maria Valente Alves Lima Teixeira Doutora Maria Dulce Cordeiro Madeira Doutor Altamiro Manuel Rodrigues Costa Pereira Doutor Rui Manuel Almeida Mota Cardoso Doutor António Carlos Freitas Ribeiro Saraiva Doutor José Carlos Neves da Cunha Areias Doutor Manuel Jesus Falcão Pestana Vasconcelos Doutor João Francisco Montenegro Andrade Lima Bernardes Doutora Maria Leonor Martins Soares David Doutor Rui Manuel Lopes Nunes Doutor José Eduardo Torres Eckenroth Guimarães Doutor Francisco Fernando Rocha Gonçalves Doutor José Manuel Pereira Dias de Castro Lopes Doutor António Albino Coelho Marques Abrantes Teixeira Doutor Joaquim Adelino Correia Ferreira Leite Moreira Doutora Raquel Ângela Silva Soares Lino 6 Professores Jubilados ou Aposentados Doutor Abel Vitorino Trigo Cabral Doutor Alexandre Alberto Guerra Sousa Pinto Doutor Álvaro Jerónimo Leal Machado de Aguiar Doutor Amândio Gomes Sampaio Tavares Doutor António Augusto Lopes Vaz Doutor António Carvalho Almeida Coimbra Doutor António Fernandes da Fonseca Doutor António Fernandes Oliveira Barbosa Ribeiro Braga Doutor António José Pacheco Palha Doutor António Manuel Sampaio de Araújo Teixeira Doutor Belmiro dos Santos Patrício Doutor Cândido Alves Hipólito Reis Doutor Carlos Rodrigo Magalhães Ramalhão Doutor Cassiano Pena de Abreu e Lima Doutor Daniel Santos Pinto Serrão Doutor Eduardo Jorge Cunha Rodrigues Pereira Doutor Fernando Tavarela Veloso Doutor Francisco de Sousa Lé Doutor Henrique José Ferreira Gonçalves Lecour de Menezes Doutor Jorge Manuel Mergulhão Castro Tavares Doutor José Carvalho de Oliveira Doutor José Fernando Barros Castro Correia Doutor José Luís Medina Vieira Doutor José Manuel Costa Mesquita Guimarães Doutor Levi Eugénio Ribeiro Guerra Doutor Luís Alberto Martins Gomes de Almeida Doutor Manuel António Caldeira Pais Clemente Doutor Manuel Augusto Cardoso de Oliveira Doutor Manuel Machado Rodrigues Gomes Doutor Manuel Maria Paula Barbosa Doutor Maria da Conceição Fernandes Marques Magalhães Doutor Maria Isabel Amorim de Azevedo Doutor Mário José Cerqueira Gomes Braga Doutor Serafim Correia Pinto Guimarães Doutor Valdemar Miguel Botelho dos Santos Cardoso Doutor Walter Friedrich Alfred Osswald 7 Ao abrigo do Art.º 8º do Decreto-Lei n.º388/70 fazem parte desta dissertação as seguintes publicações: I. Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP, Valente J, Bettencourt P, Fraga J, Gama V. Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tracking echocardiography study. Sampaio F, Pimenta J, Bettencourt N, Fontes- Carvalho R, Silva AP, Valente J, Bettencourt P, Fraga J, Gama V. Liver Int. 2013;33:1158-65 II. Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP, Valente J, Bettencourt P, Fraga J, Gama V. Left atrial function is impaired in cirrhosis: a speckle tracking echocardiographic study. Hepatol Int 2014; 8:146-53 III. Sampaio F, Lamata P, Bettencourt N, Alt SC, Ferreira N, Kowallick JT, Valente J, Kutty S, Pimenta J, Fraga J, Bettencourt P, Gama V, Schuster A. Assessment of cardiovascular physiology using magnetic resonance myocardial stress testing reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy [Submitted] IV. Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP, Valente J, Bettencourt P, Fraga J, Gama V. Systolic dysfunction and diastolic dysfunction do not influence mediumterm prognosis in patients with cirrhosis. Eur J Intern Med. 2014;25:241-6 A contribuição pessoal para a realização destes trabalhos foi a seguinte: Contribuição importante na sua concepção, na recolha do material, obtenção e análise dos dados e redacção dos manuscritos. À Joana À Inês, ao João Francisco e à Rita 17 AGRADECIMENTOS “At the outset do not be worried about this big question—Truth. It is a very simple matter if each one of you starts with the desire to get as much as possible. No human being is constituted to know the truth, the whole truth, and nothing but the truth; and even the best of men must be content with fragments, with partial glimpses, never the full fruition. In this unsatisfied quest the attitude of mind, the desire, the thirst—a thirst that from the soul must arise!—the fervent longing, are the be-all and the end-all”. Sir William Osler – The Students Life, 1905 Mesmo consciente da impossibilidade de vislumbrar mais do que fugazes lampejos da verdade, o desenvolvimento de um projecto de investigação clínica, capaz de se revestir da robustez necessária à elaboração de uma tese de doutoramento a apresentar à Faculdade de Medicina da Universidade do Porto, apresenta inúmeras dificuldades. Não posso deixar assim de agradecer a todos os que generosamente contribuíram – alimentando a insatisfação, a sede e o desejo durante a demanda – para o resultado final, na forma desta dissertação. De entre todos, o meu reconhecimento especial: Ao Professor Doutor Paulo Bettencourt, por me ter desafiado, no início, a inscrever-me na primeira edição do Programa Doutoral de Ciências Cardiovasculares, e pela confiança que em mim depositou ao aceitar ser o meu orientador. A sua inteligência e argúcia, a sua qualidade como clínico e como investigador e a sua rectidão na forma de abordar ambas as actividades são para mim um exemplo. Agradeço-lhe a disponibilidade e o auxílio na idealização e na condução dos trabalhos, na avaliação crítica dos resultados e na revisão cuidada dos artigos e desta dissertação. 18 Ao Professor Doutor Nuno Bettencourt, pela ajuda no desenho e condução dos trabalhos, na discussão dos resultados e na revisão dos manuscritos. O sucesso destes trabalhos dependeu, em boa parte, da sua capacidade de trabalho, dedicação e incentivo. A amizade que nos une, há longos anos, sai pois ainda mais consolidada desta colaboração. Ao Dr. Vasco Gama, director do Serviço de Cardiologia do Centro Hospitalar de Gaia/ Espinho, pela disponibilidade manifestada para a realização dos trabalhos naquele serviço, pelo entusiasmo e pelo interesse sempre demonstrado sobre o seu andamento e resultados. A sua energia, a constante busca pela inovação e pela melhoria e superação dos objectivos são a base da excelência atingida pelo serviço que dirige, e um modelo a seguir. Sem a sua colaboração, este projecto estaria votado ao insucesso. Aos meus colegas nos serviços de Cardiologia, Gastroenterologia e Medicina Interna – em particular ao Dr. Ricardo Fontes de Carvalho, Dr. Nuno Ferreira, Dra. Ana Paula Silva e Dr. João Valente – que me auxiliaram no recrutamento dos doentes e na realização e análise dos exames efectuados nos vários trabalhos, bem como na revisão cuidada dos manuscritos. Ao Professor Doutor Andreas Schuster, e a toda a sua equipa, pela análise das imagens de ressonância magnética adquiridas e pela discussão minuciosa dos resultados. Sem a sua colaboração desinteressada, a elaboração deste trabalho não teria sido possível. Aos enfermeiros da consulta externa de Cardiologia – Enf. José Dias e Enf. Isabel Gomes – pela disponibilidade que sempre demonstraram na colheita de amostras para os vários estudos desta tese. Devo-lhes uma palavra de gratidão e amizade. Aos técnicos da Ressonância Magnética do serviço de Radiologia, pela colaboração na aquisição das imagens para um dos estudos desta tese. O seu profissionalismo e qualidade foram indispensáveis para o sucesso alcançado. Manifesto também o meu reconhecimento aos doentes e controlos que aceitaram participar neste projecto. 19 Um agradecimento final: Ao Professor Doutor Carlos Ramalhão, pelo incentivo constante e sobretudo pela generosidade e amizade incondicionais que aumentam, diariamente, a minha dívida de gratidão para com ele. À Joana, por partilhar a vida comigo, por não me ter deixado desistir, e por ser capaz de, simultaneamente, co-orientar os trabalhos, manter uma actividade clínica e docente dedicada e gerir uma família (nos dias de hoje numerosa), e ser exemplar em todas estas tarefas. À Inês, ao João Francisco e à Rita, por serem a alegria dos meus dias e por me fazerem, periodicamente, recordar aquilo que verdadeiramente conta. Aos meus Pais, à minha irmã e restante família, pelos valores que me ensinaram e pela formação que me proporcionaram. Aos meus amigos, por o serem. Índice 21 ÍNDICE I. INTRODUÇÃO .............................................................................................................................. 23 1.1. A cardiomiopatia cirrótica ........................................................................................................ 25 1.1.1. A circulação na cirrose .................................................................................................... 25 1.1.2. Evidência experimental .................................................................................................... 26 1.1.3. Evidência clínica ................................................................................................................. 29 1.1.3.1. Disfunção sistólica ......................................................................................................... 29 1.1.3.2. Disfunção diastólica ...................................................................................................... 29 1.1.3.3. Alterações electrofisiológicas ..................................................................................... 30 1.1.4. Definição de cardiomiopatia cirrótica ......................................................................... 31 1.1.5. Importância clínica ............................................................................................................ 31 1.2. Técnicas imagiológicas para avaliação da função miocárdica.............................................. 33 II. OBJECTIVOS ................................................................................................................................... 45 III. MÉTODOS ........................................................................................................................................ 49 IV. PUBLICAÇÕES .............................................................................................................................. 55 4.1. Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tracking echocardiography study ............................................................................................................. 57 4.2. Left atrial function is impaired in cirrhosis: a speckle tracking echocardiographic study ............................................................................................................................................... 65 4.3. Assessment of cardiovascular physiology using magnetic resonance myocardial stress testing reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy. ........................................................................................................................... 73 4.4. Systolic dysfunction and diastolic dysfunction do not influence medium-term prognosis in patients with cirrhosis ........................................................................................ 93 22 Francisco Sampaio V. DISCUSSÃO .................................................................................................................................... 99 5.1. Disfunção sistólica .....................................................................................................................101 5.2. Disfunção diastólica ..................................................................................................................102 5.3. Prognóstico .................................................................................................................................104 VI. CONCLUSÕES .............................................................................................................................115 VII.RESUMO/ABSTRACT .............................................................................................................119 I. Introdução Introdução 25 1.1. A CARDIOMIOPATIA CIRRÓTICA Durante décadas, o único elo de ligação reconhecido entre cirrose hepática e a presença de disfunção cardiovascular foi o consumo excessivo de álcool. Sendo uma das etiologias mais frequentes de cirrose hepática, o álcool é igualmente uma causa reconhecida de cardiomiopatia caracterizada por dilatação das câmaras cardíacas e disfunção sistólica[1]. O termo “doença cardíaca alcoólica” terá sido utilizado pela primeira vez na literatura médica por William Mackenzie em 1902[2]. A sua etiopatogenia é complexa, envolvendo factores genéticos e ambientais, estando o efeito tóxico directo do álcool nos miócitos amplamente documentado[3-6]. A presença de uma circulação hiperdinâmica em doentes com cirrose hepática de etiologia alcoólica foi descrita na década de 50 do século XX sendo igualmente atribuída, numa fase inicial, aos efeitos do álcool na circulação periférica[7, 8]. No entanto, desde a década de 80 do século XX, vários trabalhos experimentais têm revelado a presença de várias alterações cardiovasculares associadas à cirrose, sugerindo a existência de uma cardiomiopatia cirrótica, independente da sua etiologia. 1.1.1. A circulação na cirrose As alterações hemodinâmicas na cirrose parecem relacionar-se com o desenvolvimento de hipertensão do sistema porta, resultante da instalação de fibrose e de nódulos de regeneração no parênquima hepático e consequente aumento das resistências vasculares intrahepáticas. Estas alterações foram também demonstradas em modelos animais de hipertensão portal pré-sinusoidal, sugerindo a sua correlação primária com a hipertensão portal, independentemente da existência de doença do parênquima hepático e da sua etiologia[9-11]. A hipertensão portal associa-se a um aumento dos níveis circulantes de vários mediadores – como o óxido nítrico, monóxido de carbono, endocanabinóides, adrenomedulina, factor de necrose tumoral ou o peptídeo relacionado com o gene da calcitonina – com efeito vasodilatador, quer por aumento da sua produção, quer por diminuição da sua degradação hepática[12-16]. A vasodilata- 32 Francisco Sampaio interesse crescente pelo seu estudo. A presença de disfunção diastólica foi implicada na patofisiologia desta complicação. A implantação do shunt porto-sistémico leva a um aumento do retorno venoso na circulação central[88]. O aumento da pressão arterial pulmonar, da pressão de encravamento pulmonar bem como das dimensões da aurícula esquerda e da massa ventricular observados nos doentes submetidos a esse procedimento sugerem uma incapacidade do coração em acomodar um aumento súbito da pré-carga[89, 90]. Para além disso, a presença de disfunção diastólica, avaliada pela relação E/A, associou-se a aumento de mortalidade e menor mobilização da ascite após inserção de TIPS[91, 92]. Por outro lado, foi também sugerida a associação entre disfunção sistólica, particularmente a resposta atenuada ao stress, e o prognóstico destes doentes. Ruiz-del-Arbol et al demonstraram que um débito cardíaco mais baixo se associava a risco aumentado de desenvolvimento de insuficiência renal em doentes com peritonite bacteriana espontânea[93]. Mais tarde, o mesmo grupo reportou a associação entre um débito cardíaco inferior a 6 L/min e desenvolvimento de síndrome hepatorenal, em doentes internados por ascite de grande volume[94]. Na mesma linha, Krag et al encontraram uma associação entre débito cardíaco baixo, risco de desenvolvimento de síndrome hepatorenal e mortalidade, em doentes com cirrose descompensada[95]. Estes trabalhos lançaram a hipótese da existência de um efeito causal entre disfunção sistólica e disfunção renal em doentes com cirrose descompensada, em que a incapacidade de aumentar o débito cardíaco na presença de vasodilatação se associa a um risco aumentado de complicações[96]. Mais recentemente Ruiz-del-Arbol et al relataram igualmente uma associação entre disfunção diastólica, evolução para síndrome hepatorenal e mortalidade[97]; no entanto, em contraste com os seus achados prévios, o débito cardíaco não foi preditor do risco de insuficiência renal pelo que os mecanismos patofisiológicos envolvidos na associação entre disfunção diastólica e disfunção renal não são claros. Por fim, trabalhos de outros autores não conseguiram estabelecer uma associação entre disfunção cardíaca – avaliada por técnicas ecocardiográficas modernas – e prognóstico em doentes com cirrose, contribuindo para a incerteza quanto ao impacto clínico da cardiomiopatia cirrótica[98, 99]. Em resumo, nas últimas décadas foi acumulada evidência científica abundante, proveniente quer de modelos experimentais, quer de estudos clínicos, da existência de alterações da contractilidade e do relaxamento cardíacos na cirrose hepática. No entanto, a patofisiologia desta disfunção cardiovascular é complexa e multifactorial, envolvendo alterações estruturais Introdução 33 e funcionais, a nível central e periférico. Por outro lado, a sua definição é vaga e não existem critérios de diagnóstico bem definidos e universalmente aceites, pelo que a prevalência exacta desta patologia não pode ser determinada. Finalmente, o seu impacto prognóstico, nomeadamente a sua contribuição para a mortalidade foi sugerido em alguns estudos, mas os mecanismos envolvidos nesta associação não são claros. 1.2. TÉCNICAS IMAGIOLÓGICAS PARA AVALIAÇÃO DA FUNÇÃO MIOCÁRDICA Nos últimos anos, múltiplas técnicas imagiológicas foram desenvolvidas e aplicadas na avaliação morfológica e funcional do coração. A ecocardiografia, sendo a mais antiga[100], continua também a ser, por questões de acessibilidade, portabilidade, segurança e custo, a modalidade de imagem mais utilizada[101-104]. A avaliação das dimensões das câmaras, e da massa e função ventriculares são das indicações mais frequentes para a requisição de um ecocardiograma[105]. De acordo com as recomendações actuais, a ecocardiografia é o método de imagem de primeira linha na avaliação de doentes com suspeita de insuficiência cardíaca, fornecendo informação estrutural (anatomia, volumes e massa) e funcional (incluindo a análise da função diastólica)[106]. No entanto várias limitações dos diferentes parâmetros ecocardiográficos devem ser tidas em conta aquando da sua utilização. Por exemplo, a fracção de ejecção, apesar de ser a medida mais generalizada de função sistólica global e ter, comprovadamente, importância prognóstica, não é um índice de contractilidade e depende fortemente da pré- e pós-carga, da frequência cardíaca e da função valvular[106]. O mesmo se aplica aos índices classicamente utilizados para avaliação da função diastólica[78, 107, 108]. Novos métodos ecocardiográficos entretanto desenvolvidos poderão permitir ultrapassar algumas destas limitações, permitindo uma análise quantitativa da deformação miocárdica (uma medida indirecta do encurtamento e distensão dos miócitos durante o ciclo cardíaco). Estas novas técnicas baseiam-se na determinação das velocidades relativas de diferentes pontos do miocárdio aplicando o princípio Doppler ao movimento do músculo cardíaco (Doppler tecidular) ou no cálculo da distância inicial e final entre vários pontos na imagem bidimensional através do seu seguimento ao longo do ciclo cardíaco (“speckle tracking”). A medida de deformação miocárdica define-se como strain e é expressa em percentagem. A velocidade a que a deformação miocárdica se dá, ou seja, a variação do strain num período de tempo é definida como strain rate e é expressa em 1/segundo[109, 110]. Não sendo medidas totalmente independentes das condições de carga[111-114], strain/strain rate são sobretudo determinados pela contractilida- 34 Francisco Sampaio de intrínseca dos miócitos e correlacionam-se bem com índices invasivos de contractilidade[115, 116]. A sua utilidade clínica tem sido demonstrada em diversos contextos – desde o diagnóstico de doença subclínica (onde a sua maior sensibilidade permite detectar alterações da função miocárdica em estadios precoces), à melhoria da acuidade diagnóstica na doença coronária e à monitorização terapêutica[117-122]. Foi igualmente documentado o seu potencial na avaliação do prognóstico[123-126]. Também na análise da função diastólica, os novos métodos ecocardiográficos, particularmente a análise das velocidades do miocárdio por Doppler tecidular, assumiram uma importância crescente. A velocidade de deslocamento do anel mitral no início da diástole (E’) é um parâmetro mais sensível de relaxamento que as variáveis do fluxo mitral, correlacionando-se bem com a constante Tau de relaxamento medida invasivamente[127-130]. Mais importante ainda é a boa correlação da razão entre a velocidade da onda E mitral por Doppler pulsado (E) e a velocidade da onda E’ com as pressões de enchimento do ventrículo esquerdo[130, 131]. Esta observação resulta do facto da velocidade E’ ser um indicador da quantidade do volume de sangue que entra no ventrículo esquerdo durante a fase de enchimento rápido enquanto que a velocidade da onda E representa o gradiente de pressão necessário para que essa quantidade de sangue entre no ventrículo esquerdo. Assim, a razão E/E’ reflecte a quantidade de sangue que entra no ventrículo esquerdo para um dado gradiente de pressão; uma razão E/E’ elevada representa uma pequena mudança de volume para um gradiente aurícula esquerda/ventrículo esquerdo elevado, e é um marcador de disfunção diastólica. Visto de outra forma, a velocidade da onda E depende do relaxamento, do gradiente de pressão AE/VE e da idade enquanto que a velocidade E’ depende sobretudo do relaxamento e da idade; deste modo, a razão entre as duas permite eliminar o efeito do relaxamento e da idade traduzindo apenas o gradiente de pressão entre as duas câmaras e a pressão de enchimento do ventrículo esquerdo[132]. Atendendo a estes achados, a medição das velocidades diastólicas do anel mitral por Doppler tecidular e a determinação da razão E/E’ são, de acordo com as recomendações actuais, mandatórias na avaliação ecocardiográfica da função diastólica[80]. A ressonância magnética cardíaca (RMC) tem, nos últimos anos, adquirido crescente importância na avaliação do sistema cardiovascular[133]. A sua excelente resolução espacial permitelhe definir, com exactidão, os bordos endocárdico e epicárdico, sem dependência de qualquer “janela acústica”. Deste modo, a RMC é considerada o método “gold-standard” na avaliação dos volumes cardíacos e da fracção de ejecção[133, 134]. Esta técnica permite igualmente avaliar os vários componentes da deformação miocárdica utilizando diferentes técnicas[135-138]. Finalmente, a capacidade de caracterização tecidular da RMC, permite a quantificação de áreas de Introdução 35 edema ou fibrose, com identificação precisa de lesão miocárdica (mesmo subclínica) assim como de miocárdio viável, sendo igualmente o actual “gold-standard” para a definição de viabilidade[139-141]. Algumas destas novas modalidades de imagem foram já utilizadas na avaliação de doentes com cirrose[61, 64]. 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Destes, foram excluídos 22 doentes com história de hipertensão arterial, diabetes mellitus ou de doença cardíaca relevante, com alterações electrocardiográficas significativas (não relacionadas com a doença hepática) ou com doença valvular moderada ou grave no ecocardiograma. Métodos: Todos os doentes foram submetidos a uma avaliação clínica, punção venosa para estudo analítico, electrocardiograma de 12 derivações e ecocardiograma. O estudo ecocardiográfico incluiu a determinação de dimensões e volumes das câmaras, da massa ventricular, da fracção de ejecção do ventrículo esquerdo e do débito cardíaco. A função diastólica foi avaliada de acordo com as recomendações actuais, incluindo a determinação das velocidades de deslocamento do anel mitral por Doppler tecidular. Foi ainda avaliada a deformação longitudinal do ventrículo esquerdo por speckle tracking. Um grupo de 18 indivíduos saudáveis, com distribuição etária e por género semelhante à dos doentes, foi submetido à mesma avaliação e foi usado com grupo controlo. 52 Francisco Sampaio ESTUDO 2 “Left atrial function is impaired in cirrhosis: a speckle tracking echocardiographic study” Doentes: Foi utilizado o mesmo grupo de doentes recrutados para o estudo 1. Após aplicação dos mesmos critérios de exclusão, 111 doentes foram incluídos na análise. Métodos: Para além da avaliação clínica, laboratorial e ecocardiográfica descrita no estudo 1, foi ainda estudada a deformação da aurícula esquerda por speckle tracking. Utilizou-se o mesmo grupo controlo para comparação. ESTUDO 3 “Assessment of cardiovascular physiology using magnetic resonance myocardial stress testing reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy” Doentes: para este estudo, recrutámos uma amostra de conveniência de 36 doentes estáveis, seguidos em consulta externa hepatologia por cirrose hepática, nos quais foi excluída história pregressa de hipertensão arterial, diabetes mellitus ou de doença cardíaca relevante. Métodos: Os doentes foram submetidos a avaliação clínica, laboratorial e ressonância magnética cardíaca no mesmo dia. O protocolo de ressonância magnética incluiu determinação de volumes das câmaras cardíacas, massa ventricular, fracção de ejecção de ambos os ventrículos e débito cardíaco (através da quantificação do fluxo na aorta ascendente) em repouso. Os doentes foram submetidos a stress farmacológico com dobutamina em baixa dose (10 e 20 ug/Kg/min), avaliando-se a evolução dos diferentes parâmetros (volume de ejecção, débito cardíaco, fracção de ejecção) durante a perfusão. Foi ainda avaliada a perfusão miocárdica após stress vasodilatador com adenosina e a presença de fibrose miocárdica através da pesquisa de realce tardio. As imagens obtidas foram analisadas posteriormente para quantificação dos vários componentes da deformação do ventrículo esquerdo, em repouso e sob stress. Um grupo de 8 indivíduos saudáveis foi submetido ao mesmo protocolo e usado como grupo controlo. Métodos 53 ESTUDO 4 “Systolic dysfunction and diastolic dysfunction do not influence medium-term prognosis in patients with cirrhosis” Doentes: Estudámos os 57 doentes que tiveram alta hospitalar – do grupo de 72 doentes internados por descompensação de cirrose avaliados nos estudos 1 e 2 – e os mesmos 61 doentes ambulatórios. Métodos: seguimos prospectivamente os 98 doentes durante 6 meses, avaliando a ocorrência de morte de qualquer causa. Avaliou-se a associação dos parâmetros clínicos laboratoriais e ecocardiográficos descritos naqueles estudos com a mortalidade aos 6 meses. IV. Publicações Publicações 57 CIRRHOSIS AND LIVER FAILURE Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tracking echocardiography study Francisco Sampaio 1,4 , Joana Pimenta 4 , Nuno Bettencourt 1,4 , Ricardo Fontes-Carvalho 1,4 , Ana P. Silva 3 , Jo~ ao Valente 2 , Paulo Bettencourt 4 , Jos e Fraga 3 and Vasco Gama 1 1 Cardiology Department, Centro Hospitalar de Gaia/Espinho, Espinho, Portugal 2 Internal Medicine Department, Centro Hospitalar de Gaia/Espinho, Espinho, Portugal 3 Gastroenterology Department, Centro Hospitalar de Gaia/Espinho, Espinho, Portugal 4 University of Porto Medical School, Porto, Portugal Keywords cirrhosis – echocardiography – heart failure – speckle-tracking – tissue-doppler imaging Correspondence Francisco Sampaio, Cardiology Department, Centro Hospitalar de Gaia/Espinho, Rua Conceic  ~ ao Fernandes, Vila Nova de Gaia 4430-502, Portugal Tel: 227865100 Fax: 227830209 e-mail: [email protected] Received 5 February 2013 Accepted 1 April 2013 DOI:10.1111/liv.12187 Abstract Background & Aims: Cardiac dysfunction has been described in patients with cirrhosis. Conventional echocardiographic methods are frequently unable to detect abnormalities at rest and have limitations. We aimed to evaluate cardiac function in cirrhosis patients assessing: (i) left ventricular systolic function using speckle-tracking imaging; (ii) diastolic function using a tissue-Doppler based algorithm and comparing it with previously proposed definition of diastolic dysfunction (DD). Methods: We included 109 hospitalized and ambulatory patients with cirrhosis and 18 healthy controls. Detailed echocardiographic evaluation was performed including tissue- Doppler and speckle-tracking analysis. Results: Peak systolic longitudinal strain (PLS) was lower in patients [19.99% (21.88 to 18.71) vs 22.02% (23.10 to 21.18), P=0.003]. Ejection fraction was similar in patients and controls [64% (59–67) vs 61% (60–65), P=0.42)]. Based on mitral-flow pattern, DD was present in 44 patients (40.4%). Patients without DD had higher cardiac output compared with those with DD [6.4 L/min (5.4–7.2) vs 5.6 L/min (4.6–6.8), P=0.02]. Using a tissue-Doppler based definition, the prevalence of DD was 16.5%. No differences in haemodynamic variables were found in patients with and without this definition of DD. The agreement between the two definitions of DD was weak (kappa =0.24, P=0.003). Echocardiographic abnormalities in systolic and diastolic function were not different in compensated vs decompensated patients in different Child-Pugh classes or cirrhosis aetiologies. Conclusions: Patients with cirrhosis have systolic and diastolic cardiac dysfunction at rest. Newer echocardiographic techniques may identify patients with functional impairment more accurately than conventional methods, which are more influenced by flow conditions. Cirrhotic cardiomyopathy has been recently described as a condition characterized by impaired contractile response to stress, diastolic dysfunction and electrophysiological abnormalities, in the absence of known cardiac disease (1–3). Echocardiography is an easily accessible imaging technique and the most widely used method to evaluate the cardiac function. Although several echocardiographic abnormalities have been described in cirrhosis, traditional indices of cardiac systolic function such as ejection fraction are frequently normal at rest in these patients. On the other hand, newer echocardiographic modalities like tissue Doppler imaging are mandatory when evaluating diastolic function as conventional Doppler measures are highly dependent on loading conditions. E’ velocity is a more sensitive marker of abnormal left ventricular relaxation than mitral flow derived variables (4) and E/E’ ratio has been found to reflect left ventricular filling pressure (5, 6), correlating better than natriuretic peptides with pulmonary capillary wedge pressure in a wide range of patients (7). Because of myocardial architecture, subendocardial fibres are most susceptible to damage and longitudinal left ventricular function is the first to be affected in the presence of myocardial disease (8–10). Only a few studies have used these tissue-Doppler derived indices to evaluate cardiac function in cirrhotic patients and only two have looked into myocardial deformation (11, 12). Several limitations –like image artefacts and dependence on insonation angle –are acknowledged when using tissue-Doppler. Newer speckle-tracking derived strain may overcome some of these limitations resulting Liver International (2013) ©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 1 Liver International ISSN 1478-3223 64 Francisco Sampaio function by echocardiography. J Am Soc Echocardiogr 2009; 22: 107–33. 16. Dalen H, Thorstensen A, Vatten LJ, Aase SA, Stoylen A. Reference values and distribution of conventional echocardiographic Doppler measures and longitudinal tissue Doppler velocities in a population free from cardiovascular disease. Circ Cardiovasc Imaging 2010; 3: 614–22. 17. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787–847. 18. Alexopoulou A, Papatheodoridis G, Pouriki S, et al. Diastolic myocardial dysfunction does not affect survival in patients with cirrhosis. Transpl Int 2012; 25: 1174–81. 19. Cazzaniga M, Salerno F, Pagnozzi G, et al. Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt. Gut 2007; 56: 869–75. 20. Choong CY, Herrmann HC, Weyman AE, Fifer MA. Preload dependence of Doppler-derived indexes of left ventricular diastolic function in humans. J Am Coll Cardiol 1987; 10: 800–8. 21. Thomas JD, Choong CY, Flachskampf FA, Weyman AE. Analysis of the early transmitral Doppler velocity curve: effect of primary physiologic changes and compensatory preload adjustment. J Am Coll Cardiol 1990; 16: 644–55. 22. Pimenta J, Paulo C, Gomes A, et al. B-type natriuretic peptide is related to cardiac function and prognosis in hospitalized patients with decompensated cirrhosis. Liver Int 2010; 30: 1059–66. 23. Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 2001; 37: 278–85. 24. Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 1997; 30: 474–80. 25. Kim YJ, Sohn DW. Mitral annulus velocity in the estimation of left ventricular filling pressure: prospective study in 200 patients. J Am Soc Echocardiogr 2000; 13: 980–5. 26. Nagueh SF, Lakkis NM, Middleton KJ, et al. Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999; 99: 254–61. 27. Bruch C, Gradaus R, Gunia S, Breithardt G, Wichter T. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr 2003; 16: 1031–6. 28. Vinereanu D, Nicolaides E, Tweddel AC, Fraser AG. “Pure” diastolic dysfunction is associated with long-axis systolic dysfunction. Implications for the diagnosis and classification of heart failure. Eur J Heart Fail 2005; 7: 820–8. 29. Yip G, Wang M, Zhang Y, et al. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart 2002; 87: 121–5. 30. Raedle-Hurst TM, Welsch C, Forestier N, et al. Validity of N-terminal propeptide of the brain natriuretic peptide in predicting left ventricular diastolic dysfunction diagnosed by tissue Doppler imaging in patients with chronic liver disease. Eur J Gastroenterol Hepatol 2008; 20: 865–73. 31. Merli M, Calicchia A, Ruffa A, et al. Cardiac dysfunction in cirrhosis is not associated with the severity of liver disease. Eur J Intern Med 2013; 24: 172–6. 32. Teske AJ, de Boeck BWL, Melman PG, et al. Echocardiographic quantification of myocardial function using tissue deformation imaging, a guide to image acquisition and analysis using tissue Doppler and speckle tracking. Cardiovasc Ultrasound 2007; 5: 27. 33. Little WC, Oh JK. Echocardiographic evaluation of diastolic function can be used to guide clinical care. Circulation 2009; 120: 802–9. Liver International (2013) ©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 8 Systolic and diastolic dysfunction in cirrhosis Sampaio et al. Publicações 65 ORIGINAL ARTICLE Left atrial function is impaired in cirrhosis: a speckle tracking echocardiographic study Francisco Sampaio •Joana Pimenta •Nuno Bettencourt • Ricardo Fontes-Carvalho •Ana Paula Silva •Joa ˜o Valente • Paulo Bettencourt •Jose ´Fraga •Vasco Gama Received: 22 April 2013 / Accepted: 1 August 2013 / Published online: 27 August 2013 Asian Pacific Association for the Study of the Liver 2013 Abstract Purpose Abnormalities in left ventricular systolic and diastolic function have been described in patients with cirrhosis. There are no studies on left atrial (LA) function in these patients. We aimed to evaluate LA function in cirrhosis patients using myocardial deformation imaging. Methods We included 111 hospitalized and ambulatory patients with cirrhosis and 18 healthy controls. A comprehensive echocardiographic evaluation was performed; LA strain was assessed using velocity vector imaging. Results Peak atrial longitudinal strain at the end of ventricular systole was lower in patients [41.9 % (34.4–51.0) vs. 48.0 % (42.0–57.1), p=0.02]. No differences were found in atrial strain before atrial contraction in patients and controls [17.5 % (14.3–22.4) vs. 20.7 % (14.1–26.3), p=0.14]. On multivariate linear regression analysis, E0 velocity was the only variable independently associated with peak atrial longitudinal strain (R 2 =47 %). No correlation was found between the LA volume index (LAVI) and peak atrial longitudinal strain (r= -0.136, p=0.219). Peak atrial longitudinal strain performed better than LAVI in identifying patients with elevated filling pressures (AUC =0.81 vs. 0.52). Conclusions Patients with cirrhosis have abnormal atrial reservoir function, which may be related to the same factors associated with impaired ventricular relaxation. LA enlargement in cirrhosis may not reflect elevated filling pressures and should not be used as an isolated marker of diastolic dysfunction. The atrial ‘‘pump’’ function does not seem to be affected in cirrhosis patients. Keywords Cirrhosis Echocardiography Heart failure Atrial function Speckle tracking imaging Introduction Cirrhotic cardiomyopathy refers to the presence of cardiac systolic, diastolic and electrophysiological abnormalities in patients with cirrhosis, in the absence of known heart disease [1–3]. A high prevalence of diastolic dysfunction (DD) in cirrhosis patients has been found in several studies [4–7]. Increased left atrial (LA) volume, a known marker of chronicity of DD, has also been reported in cirrhosis [8]. However, LA enlargement may be present in the absence of chronically elevated left ventricular (LV) filling pressures, and dilated atria may be seen in patients with volume overload, anemia and high-output states [9]. The mechanisms leading to LA dilatation in cirrhotic patients are not fully understood. LA dilatation and dysfunction are frequently associated. LA dysfunction may be involved in the pathophysiology of F. Sampaio (&)N. Bettencourt R. Fontes-Carvalho  V. Gama Cardiology Department, Centro Hospitalar de Gaia/Espinho, Rua Conceic¸a ˜o Fernandes, 4430-502 Vila Nova de Gaia, Portugal e-mail: [email protected] F. Sampaio J. Pimenta N. Bettencourt R. Fontes-Carvalho  P. Bettencourt Cardiovascular R&D Unit, University of Porto Medical School, Porto, Al. Prof. Hernani Monteiro, 4200-319 Porto, Portugal A. P. Silva J. Fraga Gastroenterology Department, Centro Hospitalar de Gaia/ Espinho, Rua Conceic¸a ˜o Fernandes, 4430-502 Vila Nova de Gaia, Portugal J. Valente Internal Medicine Department, Centro Hospitalar de Gaia/ Espinho, Rua Conceic¸a ˜o Fernandes, 4430-502 Vila Nova de Gaia, Portugal 123 Hepatol Int (2014) 8:146–153 DOI 10.1007/s12072-013-9469-5 66 Francisco Sampaio several conditions and may be associated with symptom onset [10]. Abnormalities in LA function have been described, using different methodologies, in LV hypertrophy, hypertension, hypertrophic cardiomyopathy, diabetes mellitus and DD [10–16]. These abnormalities are detectable before LA enlargement [15] and may be independent of LA volume [13]. Additionally, LA longitudinal strain seems to correlate better with LV filling pressures than LA volume or other echocardiographic indices such as the E/E0 ratio [17,18]. Accordingly, LA function may be a sensitive marker of cardiac dysfunction. The value of atrial function indices, particularly atrial longitudinal strain, in predicting cardiovascular events has also been demonstrated [19–21], which further stresses the potential clinical impact of atrial dysfunction. Speckle tracking echocardiography is an angle-inde- pendent method for assessing myocardial deformation. Although it is usually used for LV function analysis, previous studies have used it to assess LA function [10,12,13, 17,18,22]. However, no such studies have been performed in cirrhosis patients. To test the hypothesis that patients with cirrhosis could have abnormal LA function as a consequence of cirrhotic cardiomyopathy, we performed a detailed LA function evaluation, using myocardial deformation imaging, in patients with cirrhosis and in healthy age-matched controls. Materials and methods We prospectively evaluated 133 consecutive patients referred to our echocardiography laboratory to participate in a study of cardiac function in cirrhosis between April 2011 and November 2012. An additional analysis of this cohort has been published previously [23]. Diagnosis of cirrhosis was based on clinical, laboratory, ultrasonographic and/or biopsy criteria. Our sample was composed of a group of 61 ambulatory patients followed in an outpatient hepatology clinic and a group of 72 patients hospitalized because of decompensated cirrhosis (defined by the presence of encephalopathy, ascites, variceal bleeding and/or jaundice). A group of 18 healthy controls, with similar age and sex distribution as the patient group, was recruited among hospital staff. Patients and controls underwent clinical evaluation, blood sample collection, 12-lead ECG and echocardiography on the same day. Patients with a known history of hypertension, diabetes or other relevant cardiac disease were excluded; patients with significant ECG abnormalities or more than mild valvular heart disease on echocardiography were also excluded. The investigation conforms with the principles outlined in the Declaration of Helsinki. The local ethics committee approved the study protocol, and patients or their relatives gave informed consent. Echocardiography A single experienced operator performed the echocardiograms, using a commercially available ultrasound system (iE33, Philips Medical Systems, Best, The Netherlands) equipped with a broadband S5-1 transducer. Cardiac chamber dimensions and volumes and LV mass were measured according to current recommendations [24]. DD was diagnosed and graded according to the current recommendations for the evaluation of LV diastolic function by echocardiography [9]. Pulsed-wave Doppler, with a 3-mm sample placed between the tips of the mitral leaflets, was used to assess LV inflow velocities. Pulsed-wave tissue-Doppler velocities were acquired in the apical four-chamber view, with the sample positioned at the septal and lateral mitral annulus. Velocities were recorded at end expiration and averaged over three consecutive cardiac cycles. Mean systolic (S0) and early- (E0) and late diastolic (A0) velocities were considered for the analysis. For LA strain assessment, two-dimensional grey-scale images were acquired in the apical four- and two-chamber views, with a frame rate of 60–100 fps. Three cardiac cycles were stored digitally. Analysis was performed using the velocity vector imaging software (SyngoVVI 2.0, Siemens Medical Solutions USA Inc., Mountain View, CA) more than a month after the acquisition by one observer blinded to the clinical and echocardiographic data. This software automatically tracks the LA endocardial border (from a few reference points manually defined by the operator) displaying velocity vectors throughout the cardiac cycle. Two-dimensional strain is obtained by tracking and comparing the relative position of speckles throughout the cardiac cycle. Strain curves are displayed for each of the six segments automatically generated by the software. Zero strain was set at the QRS onset. Using this reference point, the LA strain pattern consists of a positive wave that peaks at the end of ventricular systole followed by a decrease after the opening of the mitral valve and by a second peak before the start of atrial contraction (Fig. 1). Peak LA strain at the end of ventricular systole (PALS)— reflecting LA reservoir or ‘‘diastolic’’ function—and peak atrial strain just before atrial contraction (PACS)—a marker of LA pump or ‘‘systolic’’ function—were measured from the average strain curves. Patients with inadequate tracking in more than two segments were excluded from the analysis. Hepatol Int (2014) 8:146–153 147 123 Publicações 67 Reproducibility Reproducibility of PALS and PACS measurements was assessed in ten randomly selected subjects. For intraobserver variability, a second measurement was performed by the same operator, more than a month after the initial analysis. For interobserver variability, the same loops were analyzed by a second operator. Statistical analysis Data were stored and analyzed using IBM SPSS Statistics, version 20.0 (Armonk, NY: IBM Corp.). Results are presented as median (25th–75th percentile) for quantitative variables and as n(%) for categorical variables. A significance level of 5 % was used. Differences in continuous variables between groups were compared using the Mann–Whitney test, and the v 2 test was used to compare proportions. Predictors of PALS and the LA volume index (LAVI) were evaluated by linear regression analysis. In order to achieve a normal distribution in the study sample, PALS and LAVI were logarithmized. Univariate predictors were included in a multivariable model, built using a stepwise forward procedure. Receiver-operat- ing characteristic (ROC) curve analysis was used to evaluate the performance of PALS and LAVI in detecting elevated LV filling pressures. Bland–Altman analysis was performed to assess intra- and interobserver agreement. Results Clinical and standard LV echocardiographic parameters have been previously published [23] and are summarized in Table 1. Briefly, 111 patients of the original sample were included; 22 patients of the original sample were excluded based on the exclusion criteria. The cirrhosis etiology was mainly alcoholic. Thirty-eight patients (34.2 %) were in Child–Pugh class A, 28 (25.2 %) were in class B, and 45 (40.5 %) were in class C. Large or medium volume ascites was observed in 45 (40.5 %) patients. Patients had higher LAVI compared to controls [39.8 (29.8–44.7) vs. 30.4 (22.3–33.7), p\0.001]. The prevalence of DD in our sample was 16.2 % (vs. 0 % in the control group). Of these, 70.6 % had grade 1 and 29.4 % had grade 2 DD. LA function Correct border tracking in C10 segments was achieved, and global LA strain values were available in 84 patients and 14 controls. There were no differences in age [54 (48–63) vs. 51 (49–57), p=0.26] or gender (81 vs. 71 % males, p=0.48) between the two groups. Peak LA strain at the end of ventricular systole (PALS) was lower in patients compared to controls [41.9 % (34.4–51.0) vs. 48.0 % (42.0–57.1), p=0.02]. Peak atrial strain before atrial contraction (PACS) was similar in patients and controls [17.5 % (14.3–22.4) vs. 20.7 % (14.1–26.3), p=0.14]. The associations between logarithmized PALS (LnPALS) and demographic characteristics, etiology and staging of chronic liver disease, physical exam parameters, and other echocardiographic measures were evaluated using univariate linear regression analysis (Table 2). Variables with a significant association with LnPALS were included in a multivariable linear model. E0velocity was the only independent predictor of LnPALS [b=0.082, 95 % confidence interval (CI) 0.062–0.102, p\0.001]. R 2 for the model was 47 %. A similar linear regression analysis was performed to evaluate predictors of logarithmized LAVI (LnLAVI). Fig. 1 Velocity vectors and corresponding longitudinal strain curves in six left atrial segments in the apical four-chamber view. Peak atrial longitudinal strain (PALS) was measured at the end of ventricular systole, reflecting atrial reservoir function. Peak atrial strain just before atrial contraction (PACS) reflects atrial pump function 148 Hepatol Int (2014) 8:146–153 123 68 Francisco Sampaio Hemoglobin (b= -0.033, 95 % CI -0.054 to -0.012, p=0.003), stroke volume (b=0.005, 95 % CI 0.002–0.007, p=0.001) and LV end-diastolic volume (b=0.003, 95 % CI 0.001–0.005, p=0.006) were independently associated with LnLAVI. R 2 for the model was 38 %. We found a significant correlation between PALS and mean E/E0ratio (Spearman’s q= -0.47, p\0.001). LAVI did not correlate with E/E0(Spearman’s q=0.05, p=0.602; Fig. 2). On ROC curve analysis, using an E/E0 ratio C10 as a surrogate marker of elevated LV pressures, PALS performed better than LAVI in predicting increased filling pressures (AUC =0.81, 95 % CI 0.71–0.90 vs. 0.52, 95 % CI 0.39–0.64, p\0.001; Fig. 3). Best cutoff values and corresponding sensitivities and specificities are presented in Table 3. The mean differences in PALS measurements were 0.3 % (95 % CI -1.4 to 1.9) and 0.6 % (95 % CI -1.6 to 2.7) for intra- and interobserver agreement, respectively. In PACS, the mean differences were 0.4 % (95 % CI -0.4 to 1.2) for intraobserver and 0.8 % (95 % CI -0.9 to 2.6) for interobserver agreement. Discussion Our results show that patients with cirrhosis have an abnormal LA compliance at rest, which is related to LV relaxation. LA contraction seems to be preserved. Using deformation imaging, we found that patients with cirrhosis have reduced PALS, reflecting impaired LA reservoir function. Peak atrial longitudinal strain was, on linear regression analysis, not associated with etiology, clinical status, hemodynamic variables or LA volume. Accordingly, compromised LA reservoir function may be a manifestation of cirrhotic cardiomyopathy. This is, to the best of our knowledge, the first study to evaluate atrial function in cirrhosis using deformation imaging. Atrial reservoir function has been found to be dependent on mitral annulus descent besides atrial compliance [25, 26], since LV ejection occurs at the same time of the LA reservoir phase. We found an association between LnPALS and indices of LV systolic function (S0velocity and LV longitudinal strain) using linear regression analysis. However, E0velocity (a sensitive marker of ventricular relaxation) was the only variable independently associated with LnPALS in multivariate analysis, suggesting that the same processes that impair ventricular relaxation play a major role in LA compliance. Atrial dysfunction has been reported in several other conditions [10–16,27], mainly characterized by LV DD. This may be explained by the effect on LA relaxation of the backward transmission of increased LV filling pressures. The strong correlation between PALS and invasively determined filling pressures found by other authors supports this hypothesis [17,18]. In our work, we also found a correlation between the atrial longitudinal strain and E/E0 ratio (a non-invasive estimate of LV filling pressures) on univariate analysis. However, the association between LV and LA dysfunction has been suggested to depend mainly on fibrotic processes that affect the subendocardial layers of both the LV and LA walls [10,27,28]. The relation between LA stiffness and changes in extracellular matrix composition and the expression of cytoskeletal proteins has been demonstrated in animal models of DD [29]. The same Table 1 Clinical, laboratorial and echocardiographic characteristics of patients Age 54 (48–64) Male gender (n, %) 88 (79.3) Cirrhosis etiology Alcoholic (n, %) 74 (66.7) Viric (n, %) 28 (25.2) Other (n, %) 9 (8.1) Beta-blocker use (n, %) 54 (48.6) Child-Pugh class A (n, %) 38 (34.2) B (n, %) 28 (25.2) C (n, %) 45 (40.5) MELD score 14 (10–18) Heart rate 72 (60–83) Mean blood pressure 90 (80–98) Blood analysis Hemoglobin (g/dl) 11.9 (10.3–13.6) Platelet count (910 9 /l) 98 (57–126) Creatinine (mg/dl) 0.68 (0.50–0.91) Sodium (mEq/l) 137 (133–140) Total bilirubin (mg/dl) 1.81 (1.09–3.80) Albumin (g/dl) 3.30 (2.60–3.90) NT-ProBNP (pg/ml) 193 (64–399) CRP (mg/dl) 0.84 (0.25–2.48) INR 1.43 (1.28–1.75) Echocardiography Left atrial volume index (ml/m 2 ) 39.8 (29.8–44.7) Left ventricle diastolic diameter (mm) 51 (47–55) Left ventricle systolic diameter (mm) 32 (28–35) Left ventricular mass (g) 148 (121–188) Left ventricular ejection fraction (%) 63 (58–67) Ejection fraction \55 % (n, %) 11 (9.9) Cardiac output (l/min) 6.1 (5.1–7.1) E/Aratio 1.03 (0.82–1.34) Deceleration time (ms) 239 (201–280) E0velocity (cm/s) 9.56 (7.43–11.72) E/E0ratio 8.57 (6.80–10.38) Hepatol Int (2014) 8:146–153 149 123 Publicações 69 changes have been implied in the pathogenesis of cirrhotic cardiomyopathy [8,30] and may partially explain our finding of an independent association between PALS and E0. Additionally, LV fibrosis has also been documented in patients with cirrhosis using magnetic resonance imaging [31]. We did not find an association between PALS and clinical status as assessed by the Child-Pugh score or the Fig. 2 Correlations between peak atrial longitudinal strain (a) and left atrial volume index (b) with E/E0ratio Table 2 Univariate linear regression analysis for predictors of left atrial peak longitudinal strain Dependent variable logarithmized left atrial peak longitudinal strain, TAPSE tricuspid annulus plane systolic excursion a Defined as eGFR \60 ml/ min/1.73 m 2 b95 % Confidence interval p Age (per year) -0.007 -0.013 to -0.001 0.023 Male gender (vs. female) 0.147 -0.007 to 0.302 0.061 Alcoholic etiology (vs. other) -0.116 -0.243 to 0.011 0.072 Large/medium volume ascites (vs. small/none) 0.038 -0.091 to 0.167 0.563 Child-Pugh score [10 0.124 -0.003 to 0.251 0.056 Beta-blocker use (vs. none) -0.100 -0.222 to 0.023 0.109 Diuretic use (vs. none) 0.013 -0.113 to 0.139 0.839 Hemoglobin (per g/dl) -0.037 -0.064 to -0.010 0.008 Renal failure a 0.177 -0.082 to 0.435 0.178 Serum sodium (per mEq/l) -0.010 -0.022 to 0.002 0.087 Mean arterial pressure (per mmHg) -0.003 -0.008 to 0.001 0.155 Heart rate (per beat/min) 0.003 -0.001 to 0.007 0.216 Left atrial volume index (per ml/m 2 )-0.004 -0.010 to 0.001 0.125 Left ventricle end-diastolic volume (per ml) 0.001 -0.002 to 0.002 0.694 Left ventricular mass (per g) 0.001 -0.002 to 0.001 0.523 Left ventricular ejection fraction 0.008 -0.001 to 0.017 0.075 Stroke volume 0.001 -0.002 to 0.003 0.689 Cardiac output (per l/min) 0.030 -0.005 to 0.065 0.092 E/Aratio 0.154 -0.020 to 0.328 0.082 Deceleration time (per ms) -0.001 -0.002 to 0.001 0.062 Isovolumetric relaxation time (per ms) -0.003 -0.005 to -0.001 0.005 S0velocity (per cm/s) 0.065 0.034 to 0.096 \0.001 E0velocity (per cm/s) 0.068 0.048 to 0.087 \0.001 A0velocity (per cm/s) 0.046 0.015 to 0.076 0.004 E/E0ratio -0.052 -0.073 to -0.031 \0.001 Left ventricular longitudinal strain -0.049 -0.068 to -0.029 \0.001 TAPSE (per mm) 0.012 -0.002 to 0.026 0.083 150 Hepatol Int (2014) 8:146–153 123 70 Francisco Sampaio presence of medium or large ascites. LAVI was also not different between these groups. Although some authors have documented a direct relation between thee degree of liver dysfunction and cirrhotic cardiomyopathy, more recent studies, using modern echocardiographic methods, have failed to do so [6,7,23,32]. The association between DD and liver disease severity in previous studies may be related to the influence of flow conditions (such as lower cardiac output in patients with ascites) on conventional PW-Doppler parameters, used on those studies. Since diuretics and beta-blockers, which may affect loading conditions and contractility, were not withdrawn before the evaluation, our results could reflect the effect of these drugs. However, in linear regression analysis, the use of beta-blockers or diuretics was not associated with LnPALS. Besides, we found no significant differences in PALS between patients with or without diuretics or betablockers (data not shown). Although we cannot definitely exclude an effect of pharmacological treatment, these findings argue against an important influence of betablockers or diuretics on our results. LAVI was higher in patients compared to controls. On multivariate linear regression analysis, LnLAVI was associated with stroke volume, LV end-diastolic volume and hemoglobin. This is in accordance with the known influence of load and high-output states (including chronic anemia) on LA dimensions [9,20,33]. We did not find a correlation between PALS and LAVI in our sample. Besides, LAVI did not correlate with the E/E0ratio and performed poorly in the identification of patients with elevated filling pressures compared to PALS. A better correlation with pulmonary capillary wedge pressure (PCWP) [17,18] and the superiority of PALS over LA volume in the identification of patients with DD and elevated filling pressures [12–14] have been repeatedly reported. The finding of increased LA volume in cirrhosis is in line with previous reports [8,32,34]. It has been attributed to DD and increased filling pressures in that setting [8]. Although increased LA volume usually reflects chronically elevated LV filling pressures in DD, the mechanisms leading to LA enlargement in cirrhosis are not clear, and there are some conflicting data. The currently accepted theory states that blood pooling in the splanchnic bed in cirrhosis results in central hypovolemia. However, increased levels of atrial natriuretic peptide, a marker of volume overload, have been described in decompensated cirrhosis [8]. A high thoracic fluid content, which usually reflects central volemia, has also been reported in patients with decompensated cirrhosis [35]. This suggests that volemia may vary significantly in cirrhosis and that different hemodynamic factors may be implied in LA enlargement. Our results suggest that atrial dilatation is not exclusively related to DD and probably should not be used as an isolated marker of DD in that setting. Peak atrial strain just before atrial contraction, reflecting LA ‘‘pump’’ function, was not different in patients and controls. Previous studies have reported a compensatory increase in atrial contractility in ischemic cardiomyopathy Fig. 3 Receiver-operating characteristic (ROC) curves of peak atrial longitudinal strain (a) and left atrial volume index (b) in predicting an E/E0 ratio C10. AUC area under the curve Table 3 Receiver operating characteristics analysis of left atrial echocardiographic parameters to predict an E/E0ratio C10 Cutoff value Sensitivity (95 % CI) Specificity (95 % CI) AUC PALS 47.1 96.8 (83.3–99.9) 54.7 (40.4–68.4) 0.81 LAVI 29.8 40 (24.9–56.7) 82.9 (72.0–90.8) 0.52 Hepatol Int (2014) 8:146–153 151 123 Publicações 71 or hypertension [36,37], while others have shown a decrease in atrial systolic function in patients with systolic [14,38] and diastolic [10,12] heart failure. A lower impact of DD on LA pump function (as compared to PALS) has been suggested [15], and PACS seems to correlate worse than PALS with LV filling pressures [18]. Liu et al. [39] found that LA DD occurs prior to LA systolic dysfunction in patients with coronary artery disease. This may also be the case in cirrhosis. Nazar et al. [7] recently reported that 84 % of cirrhotic patients had normal or only mild DD and that invasively determined PCWP was normal in all patients. The prevalence of DD in our sample was 16.2 %, and only 29.4 % of those had grade 2 DD. A mild degree of DD may not be severe enough to significantly affect LA pump function in these patients. Limitations This is a single-center study performed in patients mainly with alcoholic cirrhosis. We did not perform invasive hemodynamic measurements and used echocardiographic surrogate markers of LV filling pressures. Previous reports have questioned the value of the E/E0ratio in identifying patients with elevated PCWP. However, this seems to be more relevant in patients with dilated ventricles, severely depressed systolic function and/or significant mitral regurgitation [40,41]. None of our patients had these abnormalities. We did not perform any imaging technique able to detect LA fibrosis. Therefore, although the relation between LA dysfunction and fibrosis has been documented in other settings [27,42], their association in cirrhosis remains speculative. Three-dimensional echocardiography, which could be more accurate in evaluating LA volume [43], was not used in this study. Prognosis was not evaluated, and so the clinical impact of our findings in cirrhotic patients remains to be determined. Conclusion Patients with cirrhosis have evidence of abnormal LA function at rest, which is detectable by newer echocardiographic techniques. LA function parameters are potential additional markers of cirrhotic cardiomyopathy. Our results also show that LA dysfunction is related to diastolic LV dysfunction, supporting the existence of common pathogenic mechanisms between the two. LA strain during ventricular systole correlated better than LAVI with LV filling pressures, suggesting that LA enlargement in cirrhosis may have other causes and should not be used as an isolate marker of DD. Conflict of interest Francisco Sampaio, Joana Pimenta, Nuno Bettencourt, Ricardo Fontes-Carvalho, Ana Paula Silva, Joa ˜o Valente, Paulo Bettencourt, Jose ´Fraga and Vasco Gama declare that they have no conflict of interest. Compliance with Ethical Requirements All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. References 1. Møller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut 2008;57:268–278 2. Alqahtani SA, Fouad TR, Lee SS. Cirrhotic cardiomyopathy. Semin Liver Dis 2008;28:59–69 3. Wong F. Cirrhotic cardiomyopathy. Hepatol Int 2009;3:294–304 4. Alexopoulou A, Papatheodoridis G, Pouriki S, Chrysohoou C, Raftopoulos L, Stefanadis C, et al. Diastolic myocardial dysfunction does not affect survival in patients with cirrhosis. 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Eur J Echocardiogr 2000;1:55–65 Hepatol Int (2014) 8:146–153 153 123 Publicações 73 1 TITLE: Assessment of cardiovascular physiology using magnetic resonance myocardial stress testing reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy AUTHORS: Francisco Sampaioa,b; Pablo Lamatac,d; Nuno Bettencourta,b; Sophie Charlotte Alte; Nuno Ferreiraa; Johannes Tammo Kowallickf,g; Joana Pimentab; Shelby Kuttyh; José Fragai; Paulo Bettencourtb; Vasco Gamaa; Andreas Schusterc,g,j. INSTITUTIONS: a- Cardiology Department, Centro Hospitalar de Gaia/Espinho, Portugal. b- University of Porto Medical School, Porto, Portugal. c- Division of Imaging Sciences and Biomedical Engineering, The Rayne Institute, Kings College London, St. Thomas’ Hospital, London, United Kingdom. d- Department of Computer Science, University of Oxford, United Kingdom. e- Department of Pediatric Cardiology and Intensive Care Medicine, Georg-August University, Göttingen, Germany. f- Institute for Diagnostic and Interventional Radiology, Georg-August University, Göttingen, Germany. g- DZHK (German Centre for Cardiovascular Research) Göttingen, Germany. h- University of Nebraska Medical Center/ Children's Hospital and Medical Center, Omaha, NE, United States of America. i- Gastroenterology Department, Centro Hospitalar de Gaia/Espinho, Portugal. j- Department of Cardiology and Pneumology, Georg-August University, Göttingen, Germany. CORRESPONDENCE: Francisco Sampaio Cardiology Department, Centro Hospitalar de Gaia/Espinho. Rua Conceição Fernandes 4430-502 Vila Nova de Gaia, Portugal PHONE: 227865100 FAX: 227830209 E-MAIL: [email protected] 80 Francisco Sampaio 8 lower dose (the higher dose having mainly a positive chronotropic effect) while patients may also have a delayed response of longitudinal strain to dobutamine, with some strain still further developing at 20 μg/Kg/min. Several abnormalities in cardiomyocyte structure and function – including decreased density and down-regulation of beta-adrenergic receptors and impaired intracellular signaling pathways - have been described in animal models of cirrhosis[25,26] and may account for our findings. Compared to controls, patients also had a smaller increase of GCS with 10 μg/Kg/min of dobutamine; the response of GCS to 20 μg/Kg/min did not differ between the two groups. This also suggests a delayed response of circumferential strain to inotropic stimuli in cirrhosis with patients requiring higher doses of dobutamine (or more time) to equalize with the controls. Ejection fraction showed a similar behaviour: patients had a smaller improvement at the dose of 10 μg/Kg/min of dobutamine but no differences were found between the groups at 20 μg/Kg/min. The response of GRS to dobutamine was not different in patients and controls; this is in line with previous studies in ischemic heart disease patients, which have reported radial strain to be the last component of myocardial mechanics to be affected by ischemia[27]. Although previous studies have reported an abnormal cardiac response to exercise or pharmacological stress in cirrhotic patients using echocardiography and SPECT[28-30], the role of dobutamine stress testing in diagnosing cirrhotic cardiomyopathy is still a matter of debate, since its ability to detect abnormalities – mainly changes in volumes and EF – has been inconsistent using these imaging modalities[8,9], particularly in patients with mild disease. The role of dobutamine stress MRI in cirrhosis has not been previously studied. Myocardial deformation analysis in this setting has also never been reported, either with CMR or echocardiography (probably because its feasibility under stress with the latter may be limited). Unlike echo, CMR does not depend on a good “acoustic window” for image acquisition, and its feasibility in quantifying strain during dobutamine stress has been demonstrated has been demonstrated both in healthy volunteers and in patients with ischemic cardiomyopathy[13,31]. Our findings may explain previous negative results[9] since preserved radial mechanics and a normal response of circumferential strain to higher doses of dobutamine, may contribute to a normal EF response during these doses, despite the smaller longitudinal strain increase. Cardiac output increased less significantly in patients than in controls. This seems to be explained by the higher increase in stroke volume found in controls, since heart rate variation was similar in the two groups. We also found a significant correlation between the dobutamine-induced changes of GLS and stroke volume. According to these observations, the inability to increase cardiac output under stress conditions that has been reported as a feature of cirrhotic cardiomyopathy may be at least partially explained by longitudinal myocardial dysfunction and not only from chronotropic incompetence. As previously mentioned there was a different behaviour of GLS under 10 and 20 Publicações 81 9 μg/Kg/min of dobutamine in patients and controls. As in controls the maximal inotropic effect was achieved with 10 μg/Kg/min with predominant positive chronotropic effect (that does not lead to an increase in stroke volume) at higher doses, it is possible that differences in cardiac output between patients and controls may have been much more significantly different at 10 μg/Kg/min than at 20 μg/Kg/min. Unfortunately, with did not acquire a flow imaging sequence at the lower dose, that would have allowed us to prove this hypothesis. A lower cardiac output has been associated with an increased risk of developing hepatorenal syndrome in patients with cirrhosis[32]. However, other studies have failed to establish a relation between cardiac dysfunction and prognosis[33-35], and consequently, this hypothesis remains speculative. Resting hemodynamic conditions may influence inotropic response to pharmacological stress, and our results might have been related to differences in volemia (particularly in the presence of diuretics), or neuro-humoral stimulation. However, only 7 patients were on diuretics and we could not find any differences in inotropic response between them and the other patients; we also failed to find differences in cardiac chambers size between patients and controls. On the other hand, resting heart rate, blood pressure and cardiac output were similar in patients and controls. Taken altogether, these findings argue against an effect of different basal hemodynamics on our results. Under adenosine stress, we did not detect ischemia, which could have influenced inotropic response to dobutamine, in any subject. Although a quantitative perfusion analysis was not performed, our methodology has been shown to be highly accurate in detecting functionally significant coronary artery disease[15]. In contrast with a previous study[36], we did not find LGE in any patient. The difference in disease severity between the two studies probably accounts for these findings since myocardial fibrosis may only be detectable in more advanced disease states as a result of the chronic activation of the reninangiotensin-aldosterone system. Limitations: This is a single center study performed in patients mainly with alcoholic cirrhosis and mild disease. We aimed to evaluate the contractile response to dobutamine stress with the maximum extent of inotropic response expected with doses of 10-20 μg/Kg/min of dobutamine[37]. However we cannot exclude that a full test (40 μg/Kg/min) would have potentially added valuable information despite the fact that we didn’t observe significant perfusion defects with adenosine stress. There is no widely accepted gold-standard method to diagnose cirrhotic cardiomyopathy; on the other hand, there are no well-established normal values of CMR-derived strain parameters at rest and under pharmacological stress. Hence, the diagnostic accuracy of our methodology cannot be objectively determined and definitive cut-offs cannot be provided. 82 Francisco Sampaio 10 We could not perform a T1-mapping analysis, which might have allowed us to detect the presence of diffuse myocardial fibrosis. CONCLUSIONS Patients with cirrhosis show inotropic incompetence to pharmacological stress, due to intrinsic myocardial dysfunction. CMR with myocardial deformation analysis may be a sensitive diagnostic tool to identify abnormal inotropic responses to stress already present at early disease states, which may be difficult to detect with other non-invasive imaging modalities. The significance of this impaired response to pharmacological stress in cirrhotic cardiomyopathy and its prognostic implications should be further explored in future prospective clinical investigations. LIST OF ABBREVIATIONS: SPECT: Single-photon emission computed tomography EF: Ejection fraction CMR: Cardiovascular magnetic resonance FT: Feature tracking GLS: Global longitudinal strain GRS: Global radial strain GCS: Global circumferential strain LGE: late gadolinium enhancement COMPETING INTERESTS: The authors have no competing interests to declare AUTHORS’ CONTRIBUTIONS FS and NB were involved in the conception and design of the study as well as data collection, analysis, interpretation, and drafting of the manuscript. 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Alexopoulou A, Papatheodoridis G, Pouriki S, Chrysohoou C, Raftopoulos L, Stefanadis C, Pectasides D: Diastolic myocardial dysfunction does not affect survival in patients with cirrhosis. Transpl Int 2012, 25:1174-1181. 36. Lossnitzer D, Steen H, Zahn A, Lehrke S, Weiss C, Weiss KH, Giannitsis E, Stremmel W, Sauer P, Katus HA, Gotthardt DN: Myocardial late gadolinium enhancement cardiovascular magnetic resonance in patients with cirrhosis. J Cardiovasc Magn Reson 2010, 12:47. 37. Jewitt D, Birkhead J, Mitchell A, Dollery C: Clinical cardiovascular pharmacology of dobutamine. A selective inotropic catecholamine. Lancet 1974, 2:363-367. 86 Francisco Sampaio 14 Figure 1 – Strain and ejection fraction response to pharmacological stress Percentual variation of strain parameters and ejection fraction with 10 μg/Kg/min and 20 μg/Kg/min of dobutamine in patients and controls. GLS – global longitudinal strain; GCS – global circumferential strain; GRS – global radial strain; EF – ejection fraction. Publicações 87 15 Figure 2 – Blunted response of strain to dobutamine. Representative example of the blunted response of longitudinal and circumferential strain to dobutamine in a patient, as compared to a control. Values written in the diagrams correspond to peak strain (%) and time to peak strain (ms), respectively. 88 Francisco Sampaio 16 Table 1 – Clinical and laboratorial characteristics of patients and controls Patients (n=36) Controls (n=8) p Age 54 (48-61) 52 (45-54) 0.12 Male gender (n,%) 30 (83.3) 5 (62.5) 0.33 Cirrhosis aetiology Alcoholic (n,%) Viric (n,%) Other (n,%) 21 (58.3) 10 (27.8) 5 (13.9) Child-Pugh score 5 (5-7) MELD score 9 (7-11) Diuretic use (n,%) 7 (19,4%) Heart rate 72 (58-78) 69 (51-72) 0.20 Mean blood pressure 98 (88-106) 100 (99-104) 0.64 Blood analysis Haemoglobin (g/dL) Platelet count (x109/L) Creatinine (mg/dL) Sodium (mEq/L) Total bilirubin (mg/dL) Albumin (g/dL) NT-ProBNP (pg/mL)) CRP (mg/dL) INR 13.4 (11.5-15.3) 101 (76-142) 0.63 (0.52-0.79) 139 (137-141) 0.92 (0.61-1.30) 4.1 (3.6-4.5) 58 (30-140) 0.25 (0.11-0.52) 1.2 (1.1-1.3) 14.4 (13.6-15.5) 225 (182-256) 0.74 (0.49-0.95) 142 (140-143) 0.34 (0.22-0.48) 4.6 (4.5-4.9) 32 (22-53) 0.16 (0.06-0.38) 1.0 (0.9-1.1) 0.21 <0.001 0.66 0.035 <0.001 0.005 0.20 0.42 0.001 CRP = C-Reactive Protein; INR = International Normalized Ratio; MELD = Model for End-Stage Liver Disease; NT-proBNP = N-terminal pro–B-type natriuretic peptide. Publicações 89 17 Table 2 – CMR parameters at rest of patients and controls Patients (n=36) Controls (n=8) p Left atrial volume (ml/m2) 44.9 (36.1-51.9) 44.2 (37.5-49.4) 0.92 Right atrial area (cm2) 21 (18-23) 22 (20-25) 0.35 Left ventricular diastolic volume (ml/m2) 75.1 (65.1-92.1) 87.7 (74.1-94.6) 0.27 Left ventricular systolic volume (ml/m 2 ) 24.4 (19.1-28.9) 28.0 (23.2-33.3) 0.19 Left ventricular ejection fraction (%) 67 (64-72) 66.0 (64-70) 0.66 Left ventricular mass (g/m2) 54.7 (46.7-62.0) 55.7 (45.7-63.5) 0.96 Right ventricular diastolic volume (ml/m2) 84.5 (67.9-92.2) 84.1 (70.5-97.7) 0.46 Right ventricular ejection fraction (%) 57 (52-62) 58 (56-61) 0.46 Cardiac output (l/min) 6.5 (5.1-7.9) 6.1 (5.1-6.6) 0.74 GLS (%) -18.9 (-16.0 to -20.5) -19.0 (-16.1 to -20.6) 0.96 Time to Peak GLS (ms) 263 (206-317) 253 (225-281) 0.96 GCS (%) -27.5 (-24.1 to -30.6) -27.7 (-24.9 to -30.1) 0.84 Time to Peak GCS (ms) 264 (208-315) 223 (216-316) 0.71 GRS (%) 33.9 (25.4-39.1) 39.1 (34.8-41.8) 0.80 Time to Peak GRS (ms 275 (216-308) 223 (215-303) 0.36 GCS = Global Circumferential Strain; GLS = Global Longitudinal Strain; GRS = Global Radial Strain 96 Francisco Sampaio of the patients had grade 2 diastolic dysfunction) as compared to other populations [8,9,21] and a longer follow-up may explain these differences. However, since invasively determined cardiac output was not an independent predictor of mortality or of the development of hepatorenal syndrome –in contrast with previous findings of the same authors [13] –the pathophysiological link between diastolic dysfunction and these outcomes remains unclear. In our work, systolic function, even when assessed by left ventricular longitudinal strain (a more sensitive and less load-dependent index of myocardial function [23,24]), was not a significant predictor of prognosis. A lack of differences in left ventricular longitudinal strain between patients with compensated and decompensated cirrhosis has been previously reported [8,9]. According to Nazar et al. [8], this can be considered as an evidence of contractile dysfunction in cirrhosis, since an increase in myocardial strain would have been expected in patients with higher sympathetic activation. While this interpretation could also be applied to our results, the absence of an association between left ventricular strain and survival even in the group of hospitalized (hence more decompensated) patients suggests that left ventricular longitudinal strain is not useful in identifying patients at increased risk of dying. These results contrast with findings in heart failure patients, in which left ventricular longitudinal strain has been found to be superior to ejection fraction in predicting outcomes [16,25]; the same was observed in patients hospitalized with acute heart failure who also have an intense activation of the sympathetic and renin–angiotensin– aldosterone systems [26]. Taken altogether these findings argue against a significant effect of myocardial systolic dysfunction on short-term prognosis of cirrhotic patients. Blood pressure was an independent predictor of mortality. Both cardiac output and peripheral vascular resistances determine arterial blood pressure. Since cardiac output was not related to mortality, the association between blood pressure and prognosis is likely to be Fig. 1. Probability of survival according to Child–Pughscore and mean blood pressure. Cumulative 6-monthssurvival in patients with Child–Pugh score above and below 10 points (upper panel, log rank test p b0.001) and in patients with mean blood pressure above and below 91 mm Hg (lower panel, log rank test p = 0.008). 244 F. Sampaio et al. / European Journal of Internal Medicine 25 (2014) 241–246 Publicações 97 explained mainly by peripheral vascular resistances, i.e., patients with more vasodilatation are at increased risk. Other authors have reported that a low cardiac output could identify patients at risk of developing hepatorenal syndrome and of dying [11–13]. Since the lack of prognostic impact of cardiacoutput in our population could just be explained by the inclusion of patients with mild disease, we performed an isolate analysis of the group of hospitalized patients. Although a cardiac output below the median was significantly associated with 6-months mortality in univariate analysis, this association was lost after adjusting for Child class. A progressive decrease in cardiac output during the course of liver disease has been reported [11,22], and probably accounts for this finding. Besides, we found no significant differences in cardiac output in patients who died during the index hospitalization and those who were discharged (data not shown). These conflicting results may be explainedby thefact that the causes of death in ourgroup were varied and not only related to renal/multiorgan failure. We did not analyse only those dying of hepatorenal syndrome since the small number of events would have significantly limited the statistical analysis. However, in their recent report, Ruíz-del-Árbol et al. also failed to find differences in cardiac output between patients who developed hepatorenal syndrome during follow-up and those who did not [22]; in fact the only significant difference in haemodynamic measurements found between those two groups was mean arterial pressure which is concordant with our own results. Elevated NT-ProBNP levels were related to mortality in the overall sample, but this association was lost after adjusting for Child score. A direct relation between natriuretic peptide levels and liver disease severity has been consistently reported [4,27]. However, Pimenta et al. found that BNP levels above the median were independent predictors of 6-month mortality in a cohort of hospitalized patients [12]. We could not replicate these findings, when looking only at the group of hospitalized patients. There are some possible explanations for these results.Wemeasured NT-ProBNPonly atadmission;itispossiblethat,just like in heart failure, discharge and particularly the evolution of natriuretic peptide levels during the hospital stay [28,29], would be a more important prognostic marker than a single measurement. We used NT-ProBNP instead of BNP, and the two molecules have slightly different characteristics [30] (half-life, clearance mechanisms), which may, hypothetically, have influenced the results. Finally, NT-ProBNP levels were relatively low in our sample, even when looking only at patients discharged after a hospitalization; this small range of low values may not be able to differentiate patients at increased risk of death. Patients who died during the index hospitalization had significantly higher NT-ProBNP levels than patients who were discharged. This suggests that BNP may, in fact, be useful in identifying higher risk patients. 4.1. Limitations Our study was performed in a single centre and included mainly patients with alcoholic cirrhosis and different disease severity. We excluded patients with diabetes, which is frequent in cirrhotic patients and is a known cause of cardiac disease; hence our conclusions cannot be extended to this subset of patients. We did not perform invasive haemodynamic studies or neurohormonal measurements (besides NT-ProBNP), which would have allowed us to accurately assesscentral and peripheral haemodynamic status and to correlate them with prognosis. It would add to our analysis evaluating whether echocardiographic parameters of myocardial dysfunction could predict cardiovascular deaths. However, the study was not designed to perform such analysis and would be underpowered to draw firm conclusions due to the limited number of deaths in this category. 5. Conclusion Cardiac function is not related to medium-term mortality in cirrhosis, which seems to be mainly determined by liver disease severity and associated haemodynamic changes. Although systolic dysfunction and diastolic dysfunction have been documented in patients with cirrhosis, these abnormalities may not be severe enough to independently influence the medium-term prognosis. However, we cannot exclude that cardiac dysfunction may act as a contributing factor to the development of complications of cirrhosis (like hepatorenal syndrome or haemorrhage), or to their irreversibility. On the other hand, its potential effect on long-term survival remains unclear and warrants further study. Table 4 Cox regression model for predictors of all-cause death within 6 months after discharge in hospitalized patients. Hazard ratio 95% confidence interval p Age N54 years 0.88 0.37–2.11 0.769 Alcoholic aetiology (vs other) 0.47 0.19–1.15 0.098 Mean blood pressure N85 mm Hg 0.54 0.22–1.31 0.172 Heart rate N75 bpm 1.57 0.64–3.83 0.326 Child–Pugh score N10 points 5.08 1.49–17.4 0.010 MELD a score N15 points 1.22 0.51–2.95 0.654 Haemoglobin N10.8 g/dL 0.71 0.29–1.71 0.443 Renal Insufficiency b 1.28 0.43–3.83 0.661 Serum sodium N135 mEq/L 1.04 0.43–2.51 0.926 Total bilirubin N2.47 mg/dL 1.22 0.51–2.94 0.659 Albumin N2.85 g/dl 0.35 0.13–0.90 0.030 CRP c N1.60 mg/dL 2.63 1.00–6.93 0.050 NT-ProBNP d N295 pg/mL 2.39 0.91–6.30 0.077 Left atrial volume index N40 ml/m 2 0.90 0.38–2.17 0.820 Left ventricle end-diastolic volume N96 mL 0.54 0.22–1.32 0.179 Left ventricular mass N146 g 0.59 0.24–1.44 0.244 Left ventricular ejection fraction N55% 1.26 0.29–5.42 0.759 Cardiac output N6.7 L/min 0.32 0.12–0.84 0.021 Left ventricular longitudinal strain N−19.8% 1.67 0.61–4.60 0.322 Diastolic dysfunction e (versus none) 0.51 0.12–2.18 0.360 E/E′ratio N10 1.07 0.43–2.69 0.880 QTc interval N440 ms 0.39 0.13–1.18 0.096 a Model for end-stage liver disease. b Defined as glomerular filtration rate b60 mL/min/1.73 m 2 using the MDRD formula. c C reactive protein. d Aminoterminal portion of pro-b-type natriuretic peptide. e Diastolic dysfunction defined as septal e′b8 cm/s, lateral e′b10 cm/s and left atrial volume ≥34 mL/m 2 [20]. 245F. Sampaio et al. / European Journal of Internal Medicine 25 (2014) 241–246 98 Francisco Sampaio Learning points •Cirrhotic cardiomyopathy is a condition characterized by impaired contractile response to stress, diastolic dysfunction and electrophysiological abnormalities, in the absence of known cardiac disease. •An association between cardiac dysfunction and a worse prognosis in patients with cirrhosis has been suggested. •In the present study, using sensitive and less load-dependent echocardiographic methods, we could not find an association between any indices of myocardial function and 6 month mortality. •Liver disease severity and peripheral and associated haemodynamic changesseemtobethemaindeterminantsofmedium-termprognosis. Conflict of interests The authors have no conflict of interest to declare. References [1] Alqahtani SA, Fouad TR, Lee SS. Cirrhotic cardiomyopathy. Semin Liver Dis 2008;28:59–69. [2] Moller S, Henriksen JH. Cardiovascular complications of cirrhosis. 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[8] Nazar A, Guevara M, Sitges M, Terra C, Solà E, Guigou C, et al. LEFT ventricular function assessed by echocardiography in cirrhosis: relationship to systemic hemodynamics and renal dysfunction. J Hepatol 2013;58:51–7. [9] Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva AP, Valente J, et al. Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tracking echocardiography study. Liver Int 2013;33:1158–65. [10] Cazzaniga M, Salerno F, Pagnozzi G, Dionigi E, Visentin S, Cirello I, et al. Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt. Gut 2007;56:869–75. [11] Krag A, Bendtsen F, Henriksen JH, Møller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut 2010;59:105–10. [12] Pimenta J, Paulo C, Gomes A, Silva S, Rocha-Gonçalves F, Bettencourt P. B-type natriuretic peptide is related to cardiac function and prognosis in hospitalized patients with decompensated cirrhosis. Liver Int 2010;30:1059–66. [13] Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439–47. [14] Ruiz-del-Arbol L, Urman J, Fernández J, González M, Navasa M, Monescillo A, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210–8. [15] Yu CM, Sanderson JE, Marwick TH, Oh JK. Tissue Doppler imaging a new prognosticator for cardiovascular diseases. J Am Coll Cardiol 2007;49:1903–14. [16] Stanton T, Leano R, Marwick TH. Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring. Circ Cardiovasc Imaging 2009;2:356–64. [17] Nahum J, Bensaid A, Dussault C, Macron L, Clémence D, Bouhemad B, et al. Impact of longitudinal myocardial deformation on the prognosis of chronic heart failure patients. Circ Cardiovasc Imaging 2010;3:249–56. [18] Liu YW, Su CT, Sung JM, Wang SP, Su YR, Yang CS, etal. Association of left ventricular longitudinal strain with mortality among stable hemodialysis patients with preserved left ventricular ejection fraction. Clin J Am Soc Nephrol 2013;8:1564–74. [19] Ersboll M, Valeur N, Mogensen UM, Andersen MJ, Moller JE, Velazquez EJ, et al. Prediction of all-cause mortality and heart failure admissions from global left ventricular longitudinal strain in patients with acute myocardial infarction and preserved left ventricular ejection fraction. J Am Coll Cardiol 2013;61:2365–73. [20] 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. J Am Soc Echocardiogr 2009;22:107–33. [21] Alexopoulou A, Papatheodoridis G, Pouriki S, Chrysohoou C, Raftopoulos L, Stefanadis C, et al. Diastolic myocardial dysfunction does not affect survival in patients with cirrhosis. Transpl Int 2012;25:1174–81. [22] Ruiz-Del-Arbol L, Achecar L, Serradilla R, Rodriguez-Gandia MA, Rivero M, Garrido E, et al. Diastolic dysfunction is a predictor of poor outcomes in patients with cirrhosis, portal hypertension and a normal creatinine. Hepatology 2013;58:1732–41. [23] Bijnens BH, Cikes M, Claus P, Sutherland GR. Velocity and deformation imaging for the assessment of myocardial dysfunction. Eur J Echocardiogr 2009;10:216–26. [24] Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, et al. Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr 2011;12:167–205. [25] Mignot A, Donal E, Zaroui A, Reant P, Salem A, Hamon C, et al. Global longitudinal strain as a major predictor of cardiac events in patients with depressed left ventricular function: a multicenter study. J Am Soc Echocardiogr 2010;23:1019–24. [26] Cho G-Y, Marwick TH, Kim H-S, Kim M-K, Hong K-S, Oh D-J. Global 2-dimensional strain as a new prognosticator in patients with heart failure. J Am Coll Cardiol 2009;54:618–24. [27] Yildiz R, Yildirim B, Karincaoglu M, Harputluoglu M, Hilmioglu F. Brain natriuretic peptide and severity of disease in non-alcoholic cirrhotic patients. J Gastroenterol Hepatol 2005;20:1115–20. [28] Bettencourt P, Azevedo A, Pimenta J, Friões F, Ferreira S, Ferreira A. N-terminal- pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004;110:2168–74. [29] Cheng V, Kazanagra R, Garcia A, Lenert L, Krishnaswamy P, Gardetto N, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37:386–91. [30] Kim HN, Januzzi Jr JL. Natriuretic peptide testing in heart failure. Circulation 2011;123:2015–9. 246 F. Sampaio et al. / European Journal of Internal Medicine 25 (2014) 241–246 V. Discussão Discussão 101 Nos estudos desenvolvidos no âmbito desta tese, foi possível documentar, utilizando métodos não invasivos de imagiologia cardíaca, alterações da função cardíaca em doentes com cirrose hepática de diferentes etiologias, quer em repouso quer sob estimulação farmacológica. Estes achados suportam assim a existência de uma cardiomiopatia cirrótica previamente caracterizada como uma disfunção miocárdica intrínseca relacionada com a cirrose e independente da sua etiologia[85]. 5.1 DISFUNÇÃO SISTÓLICA Da análise do estudo 1 pode-se concluir que os doentes com cirrose apresentam alterações da função sistólica – traduzida pela redução da deformação longitudinal do ventrículo esquerdo – apesar da fracção de ejecção ser normal em mais de 90% dos doentes. Este achado é consistente com o de outros estudos em que métodos de deformação miocárdica foram úteis na identificação de doença cardíaca subclínica[117-120] ou de disfunção sistólica na insuficiência cardíaca com fracção de ejecção preservada[142-145] e sugerem que, tal como naquelas entidades, a deformação longitudinal do ventrículo esquerdo é também o primeiro parâmetro de função sistólica a ser afectado na cirrose hepática. A arquitectura do ventrículo esquerdo, nomeadamente a orientação longitudinal das fibras endocárdicas – mais susceptíveis aos efeitos de agressões como a isquemia, sobrecarga de volume ou de pressão – fornece a base patofisiológica destas observações. Em contraste, as vertentes radial e circunferencial da deformação miocárdica apenas são afectadas em estádios muito mais avançados de doença, quando as fibras das camadas média e subepicárdica que as determinam são atingidas. Este facto pode justificar a normalidade da fracção de ejecção – muito dependente do espessamento miocárdico no sentido radial – na nossa população, sugerindo que este índice possa ser um marcador insensível e tardio de disfunção sistólica. No mesmo sentido, no estudo 3, verificámos que os doentes com cirrose, mesmo em estádios precoces da doença, apresentam uma resposta diminuída da deformação longitudinal à 102 Francisco Sampaio estimulação com dobutamina e que esta se correlaciona com um menor aumento do débito cardíaco nos doentes, quando comparados com um grupo controlo. Esta observação confirma a incompetência inotrópica em resposta a exercício físico ou estímulo farmacológico documentada em estudos prévios[51-54]. A resposta da deformação circunferencial e radial e da fracção de ejecção à estimulação adrenérgica (particularmente em doses mais elevadas), não se encontrava significativamente alterada neste estudo, comprovando, uma vez mais, a maior sensibilidade da deformação longitudinal na identificação de disfunção miocárdica precoce. No estudo 1, não conseguimos correlacionar a disfunção sistólica em repouso com o estado clínico ou com a gravidade da doença. No entanto, no estudo 3 não encontramos diferenças significativas nos índices de deformação entre doentes e controlos. Uma possível explicação para esta aparente discrepância poderá ser o efeito da estimulação adrenérgica mais intensa nos doentes mais graves e/ou descompensados que, partindo hipoteticamente de valores piores, resultaria num strain semelhante ao dos doentes compensados, com menor estimulação inotrópica. Por outro lado, o estudo 3 não foi desenhado para detectar diferenças em repouso entre os grupos, não tendo poder estatístico para o fazer dada a reduzida dimensão da amostra. Os nossos achados estão, porém, em linha com o de outros autores que também não conseguiram correlacionar o grau de disfunção sistólica com a gravidade da doença[61, 99]. Em resumo, os nossos resultados sustentam a existência de disfunção sistólica em doentes com cirrose, mas esta poderá apenas ser detectável através de técnicas de análise de deformação miocárdica; os índices convencionais de função sistólica (como a fracção de ejecção) poderão manter-se normais na maioria dos doentes, sendo afectados apenas na presença de atingimento cardíaco significativo. Poderá assim justificar-se, no futuro, incluir estes novos parâmetros nos critérios de suporte para o diagnóstico de cardiomiopatia cirrótica. 5.2. DISFUNÇÃO DIASTÓLICA Foi igualmente possível encontrar evidência de disfunção diastólica na população estudada nos nossos trabalhos. Contudo, a prevalência desta alteração variou consoante a metodologia adoptada. Utilizando os critérios de diagnóstico de cardiopatia cirrótica propostos em 2005[85], documentámos uma prevalência de disfunção diastólica de 40,4%; estes achados são semelhantes aos de estudos prévios utilizando a mesma metodologia[61, 91, 98, 99]. No entanto encontramos também diferenças nas condições de fluxo nos doentes com esta definição de disfunção diastólica. As limitações da avaliação da função diastólica com base no padrão de enchimento do ventrículo esquerdo por Doppler pulsado, nomeadamente a dependência das condições Discussão 103 de carga, são conhecidas e podem ser particularmente relevantes nos doentes com cirrose. Como descrito previamente, a circulação da cirrose caracteriza-se por hipovolémia central em consequência da vasodilatação arteriolar esplâncnica; a diminuição da pré-carga resulta, por si só, na diminuição da velocidade da onda E, mesmo em indivíduos normais, o mesmo se verificando com aumentos da frequência cardíaca[78, 107, 108]. Estes factos podem justificar a elevada prevalência de um padrão de enchimento ventricular caracterizado pela inversão da relação E/A, independentemente da presença de atraso do relaxamento ventricular, nos doentes com cirrose. O nosso achado de débito cardíaco mais baixo (podendo traduzir menor pré-carga) nos doentes com inversão da relação E/A parece suportar esta hipótese. A relação deste padrão com a gravidade da doença sugerida em estudos prévios[67, 68], pode ter uma explicação idêntica uma vez que os doentes mais descompensados exibem igualmente sinais de maior vasodilatação periférica. A prevalência de disfunção diastólica diminuiu significativamente com a aplicação das recomendações actuais para a avaliação de função diastólica por ecocardiografia[80]; mais importante, a concordância entre as duas definições foi fraca, reforçando a ideia que os critérios de diagnóstico baseados no fluxo transmitral não são adequados para identificar disfunção diastólica nestes doentes. Num estudo prévio, as pressões de enchimento ventriculares medidas invasivamente numa coorte de doentes com cirrose foram normais em todos os doentes[99], traduzindo a ausência de disfunção diastólica grave naquela população. Os nossos dados parecem confirmar esta observação e sugerem que a prevalência de disfunção diastólica pode ser menor do que a previamente descrita. A dilatação auricular esquerda é um reconhecido marcador de cronicidade de disfunção diastólica e de pressões de enchimento aumentadas[146]. Nos estudos 1 e 2, observámos que os doentes com cirrose, apresentam, efectivamente, volumes auriculares superiores aos do grupo controle. No entanto, a dilatação aurícula não é específica da disfunção diastólica e outras causas podem contribuir para este achado[80]. Na análise do estudo 2 verificámos que nenhum parâmetro de disfunção diastólica se associava independentemente ao volume auricular nesta população, sugerindo a existência de outros mecanismos para esta dilatação, no contexto específico da cirrose. De facto, apenas a hemoglobina, o volume de ejecção e o volume telediastólico do ventrículo esquerdo se associavam ao índice de volume auricular esquerdo sugerindo que as condições de volémia são os principais determinantes desta alteração, nestes doentes. Esta observação está em linha com a associação da dilatação auricular esquerda e dos níveis de peptídeo natriurético tipo A (ANP) com a volémia em doentes com cirrose relatada previamente[46]. 104 Francisco Sampaio No mesmo estudo, verificámos que a função de reservatório da aurícula esquerda – avaliada pela deformação desta câmara durante a sístole ventricular – se encontrava alterada nos doentes com cirrose e que este achado se correlacionava com a velocidade da onda E’ – um índice de relaxamento ventricular. Por outro lado, o strain auricular longitudinal permitiu identificar doentes com pressões de enchimento ventriculares melhor do que o volume da aurícula esquerda, sugerindo que este parâmetro pode reflectir a presença de disfunção diastólica significativa melhor do que o volume da aurícula esquerda, cuja interpretação deve ser cautelosa no contexto da cirrose hepática. Embora o valor prognóstico do strain longitudinal auricular tenha sido demonstrado noutros cenários[147], o impacto clínico da disfunção auricular no contexto da cirrose hepática permanece incerto. Em resumo, apesar de no decorrer dos nossos trabalhos se ter encontrado evidência da presença de disfunção diastólica na nossa população, a sua prevalência foi inferior à esperada, com base em estudos prévios; as condições de fluxo na cirrose influenciam significativamente alguns dos parâmetros comummente utilizados para a avaliação desta entidade limitando a sua aplicabilidade neste cenário. 5.3. PROGNÓSTICO No estudo 4 não encontrámos associação entre nenhum dos parâmetros ecocardiográficos, em repouso, avaliados previamente e a mortalidade aos 6 meses. A maior gravidade da doença hepática – nomeadamente classe C de Child-Pugh – e a tensão arterial mais baixa foram os únicos preditores independentes do prognóstico neste estudo. Estes dados sugerem que o grau de insuficiência hepática e as alterações hemodinâmicas associadas – nomeadamente a vasodilatação periférica com consequente hipotensão arterial – têm maior impacto prognóstico do que a presença de disfunção cardíaca “central”. A associação entre disfunção sistólica e diastólica e o prognóstico dos doentes com cirrose hepática é controversa, com resultados contraditórios entre vários trabalhos. As diferenças nas características das populações estudadas, na metodologia utilizada para avaliação e definição de disfunção miocárdica, assim como diferentes tempos de seguimento e definição de eventos podem justificar a aparente contradição nos resultados. Os nossos resultados são sobreponíveis aos de outros autores que também não foram capazes de encontrar qualquer relação entre disfunção miocárdica e sobrevida[98, 99]. Por outro lado, estudos anteriores relataram uma associação entre disfunção diastólica – avaliada por ecocardiografia e definida como inversão da relação E/A do fluxo diastólico mitral – e aumento da mortalidade após inserção de shunt Discussão 105 portossistémico[91, 92]. No entanto, como referido previamente, esta metodologia de avaliação da função diastólica apresenta inúmeras limitações e os resultados podem apenas traduzir diferentes condições hemodinâmicas, nomeadamente maior vasodilatação periférica nos doentes mais descompensados. A discrepância entre estes resultados e os observados noutras patologias como a insuficiência cardíaca – em que o padrão de inversão E/A se associa ao melhor prognóstico[148-150] – parece suportar esta hipótese. Uma associação entre débito cardíaco mais baixo (traduzindo indirectamente disfunção sistólica) e risco de desenvolvimento de insuficiência renal e mortalidade em doentes com cirrose descompensada[94, 95] foi também descrita por outros autores. No grupo de doentes descompensados incluídos no nosso trabalho o débito cardíaco mais baixo também se associou à mortalidade a 6 meses, na análise univariada. No entanto, esta associação perdeu o seu significado após ajuste para a classe Child, sugerindo que a diminuição do débito cardíaco se relaciona directamente com a gravidade da doença hepática e alterações hemodinâmicas associadas; esta observação está em linha com relatos prévios[95, 97]. A ausência de uma associação independente entre débito cardíaco e desenvolvimento de síndrome hepatorrenal ou mortalidade foi igualmente descrita noutro trabalho recente[97]. 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Conclusões Conclusões 117 • Os doentes com cirrose hepática exibem alterações da função sistólica, quer em repouso quer sob stress farmacológico. No entanto estas alterações são subtis e podem ser detectáveis apenas com recurso a métodos de imagiologia cardíaca avançada. • A prevalência de disfunção diastólica nesta população poderá ser inferior à estimada com base em relatos prévios. A utilização de parâmetros “clássicos” de disfunção diastólica, muito influenciados pela volémia, pode não ser adequada nesta população. A sua interpretação deve ser cautelosa. • A disfunção sistólica e diastólica encontrada não parece ser suficientemente grave para influenciar o prognóstico a médio prazo, não se tendo associado à mortalidade a 6 meses. O seu potencial impacto no prognóstico a longo prazo permanece por estabelecer. VII. Resumo/Abstract Resumo/Abstract 121 RESUMO A cardiomiopatia cirrótica é uma entidade descrita nas últimas décadas, caracterizada pela presença de disfunção cardíaca crónica manifestada por atenuação da resposta contráctil ao stress e/ou anomalias do relaxamento ventricular e alterações electrofisiológicas, na ausência de outra doença cardíaca. A sua patofisiologia é complexa e não está totalmente elucidada. Estudos com modelos animais de cirrose demonstraram o envolvimento de múltiplos mecanismos, como a diminuição da densidade e função dos receptores adrenérgicos beta, alterações dos canais iónicos da membrana dos cardiomiócitos, alteração das proteínas contrácteis e da matriz extracelular, e excesso de produção de substâncias com efeitos vasodilatadores, e próapoptóticos como o óxido nítrico, citocinas pró-inflamatórias ou canabinóides endógenos. A sua prevalência real é desconhecida, muito pelo facto de poder ser bem tolerada e assintomática durante anos, em virtude da vasodilatação arteriolar esplâncnica característica da circulação na cirrose poder diminuir a sobrecarga do ventrículo esquerdo e atenuar os efeitos da disfunção muscular cardíaca. Deste modo, índices clássicos de função sistólica (como a fracção de ejecção ou o volume de ejecção) são frequentemente normais nestes doentes. A cardiomiopatia cirrótica é uma entidade descrita nas últimas décadas, caracterizada pela presença de disfunção cardíaca crónica manifestada por atenuação da resposta contráctil ao stress e/ ou anomalias do relaxamento ventricular e alterações electrofisiológicas, na ausência de outra doença cardíaca. A relação entre a gravidade da doença hepática e o atingimento cardíaco sugerida em alguns estudos também não está totalmente esclarecida, bem como a influência das alterações cardíacas no prognóstico dos doentes cirróticos. Foi assim nosso objectivo proceder a uma análise detalhada da função miocárdica, usando métodos modernos de imagiologia cardíaca não invasiva (ecocardiografia e ressonância magnética cardíaca) em doentes com cirrose hepática de diferentes etiologias, tentando encontrar novos marcadores de cardiomiopatia cirrótica, bem como avaliar a correlação entre disfunção cardiovascular e a etiologia e gravidade da doença hepática e o potencial impacto prognóstico das alterações encontradas.