Análise da função miocárdica sistólica e diastólica na ... · Ao Dr. Vasco Gama, director do Serviço de Cardiologia do Centro Hospitalar de Gaia/ Espinho, pela disponibilidade

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 àFaculdade 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 CabralDoutor Alexandre Alberto Guerra Sousa PintoDoutor Álvaro Jerónimo Leal Machado de AguiarDoutor Amândio Gomes Sampaio TavaresDoutor António Augusto Lopes VazDoutor António Carvalho Almeida CoimbraDoutor António Fernandes da FonsecaDoutor António Fernandes Oliveira Barbosa Ribeiro BragaDoutor António José Pacheco PalhaDoutor António Manuel Sampaio de Araújo TeixeiraDoutor Belmiro dos Santos PatrícioDoutor Cândido Alves Hipólito Reis Doutor Carlos Rodrigo Magalhães RamalhãoDoutor Cassiano Pena de Abreu e LimaDoutor Daniel Santos Pinto SerrãoDoutor Eduardo Jorge Cunha Rodrigues Pereira Doutor Fernando Tavarela VelosoDoutor Francisco de Sousa LéDoutor Henrique José Ferreira Gonçalves Lecour de MenezesDoutor Jorge Manuel Mergulhão Castro TavaresDoutor José Carvalho de OliveiraDoutor José Fernando Barros Castro CorreiaDoutor José Luís Medina VieiraDoutor José Manuel Costa Mesquita GuimarãesDoutor Levi Eugénio Ribeiro GuerraDoutor Luís Alberto Martins Gomes de AlmeidaDoutor Manuel António Caldeira Pais ClementeDoutor Manuel Augusto Cardoso de OliveiraDoutor Manuel Machado Rodrigues GomesDoutor Manuel Maria Paula BarbosaDoutor Maria da Conceição Fernandes Marques MagalhãesDoutor Maria Isabel Amorim de AzevedoDoutor Mário José Cerqueira Gomes BragaDoutor Serafim Correia Pinto GuimarãesDoutor Valdemar Miguel Botelho dos Santos CardosoDoutor 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 echocar-

diographic 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 physi-

ology 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 medium-

term 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

Aos meus Pais e à minha Irmã

À minha Família

Aos meus Amigos

Ao Professor Doutor Paulo Bettencourt

Ao Professor Doutor Carlos Ramalhão

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 verda-

de, 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 agrade-

cer 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 con-

dução 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 depen-

deu, 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 exa-

mes 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 colabo-

ração 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 aqui-

sição 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 partici-

par neste projecto.

19

Um agradecimento final:

Ao Professor Doutor Carlos Ramalhão, pelo incentivo constante e sobretudo pela genero-

sidade 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 for-

mação 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 car-

díaca alcoólica” terá sido utilizado pela primeira vez na literatura médica por William Macken-

zie 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 pre-

sença 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, independente-

mente 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-

26

Francisco Sampaio

ção arteriolar esplâncnica resultante, com “pooling” de sangue na periferia, contribui para uma

“hipovolémia central” com activação secundária, via baroreceptores, de sistemas vasoconstri-

tores de regulação da pressão arterial como o sistema nervoso simpático, o sistema renina-

angiotensina-aldosterona, e a secreção de arginina-vasopressina. O aumento do débito e da

frequência cardíaca daí resultantes e que caracterizam a circulação hiperdinâmica da cirrose

constituem, assim, um mecanismo compensatório que permite manter um “volume arterial

efetivo” normal nas fases mais precoces da doença. No entanto, a activação destes sistemas

promove igualmente retenção renal de sódio e água, contribuindo para o desenvolvimento de

ascite e edema, assim como de disfunção renal por hipoperfusão secundária à vasoconstrição

arteriolar. De facto, nas fases mais avançadas da doença, a incapacidade de aumentar o débito

cardíaco poderá ser um mecanismo importante no desenvolvimento de síndrome hepatorre-

nal, que se associa normalmente a mau prognóstico[17, 18].

1.1.2. Evidência experimental

No entanto a disfunção cardiovascular na cirrose não parece limitar-se à circulação perifé-

rica e vários estudos experimentais, em modelos de cirrose, documentaram diferentes altera-

ções estruturais e funcionais no cardiomiócito, resultando em disfunção contráctil. Múltiplos

mecanismos fisiopatológicos estão envolvidos.

A disfunção dos receptores adrenérgicos beta parece ser um achado universal na cardio-

patia cirrótica e explica parcialmente a incompetência cronotrópica e inotrópica descrita na

cirrose[10]. Diversos mecanismos contribuem, por sua vez, para esta disfunção. A constante esti-

mulação do sistema nervoso simpático envolvida na fisiopatologia da circulação hiperdinâmica,

levam à diminuição da densidade e dessensibilização destes receptores[19, 20]. Por outro lado, os

mecanismos de sinalização intracelular, envolvidos na transdução do sinal após a activação dos

receptores adrenérgicos beta, e que regulam os movimentos do cálcio intracelular através da

cascata adenilcíclase – AMP cíclico – proteína cínase A podem estar igualmente comprometi-

dos na cirrose. Alterações na expressão genética dos reguladores desta cascata, com aumento

da expressão de proteínas G inibitórias e de outros mediadores que resultam na inibição da

adenilcíclase e na degradação acelerada do AMP cíclico foram documentadas e envolvidas na

patofisiologia da cardiomiopatia cirrótica[21, 22]. Finalmente, foram ainda descritas alterações das

características físicas da membrana celular dos cardiomiócitos, com aumento do conteúdo de

colesterol e da razão colesterol/fosfolípidos membranares, resultando em diminuição da flui-

dez da membrana. Esta alteração afecta a função de todos os receptores transmembranares,

Introdução

27

incluindo os receptores adrenérgicos beta, inibindo o seu acoplamento com as proteínas Gs e

deteriorando ainda mais a função do já reduzido número de receptores membranares[23, 24]. A

redução da produção de AMP cíclico em resposta à estimulação adrenérgica e a sua correlação

com a fluidez da membrana foram demonstradas em modelos animais de cirrose e explicam a

hiporeactividade às catecolaminas observada na cirrose[23, 25].

Tendo em conta o efeito cronotrópico, inotrópico e lusitrópico positivo da estimulação

adrenérgica nos cardiomiócitos, as alterações dos bloqueadores beta encontradas em modelos

de cirrose desempenham, provavelmente, um papel importante na disfunção sistólica e diastó-

lica descrita nos doentes cirróticos.

Para além da disfunção dos receptores adrenérgicos beta, as alterações das características

da membrana celular podem contribuir para as alterações nos diferentes canais iónicos encon-

tradas em vários estudos. A diminuição na densidade de canais de cálcio tipo L foi descrita num

modelo animal de cirrose[11, 26], resultando na redução da disponibilidade de cálcio intracelular e

em menor contractilidade cardíaca. Foram igualmente documentadas alterações dos diferentes

tipos de canais de potássio, com diminuição da sua condutância e da densidade das correntes

de potássio em miócitos de ratos, resultando numa maior duração do potencial de acção[27].

Esta observação pode justificar o prolongamento do intervalo QT descrito em doentes com

cirrose.

Por outro lado, foram encontradas alterações ultraestruturais das proteínas contrácteis

e da matriz extracelular. O aumento da expressão da isoforma beta das cadeias pesadas de

miosina, alterações na modulação da titina (uma proteína do citosqueleto que é a principal

determinante da tensão passiva do cardiomiócito) e um aumento do colagénio tipo I na matriz

extracelular (relativamente à forma mais complacente de colagénio tipo III) podem desempe-

nhar um papel importante na disfunção sistólica e diastólica na cirrose[28, 29].

Uma segunda vertente da fisiopatologia da cardiomiopatia cirrótica relaciona-se com o efei-

to cardiodepressor de diferentes substâncias, que se acumulam como resultado da insuficiência

hepática e do desenvolvimento de shunts porto-sistémicos.

O sistema dos canabinoides tem uma expressão muito reduzida em indivíduos normais. Este

sistema de sinalização celular é activado pela ligação de canabinoides endógenos ou exógenos

a receptores próprios (CB1 e CB2) expressos em múltiplos tecidos – miócitos, células endote-

liais, células musculares lisas e células do sistema imune[30]. Na cirrose, há evidência de aumen-

to de produção de endocanabinóides endógenos nomeadamente anandamida que, actuando

através da ligação a receptores CB1, exercem um efeito vasodilatador e inotrópico negativo

28

Francisco Sampaio

via activação de uma proteina G inibitória e diminuição da produção de AMP cíclico[31]. Este

mecanismo agrava assim a diminuição da resposta contráctil dos miócitos após estimulaçao

adrenérgica e a sua inibição através de antagonistas específicos dos receptores CB-1 parece

reverter este efeito[32]. O excesso de endocanabinoides promove ainda a apoptose dos hepa-

tócitos favorecendo o agravamento da hipertensão portal e da circulação hiperdinâmica[33, 34].

O óxido nítrico desempenha um papel importante na fisiopatologia da cardiomiopatia cir-

rótica. O aumento da expressão da forma indutível da síntase do óxido nítrico (iNOS), pos-

sivelmente relacionada com níveis aumentados de citocinas pró-inflamatórias como o factor

de necrose tumoral a (TNF-a) e a interleucina 1b está demonstrado em modelos animais de

cirrose[35, 36]. Para além dos efeitos na circulação periférica referidos previamente, esta forma

de óxido nítrico exerce um efeito inotrópico negativo no cardiomiócito através da estimulação

do sistema guanilcíclase – GMP cíclico – proteína cinase G que resulta numa diminuição da

entrada de cálcio pela inibição quer dos canais de cálcio tipo L quer dos receptores rianodí-

nicos do retículo sarcoplasmático[26, 37]. A indução da apoptose é outro dos mecanismos pelo

qual este mediador exerce o seu efeito cardiotóxico[38]. Tal como no sistema dos canabinoides,

também com a inibição deste sistema por antagonistas do óxido nítrico se observou uma re-

versão da disfunção cardíaca[39, 40].

Os mesmos mecanismos fisiopatológicos são partilhados pelo monóxido de carbono, cuja

produção está igualmente aumentada na cirrose como consequência da estimulação do siste-

ma nervoso simpático e da acumulação de citocinas pró-inflamatórias. De igual modo, a inibi-

ção deste sistema associa-se a melhoria da contractilidade do músculo cardíaco[41].

Mais recentemente, foi sugerido o papel da activação do factor nuclear kB (NF-kB), um fac-

tor de transcrição que regula várias respostas celulares, na disfunção cardiovascular da cirrose.

Num modelo animal de cirrose, foram encontrados níveis aumentados de NF-kB e TNF-a, e

a inibição daquele factor resultou numa redução significativa dos níveis de TNF-a e numa me-

lhoria da contractilidade[42]. Estes dados sugerem que os níveis de TNF-a estão dependentes

da activação deste factor de transcrição e reforçam a importância da expressão das citocinas

na fisiopatologia da cardiomiopatia cirrótica.

Para além do seu papel na contractilidade, o papel de citocinas como o TGF-b na indução de

fibrose e apoptose está bem documentado; níveis aumentados deste mediador foram encon-

trados na cirrose e podem igualmente contribuir para a disfunção contráctil[43, 44].

Introdução

29

1.1.3. Evidência clínica

1.1.3.1. Disfunção sistólica

A utilização de testes não invasivos de imagiologia cardíaca tem permitido evidenciar ano-

malias cardíacas morfológicas e funcionais em doentes com cirrose. No entanto, embora se

tenha observado um aumento do volume das câmaras esquerdas em alguns estudos, as altera-

ções das dimensões cardíacas e da massa ventricular, em repouso, parecem ser modestas[45-47].

Do mesmo modo, índices de função sistólica como a fracção de ejecção são frequentemente

normais em condições de repouso, em consequência da diminuição da pós-carga característica

da circulação na cirrose[48-50]. A disfunção sistólica nestes doentes poderá no entanto ser reve-

lada em situações de stress. Vários autores demonstraram que doentes com cirrose exibem

uma variação anormal do débito cardíaco, frequência cardíaca e da fracção de ejecção do ven-

trículo esquerdo e aumentos das pressões de enchimento ventriculares em resposta ao exer-

cício físico[51-54]. A incompetência inotrópica e cronotrópica parece ser assim um dos achados

clínicos mais consistentes da cardiomiopatia cirrótica. Respostas semelhantes foram encontra-

das em resposta a stress farmacológico com vasoconstritores[55, 56] ou alterações posturais[57].

No entanto o papel dos testes de sobrecarga com dobutamina, frequentemente utilizados na

avaliação de reserva contráctil[58], no diagnóstico da cardiomiopatia cirrótica é controverso,

com resultados díspares em diferentes estudos[59, 60].

Mais recentemente, a utilização de técnicas ecocardiográficas modernas permitiu a detec-

ção de alterações da função sistólica ventricular também em condições de repouso[61].

1.1.3.2. Disfunção diastólica

As alterações previamente descritas nas proteínas contrácteis e na matriz extracelular, as-

sim como os achados de hipertrofia ventricular, fibrose e edema subendocárdico relatados,

desde há várias décadas, em diferentes séries de autópsias de doentes com cirrose de várias

etiologias[62, 63], fornecem a base patofisiológica da disfunção diastólica na cirrose.

A presença de fibrose intramiocárdica foi igualmente documentada em doentes com cirro-

se, utilizando ressonância magnética cardíaca[64].

A ecocardiografia tem sido, no entanto, a técnica mais utilizada para a avaliação clínica da

função diastólica na cirrose. Durante muitos anos, esta análise baseou-se na avaliação, por

Doppler pulsado, do fluxo de sangue através da válvula mitral durante a diástole[65]. Usando

este método, vários autores encontraram sinais de disfunção diastólica em cerca de 50% dos

doentes com cirrose[66]. Pozzi et al descreveram um aumento da velocidade da onda A, inversão

30

Francisco Sampaio

da relação E/A e prolongamento do tempo de desaceleração da onda E – sugerindo atraso do

relaxamento ventricular – em doentes com cirrose e ascite de grande volume, comparativa-

mente com um grupo controlo; após paracentese evacuadora, os autores observaram melho-

ria parcial destes índices de enchimento ventricular[67]. Achados semelhantes foram relatados

por Wong et al[68], sugerindo que a presença de disfunção diastólica se possa relacionar com

a gravidade da doença hepática e com a presença de ascite. Contrariamente, Finucci et al não

encontraram relação entre o tempo de desaceleração da onda E e a presença de ascite[69]. A

dilatação da aurícula esquerda – um reconhecido marcador de cronicidade de disfunção dias-

tólica[70, 71] – foi igualmente encontrada nestes estudos. Do mesmo modo, níveis aumentados

de peptídeo natriurético tipo A (ANP) – produzido nas aurículas em resposta ao estiramento

das fibras auriculares[72] – foram descritos em doentes com cirrose, podendo também traduzir

disfunção diastólica.

No entanto, a análise ecocardiográfica da função diastólica baseada no fluxo mitral apre-

senta várias limitações[73-77]. Em particular, alterações na pré-carga e na frequência cardíaca,

podem influenciar significativamente o padrão do fluxo através da válvula mitral, mesmo em

indivíduos normais[78, 79]. Este aspecto pode ser particularmente relevante nos doentes com cir-

rose hepática, atendendo às alterações hemodinâmicas associadas a esta doença. A associação

da dilatação auricular esquerda e dos níveis de ANP com a volémia demonstrada em doentes

com cirrose parece apoiar esta hipótese[46]. Atendendo a estas questões, foram elaboradas

recomendações mais recentes para avaliação da função diastólica, nas quais as novas técnicas

ecocardiográficas, como o Doppler tecidular, assumem um papel preponderante na avaliação

funcional da diástole; os parâmetros derivados do fluxo são usados em segunda linha como

complemento dos primeiros[80].

1.1.3.3. Alterações electrofisiológicas

A presença de prolongamento do intervalo QT parece ser um achado frequente em do-

entes com cirrose independentemente da sua etiologia, tendo sido descrito em até 50% dos

casos[81, 82]. O grau de prolongamento relaciona-se com a gravidade da doença hepática embora

esta alteração tenha sido encontrada mesmo em estádios mais precoces[83]. O prolongamento

do intervalo QT parece associar-se a alterações no acoplamento electromecânico, i.e, na rela-

ção temporal entre a sístole elétrica e a sístole mecânica[84].

Introdução

31

1.1.4. Definição de cardiomiopatia cirrótica

Baseando-se na evidência disponível até então, um grupo de trabalho reunido no Congresso

Mundial de Gastroenterologia de 2005 elaborou uma proposta de definição de cardiomiopatia

cirrótica, descrevendo-a como uma disfunção cardíaca crónica caracterizada por atenuação da

resposta contráctil ao stress e/ou anomalia do relaxamento ventricular e por alterações elec-

trofisiológicas, na ausência de outra doença cardíaca[85]. Os critérios de diagnóstico propostos

por este grupo são apresentados na tabela 1.

Critérios de diagnóstico

Disfunção Sistólica

Resposta anormal do débito cardíaco após exercício ou estimulação farmacológica

Fracção de ejecção em repouso ≤55%

Disfunção Diastólica

Relação E/A <1 (corrigida para a idade)

Tempo de desaceleração da onda E > 200 mseg

Tempo de relaxamento isovolumétrico > 80 mseg

Critérios de suporte

Alterações electrofisiológicas

Resposta cronotrópica diminuída

Dilatação da aurícula esquerda

Hipertrofia ventricular esquerda

Níveis de peptídeos natriuréticos aumentados

Níveis de troponina aumentados

1.1.5. Importância clínica

O impacto clínico da cardiomiopatia cirrótica não é claro. A vasodilatação periférica carac-

terística da circulação na cirrose resulta numa diminuição da pós-carga imposta ao ventrículo

esquerdo que pode mascarar a disfunção contráctil. Assim, a cardiomiopatia cirrótica parece

ser bem tolerada e não causar sintomas durante longos períodos.

No entanto, a descrição de casos de insuficiência cardíaca após transplante hepático ou

implantação de shunt porto-sistémico (TIPS), em doentes sem história prévia de doença car-

diovascular[86, 87], sugeriram a potencial relevância clínica desta entidade e desencadearam um

32

Francisco Sampaio

interesse crescente pelo seu estudo. A presença de disfunção diastólica foi implicada na pato-

fisiologia 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 ven-

tricular 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 demonstra-

ram 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 desenvol-

vimento 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 compli-

cações[96].

Mais recentemente Ruiz-del-Arbol et al relataram igualmente uma associação entre disfun-

ção 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 do-

entes 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, provenien-

te 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, nomeada-

mente a sua contribuição para a mortalidade foi sugerido em alguns estudos, mas os mecanis-

mos 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 ava-

liação morfológica e funcional do coração.

A ecocardiografia, sendo a mais antiga[100], continua também a ser, por questões de acessibili-

dade, 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 frequen-

tes 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 fun-

cional (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 exem-

plo, 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 mio-

cárdio 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 defor-

mação 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, particular-

mente a análise das velocidades do miocárdio por Doppler tecidular, assumiram uma impor-

tância 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]. Atenden-

do 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 impor-

tância na avaliação do sistema cardiovascular[133]. A sua excelente resolução espacial permite-

lhe 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]. Final-

mente, 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 via-

bilidade[139-141].

Algumas destas novas modalidades de imagem foram já utilizadas na avaliação de doentes

com cirrose[61, 64]. No entanto, dado o pequeno número de estudos e doentes envolvidos, a sua

utilidade na detecção de alterações morfológicas e funcionais neste contexto é ainda incerta e

o seu potencial papel no diagnóstico da cardiomiopatia cirrótica não está estabelecido.

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II. Objectivos

Objectivos

47

Com o conjunto de trabalhos que desenvolvemos pretendemos proceder a uma análise

detalhada da função cardíaca sistólica e diastólica, usando métodos de imagiologia cardíaca não

invasiva (ecocardiografia e ressonância magnética cardíaca) em doentes com cirrose hepática

de diferentes etiologias, em condições de repouso e sob stress farmacológico.

Foram definidos como objectivos:

- Encontrar novos marcadores de cardiomiopatia cirrótica, através da utilização de mé-

todos de imagem mais modernos, com determinação de parâmetros mais sensíveis de

disfunção miocárdica.

- Avaliar a correlação entre disfunção cardiovascular e a etiologia e gravidade da doença

hepática.

- Avaliar o potencial impacto prognóstico dos diferentes parâmetros analisados.

III. Métodos

Métodos

51

ESTUDO 1

“Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler and speckle tra-

cking echocardiography study”

Doentes: Neste trabalho foram avaliados 131 doentes com cirrose hepática (72 doentes

internados por descompensação de cirrose e 59 doentes ambulatórios, seguidos em consulta

externa de hepatologia), referenciados ao laboratório de ecocardiografia entre Abril de 2011

e Outubro de 2012. Destes, foram excluídos 22 doentes com história de hipertensão arterial,

diabetes mellitus ou de doença cardíaca relevante, com alterações electrocardiográficas signifi-

cativas (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 ecocar-

diográfico 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 longitu-

dinal 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 echocardiogra-

phic study”

Doentes: Foi utilizado o mesmo grupo de doentes recrutados para o estudo 1. Após aplica-

ção 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 mes-

mo grupo controlo para comparação.

ESTUDO 3

“Assessment of cardiovascular physiology using magnetic resonance myocardial

stress testing reveals impaired contractile reserve in patients with cirrhotic car-

diomyopathy”

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 mag-

nética cardíaca no mesmo dia. O protocolo de ressonância magnética incluiu determinação

de volumes das câmaras cardíacas, massa ventricular, fracção de ejecção de ambos os ventrí-

culos 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 vá-

rios 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 ocorrên-

cia 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

C IRRHOS IS AND L IVER FAILURE

Systolic and diastolic dysfunction in cirrhosis: a tissue-Doppler andspeckle tracking echocardiography studyFrancisco Sampaio1,4, Joana Pimenta4, Nuno Bettencourt1,4, Ricardo Fontes-Carvalho1,4, Ana P. Silva3,Jo~ao Valente2, Paulo Bettencourt4, Jos�e Fraga3 and Vasco Gama1

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

AbstractBackground & Aims: Cardiac dysfunction has been described in patients withcirrhosis. Conventional echocardiographic methods are frequently unable todetect abnormalities at rest and have limitations. We aimed to evaluatecardiac function in cirrhosis patients assessing: (i) left ventricular systolicfunction using speckle-tracking imaging; (ii) diastolic function using atissue-Doppler based algorithm and comparing it with previously proposeddefinition of diastolic dysfunction (DD). Methods: We included 109 hospi-talized and ambulatory patients with cirrhosis and 18 healthy controls.Detailed echocardiographic evaluation was performed including tissue-Doppler and speckle-tracking analysis. Results: Peak systolic longitudinalstrain (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 inpatients and controls [64% (59–67) vs 61% (60–65), P = 0.42)]. Based onmitral-flow pattern, DD was present in 44 patients (40.4%). Patients withoutDD 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 baseddefinition, the prevalence of DD was 16.5%. No differences in haemodynam-ic 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 func-tion were not different in compensated vs decompensated patients in differ-ent Child-Pugh classes or cirrhosis aetiologies. Conclusions: Patients withcirrhosis have systolic and diastolic cardiac dysfunction at rest. Newer echo-cardiographic techniques may identify patients with functional impairmentmore accurately than conventional methods, which are more influenced byflow conditions.

Cirrhotic cardiomyopathy has been recently describedas a condition characterized by impaired contractileresponse to stress, diastolic dysfunction and electro-physiological abnormalities, in the absence of knowncardiac disease (1–3).

Echocardiography is an easily accessible imagingtechnique and the most widely used method to evaluatethe cardiac function. Although several echocardio-graphic abnormalities have been described in cirrhosis,traditional indices of cardiac systolic function such asejection fraction are frequently normal at rest in thesepatients. On the other hand, newer echocardiographicmodalities like tissue Doppler imaging are mandatorywhen evaluating diastolic function as conventionalDoppler measures are highly dependent on loadingconditions. E’ velocity is a more sensitive marker of

abnormal left ventricular relaxation than mitral flowderived variables (4) and E/E’ ratio has been found toreflect left ventricular filling pressure (5, 6), correlatingbetter than natriuretic peptides with pulmonary capil-lary wedge pressure in a wide range of patients (7).

Because of myocardial architecture, subendocardialfibres are most susceptible to damage and longitudinalleft ventricular function is the first to be affected in thepresence of myocardial disease (8–10). Only a few stud-ies have used these tissue-Doppler derived indices toevaluate cardiac function in cirrhotic patients and onlytwo have looked into myocardial deformation (11, 12).Several limitations – like image artefacts and depen-dence on insonation angle – are acknowledged whenusing tissue-Doppler. Newer speckle-tracking derivedstrain may overcome some of these limitations resulting

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in better reproducibility (13). We aimed to detect rest-ing myocardial dysfunction in patients with cirrhosis ofdifferent aetiologies, using these newer and potentiallymore accurate echocardiographic methods.

Patients and methods

We prospectively evaluated 131 consecutive patientsreferred per study protocol, to our echocardiographylaboratory between April 2011 and October 2012, with adiagnosis of cirrhosis based on clinical, laboratory, ultra-sonographic and/or biopsy criteria. Our population wascomposed by a group of 72 patients hospitalizedbecause of decompensated cirrhosis (defined by thepresence of encephalopathy, ascites, variceal bleeding,and/or jaundice) and a group of 59 ambulatory patientsfollowed in an outpatient hepatology clinic.

All patients underwent clinical evaluation, bloodsample collection, 12-lead ECG and echocardiographyon the same day.

Patients with a known history of hypertension, cardiacdisease or relevant ECG abnormalities were excluded;patients with significant (i.e. more than mild) valvularheart disease on echocardiography were also excluded.

A group of 18 healthy controls, recruited among hos-pital staff, with similar age and sex distribution as thepatient group, was also submitted to clinical, analytical,ECG and echocardiographic evaluation.

The local Ethic’s Committee approved the studyprotocol and patients or their relatives gave informedconsent.

Echocardiography

A single experienced operator performed the echocar-diograms using a commercially available ultrasoundsystem (iE33; Philips Medical Systems, Best, the Nether-lands) equipped with a broadband S5-1 transducer.Images were digitally stored for posterior offline analy-sis. Cardiac chambers dimensions and volumes and leftventricular mass were measured according to the cur-rent recommendations (14). Mitral inflow velocitieswere assessed using pulsed-wave (PW) Doppler in theapical four-chamber view, with a 3 mm sample placedbetween the tips of the mitral leaflets; velocities wererecorded at end-expiration and averaged over three con-secutive cardiac cycles. PW Doppler was also used torecord left ventricular outflow tract velocities in the api-cal five-chamber view. PW tissue-Doppler velocitieswere acquired at end-expiration, in the apical four-chamber view, with the sample positioned at the septaland lateral mitral annulus; the average of three consecu-tive heartbeats was recorded.

For strain assessment, two-dimensional grey-scale images were acquired in the apical four- andtwo-chamber views, with a frame rate of 60–100 fps.Three cardiac cycles were digitally stored and analysiswas performed using the Velocity Vector Imaging (VVI)

software (SyngoVVI 2.0; Siemens Medical SolutionsUSA Inc., Mountain View, CA, USA) more than amonth after the acquisition, by one observer blinded toclinical and echocardiographic data. This software auto-matically tracks the endocardial border (from a few ref-erence points manually defined by the operator)displaying velocity vectors throughout the cardiac cycle.Two-dimensional strain is obtained by tracking andcomparing the relative position of speckles throughoutthe cardiac cycle (Fig. 1).

Reproducibility

Reproducibility of VVI derived strain was assessed in 10randomly selected subjects. For intraobserver variability,the same operator performed a second measurementmore than a month after the initial analysis. For inte-robserver variability, the same loops were analysed by asecond operator.

Statistical analysis

Data were stored and analysed using IBM SPSS Statis-tics, Version 20.0 (IBM Corp., Armonk, NY, USA).Results are presented as median (25th–75th percentile)for quantitative variables and as n (%) for categoricalvariables. A significant level of 5% was used.

Differences in continuous variables between groupswere compared using the Mann–Whitney or the Krus-kal–Wallis tests. The Chi-squared test was used to compareproportions. Kappa measure was used to determine theagreement between definitions of diastolic dysfunction.Coefficients of variation were calculated to assess intra-and interobserver variability.

Results

Twenty-two patients of the original sample wereexcluded from further analysis based on the exclusioncriteria.

Clinical and laboratorial characteristics of the 109patients included and of the controls are shown inTable 1. A history of active alcohol consumption at thetime of the exam or hospital admission was reported by43.7% of the patients with alcoholic aetiology.

Echocardiographic variables of patients and controlsare displayed in Table 2.

Patients had larger left atrial volumes and highercardiac output; left ventricle dimensions, mass and ejec-tion fraction (EF) did not differ between patients andcontrols.

Systolic function

Only ten patients (9.2%) had a left ventricular EF below55%. Seven of these patients had decompensatedcirrhosis and five had alcoholic aetiology; these differ-ences did not reach the statistical significance.

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Fig. 1. velocity vectors and corresponding longitudinal strain curves in 6 left ventricular segments, in the apical 4-chamber view.

Table 1. Demographical, clinical and laboratorial characteristics of patients and controls

Patients (n = 109) Controls (n = 18) P

Age 54 (48–64) 51 (49–58) 0.23Male gender (n, %) 86 (78.9) 13 (72.2) 0.55Cirrhosis aetiologyAlcoholic (n, %) 73 (67.0)Viric (n, %) 27 (24.8)Other (n, %) 9 (8.2)Beta-blocker use (n, %) 54 (49.5)

Child-Pugh ClassA (n, %) 37 (33.9)B (n, %) 27 (24.8)C (n, %) 45 (41.3)

MELD score 14 (10–18)Heart rate 72 (60–82) 63 (60–70) 0.04Mean blood pressure 90 (80–98) 90 (81–95) 0.85Blood analysisHaemoglobin (g/dl) 11.8 (10.2–13.6) 14.8 (13.9–15.3) <0.001Platelet count (9109/L) 98 (60–131) 237 (181–281) <0.001Creatinine (mg/dl) 0.69 (0.50–0.91) 0.79 (0.67–0.85) 0.23Sodium (mEq/L) 137 (133–139) 142 (140–143) <0.001Total bilirubin (mg/dl) 1.87 (1.09–3.90) 0.44 (0.35–0.92) <0.001Albumin (g/dl) 3.20 (2.60–3.95) 4.65 (4.43–4.97) <0.001NT-ProBNP (pg/ml) 194 (74–399) 34 (15–86) <0.001CRP (mg/dl) 0.84 (0.26–2.69) 0.13 (0.04–0.34) 0.001INR 1.45 (1.28–1.75) 1.0 (0.95–1.08) <0.001

MELD, model for end-stage liver disease; NT-ProBNP, aminoterminal B type natriuretic peptide; CRP, C reactive protein; INR, international normalized

ratio.


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Tissue-Doppler mitral annulus systolic velocities (S’)were not different in patients and controls. [9.19 cm/s(8.21–10.32) vs 8.71 cm/s (8.17–9.46), P = 0.28]. How-ever, peak systolic longitudinal strain (PLS) was lower(i.e. less negative) in patients [�19.99% (�21.88 to�18.71) vs �22.02% (�23.10 to �21.18), P = 0.003].PLS was not different in hospitalized and ambulatorypatients [�20.51% (�22.33 to �19.04) vs �19.00%(�21.54 to �18.20), P = 0.10] or between differentChild-Pugh classes [�20.81% (�23.45 to �18.92) vs�19.61% (�21.29 to �18.90), vs �19.02% (�21.55 to�18.25) P = 0.23]. There were also no differences inPLS in patients previously treated with beta-blockers,compared with the rest of the patients [�20.16%(�23.04 to �18.66) vs �19.90% (�21.55 to �18.71),P = 0.57]. We found a non-significant trend towardslower strain in alcoholic vs other aetiologies [�19.42%(�21.42 to �18.47) vs �20.87% (�22.67 to �19.01),P = 0.09]. There were no differences in left ventricularvolumes [99 ml (79–120) vs 99 ml (80–117), P = 0.91]or ejection fraction [64% (59–69) vs 62% (57–66),P = 0.11] between those two groups. Alcoholic patientswere older than patients with other aetiologies [59 (46–59) vs 51 (46–59), P = 0.03]. Peak longitudinal strainwas not different in patients with a history of activealcohol consumption vs the others [�19.39% (�21.88to �18.84) vs �19.68% (�21.65 to �18.40), P = 0.83].

Patients with EF <55% had significantly lowerPLS compared with patients with FE � 55%[�16.73% (�20.49 to �13.99) vs �20.19% (�22.33to �18.77), P = 0.013].

Right ventricular function evaluated by tricuspidannulus plane systolic excursion (TAPSE) was not dif-ferent between patients and controls [25.4 mm (22.0–28.2) vs 23.1 mm (21.5–26.2), P = 0.11].

Coefficients of variation for intra- and interobservervariability were 1.84 and 2.36% respectively.

Diastolic function

Compared with controls, cirrhotic patients had lowerE/A ratio, longer E wave deceleration time (DT), lower

mean E’ wave velocity and higher mean E/E’ ratio(Table 2).

Using the diagnostic criteria of the 2005 World Con-gress of Gastroenterology (1), diastolic dysfunction(DD), defined as an E/A ratio <1.0, DT >200 ms andisovolumetric relaxation time (IVRT) >80 ms, waspresent in 44 patients (40.4%). Compared with thosewithout DD, these patients were older, had lower car-diac output, lower E/A ratio, longer DT and IRVT(these three are part of the definition), lower E’ velocityand higher E/E’ ratio. Mean blood pressure, heart rate,cardiac volumes, left ventricular mass, NT-ProBNP lev-els (both in compensated and decompensated patients),TAPSE, S’ velocity, PLS and QTc interval were not dif-ferent between patients with and without DD. Theprevalence of diastolic dysfunction was not different incompensated and decompensated cirrhosis (33.3% vs44.3%, P = 0.26) or between different Child-Pugh clas-ses (Table 3 – definition 1).

According to the algorithm of the current recom-mendations for grading diastolic function by echocardi-ography (15), DD is diagnosed in the presence ofreduced tissue-Doppler mitral annulus velocities (septale’ <8 cm/s and lateral e’ <10 cm/s) and enlarged leftatria (� 34 ml/m2). Using this definition, the preva-lence of DD in our sample was 16.5%. There was only aweak agreement between the two definitions of DD(kappa = 0.24, P = 0.003).

Patients with these criteria of DD were older, hadlarger left atrial volumes, lower E/A ratio, longer DTand IRVT, lower S’ and E’ velocities, higher E/E’ratio and lower PLS. Cardiac output, mean bloodpressure, heart rate, left ventricular mass, TAPSE andQTc interval were not different between patients withand without DD, using this definition (Table 3 – def-inition 2). Patients with compensated cirrhosis andDD had higher NT-ProBNP than compensatedpatients without DD [133.5 pg/ml (70.8–267.5) vs59.0 pg/ml (22.0–131.0), P = 0.05]. This finding wasnot observed in patients with decompensated cirrhosis[193.5 pg/ml (94.0–399.0) vs 319.5 pg/ml (160.2–663.7), P = 0.30].

Table 2. Echocardiographic data of patients and controls

Patients (n = 109) Controls (n = 18) P

Left atrial volume (ml) 70 (54–83) 54 (37–61) 0.001Left atrial volume index (ml/m2) 39.8 (29.9–44.7) 30.4 (22.3–33.7) <0.001Left ventricle diastolic diameter (mm) 51 (47–55) 49 (47–53) 0.21Left ventricle systolic diameter (mm) 32 (28–35) 32 (27–33) 0.67Left ventricle diastolic volume (ml) 99 (79–119) 92 (78–114) 0.41Left ventricular mass (g) 148 (121–188) 145 (119–160) 0.19Left ventricular mass index (g/m2) 84 (70.5–103) 76 (65–88) 0.06Left ventricular ejection fraction (%) 64 (59–67) 61 (60–65) 0.42Cardiac output(L/min) 6.1 (5.0–7.1) 5.2 (4.6–5.8) 0.01E/A ratio 1.03 (0.81–1.35) 1.29 (1.14–1.53) 0.02Deceleration time (ms) 239 (203–280) 196 (176–224) 0.001E’ velocity (cm/s) 9.56 (7.42–11.72) 11.01 (9.76–12.55) 0.031E/E’ ratio 8.57 (6.79–10.36) 6.72 (6.09–7.83) 0.001



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The prevalence of diastolic dysfunction was notdifferent in compensated and decompensated cirrhosis(15.4% vs 17.1%, P = 0.8), in different Child-Pugh clas-ses or in alcoholic vs nonalcoholic aetiology (8.3% vs20.5%, P = 0.11).

Electrophysiological abnormalities

Patients had longer QTc intervals than controls [426 ms(410–448) vs 406 ms (382–417), P = 0.008]. A QTc>440 ms was observed in 30.3% of the patients; NT-proBNP levels of those patients did not differ from therest of the sample.

Discussion

Our results, in a large cohort of patients with cirrhosisof different aetiologies, suggest that subclinical systolicand diastolic dysfunction are frequent at rest and thatnewer echocardiographic modalities are able to detectthese abnormalities.

Using speckle-tracking derived strain, we found thatpatients with cirrhosishad reduced longitudinal left

ventricular systolic function, despite still having normalejection fraction. This observation was independent ofaetiology or clinical status, which supports the presenceof an intrinsic myocardial systolic dysfunction in cirrho-sis. Reduced LV longitudinal function has been docu-mented in several other conditions, being consideredthe first manifestation of cardiac impairment (8–10).The increased susceptibility to damage of the longitudi-nally oriented endocardial fibres compared with theradial fibres of the middle myocardium layer furnish therational to this observation. Two previous studies havelooked into left ventricular longitudinal function incirrhosis. Kazankov et al have reported reduced mitralannulus longitudinal displacement velocities, usingtissue-Doppler in patients with cirrhosis (11), comparedwith healthy controls. There was no relation betweenechocardiographic measures and aetiology or clinicalstatus. Our study, confirms these findings, in a largerpopulation, using a more reproducible, angle-indepen-dent echocardiographic method. A very recent study hasevaluated left ventricular longitudinal strain usingspeckle tracking (12) in 50 patients and found no differ-ences in patients with and without ascites; however, a

Table 3. clinical, echocardiographic and electrocardiographic characteristics of patients with and without diastolic dysfunction (DD)

Definition 1

P

Definition 2

PWith DD, n = 44 Without DD, n = 65 With DD, n = 18 Without DD, n = 91

Age 63 (57–69) 51 (44–58) <0.001 65 (59–67) 53 (46–62) <0.001Child-Pugh ClassA (n, %) 15 (40.5) 22 (59.5) 0.99 7 (18.9) 30 (81.1) 0.15B (n, %) 11 (40.7) 16 (59.3) 7 (25.9) 20 (74.1)C (n, %) 18 (40) 27 (60) 14 (8.9) 41 (91.1)

MELD score 14 (9–17) 14 (10–18) 0.36 12 (7–15) 14 (10–18) 0.13Mean bloodpressure (mmHg)

90.7 (82.7–97.3) 88.2 (77.2–99.2) 0.61 91.3 (83.1–95.1) 89.7 (78.0–98.5) 0.83

Heart rate (bpm) 72 (60–80) 72 (59–84) 0.84 63 (52–79) 72 (60–83) 0.06NT-ProBNP (pg/ml) 200 (90–555) 177 (61–344) 0.21 201 (61–420) 189 (78–399) 0.90Left atrial volumeindex (ml/m2)

37.9 (26.9–44.5) 40.8 (32.8–46.1) 0.17 43.9 (40.1–49.4) 38.6 (29.0–44.7) 0.006

Left ventricle diastolicvolume (ml)

91 (74–117) 103 (83–120) 0.16 87 (77–119) 101 (82–119) 0.54

Left ventricular massindex (g/m2)

90.5 (69.3–108) 83.0 (71.5–99.5) 0.34 96 (71–113) 83 (70–101) 0.09

Cardiac output (L/min) 5.6 (4.7–6.8) 6.4 (5.4–7.2) 0.02 5.7 (4.5–7.0) 6.1 (5.2–7.2) 0.24IVRT (ms) 118 (103–139) 98 (80–116) <0.001 132 (110–147) 103 (85–121) <0.001E/A ratio 1.03 (0.81–1.35) 1.29 (1.14–1.53) 0.02 0.79 (0.70–0.95) 1.10 (0.86–1.37) 0.002Deceleration time (ms) 239 (203–280) 196 (176–224) 0.001 312 (233–343) 236 (200–269) 0.003S’ velocity (cm/s) 8.87 (8.07–10.35) 9.19 (8.21–10.32) 0.55 8.05 (7.28–9.44) 9.26 (8.33–10.50) 0.004E’ velocity (cm/s) 11.01 (9.76–12.55) 9.56 (7.42–11.72) 0.03 6.99 (5.76–7.57) 10.07 (8.65–11.95) <0.001E/E’ ratio 8.57 (6.79–10.36) 6.72 (6.09–7.83) 0.001 11.92 (8.79–12.95) 8.19 (6.75–9.85) 0.001TAPSE (mm) 0.31 27.0 (22.5–29) 25.3 (21.7–28.0) 0.48PLS (%) �19.39 (�18.04 to

�21.38)�20.71 (�18.08 to�22.51)

0.11 �19.10 (�17.04 to�20.67)

�20.33 (�18.82to �22.48)

0.03

QTc interval (ms) 429 (418–449) 420 (402–448) 0.10 433 (402–456) 425 (411–448) 0.80

Definition 1: E/A ratio <1.0, deceleration time >200 ms and IVRT >80 ms (1); Definition 2: septal e’ <8 cm/s, lateral e’ <10 cm/s and left atrial volume

� 34 ml/m2 (15).

DD, diastolic dysfunction; MELD, model for end-stage liver disease; NT-ProBNP, aminoterminal B type natriuretic peptide; IVRT, isovolumetric relaxa-

tion time; TAPSE, tricusid annulus plane systolic excursion; PLS, left ventricular peak longitudinal strain.



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control group was lacking. Our findings, in a larger andcontrolled sample, support and expand those results.The absence of differences in strain between compen-sated and decompensated patients may be explained bya normal increase in longitudinal strain in response tostress in decompensated patients without significantsystolic dysfunction, which would blur the effect of ablunted response to stress in decompensated patientswith systolic dysfunction. The net effect would be asimilar strain in both the groups.

Unlike Kazankov et al, we did not find differences inmean S’ velocity between patients and controls. Thisapparent conflicting result probably relates to the pres-ence of ‘supranormal’ velocities in some patients with anhyperdynamic circulation. Most of the patients in ourstudy were in Child B-C class and had higher cardiac outputcompared with those of that study. Nineteen patients(17.4%) in our sample had S’ � 11 cm/s, the upper refer-ence limit (defined as the mean plus two standard devia-tions) in a population of healthy individuals (16) andthese patients had higher cardiac output than patientswith normal S’. Besides, mitral ring displacement andactive muscle deformation are not equivalent concepts.

The 2005 World Congress of Gastroenterology pro-posed a resting EF <55% to define systolic dysfunctionin patients with cirrhosis (1). According to this, only9.2% of the patients of our sample had a reduced EF.The use of EF to evaluate systolic function has severallimitations. Ejection fraction is not an index of contrac-tility and depends on loading conditions, heart rate andvalvular function (17). Besides, EF relies on accuratetracing of endocardial borders with frequent underesti-mation of ventricular volumes. Therefore, a ‘normal’ejection fraction may not reflect normal contractilefunction and this may be particularly true in cirrhosis.Our finding of a significantly lower PLS in patients withan EF <55% compared with patients with normal EF,suggests that EF may be an insensitive (albeit specific)and probably late marker of systolic dysfunction incirrhosis, identifying only patients with more severemyocardial dysfunction.

Using the 2005 World Congress of Gastroenterologycriteria, diastolic dysfunction was highly prevalent inour sample, in line with several previous reports (11, 12,18, 19). These criteria were based exclusively on mitralflow derived parameters, which are influenced not onlyby relaxation, but also by flow conditions. The effect ofpreload, heart rate and cardiac output on mitral flowpattern has been previously acknowledged (15, 20, 21).According to the currently accepted theory, blood pool-ing in the splanchnic bed in cirrhosis results in centralhypovolaemia and reduced preload. This would, alongwith faster heart rates, result in lower mitral E wavevelocities and lower E/A ratios, regardless of the pres-ence of impaired relaxation (20). That might explain thehigh prevalence of a delayed relaxation pattern in allechocardiographic studies in cirrhosis, as well as thereported relation between DD and liver disease severity.

In fact, in our study, patients with this definition of DD,had lower cardiac output compared with patients with-out DD, which supports the notion of flow-dependenceof mitral variables. Besides, we could not find the differ-ences in left atrial volume – a known marker of DDchronicity – between the two groups.

On the other hand, Pimenta et al (22), using imped-ance cardiography, found that patients with decompen-sated cirrhosis had high thoracic fluid content, whichusually reflects central volaemia. This suggests thatpatients with cirrhosis may have markedly different hae-modynamic conditions during the course of their ill-ness. Therefore, PW-Doppler mitral criteria may not besuitable to correctly identify patients with abnormalrelaxation, reflecting also different flow conditions. Thelimited agreement between the two DD definitions thatwe have tested further supports this hypothesis.

According to the most recent recommendations forthe evaluation of diastolic function by echocardiography(15), tissue-Doppler derived parameters play a majorrole in the diagnostic work-up of DD. E’ is a sensitivemarker of abnormal relaxation with a good correlationwith tau (the time constant of ventricular relaxation)(4, 23, 24). On the other hand, E’ can be used to correctthe effect of relaxation on E velocity; hence the E/E’ ratiocan be used to estimate LV filling pressures. A good cor-relation between this index and filling pressure has beenconsistently reported in multiple scenarios (5, 25, 26).We used the proposed algorithm of these recommenda-tions and defined DD as reduced tissue-Doppler mitralannulus velocities and enlarged left atria. Applying thesecriteria, the prevalence of DD in our sample was lowerthan when using mitral flow parameters. We found nodifferences in haemodynamic variables in patients withand without this definition of DD, supporting a relativeload-independence of the method. However, patientswith DD had differences in other indices of diastolicfunction not included in the definition (E/A ratio, DTand IVRT) and significantly lower S’ velocity and PLS.In fact, the presence of longitudinal systolic dysfunctionin patients with diastolic heart failure has been consis-tently reported (27–29). This suggests that tissue-Dopplerbased criteria may be more specific than mitral flowderived variables for the identification of cirrhoticpatients with more serious myocardial dysfunction. Afew previous studies have used tissue-Doppler inassessing diastolic function in cirrhosis (11, 12, 18, 30).However, most of them still based the diagnosis onPW-Doppler parameters and tissue-Doppler was mainlyused to differentiate between normal and pseudo-nor-mal E/A patterns. This approach, although widely usedin clinical practice, is different from the one proposedby the consensus recommendations and may explain thedifference in the prevalence of DD in our study. Nazaret al recently reported that 84% of cirrhotic patientshad normal or only mild DD and that invasively deter-mined pulmonary capillary wedge pressure was normalin all patients (12). Taken altogether, these and our



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findings raise the possibility that the prevalence of DDrelated to intrinsic ventricular pathology may be lessfrequent than previously assumed.

As cirrhosis aetiology is mainly alcoholic in our sam-ple, we cannot exclude that our results reflect alcoholicrather than cirrhotic cardiomyopathy. However, whenwe compared systolic function parameters in alcoholicpatients vs the others, found only a trend towards lowerstrain in alcoholics and no differences in left ventricularvolumes or ejection fraction between the two groups.The prevalence of diastolic dysfunction also did notdiffer in the two groups. Other authors have reportedsimilar results (11, 12, 31). Taken altogether, these findingsargue against an exclusive alcohol effect on our results.

Although NT-ProBNP levels were correlated withseverity of cirrhosis in our sample (data not shown), wedid not find a correlation between NT-ProBNP and car-diac dysfunction, in contrast to other studies (30). How-ever, when patients with decompensated cirrhosis wereexcluded from the analysis, NT-ProBNP levels werehigher in patients with evidence of diastolic dysfunction.This may be because of the influence of cardiac, hepaticand renal dysfunction and their mutual interactions onNT-ProBNP levels, which is probably more significantin decompensated/hospitalized patients. In this sce-nario, natriuretic peptides may be a global risk markerreflecting multi-organic dysfunction. The associationbetween natriuretic peptides and prognosis (22) seemsto support this hypothesis.

Limitations

This is a single centre study performed in patientsmainly with alcoholic cirrhosis and different diseaseseverity.

An accepted gold-standard method to diagnose cir-rhotic cardiomyopathy is still lacking. We did not per-form a dobutamine stress test, which might have beenuseful in revealing systolic dysfunction. Neither did weperform invasive haemodynamic measurements whichwould have allowed us to correlate our echocardio-graphic findings with accurate parameters of systolic anddiastolic function, systemic haemodynamics and degreeof portal hypertension. Hence, we cannot objectivelyassess the diagnostic performance of tissue-Doppler andspeckle tracking and can only suggest that they may bemore adequate based on consistent and increasinglyrobust evidence in other areas of cardiovascular disease.Besides, limitations and pitfalls of these new modalitiesare well recognized (32). In particular, there are somesituations in which tissue Doppler velocities and E/E’ ratiomay not correlate with LV filling pressures (33); however,none of them seems to apply to this population.

Conclusions

Patients with cirrhosis have evidence of both systolicand diastolic dysfunction at rest. Our results suggest

that newer echocardiographic techniques may identifypatients with functional impairment more accuratelythan conventional echocardiographic methods. Theclinical significance of these abnormalities merits furtherinvestigation.

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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 • Joao 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 cir-

rhosis. 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 com-

prehensive echocardiographic evaluation was performed;

LA strain was assessed using velocity vector imaging.

Results Peak atrial longitudinal strain at the end of ven-

tricular 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 (R2 = 47 %). No cor-

relation 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 fac-

tors 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 � Heartfailure � 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 dis-

ease [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 pres-

sures, and dilated atria may be seen in patients with volume

overload, anemia and high-output states [9]. The mecha-

nisms 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

Conceicao 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. FragaGastroenterology Department, Centro Hospitalar de Gaia/

Espinho, Rua Conceicao Fernandes, 4430-502 Vila Nova de

Gaia, Portugal

J. Valente

Internal Medicine Department, Centro Hospitalar de Gaia/

Espinho, Rua Conceicao 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 hypertro-

phy, hypertension, hypertrophic cardiomyopathy, diabetes

mellitus and DD [10–16]. These abnormalities are detect-

able 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, pre-

vious 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 echocardiogra-

phy 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 echocardio-

grams, 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 recommenda-

tions [24]. DD was diagnosed and graded according to the

current recommendations for the evaluation of LV dia-

stolic 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 veloci-

ties. Pulsed-wave tissue-Doppler velocities were acquired

in the apical four-chamber view, with the sample posi-

tioned 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, Sie-

mens 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 car-

diac 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 mar-

ker 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.

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Reproducibility

Reproducibility of PALS and PACS measurements was

assessed in ten randomly selected subjects. For intraob-

server 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.


Data were stored and analyzed using IBM SPSS Statistics,

version 20.0 (Armonk, NY: IBM Corp.). Results are pre-

sented as median (25th–75th percentile) for quantitative

variables and as n (%) for categorical variables. A signif-

icance level of 5 % was used.

Differences in continuous variables between groups were

compared using the Mann–Whitney test, and the v2 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. Uni-

variate 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 LnPALSwere included in

a multivariable linear model. E0 velocity was the only

independent predictor of LnPALS [b = 0.082, 95 % confi-

dence interval (CI) 0.062–0.102, p\ 0.001]. R2 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

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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 inde-

pendently associated with LnLAVI. R2 for the model was

38 %.

We found a significant correlation between PALS and

mean E/E0 ratio (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 res-

ervoir 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 (S0 velocity and LV

longitudinal strain) using linear regression analysis. How-

ever, E0 velocity (a sensitive marker of ventricular relaxa-

tion) 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 pres-

sures. The strong correlation between PALS and invasively

determined filling pressures found by other authors sup-

ports 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 (9109/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/m2) 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/A ratio 1.03 (0.82–1.34)

Deceleration time (ms) 239 (201–280)

E0 velocity (cm/s) 9.56 (7.43–11.72)

E/E0 ratio 8.57 (6.80–10.38)

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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/E0 ratio

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

excursiona Defined as eGFR\60 ml/

min/1.73 m2

b 95 % 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 failurea 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/m2) -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/A ratio 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

S0 velocity (per cm/s) 0.065 0.034 to 0.096 \0.001

E0 velocity (per cm/s) 0.068 0.048 to 0.087 \0.001

A0 velocity (per cm/s) 0.046 0.015 to 0.076 0.004

E/E0 ratio -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

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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 beta-

blockers (data not shown). Although we cannot definitely

exclude an effect of pharmacological treatment, these

findings argue against an important influence of beta-

blockers or diuretics on our results.

LAVI was higher in patients compared to controls. On

multivariate linear regression analysis, LnLAVI was asso-

ciated with stroke volume, LV end-diastolic volume and

hemoglobin. This is in accordance with the known influ-

ence 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/E0 ratio 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 ele-

vated 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 dif-

ferent 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/E0 ratio 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

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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 measure-

ments and used echocardiographic surrogate markers of LV

filling pressures. Previous reports have questioned the

value of the E/E0 ratio 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 set-

tings [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 echocardio-

graphic 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, Joao 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.

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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]

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ABSTRACT

Background: Liver cirrhosis has been shown to affect cardiac performance. However cardiac

dysfunction may only be revealed under stress conditions. The value of non-invasive stress tests in

diagnosing cirrhotic cardiomyopathy is unclear. We sought to investigate the response to

pharmacological stimulation with dobutamine in patients with cirrhosis using cardiovascular magnetic

resonance.

Methods: Thirty-six patients and eight controls were studied. Conventional volumetric and

myocardial deformation parameter analysis using feature tracking at rest and during low to

intermediate dose dobutamine stress were performed.

Results: Whilst volumetry based parameters were similar between patients and controls at rest,

patients had a smaller increase in cardiac output during stress (p=0.015). Ejection fraction increase

was impaired in patients during 10 μg/Kg/min dobutamine as compared to controls (6.9% vs. 16.5%,

p=0.007), but not with 20 μg/Kg/min (12.1% vs. 17.6%, p=0.12). This was paralleled by an impaired

improvement in circumferential strain with low dose (median increase of 14.4% vs. 30.9%, p=0.03),

but not with intermediate dose dobutamine (median increase of 29.4% vs. 33.9%, p=0.54). There was

an impaired longitudinal strain increase in patients as compared to controls during low (median

increase of 6.6% vs 28.6%, p<0.001) and intermediate dose dobutamine (median increase of 2.6%vs,

12.6% p=0.016). Radial strain response to dobutamine was similar in patients and controls (p>0.05).

Conclusion: Cirrhotic cardiomyopathy is characterized by an impaired cardiac pharmacological

response that can be detected with magnetic resonance myocardial stress testing. Deformation

analysis parameters may be more sensitive in identifying abnormalities in inotropic response to stress

than conventional methods.

KEYWORDS:

Liver; Cardiomyopathy; Magnetic resonance imaging; Feature Tracking; Strain; Dobutamine stress

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BACKGROUND

Systolic and diastolic dysfunction, as well as electrophysiological abnormalities have been described in

patients with cirrhosis[1-3]. Although previous studies have reported the presence of myocardial

dysfunction at resting states[4-6], cirrhotic cardiomyopathy is usually clinically silent and may only be

unmasked during physiological or inotropic stress[7].

Pharmacological stress tests using echocardiography or SPECT are often used in cirrhotic patients

for diagnosing coronary artery disease before liver transplantation. Although blunted responses of

stroke volume and ejection fraction (EF) to dobutamine have also been reported[8], other studies

have questioned these findings, particularly in patients with mild disease[9]. Therefore, most authors

recommend that dobutamine stress tests should be reserved for excluding ischaemic heart disease

before liver transplantation[10].

Cardiovascular magnetic resonance (CMR) has evolved into the gold standard methodology for

assessment of cardiac morphology and volumes[11,12]. Myocardial strain – which may reflect systolic

function more accurately than conventional, highly load dependent, indices such as ejection fraction –

can also be assessed using CMR, both at rest and during inotropic stimulation with dobutamine[13].

The response of strain to stress has not been previously studied in patients with cirrhosis.

To test the hypothesis that a pharmacological stress test could reveal systolic incompetence in

patients with cirrhosis, we performed a comprehensive analysis of systolic function during

pharmacological stress, using CMR.

METHODS

The study protocol was approved by the local ethics committee and complies with the declaration of

Helsinki. Written informed consent was obtained from all participants.

Thirty-six patients with cirrhosis followed in a hepatology outpatient clinic, able to comply with the

instructions during the exam, were recruited and referred to CMR. The diagnosis of cirrhosis was

based on clinical, laboratory, ultrasonographic and/or biopsy criteria. Patients with a known history

of hypertension, diabetes, cardiac disease or relevant ECG abnormalities were excluded. Patients

with large volume ascites and/or unable to tolerate breath-holding, renal insufficiency (creatinine

clearance ≤ 60 ml/min/1.73m2) or standard contraindications to CMR or gadolinium were also

excluded.

A group of eight healthy individuals, with similar age and sex distribution as the patient group,

without known cardiovascular risk factors or cardiac disease, referred to CMR for another indication

and with a completely normal scan, was used as control.

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CMR acquisition

Patient preparation

Patients were instructed to refrain from smoking, coffee, tea, aminophylline, for 24 h before the scan.

Beta-blockers were suspended 48 hours before the study.

CMR protocol

Images were acquired using a 1.5T scanner (Siemens Symphony TIM; Siemens, Erlangen, Germany)

with a 6-channel anterior chest coil and spinal coils within the gantry table.

Cine imaging

After scout images, cine images using a retrospective ECG-gated balanced steady state free-

precession sequence were acquired during brief periods of end-expiratory breath-hold. Two-, four

and three-chamber orientations, as well as multiple equidistant short-axis planes (slice thickness 8

mm; gap 2 mm) allowing coverage of the entire cardiac volume were performed. Thirty phases were

obtained per cardiac cycle.

For dobutamine stress imaging, 3 long-axis and 3 short-axis slices (basal, mid-ventricular and apical)

were acquired, in order to cover 16 myocardial segments[14]. Dobutamine was infused intravenously

at 3-minute stages at doses of 10 and 20 μg/Kg/min. Repeat short-axis images as well as long-axis

images were acquired at the end of each stage. During dobutamine infusion, patient symptoms, heart

rate, blood pressure, and electrocardiogram were monitored.

Aortic flow imaging

Aortic flow was measured using one-direction “through-plane” motion-encoded cine gradient echo

sequences (slice thickness 5 mm; in-plane resolution ≤1 mm), centered in ascending aorta and aligned

orthogonally to the expected main blood flow direction in two spatial directions, at the level of the

pulmonary bifurcation. Velocity encoding sensitivity (Venc) was adapted to the expected velocities

(typically 150 for the rest images and 300 during the dobutamine-stress acquisitions). Thirty frames

were acquired per cardiac cycle using a free-breathing technique with 3 excitations per k-space line.

Perfusion imaging

Our protocol for stress perfusion imaging has been previously described[15]. Maximal hyperemia was

achieved with intravenous adenosine (140 μg.kg−1.min−1) infusion for 5 min. Within the last 2 min of

infusion, an intravenous bolus of 0.07 mmol/Kg of gadobutrol (Gadovist, Bayer HealthCare

Pharmaceuticals, Berlin, Germany), was injected. Three short-axis slices (basal, mid-ventricular and

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apical) were imaged during the first pass of the bolus of gadolinium using a gradient echo pulse

sequence with a single saturation pre-pulse per R–R interval shared over the three slices. Patients

were asked to hold their breath on full expiration for the duration of the first pass of the gadolinium

bolus.

Late Gadolinium enhancement

Late gadolinium-enhancement (LGE) was assessed using a phase-sensitive inversion-recovery

sequence ≥10 minutes after the administration of 0.2 mmol/kg of gadobutrol.

CMR analysis

Images were anonymized and analysis was performed by operators blinded to clinical data.

A commercially available software (CMR42; Circle Cardiovascular Imaging Inc., Calgary, Canada) was

used to assess left and right ventricular volumes and function, from the short-axis cine images. Phase-

contrast pulse sequences at rest and peak dobutamine dose were analyzed with the same software,

to determine cardiac output.

Feature tracking (FT), a technique analogous to echocardiographic speckle tracking, which allows

tracking of tissue voxel motion of CMR cine images[16-19] was used to assess left ventricular strain.

Four-, two- and three-chamber views were used to calculate longitudinal strain. Radial strain and

circumferential strain were derived from the three short-axis planes. Global longitudinal strain (GLS),

global radial strain (GRS) and global circumferential strain (GCS) were defined as the mean strain of

the three individual planes. Measurements were performed at rest and at each stage of dobutamine

infusion.

For the stress perfusion analysis, perfusion defects were defined as subendocardial or transmural

visually dark myocardial areas when compared with remote healthy myocardium, persisting for at

least 10 frames.

Reproducibility

Reproducibility of FT derived strain was assessed in 10 randomly selected subjects. For this, the

measurements were repeated more than 4 weeks after the initial analysis.

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Data were stored and analyzed using IBM SPSS Statistics, Version 20.0 (IBM Corp., Armonk, NY,

USA). Results are presented as median (25th–75th percentile) for quantitative variables and as n (%)

for categorical variables. A significance level of 5% was used.

The Mann–Whitney test was used to evaluate differences in continuous variables between groups.

The Chi-squared test was used to compare proportions. Spearman’s coefficient was used to test

correlations. Bland–Altman analysis was performed for reproducibility testing.

RESULTS

Clinical characteristics and laboratorial characteristics of patients and controls are shown in table 1.

Most patients (n=27, 75%) were in Child-Pugh class A, eight patients (17.8%) were in class B and only

one patient was in class C.

CMR –derived morphological and functional parameters were similar at rest in patients and controls

(table 2). We found no differences in resting GLS, GCS or GRS between patients and controls.

Child-Pugh class A patients had a trend towards lower left atrial volume compared to patients with

more severe (class B and C) disease 43.3 ml/m2 (35.4-49.5) vs 47.6 ml/m2 (44.1-56.7); p=0.08. No

differences in any of the other parameters were found, in resting conditions, between these two

groups of patients.

Dobutamine stress

The response of hemodynamic and strain parameters to increasing doses of dobutamine is shown in

table 3 and figures 1 and 2. Compared to controls, patients had a smaller increase of stroke volume

and cardiac output during dobutamine perfusion. There was no difference in heart rate response to

stress in the two groups. The increase in EF was lower in patients than in controls at the dose of 10

μg/Kg/min of dobutamine (median percentual increase of 6.9% (3.5-12.1) vs 16.5% (8.5-23.3),

p=0.007), but not at 20 μg/Kg/min (median percentual increase of 12.1% (6.8-17.9) vs 17.6% (10.4-

28.0), p=0.12). The improvement in GLS during the perfusion was significantly lower in patients

compared to controls, both at 10 μg/Kg/min (median percentual increase of 28.6% (6.6% (-5.8-17.0)

vs 18.9-54.4), p<0.001) and at 20 ug/Kg/min (median percentual increase of 2.6% (-5.5-16.7) vs 12.6%

(10.4-29.2), p=0.016). Global circumferential strain increased less significantly in patients as compared

to controls at 10 μg/Kg/min (median percentual increase of 14.4% (0.6-22.9) vs 30.9% (8.6-41.5),

p=0.03); the response of GCS to 20 μg/Kg/min of dobutamine was not significantly different between

the two groups (median percentual increase of 29.4% (10.9-41.1) vs 33.9% (16.7-48.5), p=0.54). The

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response of GRS to pharmacological stress was not different in patients versus controls (median

percentual increase of 7.7% (-2.4-15.2) vs 13.6% (5.7-26), p=0.11 at 10 μg/Kg/min of dobutamine and

4.3% (0.6-8.1) vs 3.1% (-0.2-9.3), p=0.82 at 20 μg/Kg/min of dobutamine).

We found no differences in the response of hemodynamic and strain parameters to dobutamine

between patients in Child-Pugh class A versus the others or between patients on diuretics versus

patients without prior diuretic use.

There was a correlation between the percentual change of GLS and the percentual change in left

ventricular stroke volume (Spearman’s rho =0.42, p=0.007). Changes in stroke volume and GCS

(Spearman’s rho =0.11, p=0.48) or GRS (Spearman’s rho =0.07, p=0.69) were not correlated.

Stress perfusion and late gadolinium enhancement

No perfusion abnormalities were detected in any subject during adenosine stress. There was no LGE

in patients and controls.

Reproducibility

The mean differences and confidence intervals between repeated strain measurements are displayed

in Table 4. Reproducibility was similar at rest and with dobutamine stress.

DISCUSSION

Our results suggest that a dobutamine stress test can be useful in revealing systolic abnormalities in

patients with mild cirrhosis. Using cardiovascular magnetic resonance derived strain, we have shown

that, during low- to intermediate dose dobutamine stimulation, patients with cirrhosis had a smaller

improvement in longitudinal and a delayed increase in circumferential strain compared to controls.

This is, to the best of our knowledge, the first study to evaluate myocardial deformation during

stress in cirrhosis.

Subendocardial fibre damage with consequent left ventricular longitudinal function impairment are

usually the first manifestations of myocardial disease[20-22]. Longitudinal dysfunction was previously

documented in cirrhosis, at rest[5,6], using echocardiography. In the present study, we could not find

differences in any CMR parameters at rest between patients and controls. This may be related to the

early stage of disease of the majority of the patients. Patients exhibited a blunted response of GLS to

dobutamine, compared to controls. The normal response of strain to dobutamine is an initial

increment followed by a plateau or decrement (when filling is reduced by increased heart-rate)[23,24].

Our results are in line with this pattern. However, in controls there was a decrease in longitudinal

strain with 20 μg/Kg/min (compared to 10 μg/Kg/min). This pattern was not observed in the patient

group suggesting that, in controls, the maximal inotropic effect of dobutamine is achieved with the

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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

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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 renin-

angiotensin-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.

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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.

JP and PB participated in the conception and design of the study, interpretation of the data and

revision of the manuscript.

NF was involved in data acquisition and revision of the manuscript.

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JF and VG were involved in in data gathering and revision of the manuscript.

AS, PL, SCA, JTK and SK were involved in data analysis and revision of the manuscript for important

content.

All authors read and approved the final manuscript.

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16. Hor KN, Gottliebson WM, Carson C, Wash E, Cnota J, Fleck R, Wansapura J, Klimeczek P, Al-Khalidi

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Cardiovascular Magnetic Resonance myocardial feature tracking: a feasibility study. J

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cardiovascular magnetic resonance myocardial feature tracking. J Cardiovasc Magn Reson 2012,

14:43.

19. Padiyath A, Gribben P, Abraham JR, Li L, Rangamani S, Schuster A, Danford DA, Pedrizzetti G, Kutty S:

Echocardiography and cardiac magnetic resonance-based feature tracking in the assessment

of myocardial mechanics in tetralogy of Fallot: an intermodality comparison. Echocardiography

2013, 30:203-210.

20. Poulsen SH, Andersen NH, Heickendorff L, Mogensen CE: Relation between plasma amino-

terminal propeptide of procollagen type III and left ventricular longitudinal strain in

essential hypertension. Heart 2005, 91:624-629.

21. Cardim N, Oliveira AG, Longo S, Ferreira T, Pereira A, Reis RP, Correia JM: Doppler tissue imaging:

regional myocardial function in hypertrophic cardiomyopathy and in athlete's heart. J Am Soc

Echocardiogr 2003, 16:223-232.

22. Andersen NH, Poulsen SH, Eiskjaer H, Poulsen PL, Mogensen CE: Decreased left ventricular

longitudinal contraction in normotensive and normoalbuminuric patients with Type II

diabetes mellitus: a Doppler tissue tracking and strain rate echocardiography study. Clin Sci

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23. Mor-Avi V, Lang RM, Badano LP, Belohlavek M, Cardim NM, Derumeaux G, Galderisi M, Marwick T,

Nagueh SF, Sengupta PP, 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.

24. Bijnens BH, Cikes M, Claus P, Sutherland GR: Velocity and deformation imaging for the

assessment of myocardial dysfunction. Eur J Echocardiogr 2009, 10:216-226.

25. Lee SS, Marty J, Mantz J, Samain E, Braillon A, Lebrec D: Desensitization of myocardial beta-

adrenergic receptors in cirrhotic rats. Hepatology 1990, 12:481-485.

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26. Gerbes AL, Remien J, Jungst D, Sauerbruch T, Paumgartner G: Evidence for down-regulation of beta-

2-adrenoceptors in cirrhotic patients with severe ascites. Lancet 1986, 1:1409-1411.

27. Reant P, Labrousse L, Lafitte S, Bordachar P, Pillois X, Tariosse L, Bonoron-Adele S, Padois P, Deville C,

Roudaut R, Dos Santos P: Experimental validation of circumferential, longitudinal, and radial 2-

dimensional strain during dobutamine stress echocardiography in ischemic conditions. J Am

Coll Cardiol 2008, 51:149-157.

28. Kelbaek H, Rabol A, Brynjolf I, Eriksen J, Bonnevie O, Godtfredsen J, Munck O, Lund JO:

Haemodynamic response to exercise in patients with alcoholic liver cirrhosis. Clin Physiol 1987,

7:35-41.

29. Wong F, Girgrah N, Graba J, Allidina Y, Liu P, Blendis L: The cardiac response to exercise in

cirrhosis. Gut 2001, 49:268-275.

30. Krag A, Bendtsen F, Mortensen C, Henriksen JH, Moller S: Effects of a single terlipressin

administration on cardiac function and perfusion in cirrhosis. European journal of gastroenterology

& hepatology 2010, 22:1085-1092.

31. Schuster A, Paul M, Bettencourt N, Morton G, Chiribiri A, Ishida M, Hussain S, Jogiya R, Kutty S, Bigalke

B, et al: Cardiovascular magnetic resonance myocardial feature tracking for quantitative

viability assessment in ischemic cardiomyopathy. International journal of cardiology 2013, 166:413-

420.

32. 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, 59:105-110.

33. Sampaio F, Pimenta J, Bettencourt N, Fontes-Carvalho R, Silva A-P, Valente J, Bettencourt P, Fraga J,

Gama V: Systolic dysfunction and diastolic dysfunction do not influence medium-term

prognosis in patients with cirrhosis. Eur J Intern Med. 2014; 25:241-246.

34. Nazar A, Guevara M, Sitges M, Terra C, Solà E, Guigou C, Arroyo V, Ginès P: LEFT ventricular

function assessed by echocardiography in cirrhosis: Relationship to systemic hemodynamics

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35. 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.

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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.

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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.

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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.

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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/m2) 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

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Table 3 – Hemodynamic and strain response to dobutamine

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Table 4 – Variability of different strain parameters at rest and during dobutamine stress.

Parameter Mean difference (%) 95% CI p

Rest

GLS 0.17 -0.83-0.87 0.96

GRS 0.92 -3.11-3.29 0.96

GCS 0.47 -0.21-1.15 0.24

Dobutamine10 ug/Kg/min

GLS 0.49 -1.01-2.0 0.29

GRS 0.64 -3.01-4.29 0.68

GCS 0.45 -0.51-1.41 0.31

Dobutamine 20 ug/Kg/min

GLS 0.56 -0.53-1.66 0.17

GRS 2.02 0.09-3.94 0.04

GCS 0.39 -0.39-1.18 0.17

GLS = Global Longitudinal Strain; GRS = Global Radial Strain; GCS = Global Circumferential Strain

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Original Article

Systolic dysfunction and diastolic dysfunction do not influencemedium-term prognosis in patients with cirrhosis

Francisco Sampaio a,b,⁎, Joana Pimenta b, Nuno Bettencourt a,b, Ricardo Fontes-Carvalho a,b, Ana-Paula Silva c,João Valente d, Paulo Bettencourt b, José Fraga c, Vasco Gama a

a Cardiology Department, Centro Hospitalar de Gaia/Espinho, R. Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugalb University of Porto Medical School, Al. Prof. Hernani Monteiro, 4200-319 Porto, Portugalc Gastroenterology Department, Centro Hospitalar de Gaia/Espinho, R. Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugald Internal Medicine Department, Centro Hospitalar de Gaia/Espinho, R. Conceição Fernandes, 4434-502 Vila Nova de Gaia, Portugal

a b s t r a c ta r t i c l e i n f o

Article history:Received 25 September 2013Received in revised form 10 January 2014Accepted 13 January 2014Available online 31 January 2014

Keywords:CirrhosisEchocardiographyPrognosisCardiac function

Objective:Myocardial dysfunction has been described in patients with cirrhosis andmay contribute to haemody-namic disturbances in advanced disease states. However, the prognostic impact of cardiac systolic and diastolicdysfunction in cirrhosis is controversial.We aimed to evaluate the performance of echocardiographic parametersof cardiac function as medium-term prognostic markers, in a cohort of cirrhotic patients.Methods:Ninety-eight patients (52 discharged after hospitalization for decompensated cirrhosis and 46 ambula-tory) were prospectively evaluated. A comprehensive echocardiographic study, including tissue-Doppler andspeckle tracking analysis, was performed at baseline. Patients were followed-up for 6 months for the occurrenceof death.Results: Twenty patients died during the follow-up. None of the echocardiographic parameters were associatedwith the occurrence of death. A Child score N 10 points (HR 13.1, 95% CI 3.79–45.0, p b 0.001) and amean arterialpressure below the median (HR 3.2, 95% CI 1.14–8.80, p = 0.028) were the only independent predictors ofmortality in Cox regression multivariate analysis. In previously hospitalized patients, cardiac output, C-reactiveprotein and albumin levels were associated with 6-month mortality in univariate analysis; this association waslost after adjusting for Child score.Conclusions:Medium-termmortality in cirrhosis seems to be mainly determined by liver disease severity ratherthan bymyocardial dysfunction.Modern echocardiographic indices of systolic and diastolic function do not seemto be useful in identifying patients at increased risk of dying.

© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction

Cirrhotic cardiomyopathy has been described as a condition charac-terized by impaired contractile response to stress, diastolic dysfunctionand electrophysiological abnormalities, in the absence of known cardiacdisease [1–3]. Although previous studies have reported a direct relationbetween myocardial dysfunction and liver disease severity [4,5], thesefindingswere not replicated in recentworks [6–9]. Diastolic dysfunctionhas also been related to adverse prognosis after TIPS insertion [10].

On the other hand, a low cardiac output has been associatedwith thedevelopment of hepatorenal syndrome and mortality in patients withadvanced cirrhosis [11–14]. It has been suggested that myocardialdysfunction may contribute to the inability to increase cardiac outputunder stress conditions in these patients [8,13].

Newer echocardiographicmodalities, such as tissue-Doppler imagingand speckle tracking, which are able to quantitate myocardial displace-ment and deformation, have emerged as important prognostic markersin different clinical settings [15–19]. The role of cardiac function –

which may be more accurately assessed by these imaging modalities –in the pathogenesis of circulatory dysfunction in cirrhosis and itsprognostic implications remains unclear.

We aimed to evaluate the value of a detailed echocardiographicevaluation of cardiac systolic and diastolic function in predictingmedium-term mortality in patients with cirrhosis.

2. Methods

Weprospectively evaluated a group of 72 consecutively hospitalizedpatients with decompensated cirrhosis (defined as encephalopathy,

European Journal of Internal Medicine 25 (2014) 241–246

Abbreviations: TIPS, transjugular intrahepatic portosystemic shunt; HR, hazard ratio;NT-ProBNP, aminoterminal portion of pro-b-type natriuretic peptide; MELD, model forend-stage liver disease.⁎ Corresponding author at: Cardiology Department, Centro Hospitalar de Gaia/Espinho,

Rua Conceição Fernandes, 4430-502 Vila Nova de Gaia, Portugal. Tel.: +351 227865100;fax: +351 227830209.

E-mail addresses: [email protected] (F. Sampaio),[email protected] (J. Pimenta), [email protected] (N. Bettencourt),[email protected] (R. Fontes-Carvalho), [email protected] (A.-P. Silva),[email protected] (J. Valente), [email protected] (P. Bettencourt),[email protected] (J. Fraga), [email protected] (V. Gama).

0953-6205/$ – see front matter © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.ejim.2014.01.011

Contents lists available at ScienceDirect

European Journal of Internal Medicine

j ourna l homepage: www.e lsev ie r .com/ locate /e j im

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ascites, variceal bleeding, and/or jaundice) and 61 ambulatory patientsfollowed in an outpatient hepatology clinic, enrolled in the studybetween April 2011 and November 2012. The diagnosis of cirrhosiswas based on clinical, laboratory, ultrasonographic and/or biopsycriteria.

All patients underwent a comprehensive echocardiographic evalua-tion. Diastolic function was evaluated according to the most recentõrecommendations [20], with tissue-Doppler mitral annulus velocitiesbeing the first step in the diagnostic work-up. Systolic function assess-ment included left ventricular longitudinal strain analysis from two-dimensional grey-scale images using speckle tracking. A full descriptionof the echocardiographic methods has been published elsewhere [9].Clinical evaluation, blood sample collection and 12-lead ECG wereperformed on the same day of the echocardiogram.

We excluded patients with diabetes, arterial hypertension, previousrelevant cardiac disease, significant ECG abnormalities or more thanmild valvular heart disease on echocardiography.

Patients who were discharged after the index hospitalization andambulatory patients were followed for 6 months for the occurrence ofall-cause death; the two patients submitted to hepatic transplantationduring the study period were censored at the time of the procedure.Surveillance was performed by medical contact and/or observation ofclinical records.

The study complies with the principles of the declaration of Helsinki.The local Ethics Committee approved the study protocol and patients ortheir relatives gave informed consent.

2.1. Statistical analysis

Datawas stored and analysed using IBM SPSS Statistics, Version 20.0(Armonk, NY: IBM Corp). Results are presented as median (25th–75thpercentile) for quantitative variables and as n (%) for categoricalvariables. A significance level of 5% was used.

Cox regression analysis was used to evaluate the association of inde-pendent variableswith time to outcome, expressed as hazard ratio (HR)and 95% CI. Independent continuous variables were dichotomized

according to theirmedian values (when therewas no linear relationshipbetween them and the dependent variable) or according to well-established cut-off values for defining abnormality. Survival curveswere estimated according to the Kaplan–Meier method and comparedby the log-rank test.

3. Results

Of the original sample, 22 patients were excluded based on theexclusion criteria; the 13 patients who died during the index hospitali-zation were also excluded, leaving 98 patients for subsequent analysis.

Clinical and laboratorial characteristics of the patients included areshown in Table 1. Hospitalized patients had evidence of more advanceddisease andmore dynamic circulation – lowermean blood pressure andhigher heart rate – than ambulatory patients. Hospitalized patients alsohad a higher cardiac output [6.7 L/min (5.4–7.2) vs 5.7 L/min (4.7–6.6),p = 0.01]. Other echocardiographic characteristics of the patients arepresented in Table 2.

During the follow-up period, 20 patients died (three of haemor-rhage, seven of infection, four due to hepatorenal syndrome, four dueto porto-systemic encephalopathy and two of unknown cause) andtwo were transplanted. All deaths occurred in the group of hospitalizedpatients. No patient was lost to follow-up.

In Cox regression analysis, none of the echocardiographic parame-ters were associated with the occurrence of death at 6 months(Table 3). Although NT-ProBNP levels were significantly related to theoutcome in univariate analysis, this association was lost after adjust-ment to Child–Pugh class. A Child–Pugh score N 10 points (HR 13.1,95%CI 3.79–45.0, p b 0.001) and amean arterial pressure below theme-dian (HR 3.2, 95% CI 1.14–8.80, p = 0.028) were the only independentpredictors of mortality in multivariate analysis (Fig. 1).

Since all deaths occurred in the patients discharged after a hospitali-zation, we performed an isolated analysis of this group. Child–Pughscore, C-reactive protein levels, albumin levels and cardiac output wereassociated with 6-month mortality in univariate analysis (Table 4).Besides cardiac output, no echocardiographic variable was related to

Table 1Clinical and laboratorial characteristics of patients.

Overall(n = 98)

Hospitalized(n = 52)

Ambulatory(n = 46)

p

Age 54 (47–63) 54 (46–65) 54 (48–63) 0.97Male gender (n, %) 78 (79.6) 40 (76.9) 38 (82.6) 0.49Cirrhosis aetiology 0.76Alcoholic (n, %) 65 (66.3) 37 (71.2) 28 (60.9)Viric (n, %) 24 (24.5) 12 (23.1) 12 (26.1)Other (n, %) 9 (9.2) 3 (5.7) 6 (13.0)Beta-blocker use (n, %) 47 (48) 22 (42.3) 25 (54.3) 0.23Child–Pugh class b0.001A (n, %) 38 (38.8) 4 (7.7) 34 (73.9)B (n, %) 27 (27.6) 17 (32.7) 10 (21.7)C (n, %) 33 (33.7) 31 (59.6) 2 (4.3)MELDa score 12 (9–16) 15 (13–20) 9 (7–11) b0.001Heart rate 71 (58–81) 75 (66–87) 65 (57–77) 0.008Mean blood pressure 91 (80–99) 85 (75–95) 93 (87–100) 0.001Blood analysisHaemoglobin (g/dL) 12.0 (10.4–13.7) 10.8 (9.2–12.3) 13.6 (11.9–14.7) b0.001Platelet count (×109/L) 98 (60–125) 96 (49–133) 98 (60–124) 0.90Creatinine (mg/dL) 0.67 (0.50–0.89) 0.69 (0.50–0.98) 0.67 (0.54–0.84) 0.68Sodium (mEq/L) 138 (134–140) 135 (129–138) 139 (138–141) b0.001Total bilirubin (mg/dL) 1.60 (0.87–2.92) 2.47 (1.62–5.05) 1.09 (0.67–1.44) b0.001Albumin (g/dL) 3.35 (2.70–4.00) 2.85 (2.43–3.37) 4.0 (3.47–4.40) b0.001NT-ProBNPb (pg/mL) 158 (61–325) 295 (155–518) 78 (36–156) b0.001CRPc (mg/dL) 0.58 (0.21–1.92) 1.60 (0.35–3.90) 0.37 (0.09–0.58) b0.001INRd 1.39 (1.27–1.68) 1.56 (1.39–1.82) 1.27 (1.10–1.40) b0.001

a Model for end-stage liver disease.b Aminoterminal portion of pro-b-type natriuretic peptide.c C reactive protein.d International normalized ratio.

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prognosis. Child–Pugh score was the only variable that remained signif-icantly associated with the outcome, on multivariate analysis (HR 7.9,95% CI 1.83–34.51, p = 0.006).

Thirteen patients died during the index hospitalization (seven dueto porto-systemic encephalopathy, three of hepatorenal syndrome,two of infection, and one of haemorrhage). Compared to patients whowere discharged, patients who died during the index hospitalizationhad higher MELD score [20 (18–26) vs 15 (13–20), p = 0.002],higher total bilirubin levels [4.4 mg/dl (2.6–10.3) vs 2.5 mg/dl (1.6–5.1), p = 0.04], lower albumin levels [2.5 g/dl (2.2–2.9) vs 2.8 g/dl(2.4–3.4) p = 0.02], higher C-reactive protein levels [3.5 mg/dl (1.3–21.6) vs 1.6 mg/dl (0.3–3.9), p= 0.03], higher international normalizedratio [1.9 (1.6–2.2) vs 1.6 (1.4–1.8), p = 0.04] and higher NT-ProBNPlevels [773 pg/ml (379–1971) vs 295 (155–518) p = 0.005]. Therewere no differences in echocardiographic parameters between thesegroups. The inclusion of these patients in the survival analysis did notsignificantly change the overall results: Child–Pugh score N 10 points(HR 14.2, 95% CI 4.97–40.9, p b 0.001) and a mean arterial pressurebelow the median (HR 2.17, 95% CI 1.02–4.61, p = 0.045) were theonly independent predictors of mortality.

4. Discussion

Our results suggest that medium-term prognosis in cirrhosis is notinfluenced by myocardial dysfunction. Usingmodern echocardiograph-icmodalities, we could not find an association between any echocardio-graphic parameters of systolic or diastolic function and the occurrenceof death at 6 months. Child–Pugh score and mean blood pressurewere the only independent predictors ofmortality onmultivariate anal-ysis. This suggests that liver failure and associated haemodynamicchanges are more important determinants of medium-term survivalthan “intrinsic” myocardial dysfunction.

The impact of cardiac function on the prognosis of cirrhosis has notbeen addressed until recently and is a matter of ongoing debate. Ourresults are in line with two previous works, in which an associationbetween diastolic dysfunction and mortality could also not be found[8,21]. On the other hand, Ruíz-del-Árbol et al. recently reported thatdiastolic dysfunction was related to poor outcomes in patients withcirrhosis and that E/E′ was an independent predictor of the develop-ment of hepatorenal syndrome and 1-year mortality [22]. The higherprevalence of more severe diastolic impairment in their sample (47%

Table 2Echocardiographic characteristics of patients.

Overall(n = 98)

Hospitalized(n = 52)

Ambulatory(n = 46)

p

Left atrial volume index (mL/m2) 39.7 (29.7-45.3) 40.0 (29.2–45.8) 38.9 (29.8–45.4) 0.86Left ventricle diastolic diameter (mm) 51 (47–55) 52 (47–55) 51 (46–55) 0.81Left ventricle systolic diameter (mm) 32 (28–36) 32 (28–34) 33 (29–38) 0.25Left ventricular mass (g) 148 (121–189) 146 (119–192) 150 (126–188) 0.47Left ventricular EFa b 55% (n, %) 10 (10.2) 6 (11.5) 4 (8.7) 0.75Cardiac output (L/min) 6.1 (5.0–7.1) 6.7 (5.4–7.2) 5.7 (4.7–6.6) 0.01E/A ratio 1.0 (0.8–1.4) 0.9 (0.8–1.3) 1.1 (0.9–1.4) 0.07E/E′ ratio 8.6 (6.8–10.4) 8.3 (6.6–10.3) 8.9 (7.0–10.5) 0.43Diastolic dysfunctionb (n, %) 16 (16.3) 8 (15.4) 8 (17.4) 0.79Left ventricular longitudinal strain (%) −19.5 (−21.5 to −18.5) −19.0 (−21.5 to −18.1) −19.8 (−21.6 to −19.0) 0.29

a Ejection fraction.b Diastolic dysfunction defined as septal E′ b 8 cm/s, lateral e′ b 10 cm/s and left atrial volume ≥ 34 mL/m2 [20].

Table 3Cox regression model for predictors of all-cause death within 6 months.

Hazard ratio 95% confidence interval p

Age N 54 years 1.38 0.57–3.39 0.476Alcoholic aetiology (vs other) 0.67 0.27–1.63 0.370Mean blood pressure N 91 mm Hg 0.28 0.10–0.77 0.014Heart rate N 71 bpm 1.81 0.74–4.43 0.193Child–Pugh score N 10 points 14.5 4.23–49.4 b0.001MELDa score N 12 points 10.8 2.50–46.4 0.001Haemoglobin N 12 g/dL 0.22 0.07–0.66 0.007Renal insufficiencyb 2.47 0.83–7.39 0.106Serum sodium N 138 mEq/L 0.32 0.11–0.87 0.025Total bilirubin N 1.6 mg/dL 4.56 1.52–13.6 0.007Albumin N 3.35 g/dL 0.14 0.04–0.49 0.002CRPc N 0.58 mg/dL 3.19 1.15–8.87 0.026NT-ProBNPd N 158 pg/mL 4.0 1.33–12.1 0.014Left atrial volume index N 39.7 mL/m2 0.92 0.38–2.20 0.846Left ventricle end-diastolic volume N 100 mL 0.60 0.24–1.46 0.260Left ventricular mass N 148 g 0.65 0.27–1.59 0.348Left ventricular ejection fraction N 55% 0.99 0.23–4.28 0.993Cardiac output N 6.1 L/min 0.75 0.31–1.82 0.531Left ventricular longitudinal strain N −19.5% 1.136 0.45–2.85 0.786Diastolic dysfunctione (versus none) 0.51 0.12–2.18 0.361E/E′ ratio N 10 1.14 0.45–2.85 0.786QTc interval N 440 ms 0.59 0.20–1.76 0.341

a Model for end-stage liver disease.b Defined as glomerular filtration rate b 60 mL/min/1.73 m2 using the MDRD formula.c C reactive protein.d Aminoterminal portion of pro-b-type natriuretic peptide.e Diastolic dysfunction defined as septal e′ b 8 cm/s, lateral e′ b 10 cm/s and left atrial volume ≥ 34 mL/m2 [20].

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of the patients had grade 2 diastolic dysfunction) as compared to otherpopulations [8,9,21] and a longer follow-up may explain these differ-ences. However, since invasively determined cardiac output was notan independent predictor of mortality or of the development ofhepatorenal syndrome – in contrast with previous findings of thesame authors [13] – the pathophysiological link between diastolicdysfunction and these outcomes remains unclear.

In ourwork, systolic function, evenwhen assessed by left ventricularlongitudinal strain (a more sensitive and less load-dependent index ofmyocardial function [23,24]), was not a significant predictor of progno-sis. A lack of differences in left ventricular longitudinal strain betweenpatients with compensated and decompensated cirrhosis has been pre-viously reported [8,9]. According to Nazar et al. [8], this can be consid-ered as an evidence of contractile dysfunction in cirrhosis, since anincrease in myocardial strain would have been expected in patientswith higher sympathetic activation. While this interpretation could

also be applied to our results, the absence of an association betweenleft ventricular strain and survival even in the group of hospitalized(hence more decompensated) patients suggests that left ventricularlongitudinal strain is not useful in identifying patients at increased riskof dying. These results contrast with findings in heart failure patients,in which left ventricular longitudinal strain has been found to be supe-rior to ejection fraction in predicting outcomes [16,25]; the same wasobserved in patients hospitalized with acute heart failure who alsohave an intense activation of the sympathetic and renin–angiotensin–aldosterone systems [26]. Taken altogether these findings argue againsta significant effect of myocardial systolic dysfunction on short-termprognosis of cirrhotic patients.

Blood pressure was an independent predictor of mortality. Bothcardiac output and peripheral vascular resistances determine arterialblood pressure. Since cardiac output was not related to mortality, theassociation between blood pressure and prognosis is likely to be

Fig. 1. Probability of survival according to Child–Pugh score andmean blood pressure. Cumulative 6-months survival in patients with Child–Pugh score above and below 10 points (upperpanel, log rank test p b 0.001) and in patients with mean blood pressure above and below 91 mm Hg (lower panel, log rank test p = 0.008).


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explained mainly by peripheral vascular resistances, i.e., patients withmore vasodilatation are at increased risk. Other authors have reportedthat a low cardiac output could identify patients at risk of developinghepatorenal syndrome and of dying [11–13]. Since the lack of prognos-tic impact of cardiac output in our population could just be explained bythe inclusion of patients with mild disease, we performed an isolateanalysis of the group of hospitalized patients. Although a cardiac outputbelow themedianwas significantly associatedwith 6-monthsmortalityin univariate analysis, this association was lost after adjusting for Childclass. A progressive decrease in cardiac output during the course ofliver disease has been reported [11,22], and probably accounts for thisfinding. Besides, we found no significant differences in cardiac outputin patients who died during the index hospitalization and those whowere discharged (data not shown). These conflicting results may be ex-plained by the fact that the causes of death in our groupwere varied andnot only related to renal/multiorgan failure. We did not analyse onlythose dying of hepatorenal syndrome since the small number of eventswould have significantly limited the statistical analysis. However, intheir recent report, Ruíz-del-Árbol et al. also failed to find differencesin cardiac output between patients who developed hepatorenalsyndrome during follow-up and those who did not [22]; in fact theonly significant difference in haemodynamic measurements foundbetween those two groups wasmean arterial pressure which is concor-dant with our own results.

Elevated NT-ProBNP levels were related to mortality in the overallsample, but this association was lost after adjusting for Child score. Adirect relation between natriuretic peptide levels and liver diseaseseverity has been consistently reported [4,27]. However, Pimenta et al.found that BNP levels above the median were independent predictorsof 6-month mortality in a cohort of hospitalized patients [12]. Wecould not replicate these findings, when looking only at the group ofhospitalized patients. There are somepossible explanations for these re-sults.WemeasuredNT-ProBNPonly at admission; it is possible that, justlike in heart failure, discharge and particularly the evolution of natri-uretic peptide levels during the hospital stay [28,29], would be a moreimportant prognostic marker than a single measurement. We usedNT-ProBNP instead of BNP, and the two molecules have slightly differ-ent characteristics [30] (half-life, clearance mechanisms), which may,

hypothetically, have influenced the results. Finally, NT-ProBNP levelswere relatively low in our sample, even when looking only at patientsdischarged after a hospitalization; this small range of low values maynot be able to differentiate patients at increased risk of death. Patientswho died during the index hospitalization had significantly higherNT-ProBNP levels than patients who were discharged. This suggeststhat BNP may, in fact, be useful in identifying higher risk patients.

4.1. Limitations

Our study was performed in a single centre and included mainlypatients with alcoholic cirrhosis and different disease severity.

We excluded patients with diabetes, which is frequent in cirrhoticpatients and is a known cause of cardiac disease; hence our conclusionscannot be extended to this subset of patients.

We did not perform invasive haemodynamic studies or neurohor-monal measurements (besides NT-ProBNP), whichwould have allowedus to accurately assess central and peripheral haemodynamic status andto correlate them with prognosis.

It would add to our analysis evaluating whether echocardiographicparameters of myocardial dysfunction could predict cardiovasculardeaths. However, the study was not designed to perform such analysisand would be underpowered to draw firm conclusions due to the limit-ed number of deaths in this category.

5. Conclusion

Cardiac function is not related to medium-term mortality in cirrho-sis, which seems to be mainly determined by liver disease severityand associated haemodynamic changes.

Although systolic dysfunction and diastolic dysfunction have beendocumented in patients with cirrhosis, these abnormalities may not besevere enough to independently influence the medium-term prognosis.However, we cannot exclude that cardiac dysfunction may act as a con-tributing factor to the development of complications of cirrhosis (likehepatorenal syndrome or haemorrhage), or to their irreversibility. Onthe other hand, its potential effect on long-term survival remains unclearand warrants further study.

Table 4Cox regression model for predictors of all-cause death within 6 months after discharge in hospitalized patients.

Hazard ratio 95% confidence interval p

Age N 54 years 0.88 0.37–2.11 0.769Alcoholic aetiology (vs other) 0.47 0.19–1.15 0.098Mean blood pressure N 85 mm Hg 0.54 0.22–1.31 0.172Heart rate N 75 bpm 1.57 0.64–3.83 0.326Child–Pugh score N 10 points 5.08 1.49–17.4 0.010MELDa score N 15 points 1.22 0.51–2.95 0.654Haemoglobin N 10.8 g/dL 0.71 0.29–1.71 0.443Renal Insufficiencyb 1.28 0.43–3.83 0.661Serum sodium N 135 mEq/L 1.04 0.43–2.51 0.926Total bilirubin N 2.47 mg/dL 1.22 0.51–2.94 0.659Albumin N 2.85 g/dl 0.35 0.13–0.90 0.030CRPc N 1.60 mg/dL 2.63 1.00–6.93 0.050NT-ProBNPd N 295 pg/mL 2.39 0.91–6.30 0.077Left atrial volume index N 40 ml/m2 0.90 0.38–2.17 0.820Left ventricle end-diastolic volume N 96 mL 0.54 0.22–1.32 0.179Left ventricular mass N 146 g 0.59 0.24–1.44 0.244Left ventricular ejection fraction N 55% 1.26 0.29–5.42 0.759Cardiac output N 6.7 L/min 0.32 0.12–0.84 0.021Left ventricular longitudinal strain N −19.8% 1.67 0.61–4.60 0.322Diastolic dysfunctione (versus none) 0.51 0.12–2.18 0.360E/E′ ratio N 10 1.07 0.43–2.69 0.880QTc interval N 440 ms 0.39 0.13–1.18 0.096

a Model for end-stage liver disease.b Defined as glomerular filtration rate b 60 mL/min/1.73 m2 using the MDRD formula.c C reactive protein.d Aminoterminal portion of pro-b-type natriuretic peptide.e Diastolic dysfunction defined as septal e′ b 8 cm/s, lateral e′ b 10 cm/s and left atrial volume ≥ 34 mL/m2 [20].

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Learning points

• Cirrhotic cardiomyopathy is a condition characterized by impairedcontractile response to stress, diastolic dysfunction and electrophysi-ological abnormalities, in the absence of known cardiac disease.

• An association between cardiac dysfunction and a worse prognosis inpatients with cirrhosis has been suggested.

• In the present study, using sensitive and less load-dependent echocar-diographic methods, we could not find an association between anyindices of myocardial function and 6 month mortality.

• Liver disease severity and peripheral and associated haemodynamicchanges seem to be themain determinants ofmedium-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 Dis2008;28:59–69.

[2] Moller S, Henriksen JH. Cardiovascular complications of cirrhosis. Gut 2008;57:268–78.

[3] Wong F. Cirrhotic cardiomyopathy. Hepatol Int 2009;3:294–304.[4] Henriksen JH, Gøtze JP, Fuglsang S, Christensen E, Bendtsen F, Møller S. Increased cir-

culating pro-brain natriuretic peptide (proBNP) and brain natriuretic peptide (BNP)in patients with cirrhosis: relation to cardiovascular dysfunction and severity ofdisease. Gut 2003;52:1511–7.

[5] Pozzi M, Carugo S, Boari G, Pecci V, de Ceglia S, Maggiolini S, et al. Evidence offunctional and structural cardiac abnormalities in cirrhotic patients with and with-out ascites. Hepatology 1997;26:1131–7.

[6] Kazankov K, Holland-Fischer P, Andersen NH, Torp P, Sloth E, Aagaard NK, et al. Rest-ing myocardial dysfunction in cirrhosis quantified by tissue Doppler imaging. LiverInt 2011;31:534–40.

[7] Merli M, Calicchia A, Ruffa A, Pellicori P, Riggio O, GiustoM, et al. Cardiac dysfunctionin cirrhosis is not associated with the severity of liver disease. Eur J Intern Med2013;24:172–6.

[8] Nazar A, Guevara M, Sitges M, Terra C, Solà E, Guigou C, et al. LEFT ventricular func-tion assessed by echocardiography in cirrhosis: relationship to systemic hemody-namics 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 trackingechocardiography study. Liver Int 2013;33:1158–65.

[10] Cazzaniga M, Salerno F, Pagnozzi G, Dionigi E, Visentin S, Cirello I, et al. Diastolic dys-function is associated with poor survival in patients with cirrhosis with transjugularintrahepatic portosystemic shunt. Gut 2007;56:869–75.

[11] Krag A, Bendtsen F, Henriksen JH, Møller S. Low cardiac output predicts develop-ment 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 natri-uretic peptide is related to cardiac function and prognosis in hospitalized patientswith 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. Circula-tory 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 withspontaneous bacterial peritonitis. Hepatology 2003;38:1210–8.

[15] Yu CM, Sanderson JE, Marwick TH, Oh JK. Tissue Doppler imaging a new prognosti-cator 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 longi-tudinal 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 oflongitudinal 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, et al. Association of left ventricularlongitudinal strain with mortality among stable hemodialysis patients withpreserved 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 leftventricular longitudinal strain in patients with acute myocardial infarction andpreserved 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. Recom-mendations for the evaluation of left ventricular diastolic function by echocardiogra-phy. 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 inpatients 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 forthe 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 evaluationof cardiac mechanics: ASE/EAE consensus statement on methodology and indica-tions endorsed by the Japanese Society of Echocardiography. Eur J Echocardiogr2011;12:167–205.

[25] Mignot A, Donal E, Zaroui A, Reant P, Salem A, Hamon C, et al. Global longitudinalstrain as a major predictor of cardiac events in patients with depressed left ventric-ular 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-dimensionalstrain as a new prognosticator in patients with heart failure. J Am Coll Cardiol2009;54:618–24.

[27] Yildiz R, Yildirim B, Karincaoglu M, Harputluoglu M, Hilmioglu F. Brain natriureticpeptide and severity of disease in non-alcoholic cirrhotic patients. J GastroenterolHepatol 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 heartfailure patients. Circulation 2004;110:2168–74.

[29] Cheng V, Kazanagra R, Garcia A, Lenert L, Krishnaswamy P, Gardetto N, et al. A rapidbedside test for B-type peptide predicts treatment outcomes in patients admitted fordecompensated 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. Circulation2011;123:2015–9.


V. Discussão

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Nos estudos desenvolvidos no âmbito desta tese, foi possível documentar, utilizando mé-

todos 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 carac-

terizada 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 altera-

ções 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 insufi-

ciência 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 esquer-

do, 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 defor-

mação 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 miocár-

dico 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 es-

tádios precoces da doença, apresentam uma resposta diminuída da deformação longitudinal à

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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 con-

firma 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 esta-

do 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 pio-

res, 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 amos-

tra. 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 defor-

mação 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 pa-

râmetros 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 semelhan-

tes aos de estudos prévios utilizando a mesma metodologia[61, 91, 98, 99]. No entanto encontra-

mos 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 veri-

ficando 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 pa-

drão 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 re-

comendações actuais para a avaliação de função diastólica por ecocardiografia[80]; mais impor-

tante, 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 dias-

tólica 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 pare-

cem 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 auricu-

lar nesta população, sugerindo a existência de outros mecanismos para esta dilatação, no con-

texto 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 – ava-

liada 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 iden-

tificar 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 sig-

nificativa 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 con-

texto 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 ecocardiográfi-

cos, em repouso, avaliados previamente e a mortalidade aos 6 meses. A maior gravidade da do-

ença 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 va-

sodilatação 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 sobrepo-

níveis 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 dife-

rentes condições hemodinâmicas, nomeadamente maior vasodilatação periférica nos doentes

mais descompensados. A discrepância entre estes resultados e os observados noutras pato-

logias 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 asso-

ciou 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 asso-

ciadas; 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 mortali-

dade foi igualmente descrita noutro trabalho recente[97].

No estudo 3 encontrámos uma relação entre resposta do strain longitudinal e do débito

cardíaco à estimulação inotrópica com dobutamina. Dada a hipótese de a incapacidade de

aumentar o débito cardíaco se poder associar a um risco aumentado de complicações nestes

doentes[96], é possível que, a resposta dos índices de função sistólica ao stress, mais do que

o seu valor basal, possam ser marcadores importantes de prognóstico. Esta hipótese não foi

explorada nos nossos trabalhos e poderá merecer, no futuro, melhor avaliação.

Em resumo, na nossa população, o prognóstico a médio prazo foi sobretudo influenciado

pela gravidade da doença hepática. A disfunção miocárdica documentada nos estudos prévios

não parece ser suficientemente importante para o desenvolvimento de complicações graves.

O seu potencial impacto no prognóstico a longo prazo permanece por esclarecer.

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VI. Conclusões

Conclusões

117

• Os doentes com cirrose hepática exibem alterações da função sistólica, quer em repou-

so 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 dias-

tólica, 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 me-

ses. 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 mecanis-

mos, 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 pró-

apoptóticos 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 assintomá-

tica durante anos, em virtude da vasodilatação arteriolar esplâncnica característica da circu-

lação 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 cardio-

miopatia 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 su-

gerida 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 mag-

nética 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.

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Francisco Sampaio

Com os trabalhos desenvolvidos, identificámos a existência de disfunção sistólica subclínica

– particularmente disfunção do componente longitudinal da deformação miocárdica durante a

sístole ventricular - na população estudada, quer em repouso, quer sob estimulação inotrópica,

apesar da normalidade da fracção de ejecção na maioria dos doentes. Esta disfunção foi inde-

pendente da gravidade da doença, sendo possível encontrar alterações na resposta ao stress

mesmo em indivíduos estáveis com doença ligeira. Documentámos igualmente a alteração de

vários parâmetros de função diastólica nos doentes, quando comparados com um grupo con-

trolo. No entanto, a prevalência de disfunção diastólica quando se aplicaram os critérios mais

recentes para a definição desta entidade foi significativamente inferior à previamente relatada.

Encontrámos, porém, uma associação entre alguns destes índices de disfunção diastólica e a

volémia, corroborando a sua elevada dependência das condições de carga e tornando-os, assim,

potencialmente pouco adequados para o estudo da função diastólica no contexto da cirrose

hepática. Finalmente não conseguimos encontrar uma associação entre nenhum dos parâme-

tros ecocardiográficos avaliados e o prognóstico a médio prazo. Os únicos marcadores inde-

pendentes de mortalidade aos 6 meses foram a tensão arterial média e a gravidade da doença

hepática avaliada pela classificação de Child-Pugh.

Concluímos assim que os doentes com cirrose hepática exibem sinais de disfunção sistólica

e diastólica, mas que esta parece ser subtil, podendo ser detectável apenas com recurso a mé-

todos de imagiologia cardíaca avançada. Neste sentido a disfunção miocárdica encontrada não

parece ser suficientemente grave para influenciar o prognóstico a médio prazo. A mortalidade

a 6 meses parece ser muito mais influenciada pela gravidade da insuficiência hepática e pelas

alterações hemodinâmicas que lhe estão associadas.

Resumo/Abstract

123

ABSTRACT

Cirrhotic cardiomyopathy has been described as a condition characterized by impaired con-

tractile response to stress, diastolic dysfunction and electrophysiological abnormalities, in the

absence of known cardiac disease. The pathophysiology of this condition is complex and not

fully understood. Experimental evidence of decreased density and down-regulation of beta-

adrenergic receptors as well as hypo-responsiveness of cardiomyocytes to beta-adrenergic

agonists has been found in animal models of cirrhosis. Dysfunction of several ion channels

on the plasma membrane, changes in contractile proteins and extracellular matrix, as well as

excess production of different substances (nitric oxide, pro-inflammatory cytokines or endo-

genous cannabinoids) with vasodilator and pro-apoptotic effect have also been involved. Cir-

rhotic cardiomyopathy seems to be well tolerated and asymptomatic for years and its real pre-

valence is unknown. Splanchnic arterial vasodilatation may unload the left ventricle and mask

the presence of cardiac insufficiency. In fact, conventional indices of systolic function such as

ejection fraction are usually normal in these patients. Hence, although some diagnostic criteria

have been previously proposed, they are controversial and an accepted gold-standard method

to diagnose cirrhotic cardiomyopathy is still lacking. On the other hand, the correlation betwe-

en liver disease severity and the degree of cardiac dysfunction is unclear and the influence of

cardiac abnormalities in cirrhosis natural history is also undetermined.

We aimed to perform a comprehensive analysis of left ventricular function, using advanced

non-invasive imaging modalities, in patients with liver cirrhosis of different aetiologies, in order

to find new markers of cirrhotic cardiomyopathy and to assess their potential prognostic im-

pact. We also aimed to evaluate the correlation between cardiac dysfunction and liver disease

severity.

In our studies, we were able to find evidence of subclinical systolic dysfunction in cirrhotic

patients, mainly due to impairment of left ventricular longitudinal deformation. These abnor-

malities were present both at rest and during pharmacological stress and were irrespective

of liver disease severity. Ejection fraction was normal in the majority of the study sample. We

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Francisco Sampaio

could also find signs of diastolic dysfunction in our patients. However, when the current recom-

mendations for diagnosing diastolic dysfunction were applied, the prevalence of this entity was

lower than previously reported, using a different methodology. We found a correlation betwe-

en some of the parameters classically used to evaluate diastolic function and markers of vola-

emia. These findings support the known influence of loading conditions on those parameters,

suggesting that they may be unsuitable to assess diastolic dysfunction in cirrhosis. Finally, we

did not find an association between any echocardiographic parameters of systolic or diastolic

function and the occurrence of death at 6 months. Child-Pugh score and mean blood pressure

were the only independent predictors of mortality.

From our results, we could conclude that there is evidence of myocardial dysfunction in

cirrhotic patients. However, these abnormalities seem to be subtle and may only be detected

by advanced and sensitive imaging techniques. On the other hand, liver failure severity and

associated hemodynamic changes seem to be more important determinants of medium-term

prognosis than myocardial dysfunction.