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D 2015

Avaliação da Função Diastólicano Continuum Cardiovascular

The Evaluation of Diastolic Function in the Cardiovascular Continuum

RICARDO FONTES-CARVALHO

DISSERTAÇÃO DE CANDIDATURA AO GRAU DE DOUTOR APRESENTADA

À FACULDADE DE MEDICINA DA UNIVERSIDADE DO PORTO

MEDICINA

DISSERTAÇÃO DE CANDIDATURA AO GRAU DE DOUTORAPRESENTADA À FACULDADE MEDICINA DA UNIVERSIDADE DO PORTO

PROGRAMA DOUTORAL EM CIÊNCIAS CARDIOVASCULARES

Avaliação da Função Diastólicano Continuum Cardiovascular

The Evaluation of Diastolic Function in the Cardiovascular Continuum

Orientador: Prof. Doutor Adelino Leite-MoreiraCo-orientadores: Prof. Doutora Ana Azevedo Prof. Doutor Francisco Rocha Gonçalves

Ricardo Fontes-Carvalho

Porto • 2015

Art.º 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)

Constituição do Júri da Prova de Doutoramento

PresidenteDOUTORA MARIA AMÉLIA DUARTE FERREIRA

Diretora da Faculdade de Medicina da Universidade do Porto (por delegação reitoral)

VogaisDOUTOR FAUSTO JOSÉ DA CONCEIÇÃO ALEXANDRE PINTO

Professor Catedrático, Faculdade de Medicina da Universidade de Lisboa

DOUTOR JOAQUIM ADELINO CORREIA FERREIRA LEITE MOREIRA

Professor Catedrático, Faculdade de Medicina da Universidade do Porto

DOUTOR PAULO MIGUEL BETTENCOURT SARDINHA PONTES FERNANDO

Professor Catedrático convidado, Faculdade de Medicina da Universidade do Porto

DOUTOR LINO MANUEL MARTINS GONÇALVES

Professor Associado, Faculdade de Medicina da Universidade de Coimbra

DOUTOR LUÍS FILIPE VILELA PEREIRA DE MACEDO

Professor Associado convidado, Faculdade de Medicina da Universidade do Porto

DOUTOR ANDRÉ PEDRO LEITE MARTINS LOURENÇO

Professor Auxiliar da Faculdade de Medicina da Universidade do Porto

Corpo Catedrático da Faculdade de Medicina da Universidade do Porto

Professores Catedráticos Efectivos

DOUTOR MANUEL ALBERTO COIMBRA SOBRINHO SIMOES

DOUTORA MARIA AMELIA 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 JOSE MANUEL LOPES TEIXEIRA AMARANTE

DOUTOR JOSE 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 ANTONIO CARLOS FREITAS RIBEIRO SARAIVA

DOUTOR JOSE CARLOS NEVES DA CUNHA AREIAS

DOUTOR MANUEL JESUS FALCAO 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 JOSE MANUEL PEREIRA DIAS DE CASTRO LOPES

DOUTOR ANTÓNIO ALBINO COELHO MARQUES ABRANTES TEIXEIRA

DOUTOR JOAQUIM ADELINO CORREIA FERREIRA LEITE MOREIRA

DOUTOR RAQUEL ÂNGELA SILVA SOARES LINO

Professores Jubilados ou Aposentados

DOUTOR ABEL VITORINO TRIGO CABRAL

DOUTOR ALEXANDRE ALBERTO GUERRA SOUSA PINTO

DOUTOR ÁLVARO JERONIMO LEAL MACHADO DE AGUIAR

DOUTOR AMÂNDIO GOMES SAMPAIO TAVARES

DOUTOR ANTONIO AUGUSTO LOPES VAZ

DOUTOR ANTÓNIO CARVALHO ALMEIDA COIMBRA

DOUTOR ANTÓNIO FERNANDES DA FONSECA

DOUTOR ANTÓNIO FERNANDES OLIVEIRA BARBOSA RIBEIRO BRAGA

DOUTOR ANTÓNIO JOSÉ PACHECO PALHA

DOUTOR ANTÓNIO MANUEL SAMPAIO DE ARAÚJO TEIXEIRA

DOUTOR BELMIRO DOS SANTOS PATRICIO

DOUTOR CÂNDIDO ALVES HIPÓLITO REIS

DOUTOR CARLOS RODRIGO MAGALHÃES RAMALHÃO

DOUTOR CASSIANO PENA DE ABREU E LIMA

DOUTOR DANIEL SANTOS PINTO SERRÃO

DOUTOR EDUARDO JORGE CUNHA RODRIGUES PEREIRA

DOUTOR FERNANDO TAVARELA VELOSO

DOUTOR FRANCISCO DE SOUSA LÉ

DOUTOR HENRIQUE JOSÉ FERREIRA GONÇALVES LECOUR DE MENEZES

DOUTOR JORGE MANUEL MERGULHAO CASTRO TAVARES

DOUTOR JOSÉ CARVALHO DE OLIVEIRA

DOUTOR JOSÉ FERNANDO BARROS CASTRO CORREIA

DOUTOR JOSÉ LUÍS MEDINA VIEIRA

DOUTOR JOSÉ MANUEL COSTA MESQUITA GUIMARÃES

DOUTOR LEVI EUGÉNIO RIBEIRO GUERRA

DOUTOR LUÍS ALBERTO MARTINS GOMES DE ALMEIDA

DOUTOR MANUEL ANTÓNIO CALDEIRA PAIS CLEMENTE

DOUTOR MANUEL AUGUSTO CARDOSO DE OLIVEIRA

DOUTOR MANUEL MACHADO RODRIGUES GOMES

DOUTOR MANUEL MARIA PAULA BARBOSA

DOUTORA MARIA DA CONCEIÇÃO FERNANDES MARQUES MAGALHÃES

DOUTORA MARIA ISABEL AMORIM DE AZEVEDO

DOUTOR MÁRIO JOSÉ CERQUEIRA GOMES BRAGA

DOUTOR SERAFIM CORREIA PINTO GUIMARÃES

DOUTOR VALDEMAR MIGUEL BOTELHO DOS SANTOS CARDOSO

DOUTOR WALTER FRIEDRICH ALFRED OSSWALD

FAZEM PARTE INTEGRANTE DESTA DISSERTAÇÃO OS SEGUINTES TRABALHOS:

1. Ricardo Fontes-Carvalho, Alexandra Gonçalves, Milton Severo, Patrícia Lourenço, Francisco Rocha Gonçalves, Paulo

Bettencourt, Adelino Leite-Moreira, Ana Azevedo. Direct, inflammation-mediated and blood-pressure-mediated

effects of total and abdominal adiposity on diastolic function: EPIPorto study. Int J Cardiol 2015, in press.

Journal’s Impact Factor: 6.17

2. Ricardo Fontes-Carvalho, Joana Pimenta, Paulo Bettencourt, Adelino Leite-Moreira, Ana Azevedo. Plasma leptin

and adiponectin levels and diastolic function in the general population: data from the EPIPorto study. Expert

Opin Ther Targets. 2015 Mar 18:1-9.


3. Ricardo Fontes-Carvalho, Marta Fontes-Oliveira, Francisco Sampaio, Jennifer Mancio, Nuno Bettencourt,

Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama, Adelino Leite-Moreira. Influence of Epicardial and

Visceral Fat on Left Ventricular Diastolic and Systolic Function in Patients After Myocardial Infarction. Am J

Cardiol 2014, 114(11): 1663-9.


4. Ricardo Fontes-Carvalho, Ricardo Ladeiras-Lopes, Paulo Bettencourt, Adelino Leite-Moreira, Ana Azevedo.

Diastolic Dysfunction in the Diabetic Continuum: Association with Insulin Resistance, Metabolic Syndrome

and Diabetes. Cardiovasc Diabetol. 2015 Jan 13;14(1):4.


5. Ricardo Fontes-Carvalho, Azevedo A, Leite-Moreira A. The new grade IA of diastolic dysfunction: is it relevant

at the population level? JACC Cardiovasc Imaging. 2015 (2): 229-30.


6. Ricardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama,

Ana Azevedo, Adelino Leite-Moreira. Left Ventricular Diastolic Dysfunction and E/E’ ratio as the Strongest

Echocardiographic Predictors of Reduced Exercise Capacity After Acute Myocardial Infarction. Clin Cardiol.

2015;38(4):222-9.


7. Ricardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama, Ana

Azevedo, Adelino Leite-Moreira. Left atrial deformation analysis by speckle tracking echocardiography to predict

exercise capacity after myocardial infarction. [Under review, J Am Soc Echocardiog 2015].

8. Ricardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Vasco Gama, Adelino Leite-Moreira. The role

of a structured exercise-training program on cardiac structure and function after acute myocardial infarction:

study protocol for a randomized controlled trial. Trials. 2015 Mar 12;16(1):90.


9. Ricardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama, Ana

Azevedo, Adelino Leite-Moreira. The effect of exercise training on diastolic and systolic function after acute

myocardial infarction: a randomized study. [Under Review, Medicine 2015].

À Luísa

À Inês e ao Pedro

À minha Família

Aos meus “Mestres”, na Vida e na Medicina

Agradecimentos/ Acknowledgements

A elaboração desta tese de doutoramento constituiu um esforço de superação pessoal. Mais do que

um projeto individual, só foi possível com um amplo trabalho de equipa, a nível profissional e familiar.

De entre tantos que contribuíram, directa e indirectamente, cumpre-me manifestar especial

agradecimento:

Ao Prof. Adelino Leite-Moreira pelo seu constante incentivo, disponibilidade e exemplo de competência

científica e humanismo. Agradeço-lhe o apoio e autonomia que me deu ao longo destes anos e o voto de

confiança quando, ainda enquanto aluno, me aceitou no Serviço de Fisiologia da Faculdade de Medicina

do Porto. Recordo hoje esse momento como o primeiro pequeno passo desta longa viagem até à conclusão

desta tese. Entre tantas outras coisas, com ele aprendi as mais-valias que a compreensão da investigação

dita “básica” e de translação traz todos os dias à melhoria da minha prática clínica diária.

À Prof. Ana Azevedo por toda a sua disponibilidade e ajuda, essenciais à realização dos trabalhos desta

tese. Agradeço-lhe o grande enriquecimento pessoal trazido pelas estimulantes discussões científicas, pela

análise rigorosa das questões e pela revisão crítica, e esclarecida, de todos os trabalhos. A sua exigência

obrigou-me a um esforço contínuo de superação pessoal.

Ao Prof. Rocha Gonçalves pelo contínuo apoio e estímulo na persecução dos trabalhos. Agradeço

ainda as sempre estimulantes conversas e reflexões sobre a Vida e a Cardiologia.

Ao Dr. Vasco Gama Ribeiro pela sua incansável força, dinamismo, visão e determinação. Em poucos

anos construiu, à sua imagem, um serviço de Cardiologia que é uma referência a nível nacional e europeu.

Nele aprendi, e cresci, enquanto Homem, médico e cardiologista!

Ao Serviço de Cardiologia do Centro Hospitalar de Gaia. Dos colegas médicos, aos enfermeiros, aos

técnicos e aos auxiliares. A todos eles devo muito do que sou, e consegui, até hoje! À Dra. Madalena

Teixeira, pela ajuda na realização dos trabalhos clínicos. Ao Dr. Lino Simões pela sua amizade, pelas

estimulantes discussões sobre a Cardiologia, a vida, a política e a cultura, e pelo seu exemplo pessoal

de dedicação ao doente e à prática clinica. Ao Dr. Aníbal Albuquerque pelo exemplo de integridade, mas

sobretudo pela sua amizade e pelo contínuo apoio e palavras estímulo à execução dos trabalhos. Ao Dr.

Pedro Braga, meu orientador durante o internato de Cardiologia, tendo contribuído para fazer de mim

um melhor cardiologista. Um agradecimento especial a todo o sector da Ecocardiografia. Ao Dr. José

Ribeiro pela sua confiança, espírito de equipa e por me ter ensinado e incutido a paixão pelos desafios

da ecocardiografia. À Dra. Conceição Fonseca pela permanente energia, disponibilidade e dedicação

ao doente. Um agradecimento particular ao Dr. Francisco Sampaio – un compagnon de route – pelas

discussões científicas, pela partilha de ideias e pela sua imprescindível participação nos estudos clínicos

A todos os colegas do Serviço de Fisiologia da Faculdade de Medicina do Porto pela partilha de

conhecimentos e pela valiosa introdução ao raciocínio e método científico. Entre eles uma palavra

particular ao Prof. Paulo Chaves que me introduziu ao trabalho laboratorial e me motivou o gosto pela

ciência básica.

Aos doentes, que são a razão final desta tese! Um agradecimento especial àqueles que aceitaram

participar nos estudos clínicos.

Agradeço a todos os meus “Mestres” (muitos deles já aqui citados) que na Vida, na Medicina, na

Cardiologia e na Investigação – frequentemente de forma simultânea – contribuíram para o meu

crescimento. Sempre os recordarei e para sempre lhes estarei grato!

• • •

Deixo propositadamente para o fim, a mais importante das reflexões e o mais forte dos meus

agradecimentos. Merecem-nos a minha Família!

Agradeço-te a ti, Luísa, por tudo! Mas também por todo o teu carinho, amor, amizade e incansável

compreensão.

À Inês e ao Pedro, por terem dado um novo significado à Vida. E pela alegria que me trazem todos os

dias.

Aos meus pais. Por sempre me terem orientado para “o rumo certo” da vida. A eles devo tudo o que

sou! Espero agora saber usar os vossos sábios conselhos, mas sobretudo o vosso exemplo, para guiar os

meus filhos.

Aos meus irmãos, Ni e João. Por toda a amizade, apoio incondicional e sentimento de partilha.

Ao meu avô, Augusto. Uma fonte de inspiração. Pelo seu exemplo de vida, de inteligência e de

determinação. Tenho a certeza que gostarias de estar aqui hoje!

13

Table of Contents

ABSTRACT | RESUMO 17

CHAPTER I | INTRODUCTION 27

1. The Cardiac Cycle: Focus on Diastole 29

2. Diastolic Dysfunction Across the Cardiovascular Continuum 30

3. The Impact of Diastolic Dysfunction: Prognostic Implications 31

3.1. Diastolic Dysfunction and Heart Failure Risk 31

3.2. Diastolic Dysfunction in the Pathophysiology of Heart Failure with Preserved Ejection Fraction (HFpEF) 32

3.3. The Impact of Diastolic Function on Exercise Capacity and Quality of Life 32

4. The Evaluation of Left Ventricular Diastolic Function 34

5. The Determinants of Diastolic Dysfunction: What is Known and What is Unknown 36

5.1. Established Determinants of Diastolic Dysfunction 36

5.2. Obesity as a New Determinant of Diastolic Dysfunction: Understanding “Obesity Cardiomyopathy” 36

5.3. Diastolic Function in the Diabetic Continuum: the Role of Insulin Resistance, Metabolic Syndrome and Diabetes on Diastolic Dysfunction 38

6. Review Article: “Heart Failure with Preserved Ejection Fraction: Fighting Misconceptions for a New Approach” 39

7. Review Article: “The Pathophysiology of Heart Failure Preserved Ejection Fraction and Its Therapeutic Implications” 49

CHAPTER II | PURPOSE 69

CHAPTER III | RESULTS/ PUBLICATIONS 73

A) Determinants of Diastolic Dysfunction 77

B) The Evaluation of Diastolic Dysfunction 115

C) The Impact of Diastolic Function on Exercise Capacity 127

D) Modulation of Diastolic Function by Exercise Training 145

CHAPTER IV | DISCUSSION 167

CHAPTER V | CONCLUSIONS 175

CHAPTER VI | BIBLIOGRAPHY 179

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Foreword

This thesis is organized in six main chapters.

Chapter 1 includes a general introduction to the knowns and unknowns of diastolic function across

the several stages of the cardiovascular continuum including the determinants, methods of evaluation and

prognostic implications. The role of diastolic dysfunction as an early step in the progression to heart failure

is also discussed, particularly in the progression to heart failure with preserved ejection (HFpEF). Also, to

provide a more detailed overview on the importance of diastolic dysfunction in the pathophysiology of

HFpEF, two review articles were included at the end of this chapter.

Chapter 2 defines the main objectives of the thesis, which are schematized in the figure provided in

this chapter.

Chapter 3 describes the results, which are shown in the form of several published or submitted articles.

These manuscripts have been grouped into four sub-chapters: A) determinants of diastolic dysfunction;

B) the evaluation of diastolic dysfunction; C) the impact of diastolic function on exercise capacity; D) the

modulation of diastolic function by exercise training.

Chapter 4 provides a global overview and discussion of the major findings, how do they integrate with

previously published studies, possible implications to clinical practice and future areas of research.

The conclusions are presented in chapter 5.

Finally, chapter 6 depicts the references that were used in the introduction and discussion sections of

this thesis.

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ResumoAbstract

RESUMO | ABSTRACT

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Introdução

A disfunção diastólica (DD) do ventrículo esquerdo é frequente nas várias fases do continuum

cardiovascular, atingindo cerca de 20% da população em geral. Apesar de ser muitas vezes assintomática, a

DD é um importante preditor de prognóstico e do risco de progressão para insuficiência cardíaca. Por outro

lado, nos doentes no outro extremo do continuum cardiovascular, a DD é o principal mecanismo envolvido na

fisiopatologia da insuficiência cardíaca com fração de ejecção preservada (ICFEP), também conhecida como

insuficiência cardíaca diastólica. Assim sendo, a identificação – e correção – dos principais determinantes de

DD pode ser um importante passo para prevenir a progressão para insuficiência cardíaca. Esta abordagem

preventiva poderá ser particularmente relevante na ICFEP uma vez que, até hoje, nenhuma terapêutica ou

intervenção mostrou uma melhoria significativa do prognóstico destes doentes.

O estudo da função diastólica nas várias fases do continuum cardiovascular é importante por múltiplas

outras razões. Além do seu impacto prognóstico, desconhece-se o seu papel como determinante da capacidade

funcional dos doentes, sobretudo após o enfarte do miocárdio. A própria avaliação ecocardiográfica da função

diastólica é complexa, sobretudo a categorização em graus de DD. Ainda recentemente foi descrito um novo

grau de DD, designado grau IA, cuja prevalência e caracterização clínica são desconhecidas na população em

geral. Por outro lado, sabe-se que os volumes e função da aurícula esquerda são interdependentes da função

diastólica do ventrículo esquerdo e, portanto, as novas técnicas ecocardiográficas de avaliação da função

auricular esquerda por speckle tracking poderão ajudar na compreensão e na análise detalhada da função

diastólica. Finalmente, estudos recentes realizados em doentes com ICFEP mostraram que o exercício físico

poderá ser uma nova intervenção terapêutica capaz de melhorar a função diastólica, não estando ainda

validada em outros grupos de doentes.

Objectivos

Neste projeto pretendemos avaliar a importância da avaliação da função diastólica em várias fases do

continuum cardiovascular, identificando e analisando os seus determinantes, o papel dos novos métodos

de avaliação ecocardiográfica, o seu impacto na capacidade funcional e uma eventual modulação por um

programa estruturado de treino de exercício.

Foram objectivos específicos destes trabalhos: i) avaliar o papel da obesidade, e do padrão de

distribuição de gordura, como determinante da função diastólica, assim como os principais mecanismos

fisiopatológicos envolvidos nesta associação; ii) avaliar se o tecido adiposo epicárdico pode influenciar

diretamente a função diastólica por um efeito local/parácrino; iii) determinar se a secreção de adipocinas

(leptina e adiponectina) pode estar envolvida na associação entre a obesidade e a função diastólica; iv)

avaliar o papel da insulinorresistência, da síndrome metabólica e da diabetes como eventuais novos

determinantes de DD; v) avaliar, na população em geral, a prevalência e características clínicas dos

doentes com o novo grau IA de DD; vi) avaliar o impacto da função diastólica como determinante da

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RESUMO | ABSTRACT

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capacidade funcional em doentes após enfarte do miocárdio; vii) analisar a relação entre os volumes e

a função da aurícula esquerda com a função diastólica, assim como o seu papel enquanto preditor da

capacidade funcional; viii) avaliar se um programa estruturado de treino de exercício pode melhorar a

função diastólica num grupo de doentes após enfarte do miocárdio.

População e Métodos

Para avaliar os determinantes de disfunção diastólica foi analisado um grupo de 1063 indivíduos

provenientes de uma coorte da população em geral (estudo EPIPorto), sem doença cardiovascular

conhecida. Todos os doentes foram avaliados através da colheita de história clinica, exame físico, avaliação

antropométrica (incluindo avaliação da massa gorda por bioimpedâcia), estudo analítico (incluindo

doseamento da insulina, HOMA-IR score, leptina e adiponectina) e ecocardiografia transtorácica, com

avaliação detalhada da função diastólica.

Foi ainda analisado, de forma prospectiva, um outro grupo de 225 doentes um mês após enfarte

do miocárdio. Todos os doentes foram submetidos, no mesmo dia, a avaliação clínica, antropométrica

e ecocardiográfica (incluindo a análise dos volumes e função da aurícula esquerda por speckle tracking,

num subgrupo destes doentes), assim como a prova cardiopulmonar (para determinação do consumo

de oxigénio: VO2) e tomografia computorizada de 64 cortes (para determinação das áreas de gordura

abdominal total, subcutânea e visceral e do volume de gordura epicárdica).

Deste grupo de doentes após enfarte do miocárdio, 188 foram randomizados (1:1) para um programa

supervisionado de 8 semanas de treino de exercício (combinando treino aeróbio e de resistência) versus

tratamento convencional. No início e no fim do estudo, estes doentes foram submetidos a avaliação

seriada da função diastólica por ecocardiografia e da capacidade de exercício por prova cardiopulmonar.

Em todos os estudos a função diastólica foi avaliada de acordo com as últimas recomendações de

consenso para a avaliação da função diastólica que incluem a determinação da velocidade E’ e da relação

E/E’ do Doppler tecidular e a categorização em graus de disfunção diastólica.

Principais Resultados e Discussão

O aumento da adiposidade, principalmente da gordura visceral, revelou-se um determinante

independente da função diastólica. A associação entre a adiposidade e a DD parece ser mediada

parcialmente por um efeito endócrino, envolvendo a secreção de adipocinas, já que que o aumento dos

níveis de leptina – mas não de adiponectina – se associou de forma independente à presença de DD. Além

disso, observamos que o aumento do volume de gordura epicárdica pode também modular a função

diastólica, por um efeito local/parácrino. Estes dados permitem uma compreensão dos mecanismos

envolvidos na “cardiopatia da obesidade” e reforçam a importância da associação entre a obesidade, a

RESUMO | ABSTRACT

21

disfunção diastólica e o aumento do risco de insuficiência cardíaca, observado nos indivíduos obesos.

A função diastólica está também associada ao grau de insulinorresistência e à síndrome metabólica

e não a um efeito “glicotóxico” induzido pela hiperglicemia. Observamos ainda que surgem alterações

subclínicas da função diastólica logo em fases precoces do continuum diabético, ainda antes do

aparecimento de diabetes.

Contrariamente a anteriores descrições, verificamos que na população em geral a prevalência do novo

grau IA de DD é baixa. Deste modo, em futuros estudos, será necessário reavaliar o papel de prognóstico

deste novo grau de disfunção diastólica e a sua utilidade clínica.

Os parâmetros de função diastólica, sobretudo a relação E/E’ septal (derivada da análise do Doppler

tecidular), foram os principais determinantes ecocardiográficos de diminuição da capacidade funcional

após enfarte do miocárdio. Além disso, observamos que os volumes da aurícula esquerda, a sua função

de reservatório e o strain longitudinal (avaliados por speckle tracking) foram também determinantes

da capacidade de exercício, devido à interdependência entre a função diastólica e a função auricular

esquerda.

Finalmente, num estudo prospectivo, randomizado, realizado em doentes um mês após enfarte do

miocárdio, verificou-se que um programa de treino de exercício de 8 semanas, combinando treino aeróbio

e de resistência, não melhorou significativamente a função diastólica.

Conclusões

A disfunção diastólica tem uma prevalência crescente ao longo do continuum cardiovascular. Os

seus principais determinantes são a idade, a hipertensão arterial e a doença coronária, mas também a

obesidade e a insulinorresistência. Estas observações reforçam a visão da disfunção diastólica como uma

doença com um componente cardiometabólico.

Atendendo à crescente epidemia de obesidade, a compreensão dos mecanismos envolvidos na

cardiopatia da obesidade poderá ser clinicamente útil para a prevenção do expectável aumento da

incidência de insuficiência cardíaca nos obesos. No futuro será necessário avaliar se intervenções como

a perda de peso (pela dieta, exercício e/ou cirurgia bariátrica), a toma de insulino-sensibilizadores (como

a metformina) ou a administração de inibidores da leptina pode melhorar a função diastólica e prevenir

a progressão para insuficiência cardíaca. Atualmente, estamos a realizar um ensaio clínico de fase II que

avaliará se a administração precoce de metformina em doentes com síndrome metabólico pode melhorar

a função diastólica.

A análise da função diastólica fornece ao clínico informação adicional que tem impacto prognóstico e

funcional. Deste modo, a avaliação da função diastólica, através do cálculo da relação E/E’ e da categorização

em graus de função diastólica, deve fazer parte integrante do exame ecocardiográfico de rotina.

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RESUMO | ABSTRACT

22

Apesar de nos doentes após enfarte do miocárdio o treino de exercício não ter melhorado

significativamente a função diastólica, é expectável que programas de exercício físico sustentado possam

melhorar a estrutura e função do miocárdio, sobretudo se aplicados em fases mais precoces do continuum

cardiovascular.

• • •

RESUMO | ABSTRACT

23

Introduction

Left ventricle diastolic dysfunction (LVDD) is common in the cardiovascular continuum. It affects

about 20% of the adult population. Although frequently associated with a subclinical course, LVDD is an

important predictor of heart failure and of long-term mortality. Moreover, in patients at the other end of

the cardiovascular continuum, LVDD is the key mechanism involved in the pathophysiology of heart failure

preserved ejection fraction (HFpEF), also known as diastolic heart failure. Therefore, the identification and

correction of the main determinants of diastolic function can be of paramount importance to stop the

progression to overt heart failure. This can be especially relevant for the management of HFpEF, a disease

where no therapy or intervention has significantly improved the prognosis.

Several other unmeet needs involve the study of diastolic function in the cardiovascular continuum.

Beyond its prognostic role, the impact of LVDD on exercise capacity is not known, especially after myocardial

infarction. Moreover, the echocardiographic evaluation of diastolic function is frequently challenging,

especially the categorization diastolic function grades. Very recently, a new grade of diastolic dysfunction

– grade IA – has been described, but its prevalence and clinical characterization in the general population

are unknown. Because LV diastolic function and left atrium (LA) function are interdependent events, the

evaluation of the LA by speckle tracking can be a promising new technique giving further insight into

the comprehension of diastolic function. Finally, new therapeutic targets are needed to improve diastolic

function. Recent preliminary studies, performed in selected patients with HFpEF, have shown that a

structured program of exercise training can improve diastolic function.

Purpose

In this project we aimed to evaluate the role of left ventricular diastolic function in several phases of

the cardiovascular continuum, assessing its determinants, new methods of echocardiographic evaluation,

its impact on exercise capacity and the possible modulation by exercise training.

Specific aims were: i) to evaluate the role of obesity, and adipose tissue distribution, on diastolic

function and the underlying mechanisms (direct and indirect) involved in this association; ii) to detail if

epicardial adipose tissue can influence diastolic function by a local/paracrine mechanism; iii) to determine

if the secretion of adipokines (leptin and adiponectin), can be involved in the association between adiposity

and diastolic dysfunction; iv) to evaluate the contribution of insulin resistance, metabolic syndrome

and diabetes as novel determinants of diastolic function; v) to evaluate in the general population, the

prevalence and clinical characteristics of the new echocardiographic grade IA of diastolic dysfunction; vi)

to determine the impact of diastolic function as a predictor of reduced exercise capacity after myocardial

infarction; vii) to evaluate the relation between LA volumes and LA function with LV diastolic function

(the atrium-ventricular coupling) and its role as predictor of exercise performance; viii) to evaluate if a

structured exercise training program can improve diastolic function in patients after myocardial infarction.

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RESUMO | ABSTRACT

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Populations and Methods

To evaluate the determinants of diastolic dysfunction we evaluated a group of 1063 individuals from

the general population, without known cardiovascular disease, from the EPIPorto cohort study. All patients

had detailed data about clinical history, physical examination, anthropometric evaluation, fasting blood

sample (including insulin, leptin, adiponectin) and echocardiography.

For the evaluation of the impact of diastolic function on functional capacity, and its modulation by

exercise training, we prospectively enrolled another group of 225 patients after myocardial infarction. All

patients were submitted, on the same day, to clinical evaluation, detailed echocardiography (including the

evaluation of left atrium strain by speckle tracking analysis in a subgroup of patients), cardiopulmonary

exercise test (for determination of peak O2 consumption) and CT scan (for the evaluation of total,

subcutaneous and visceral abdominal fat area and epicardial fat volume). From this group, 188 patients

were prospectively randomized (1:1) to an 8-week supervised program of endurance and resistance

exercise training versus standard of care, with serial evaluation (at the beginning and at the end of the

study) of diastolic function by echocardiography and of exercise capacity by cardiopulmonary exercise test.

In all studies diastolic function was assessed according to the latest consensus guidelines on diastolic

function evaluation, including the determination of E’ velocity and E/E’ ratio by tissue Doppler analysis,

and the categorization in diastolic dysfunction grades.

Main Results and Discussion

First, we observed that increased adiposity parameters were independent determinants of subclinical

diastolic function, reinforcing the role of “obesity cardiomyopathy” in the link between obesity, diastolic

dysfunction and the increased risk of heart failure observed in the obese. The association was especially

relevant for visceral, rather than subcutaneous fat. We observed that an endocrine effect, through the

secretion of adipokines, could be involved, because higher leptin levels – but not of adiponectin – were

independently associated with diastolic dysfunction. Moreover, increased epicardial fat volume was

independently associated with impaired diastolic function, suggesting that a local or paracrine effect can

also play a role in this association.

Secondly, we observed that subclinical changes in left ventricular diastolic function were already

present in an early phase of glucose disturbance metabolism, even before the onset of diabetes. These

changes were mainly associated with the state of insulin resistance, and not to a “glucotoxic” effect caused

by hyperglycemia. Metabolic syndrome was also independently associated with LVDD.

Contrary to what has been previously described, in the general population we observed that the new

grade IA of diastolic dysfunction was infrequent. Future studies will evaluate if the determination of this

new grade can be clinically useful in an unselected population without cardiovascular disease.

RESUMO | ABSTRACT

25

Beyond its prognostic impact, we have now shown that resting diastolic function parameters,

especially the septal E/E’ ratio, were important determinants of reduced exercise capacity after myocardial

infarction. Moreover, the evaluation of the left atrium by speckle tracking showed that LA size, function

and strain parameters were interdependent with left ventricular diastolic function. Therefore, we found

that increased LA volumes can be used as markers of reduced functional capacity, which was associated

mainly with a decrease in the LA conduit function, but not with the LA contractile function.

Finally, in a prospective, randomized, controlled study including patients after myocardial infarction we

did not observe a significant improvement in diastolic function parameters, after an eight-week exercise-

training program.

Conclusions

Diastolic dysfunction has an increasing prevalence across the cardiovascular continuum. It is determined

by ageing, hypertension and coronary artery disease, but also by new determinants such as (visceral)

obesity and insulin resistance, reinforcing the view of diastolic dysfunction as a cardiometabolic disease.

Given the growing obesity epidemic worldwide, and the increased risk of heart failure in the obese,

this research provided important clinical insights to the comprehension of “obesity cardiomyopathy”.

Future trials will determine if new therapeutic interventions, such as weight loss (by diet, exercise and/

or bariatric surgery) and insulin sensitizers (such as metformin), can improve diastolic function and

prevent the progression to heart failure. We are now conducting a phase II clinical trial to determine if the

administration of metformin in individuals with metabolic syndrome can improve diastolic function.

The evaluation of diastolic function provides important functional and prognostic information to the

clinician. Therefore, the evaluation of diastolic function – using standard and new techniques, such as

strain analysis by speckle tracking – should be an integral part of a routine echocardiography examination.

The search for new interventions that can improve diastolic function will continue. Although after

myocardial infarction, exercise training failed to enhance diastolic function, it is plausible that long-

term exercise can improve cardiac structure and function, especially if applied in earlier phases of the

cardiovascular continuum.

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“Science may set limits to knowledge, but should not set limits to imagination”

Bertrand Russell (1872-1970)

Introduction

29

CHAPTER I | INTRODUCTION

1. THE CARDIAC CYCLE: FOCUS ON DIASTOLE

“The atria or filling chambers contract together, while the pumping chambers or ventricles are relaxing and vice versa”

Leonardo da Vinci (1452-1519)

From perhaps the first description of diastole by Leonardo da Vinci, to the most modern techniques,

indexes, and innovative imaging tools of evaluation, our understanding of left ventricular diastolic function

continues to advance. However, over many years, the evaluation of diastolic function was neglected by the

scientific and clinical community, in part due to the difficulties in the non-invasive evaluation of diastolic

function. With the new cardiac imaging technologies, a renewed interest in diastole has emerged, and this

decade can be considered the “decade of diastology” (1).

The optimal performance of the left ventricle depends on its ability to cycle between two states: a

compliant chamber in diastole, that allows the left ventricle to relax and fill at low left atrial pressures,

and a stiff chamber (rapidly rising pressure) in systole that ejects the stroke volume at arterial pressures

(2) (3). Furthermore, in response to exercise, the stroke volume must increase without a significant raise

in left atrial pressures. Therefore, left ventricular diastolic dysfunction (LVDD) can be caused by impaired

myocardial relaxation and/or increased ventricular stiffness, regardless of whether the systolic function is

normal or depressed, and whether the patient is asymptomatic or symptomatic (2) (4) (5).

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2. DIASTOLIC DYSFUNCTION ACROSS THE CARDIOVASCULAR CONTINUUM

In 1991, a panel of experts representing the full spectrum of cardiovascular disease generated an

hypothesis that framed cardiovascular disease as a chain of events that were initiated by several related

and unrelated risk factors, and progressing through several pathophysiological pathways and processes

until the development of end-stage heart disease (6), as detailed in figure 1. More importantly, this model

acknowledged that a therapeutic intervention anywhere along this chain of events could disrupt the

pathophysiological process and therefore, confer “cardioprotection” and prevent end-stage cardiovascular

disease (7).

In the meantime, the concept of the cardiovascular continuum has been validated in several critical

studies at both the mechanistic and clinical level (7) (8). It is now known that the events leading to disease

progression overlap and intertwine, and do not always occur as a sequence of discrete, tandem incidents.

Although the original concept focused on the traditional risk factors, and the consequences of coronary

artery disease, during the last years the concept of cardiovascular continuum has expanded to include other

areas such as heart failure, cerebrovascular disease, peripheral vascular disease, and renal disease (7).

Figure 1. The modern concept of the cardiovascular continuum.HFpEF: Heart Failure Preserved Ejection Fraction; HFrEF: Heart Failure reduced ejection fraction.

Adapted from Dzau et al, Circulation. 2006 (7)

In this project we aimed to evaluate the role of diastolic function in individuals and patients in different

steps of the cardiovascular continuum. LVDD is frequent, showing increasing prevalence throughout the

cardiovascular continuum. In the community, subclinical LVDD affects between 20-30 % of the general

population (9) (10) (11) (12), depending on the criteria used for its definition and the general characteristics

of the studied population.

In several phases of the cardiovascular continuum, the evaluation of diastolic function is also clinically

relevant providing significant prognostic information. Even in asymptomatic individuals, subclinical diastolic

dysfunction is a marker of cardiac remodeling. It is considered an intermediate step in the cardiovascular

continuum, being associated with the progression to heart failure and adverse outcomes (13). Also, in

latter phases of the cardiovascular continuum (such as in patients after myocardial infarction or with heart

failure) diastolic dysfunction is an important prognostic marker (1) (14).

31

3. THE IMPACT OF DIASTOLIC DYSFUNCTION: PROGNOSTIC IMPLICATIONS

3.1. Diastolic Dysfunction and Heart Failure Risk

In heart failure (HF) progression, alterations in myocardial structure and function appear before the

onset of symptoms, a process known as myocardial remodeling (15). Heart failure guidelines define the

classification according to the ACCF/AHA stages of heart failure (Stages A, B C and D), recognizing that both

risk factors and abnormalities of cardiac structure and function are associated with the onset of clinical

heart failure (16) (17). These stages are progressive and inviolate, and once a patient moves to a higher

stage, regression to an earlier stage of heart failure is not possible.

Prospective studies have shown that asymptomatic diastolic dysfunction is associated with the

development of symptomatic heart failure and increased long-term mortality (9) (18) (19). Therefore, an

individual with diastolic dysfunction, but without symptoms of heart failure, is classified has having a stage

B in the ACCF/AHA classification of heart failure (20), as shown in figure 2.

Figure 2. Risk factors for subclinical diastolic dysfunction and mechanisms involved in the progression

from subclinical diastolic dysfunction to HFpEF.

Several risk factors can contribute to the development of subclinical diastolic dysfunction (stage B Heart Failure). At a latter stage, other cardiac and extra-cardiac mechanisms are responsible for the progression from subclinical diastolic dysfunction to clinical heart failure (stages C and D).

It is known that the survival decreases significantly once symptoms appear (stages C and D of heart failure) but the duration and survival of stages A and B is not well established.


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3. The Impact of Diastolic Dysfunction: prognostic implications

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3.2. Diastolic Dysfunction in the Pathophysiology of Heart Failure with Preserved Ejection Fraction (HFpEF)

Heart failure with Preserved Ejection Fraction (HFpEF), also known as diastolic heart failure,

accounts for approximately 50% of heart failure patients (21) (22), but its prevalence is increasing (21).

LVDD is present in nearly all of HFpEF patients (23) (24) and, therefore, current consensus guidelines

recommend that evidence of abnormal LV diastolic function is required for the diagnosis of HFpEF (17)

(25). Nevertheless, the pathophysiology of HFpEF is complex, and involves several other cardiac and non-

cardiac factors, including loss of chronotropic reserve, ventriculo-vascular coupling mismatch, changes in

systemic and pulmonary vascular function, impaired left atrium function, water and sodium retention and

numerous comorbidities (2) (26) (27), as summarized in figure 2. Furthermore, most patients with heart

failure, irrespective of ejection fraction, have abnormalities in both systolic and diastolic dysfunction (3).

For a more detailed overview on the role of diastolic dysfunction in the pathophysiology of heart

failure with preserved ejection, two review articles were included at the end of this first chapter (4) (26).

3.3. The Impact of Diastolic Function on Exercise Capacity and Quality of Life

Beyond its prognostic impact and association with adverse clinical outcome, LVDD is also associated

with impaired quality of life (11), probably due to reduced exercise capacity. The evaluation of the main

determinants of reduced exercise capacity is complex because it is caused by simultaneous changes in

both cardiac and non-cardiac factors. Nevertheless, several studies have shown a poor relation between

exercise capacity and systolic function, especially when assessed by ejection fraction (28). On the contrary,

in small and selected groups of patients, LVDD was an important and independent determinant of reduced

exercise capacity, namely in patients with systolic heart failure (29-31), heart failure preserved ejection

fraction (32) and in patients referred for exercise echocardiography (28).

Several pathophysiological mechanisms can explain the association between worse diastolic function

and reduced exercise performance. In patients with LVDD, impaired relaxation and increased filling

pressures cause a reduction in left ventricular filling, thus decreasing the stroke volume response to

exercise (2). Moreover, increased end-diastolic pressure leads to increased pulmonary capillary wedge

pressure, which negatively affects the gas-exchange response during exercise and causes the sensation of

exertion dyspnea (33).

After myocardial infarction, exercise capacity is an important predictor of cardiovascular outcomes,

decreased quality of life and disability (33) (34). However, in these patients, the information on the

relative contribution of diastolic and systolic function as predictors of reduced functional capacity is

sparse, especially using modern echocardiographic parameters. Therefore, in this project we also aimed

to evaluate the impact of diastolic function as a predictor of reduced functional capacity after myocardial

infarction.


3. The Impact of Diastolic Dysfunction: prognostic implications

33

Recent studies have shown that exercise training can be a new intervention to improve diastolic

function. In selected groups of patients with HFpEF the combination of endurance and resistance training

significantly enhanced diastolic function and improved exercise capacity and quality of life (32). Thus, we

aimed to evaluate whether a structured program of exercise training could improve diastolic function in

patients after myocardial infarction.

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4. THE EVALUATION OF LEFT VENTRICULAR DIASTOLIC FUNCTION

The evaluation of diastolic function can be complex and challenging. It involves the characterization of

myocardial relaxation, of ventricular stiffness and of pressure changes during diastole. All these events can

be measured invasively using several hemodynamic parameters(2). However, in routine clinical practice

the assessment of diastolic function should be made non-invasively by echocardiography.

In the last two decades, the echocardiographic evaluation of diastolic function has been difficult due to

lack of consensus on the echocardiographic definition of LVDD (35) and to the limitations of the traditional

echocardiographic parameters, especially those derived from mitral inflow velocities analysis(3). More

recently, new echocardiographic techniques for the evaluation of diastolic function have appeared and the

European Association of Echocardiography and the American Society of Echocardiography published new

consensus recommendations for left ventricular diastolic function assessment(3). This document strongly

advise the systematic use of tissue Doppler-derived early mitral annulus velocity (E’ wave) and E/E’ ratio

(ratio between the E wave velocity of the diastolic mitral inflow and the E’ velocity of tissue Doppler) for

the evaluation of diastolic function. It is known that the E’ velocity is a preload-independent index of LV

relaxation (36) (37), whereas the E/E’ ratio can be used to estimate increased left ventricle filling pressures

(3) (38) (39).

Moreover, using an integrated analysis of E’ velocities with other echocardiographic parameters of

diastolic function evaluation (such as E/A ratio, E-wave deceleration time, pulmonary flow analysis and left

atrium volume), patients can be categorized in 4 grades of diastolic dysfunction: 1) normal diastolic function;

2) grade I or mild LVDD; 3) grade II or moderate LVDD and 4) grade III or severe LVDD(3). Recently, a new

grade of LVDD has been proposed – grade IA – which is an intermediate step between grades I and II of LVDD,

and has been proposed to be associated with increased risk of cardiovascular events (40). In this study, the

new grade IA of diastolic dysfunction was frequent, affecting almost 18% of a selected population of patients

from a tertiary center showing a high prevalence of cardiovascular disease and cancer. Until now, no further

information is available regarding the prevalence and clinical characteristics of this new grade of diastolic

dysfunction in the general population, a gap that we tried to evaluate in this project.

Another approach for the evaluation of left ventricular diastolic function can be the assessment of

left atrium (LA) volumes and function. Several studies have shown a significant correlation between LA

remodeling and LVDD(41). Indeed, it is stated that, whereas Doppler velocities and time measurements

reflect diastolic properties at the time of measurement, LA volumes can be considered “chronic markers”

of diastolic dysfunction and of long-term increased filling pressures (3) (35) (41).

Left atrium function encompasses 3 phases – reservoir, conduit and active contraction phases – that

can actively modulate left ventricular function, especially diastolic function (42). Therefore, the interaction

between the LA and the LV, also known as the atrium-ventricular coupling, can directly influence global

cardiac function, cardiac output and exercise capacity (43). There is a growing interest in studying the role of


4. The Evaluation of left Ventricular Diastolic Function

35

LA volumes and several indexes of LA function – especially using novel speckle tracking echocardiographic

analysis (44) (45) – as markers of diastolic dysfunction and determinants of exercise capacity. Two-

dimensional speckle tracking is a new echocardiographic tool that tracks the speckle pattern, frame by

frame, to calculate strain and strain rate. Strain represents myocardial deformation, whereas strain rate

represents the speed at which myocardial deformation occurs(46). Figure 3 illustrates the variation of LA

volumes and longitudinal strain curves across the cardiac cycle and gives an overlook of the three phases

of LA function.

Figure 3. The evaluation of left atrium function, volumes and longitudinal strain by speckle tracking analysis.

The left atrium plays an important role in the regulation of global cardiac function. It acts as a reservoir during systole, as a conduit during early diastole and as an active blood pump during late diastole.

The yellow line shows the variation of LA volumes across the cardiac cycle. The black line depicts the curve of LA longitudinal strain, showing the peak longitudinal atrial strain (PLAS) and the peak atrial contraction strain (PACS)

In the future, the evaluation of diastolic function will continue to evolve with the introduction of new

echocardiographic techniques, such as the evaluation of LV twist and torsion (3), 3D myocardial strain

(47) and left atrium analysis (48). Diastolic function can also be evaluated by cardiac magnetic resonance

using volumetric filling curves analysis, phase-contrast imaging, tagging and strain-encoded imaging (49).

A new promising technique is the use of post-contrast T1 mapping, which is a marker of diffuse myocardial

fibrosis showing a good correlation with LV stiffness (50).

A complete review on the different methods for the evaluation of diastolic function is beyond the

scope of this document. However, at the end of this chapter, one of the review articles provides additional

information on the advantages and limitations of the different echocardiographic parameters for the

evaluation of diastolic function (26)

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5. THE DETERMINANTS OF DIASTOLIC DYSFUNCTION: WHAT IS KNOWN AND WHAT IS UNKNOWN

The early identification and correction of the main determinants of subclinical diastolic dysfunction

can be important to reduce the risk of progression to overt heart failure (16) (20). This can be especially

important for the prevention of HFpEF, a disease where no therapy or intervention has shown to

significantly change the prognosis(51).

5.1. Established Determinants of Diastolic Dysfunction

Aging, hypertension and coronary artery disease are well-known determinants of left ventricular

diastolic function(9) (10) (11) (12) (52). The major determinant of LVDD is age(13) (11) with almost 70%

of individuals older than 75 years having some degree of diastolic dysfunction(9). Several studies have

also shown a strong association between diastolic dysfunction and hypertension(9) (11) (53). Because

myocardial relaxation is an active process that depends on ATP production, LVDD is frequent in patients

with coronary artery disease and, when present, is associated with worse outcome(54).

5.2. Obesity as a New Determinant of Diastolic Dysfunction: Understanding “Obesity Cardiomyopathy”

Obesity has reached global epidemic proportions worldwide(55), being nowadays a public health

concern. Obesity is associated with increased risk of death (56) and of numerous comorbidities, including

hypertension, type II diabetes mellitus, dyslipidemia, obstructive sleep apnea, certain cancers, and

atherosclerotic cardiovascular disease(57). Beyond these well-known maladaptive effects, more recent

studies have shown that obesity can also directly induce changes in cardiac structure and function,

particularly left ventricular hypertrophy and subclinical diastolic dysfunction (58) (59). Because obesity

is also independently associated with heart failure risk, it is hypothesized that diastolic dysfunction is an

important pathophysiological link between obesity and heart failure (60). These observations have given a

new insight into the recognition of “obesity cardiomyopathy” as a new entity, as stated in the recent heart

failure guidelines(16). Data from the Framingham Heart Study showed that for every 1Kg/m2 increase in

body mass index, the risk of heart failure increased 5% in men and 7% in women, with graded increases in

the risk of heart failure across all body mass index categories(60). Therefore, given the high prevalence of

obesity worldwide and the increased risk of heart failure in obese individuals, there is considerable interest

in understanding the mechanisms involved in the association between obesity, diastolic dysfunction and

heart failure(16).

In the general population, increased body mass index has been recently associated with subclinical

diastolic dysfunction(58). However, it is widely known that body mass index is an imperfect measure of


5. The Determinants of Diastolic Dysfunction: what is known and what is unknown

37

body fat, being influenced by muscle mass, body water content and others. Furthermore, the relative role

of central versus total or subcutaneous adiposity in inducing changes in cardiac structure and function

needs further clarification. Visceral fat is the metabolically most active organ, secreting adipokines and

contributing to a systemic pro-inflammatory state that can affect the cardiovascular system and diastolic

function(61). Interestingly, several studies have shown that waist circumference – which is more closely

related with excess visceral fat (62) – is a stronger determinant of myocardial infarction and cardiovascular

disease and death, when compared to body mass index or subcutaneous fat (63) (56). Therefore, in this

project we aimed to evaluate the relative role of adipose tissue distribution, especially the role of central

(and visceral) versus peripheral (and subcutaneous) fat, as determinants of LVDD.

The heart is also covered by fat, the epicardial adipose tissue(64). Epicardial fat contacts directly with the

heart and the coronary arteries, without any mechanical barrier separating it from the cardiomyocytes and

vessels, and sharing the same blood supply (65). Because epicardial fat produces several pro-inflammatory

and pro-atherogenic cytokines (66, 67) it is postulated that it can directly influence the heart. Indeed,

several studies have recognized epicardial fat as an independent determinant of the development and

progression of coronary artery disease(68) (69) (70) (71) (72). Thus, it is expected that epicardial adipose

tissue can also directly influence myocardial structure and function(73) (74) (75) (76), especially diastolic

function, by local/paracrine mechanisms. The evaluation of the effect of epicardial fat on left ventricular

diastolic function was another aim of this work.

The pathophysiological mechanisms involved in the association between obesity and LVDD are poorly

understood. Figure 4 illustrates several of these potential mechanisms (77). First, the effect could be

indirect, because obesity is associated with other cardiovascular risk factors that can cause LVDD, such as

hypertension(57). However, previous studies have shown that the association between increased adiposity

and diastolic function is independent of these traditional risk factors(58). Alternatively, obesity can directly

affect myocardial structure and function by several mechanisms, such as by increasing circulating volume

and cardiac output(78), by inducing a systemic pro-inflamatory state(61) (79) or through the secretion

of several adipokines (80, 81). In this project we aimed to evaluate the relative importance of the direct

(adiposity mediated) and indirect (blood-pressure- and inflammation-mediated) mechanisms involved in

the association between increased adiposity and diastolic function.

As previously stated, the adipose tissue is an endocrine organ that produces several substances,

called adipokines. In experimental studies, some of these adipokines (such as leptin, adiponectin and

resistin) have been shown to directly induce left ventricle remodeling and myocardial dysfunction (66, 82).

However, few data are available on the effect of adipokines as determinants of diastolic function in the

general population.

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Figure 4. Potential (direct and indirect) pathophysiological mechanisms involved in the association

between increased adiposity and diastolic dysfunction.

5.3. Diastolic Function in the Diabetic Continuum: the Role of Insulin Resistance, Metabolic Syndrome and Diabetes on Diastolic Dysfunction

Although controversial, several studies have shown that diabetes can affect cardiac structure and

function, independently of changes in blood pressure or coronary artery disease, a condition called

diabetic cardiomyopathy (83) (84). In humans, LVDD is considered the earliest manifestation of myocardial

involvement in type 2 diabetes mellitus (85) and a key component of diabetic cardiomyopathy (83).

More recent data have shown that changes in diastolic function precede the onset of diabetes, being already

present in pre-diabetic patients (86) (87), suggesting that LVDD is not caused by sustained hyperglycemia or

to a “glucotoxic” effect. Insulin resistance can be one of the main pathophysiologic mechanisms involved in

this diabetic cardiomyopathy because insulin resistance induces changes in myocardial substrate utilization

(88) (83), increases myocardial interstitial fibrosis (89), activates the sympathetic nervous system (90) and

impairs ventricular-vascular coupling by increasing arterial stiffness (91) (92).

Metabolic syndrome, or insulin resistance syndrome, is a cluster of cardiovascular risk factors with

a growing prevalence worldwide (93) that have been shown to act synergistically to increase the risk

of adverse cardiovascular events (94). Interestingly, individuals with metabolic syndrome have increased

prevalence of LVDD (95) (96) that frequently has a subclinical course (97). Few population-based studies

have evaluated LVDD in these different stages of the diabetic continuum, especially the role of insulin

resistance.

39


6. REVIEW ARTICLE

“Heart Failure with Preserved Ejection Fraction: Fighting Misconceptions for a New Approach”

Review Article

KeywordsHeart failure/therapy; stroke volume; ventricular function;

demographic aging.

Heart Failure with Preserved Ejection Fraction: Fighting Misconceptions for a New ApproachRicardo Fontes-Carvalho1,2 and Adelino Leite-Moreira1,3

Serviço de Fisiologia da Faculdade de Medicina do Porto1; Serviço de Cardiologia do Centro Hospitalar de Vila Nova de Gaia2; Centro de Cirurgia Torácica do Hospital de São João3, Porto - Portugal

Mailing address: Ricardo Fontes-Carvalho • Serviço de Fisiologia da Faculdade de Medicina do Porto - Al. Prof. Hernâni Monteiro 4200 - 319 Porto - Portugal E-mail: [email protected], [email protected] Manuscript received December 01, 2009; revised manuscript received February 17, 2010; accepted March 24, 2010.

AbstractOver the last decades, heart failure with preserved ejection

fraction (HFpEF) has received less attention by the medical and scientific communities, which led to the emergence of a number of misconceptions concerning its characteristics, diagnostic and therapeutic approach.

In recent years, new studies have changed the concepts traditionally associated with HFpEF, contributing to a new view towards this disease. This review is intended to discuss the latest evidence on HFpEF and to fight the main misconceptions associated with it in order to improve its diagnostic and therapeutic approach.

Today we have several data showing that HFpEF is a condition that requires a different clinical approach from that used in systolic heart failure (SHF). HFpEF is no longer seen as a “benign” disease because it is associated with a poor prognosis and high prevalence. Its pathophysiology is complex and not fully clarified. In addition to diastolic dysfunction, we now know that other cardiac and extracardiac factors are also involved in its onset and progression. Using recent consensus guidelines we have objective criteria for its diagnosis, especially by using the new echocardiographic parameters for assessing diastolic function, including the E/e’ ratio obtained by tissue Doppler. Finally, treatment of HFpEF remains unknown, because no therapeutic strategy has been shown to improve HFpEF prognosis. Thus, in this review we will also discuss the potentially new therapeutic targets for HFpEF.

IntroductionHeart failure (HF) represents a major and growing public

health problem, affecting 2% - 3% of adults in developed countries1.

Patients with heart failure are classically divided into two groups: those with HF with preserved ejection fraction

(HFpEF), also called diastolic HF (DHF) and those with HF and reduced ejection fraction (HFrEF), better known as systolic HF (SHF)1.

In recent decades, HFpEF has received much less attention from medical and scientific communities, a situation that is finally starting to change. Such lack of attention resulted in the gradual emergence, within the medical community, of a series of misconceptions and dogmas concerning the epidemiology, diagnosis, pathophysiology and treatment of HFpEF.

With this review, we intend to explore and tackle the major misconceptions associated with HFpEF. We will discuss the latest evidence concerning HFpEF, providing a new view on this complex syndrome, in order to improve its clinical and therapeutic approach.

Frequent misconceptions in heart failure with preserved ejection fraction

Misconception 1: HFpEF is a benign conditionUntil recently, HFpEF had been considered an essentially

“benign” disease associated with a better prognosis. Epidemiological studies have shown that the prognosis for these patients is as bad as those who have systolic HF (SHF)2,3. Patients with HFpEF have mortality rates of 29% after one year (versus 32% in patients with systolic HF), and 65% after five years (versus 68%)3.

The morbidity of HFpEF is also very high, requiring frequent admissions and a significant consumption of resources4,5. Once admitted due to HF, these patients have a high rate of readmission of 50% after one year5.

Equally worrying is the evidence showing that the survival of patients with HFpEF has not been improving in recent decades, unlike what has been observed in patients with systolic HF6. Such observation is probably related to the fact that the management and treatment of these patients are not producing the desired effects, probably due to various misconceptions concerning HFpEF.

Misconception 2: diastolic HF is an uncommon syndromeA second misconception in HFpEF is to think that this

is a clinical condition that is less common than the SHF. This is quite the opposite! We know today that HFpEF is responsible for about 50% of all patients admitted with HF, a proportion that increases with age2,4,6-8. Moreover, in the last two decades the proportion of patients with HFpEF increased

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Fontes-Carvalho & Leite-MoreiraHFpEF: fighting misconceptions for a new approach

Arq Bras Cardiol 2011;96(6):504-514

from 38% to 54% out of cases of HF6, a proportion that will continue to rise due to the progressive aging of population and expected increase in the prevalence of hypertension, obesity and diabetes.

Misconception 3: diastolic HF and systolic HF are the same condition

The classical separation of HF in HFpEF is questioned by several authors who argue that these relate to the same condition, albeit with different phenotypes9,10.

However, there are many demographic, epidemiological, histological, molecular and structural arguments, as well as some relating to ventricular function and even therapeutic effectiveness, which seem to clearly indicate that these two conditions are quite different (Table 1)6,11.

Regarding the characteristics of the population, patients with HFpEF are older, often female, and have a high prevalence of hypertension, diabetes and obesity, as well as various comorbidities such as atrial fibrillation, renal failure and anemia2-4,7,12,13 (Table 1).

The hearts of patients with systolic HF and HFpEF also have significant differences in terms of structure and ventricular function (Table 1). The hearts of patients with SHF present an eccentric ventricular modeling with increased diastolic volumes and the main anomaly occurs in LV systolic properties14 (Figure 1). By contrast, patients with HFpEF present as concentric remodeling, the volumes are normal or even reduced, and the main change occurs in the diastolic properties, with delayed relaxation and/or increased ventricular stiffness14-16 (Figure 1 and Table 1).

Other recently published studies have also shown differences at histological and molecular level. For example, analysis of endomyocardial biopsies revealed that cardiomyocytes of patients with HFpEF are structurally different, with larger diameters, greater stiffness and increased density of myofilaments, compared to patients with ICS17. Significant differences were also discovered at the molecular level. Titin is a molecule found inside the sarcomere which, given its elastic properties, is the main determinant of the stiffness of cardiomyocytes. It was found that in patients with HFpEF there is a change in the expression of the isoforms of this molecule - with increased expression of the stiffer isoform - or its degree of phosphorylation, which contributes to the increase in ventricular stiffness observed in these patients17,18. Patients with HFpEF and systolic HF also have significant differences in fibrosis and extracellular collagen matrix, due to distinct patterns of extracellular matrix metalloproteinases (MMP) and tissue inhibitors of such metalloproteinases (TIMP) activation. While in HFpEF there is a decreased degradation of extracellular matrix (resulting in increased ventricular stiffness), in dilated cardiomyopathy there is an increased matrix degradation19,20. In the HFpEF, diastolic dysfunction ca occur due to changes in the passive properties of the ventricle - particularly increased ventricular stiffness - or due to alterations in myocardial relaxation. The delay in myocardial realaxation seen in patients with HFpEF is caused by changes in calcium kinetics, especially by reduced activity

Table 1 – Comparison of characteristics of patients with systolic HF and HFpEF

Characteristics HFpEF Systolic HF

Systolic function

Ejection fraction N (or ↑) ↓↓

Ejection volume N (or ↓) ↓ (or N)

Contractility N ↓

Diastolic function

LV telediastolic pressure ↑↑ ↑

Constant relaxation time ↑↑ ↑

Relative wall thickness1 ↑ ↓

Ventricular filling rate ↓↓ ↓

Ventricular stiffness ↑↑ ↓

Myocardial stiffness ↑ N

Ventricular remodeling

LV volume N (or ↓) ↑↑

LV mass ↑ ↑

LV geometry Concentric Eccentric

Cardiomyocytes ↑ Diameter ↑ Length

Collagen extracellular matrix ↑↑ ↓ (or N or ↑)

BNP ↑ ↑↑

Age Often elderly All ages, typically 50-70

Sex Often women More common in men

Comorbidities

Hypertension +++ ++

Diabetes +++ ++

Prior myocardial infarction + +++

Obesity +++ +

Renal failure ++ 0

Atrial fibrillation ++ +

Chronic lung disease ++ 0

Abbreviations: LV - left ventricle, N - normal; ↑ - increased; ↓ - decreased; BNP - brain natriuretic peptide; The relative wall thickness describes the left ventricular geometry and is defined as the ratio between the left ventricular thickness and the left ventricular cavity diameter.

of SERCA2, the main protein responsible for the reuptake of calcium back into the sarcoplasmic reticulum21.

Finally, strong arguments related to the response to pharmacological therapy justify the separation of these two conditions. Few clinical trials performed to date on HFpEF reveal that these patients do not respond as well to therapy commonly used in systolic HF, suggesting that different pathophysiological mechanisms operate in these two conditions.

These differences mean that the therapeutic approach to HFpEF must be different from that used in systolic HF, as prescribed in the guidelines for heart failure1,22.

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Misconception 4: diastolic dysfunction is the only abnormality involved in HFpEF

The patophysiology of HFpEF is not totally understood, mainly because HFpEF affects an heterogeneous group of patients where different pathophysiological mechanisms may have a different relative importance.

Diastolic dysfunction plays a central role in the pathophysiology of this condition, since most patients present delayed myocardial relaxation and/or increased ventricular stiffness23. This is why HFpEF is often referred to as diastolic HF. More recently, after the discovery of other mechanisms that appear to contribute to the pathophysiology of this condition, the expression diastolic HF was replaced by a more general term: HFpEF 1,24.

On the other hand, we know that LV diastolic dysfunction, by itself, does not seem to be enough to cause the clinical picture of heart failure. There is an important group of patients who have diastolic dysfunction, although they remain asymptomatic and without HF25. Moreover, the prevalence of diastolic dysfunction in the general population (present in up to 25% of the population26) is much higher than the prevalence of HF. However, it remains to be explained why some patients with diastolic dysfunction have HFpEF, while others remain asymptomatic.

Beyond diastolic dysfunction: contribution of other pathophysiological mechanisms

Several studies have recently demonstrated that the pathophysiology of HFpEF involves other mechanisms, including “cardiac” and “extracardiac” factors (Figure 2)27,28.

The explanation for the symptomatic difference among patients with asymptomatic diastolic dysfunction and HFpEF may be due to the simultaneous existence of these additional pathophysiological abnormalities only in patients with HFpEF.

Among “extracardiac” abnormalities found in HFpEF, particular emphasis has been placed on the abnormalities found in the arterial vessels, including increased arterial stiffness, changes in ventricular-arterial coupling29,30, endothelial dysfunction and reduced vasodilator reserve 31.

There are other extracardiac factors potentially involved in HFpEF. It was found that in these patients, increased ventricular filling pressure is also due to an increased effective circulating volume due to increased sodium and water retention in the kidneys32. It should be stressed that in HFpEF, due to the simultaneous increase of ventricular and arterial stiffness, patients are very sensitive to small changes in the “central” volume16.

Recently, new “cardiac” factors have been found to contribute to HFpEF pathophysiology, such as chronotropic incompetence31 and changes in ventricular stretching, radial deformation and twisting, evaluated by speckle tracking analysis33.

Finally, HFpEF patophysiology is usually accessed at rest. However, several studies have shown that additional alterations occur during exercise in HFpEF patients31,34-36.

Is systolic function completely normal in HFpEF? By definition, HFpEF patients have a normal ejection

fraction. Nevertheless, because ejection fraction is an imprecise parameter for the evaluation of minor alterations in systolic function, it has been demonstrated that patients with HFpEF also have changes in systolic function assessed by Tissue

Figure 1 - Left ventricular loops and pressure-volume (P-V) ratios in systolic and diastolic dysfunction. Panels A, B and C show dashed loops and P-V ratios of a normal heart. Line 1 corresponds to the end diastolic pressure-volume relation, line 2 to P-V loop and line 3 to the end systolic pressure volume relation. In the presence of systolic dysfunction (panel B, full line) there is a decreased in ejection fraction (translated by the smaller width of the P-V loop) and a reduced myocardial contractility, expressed by the lower slope of the end systolic pressure volume relation (arrow). As opposed to that, in diastolic dysfunction (Panel C), the end diastolic pressure-volume relation is shifted upwards and to the left (gray line). That makes a certain amount of ventricular filling to be only achieved at the expense of much higher filling pressures than those observed for the same volume in a normal individual (see points A and B of panel C). (Adapted from Rev Port Cardiol, 2009. 28: p. 63-82).

A. NORMAL B. SYSTOLIC DYSFUNCTION C. DIASTOLIC DYSFUNCTION

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Doppler analysis37,38. Also, a recent study has shown that in HFpEF patients important alterations in systolic function also occur especially in response to exercise33.

Misconception 5: there are no objective criteria for the diagnosis of HFpEF

Part of the controversy and misconceptions concerning HFpEF resulted from the lack of consensus about its diagnostic criteria.

Such limitation was overcome in 2007 after the publication of a consensus document of the European Society of Cardiology with updated diagnostic criteria for HFpEF24. According to this document, three prerequisites should be fulfilled simultaneously to diagnose HFpEF: 1) symptoms and signs of HF; 2) EF> 50% in a non-dilated LV (defined as LV with a end diastolic volume < 97 ml/m2); 3) evidence of high LV filling pressures.

The demonstration of high LV filling pressures can be made by invasive hemodynamic evaluation (which is the gold-standard method, but is difficult to apply in clinical practice) or by combining several echocardiographic parameters together with natriuretic peptides quantification. By echocardiography several diastolic parameters can be obtained that allow LV filling pressures estimation39. The most widely used parameter, and also the easiest to analyse, is the E/e’ ratio, which is obtained from the ratio between the peak transmitral flow velocity (E wave) and the mitral annulus velocity, determined from Tissue Doppler analysis (the e’ wave) (Fig. 3). When the E/e’ ratio at the level of the septal wall is > 15, LV filling pressures are certainly increased, whereas a E/e’ ratio < 8 represents normal LV filling pressures24. However when the E/e’ ratio is between 8 and 15, it is necessary to combine this value with other diastolic function echocardiographic parameters, as discussed later.

The new diagnostic algorithm of HFpEF, despite a few limitations28 allowed standardizing the diagnosis of HFpEF.

Misconception 6: diastolic function evaluation by echocardiography is inaccurate and has no influence on clinical management strategies

The assessment of LV diastolic function should be an integral part of routine echocardiographic evaluation40, especially in patients with dyspnoea and/or heart failure, due to its diagnostic24 and prognostic significance41.

Initially, the diastolic function by echocardiography was mainly assessed through pulsed Doppler analysis of transmitral flow pattern. When this parameter is used alone, it is little specific, and has several limitations. This fact has led to the emergence of the (misconceived) idea that the echocardiographic assessment of diastolic function is little specific and little useful in clinical practice. Today, there are several echocardiographic parameters in the assessment of diastolic function, whose applications, advantages and limitations have been the target of a consensus document of the European and American societies of Echocardiography39, which will be briefly addressed in this study (Table 2).

Pulsed Doppler transmitral inflow patternThe analysis of transmitral flow by pulsed Doppler is easy to

obtain in almost all patients (Fig. 4, A). By analyzing transmitral filling pattern, it is possible to define four degrees of diastolic dysfunction (Fig. 3).

Nevertheless, this parameter has several limitations (Table 2)39 because when used alone, it is not possible to distinguish a normal pattern from a pseudonormal, which indicates a grade II diastolic dysfunction (Figure 3). Despite its limitations, when combined with other diastolic dysfunction parameters, the evaluation of the E/A ratio can be useful in clinical practice to support the diagnosis of HFpEF24. and give prognostic information, when a restrictive pattern is present41.

Increased ventricular stiffness

Delayed ventricular relaxation

Ventricular hypertrophy

Chronotropic incompetence

Loss of cardiac reserve

Increased central aorta stiffness

Abnormal Ventricular-arterial coupling

Limited vasodilator reserve

Hypertensive response to exercise

Endothelial dysfunction

Renin-angiotensin activation

Sodium and water retention

Anemia KIDNEYVESSELS

HEART

Figure 2 - Potencial Pathophysiological mechanisms involved in HFpEF.

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Isovolumic relaxation time (IVRT)This parameter, which assesses primarily the ventricular

relaxation, measures the time interval between aortic valve closure and mitral valve opening (Fig. 5, panel C). The normal value of IVRT is 70-90 msec, a value that increases with delayed relaxation, but shortens when filling pressures are markedly increased39.

Mitral flow propagation velocity (Vp)The mitral flow propagation velocity (Vp) is evaluated

according to Figure 5, panel A. When ventricular relaxation is delayed, the Vp slope is reduced.

Pulmonary vein flow velocity assessment The pulmonary vein flow assessment can provide several

measurements for diastolic function evaluation. However, the most reliable parameter is the Ar pulm - Ad mitral, which is the time difference between the duration of reversed pulmonary vein flow during atrial systole (Ar pulm) and the duration of the mitral A wave flow (Figure 5, B); when the Ar pulm - Ad mitral difference is > 30 msec, LV filling pressures are increased24.

Tissue Doppler assessment at the mitral annulus and E/e’ ratio

The most widely used echocardiographic parameter for diastolic function evaluation is the E/e’(see figure 4)24,40, which is the ratio of the E wave velocity from transmitral flow divided by the e’ wave velocity obtained by Doppler tissue at the mitral annulus level. By applying the pulsed tissue Doppler

at the septal or lateral side of the mitral annulus, it is possible to evaluate the velocity of the mitral annulus displacement and calculate the velocity of the systolic wave (S wave), of the early diastolic wave (E’, e’ or Ea) and of the late diastolic wave (A’, a’ or Am).

Several studies have shown that E/e’ ratio correlates closely with LV filling pressures, independently from ejection fraction values. When E/e’ ratio at the septal side of the mitral annulus is > 15, LV filling pressures are increased, whereas an E/e’ value < 8 indicates normal filling pressures. However, when the e’ is evaluated at the lateral side of the mitral annulus, and not at the septal wall, a cut-off of E/e’ > 12 (instead of 15) should be used, because displacement velocities are greater at the lateral side42.

Left atrial volumeIncreased left atrial volume (LA) (Fig. 5, D) is a morphological

marker of chronically increased diastolic filling pressures43 and is an important mortality predictor44. LA volume can also be increased in atrial fibrillation or significant mitral valve disease, therefore it is important to combine this parameter with the patient’s clinical condition and with other echocardiographic markers of diastolic dysfunction39.

Myocardial strain analysisMyocardial strain can now be evaluated by echocardiography

using speckle tracking, which can provide essential information regarding diastolic function39, and may be a more reliable marker of diastolic dysfunction than the E/e’ ratio45.

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B. Delayedrelaxation

(DD degree I)

C. Pseudonormal (DD degree II)

D. Restrictive pattern(DD degrees III and IV)

A. Normal

Figure 3 - Evaluation of different degrees of diastolic dysfunction using data obtained from the transmitral flow pattern (top) and analysis of tissue Doppler at the mitral annulus level (bottom). Legend: DD - diastolic dysfunction; DDT - diastolic deceleration time; E - transmitral flow velocity during early ventricular filling; A - transmitral flow velocity during atrial contraction; e’- Tissue Doppler velocity at the mitral annulus level during early ventricular filling.

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Table 2 – Advantages and limitations of various echocardiographic parameters of diastolic function assessment

Echocardiographic parameters Advantages Limitations

Transmitral PW inflow pattern 1. Easy to obtain in all patients2. Provides diagnostic and prognostic information

1. Pre-load dependent2. Influenced by PW sample placement

3. Difficult to analyze in atrial fibrillation, high heart rate and paced rhythms

4. Influenced by age

Tissue Doppler analysis(E/e´ratio)

1. Can be obtained in most patients2. Not influenced by preload or heart rate3. Early marker of diastolic dysfunction

4. Provides prognostic information5. Diferential diagnosis information to help exclude

constrictive pericarditis

1. Influenced by regional wall motion abnormalities (eg after myocardial infarction

2. Requires careful interpretation in patients withsignificant mitral disease

3. Some doubts about the best place for assessing e’ (septal, lateral or mean of two)

4. Difficult interpretation when E/e’ratio is between 8 and 15 5. Less reliable parameter in normal individuals and in patients

with hypertrophic or dilated cardiomyopathy

Isovolumic relaxation time (IVRT) 1. Provides the assessment of the earliest phase of diastole (relaxation)

1. Technically difficult to record two events on thesame image plane

2. Low reproducibility3. Pre-load dependent

Pulmonary vein flow assessment 1. The Ar pulm - A mitral parameter provides LV filling pressure estimation

1. Difficult to obtain in some patients2. Depends on heart rate and can not be measured in patients

with atrial fibrilation

Mitral inflow propagation velocities 1. Low reproducibility2. Dependent on pre-load and cardiac chamber size

Left atrial volume1. Provides evidence of chronically increased filling

pressures2. Provides prognostic information

1. There are other medical conditions associated with increased LA volume(mitral valve disease, atrial fibrillation, anemia)2. Is not influenced by acute variations in filling pressures

Myocardial deformation analysis 1. Not dependent on sample angle2. Potentially useful when E/e’ ratio is between 8 and 15 1. Lack of studies

Diastolic stress test1. Provides diastolic function assessment during effort

2. Especially useful in patients with unexplained dyspnea and normal filling pressures at ret

1. Technically difficult2. The same limitations from Tissue Doppler Analysis

Adapted from [43].

Figure 4 - E/e’ ratio evaluation. The left panel shows transmitral inflow Doppler pattern, with the E wave velocity (E), the A wave velocity (A), the E wave deceleration time (DT) and the duration of the A wave (Ad mitral). The right panel illustrates the e’ velocity assessment, evaluated by tissue Doppler at the lateral wall of the mitral annulus (E’ lat).

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Table 2 – Advantages and limitations of various echocardiographic parameters of diastolic function assessment

Echocardiographic parameters Advantages Limitations

Transmitral PW inflow pattern 1. Easy to obtain in all patients2. Provides diagnostic and prognostic information

1. Pre-load dependent2. Influenced by PW sample placement

3. Difficult to analyze in atrial fibrillation, high heart rate and paced rhythms

4. Influenced by age

Tissue Doppler analysis(E/e´ratio)

1. Can be obtained in most patients2. Not influenced by preload or heart rate3. Early marker of diastolic dysfunction

4. Provides prognostic information5. Diferential diagnosis information to help exclude

constrictive pericarditis

1. Influenced by regional wall motion abnormalities (eg after myocardial infarction

2. Requires careful interpretation in patients withsignificant mitral disease

3. Some doubts about the best place for assessing e’ (septal, lateral or mean of two)

4. Difficult interpretation when E/e’ratio is between 8 and 15 5. Less reliable parameter in normal individuals and in patients

with hypertrophic or dilated cardiomyopathy

Isovolumic relaxation time (IVRT) 1. Provides the assessment of the earliest phase of diastole (relaxation)

1. Technically difficult to record two events on thesame image plane

2. Low reproducibility3. Pre-load dependent

Pulmonary vein flow assessment 1. The Ar pulm - A mitral parameter provides LV filling pressure estimation

1. Difficult to obtain in some patients2. Depends on heart rate and can not be measured in patients

with atrial fibrilation

Mitral inflow propagation velocities 1. Low reproducibility2. Dependent on pre-load and cardiac chamber size

Left atrial volume1. Provides evidence of chronically increased filling

pressures2. Provides prognostic information

1. There are other medical conditions associated with increased LA volume(mitral valve disease, atrial fibrillation, anemia)2. Is not influenced by acute variations in filling pressures

Myocardial deformation analysis 1. Not dependent on sample angle2. Potentially useful when E/e’ ratio is between 8 and 15 1. Lack of studies

Diastolic stress test1. Provides diastolic function assessment during effort

2. Especially useful in patients with unexplained dyspnea and normal filling pressures at ret

1. Technically difficult2. The same limitations from Tissue Doppler Analysis

Adapted from [43].

Figure 4 - E/e’ ratio evaluation. The left panel shows transmitral inflow Doppler pattern, with the E wave velocity (E), the A wave velocity (A), the E wave deceleration time (DT) and the duration of the A wave (Ad mitral). The right panel illustrates the e’ velocity assessment, evaluated by tissue Doppler at the lateral wall of the mitral annulus (E’ lat).

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Figure 5 - Demonstration of different echocardiographic parameters used for diastolic dysfunction analysis. Panel A shows how to measure the mitral flow propagation velocity (Vp); panel B shows the pulmonary vein flow velocity assessment, from which it is possible to determine the time duration of reversed pulmonary vein flow during atrial systole (Ar pulm), that is used to calculate the Ar pulm - Ad mitral: the time difference between the Ar pulm and the duration of mitral A wave flow (see left panel, Figure 4); panel C shows how to calculate the isovolumic relaxation time (IVRT); and finally, panel D shows left atrial volume measurement, using Simpson’s method.

Diastolic stress testA great number of patients with diastolic dysfunction only

develop symptoms during exercise. Therefore, it is important to evaluate LV filling pressures in response to exercise, by conducting a diastolic stress test.

This test can evaluate the E/e’ ratio variation in response to exercise. While in individuals with normal relaxation, both E and e’ velocities increase proportionally (keeping a normal E/e’ ratio), in patients with diastolic dysfunction there is a progressive increase of the E/e’ ratio with exercise46.

In conclusion, although some limitations still exist47, diastolic function can be reliably assessed by echocardiography, using an integrated step-by-step approach, starting with E/e’ ratio evaluation. Moreover, diastolic dysfunction evaluation provides essential information for diagnosis, prognosis and management of patients with HF, particularly those with HFpEF42.

Misconception 7: there are effective strategies to treat HF with preserved EF

Probably the biggest misconception in HFpEF management is to think that there are effective therapeutic strategies for

HFpEF, or to believe that such treatment may be similar to that used in systolic HF.

Firstly, despite its clinical and epidemiological significance, HFpEF treatment remains largely empirical and not evidence based. Unlike in SHF, few randomized clinical trials have been conducted in these patients.

Secondly, the few clinical trials conducted in HFpEF patients, only evaluated the effectiveness of renin-angiotensin system inhibitors. In all such studies the results were disappointing, since there was no survival benefit by using such agents. Hence, the use of other therapeutic agents in HFpEF can only be recommended theoretically or based on data obtained from observational studies.

Finally, in recent decades, the prognosis of HFpEF has remained unchanged over time, contrasting with the survival benefit observed in SHF patients6. This observation also demonstrates that HFpEF management strategies are still not appropriate.

Use of the renin-angiotensin system modulatorsContrary to systolic HF, in HFpEF blocking the renin-

angiotensin system is less useful in terms of clinical events

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Figure 5 - Demonstration of different echocardiographic parameters used for diastolic dysfunction analysis. Panel A shows how to measure the mitral flow propagation velocity (Vp); panel B shows the pulmonary vein flow velocity assessment, from which it is possible to determine the time duration of reversed pulmonary vein flow during atrial systole (Ar pulm), that is used to calculate the Ar pulm - Ad mitral: the time difference between the Ar pulm and the duration of mitral A wave flow (see left panel, Figure 4); panel C shows how to calculate the isovolumic relaxation time (IVRT); and finally, panel D shows left atrial volume measurement, using Simpson’s method.

Diastolic stress testA great number of patients with diastolic dysfunction only

develop symptoms during exercise. Therefore, it is important to evaluate LV filling pressures in response to exercise, by conducting a diastolic stress test.

This test can evaluate the E/e’ ratio variation in response to exercise. While in individuals with normal relaxation, both E and e’ velocities increase proportionally (keeping a normal E/e’ ratio), in patients with diastolic dysfunction there is a progressive increase of the E/e’ ratio with exercise46.

In conclusion, although some limitations still exist47, diastolic function can be reliably assessed by echocardiography, using an integrated step-by-step approach, starting with E/e’ ratio evaluation. Moreover, diastolic dysfunction evaluation provides essential information for diagnosis, prognosis and management of patients with HF, particularly those with HFpEF42.

Misconception 7: there are effective strategies to treat HF with preserved EF

Probably the biggest misconception in HFpEF management is to think that there are effective therapeutic strategies for

HFpEF, or to believe that such treatment may be similar to that used in systolic HF.

Firstly, despite its clinical and epidemiological significance, HFpEF treatment remains largely empirical and not evidence based. Unlike in SHF, few randomized clinical trials have been conducted in these patients.

Secondly, the few clinical trials conducted in HFpEF patients, only evaluated the effectiveness of renin-angiotensin system inhibitors. In all such studies the results were disappointing, since there was no survival benefit by using such agents. Hence, the use of other therapeutic agents in HFpEF can only be recommended theoretically or based on data obtained from observational studies.

Finally, in recent decades, the prognosis of HFpEF has remained unchanged over time, contrasting with the survival benefit observed in SHF patients6. This observation also demonstrates that HFpEF management strategies are still not appropriate.

Use of the renin-angiotensin system modulatorsContrary to systolic HF, in HFpEF blocking the renin-

angiotensin system is less useful in terms of clinical events

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reduction or survival benefit, as demonstrated using perindopril (PEP-CHF trial)48, irbesartan (I-PRESERVE)49 or candesartan (CHARM-Preserved)50.

Role of beta blockers in HFpEFIn theory, beta blockers (BB) have various potential

benefits in HFpEF treatment: i) by reducing the heart rate they increase the duration of diastole and hence ventricular filling time; ii) they decrease myocardial oxygen requirements; iii) they lower blood pressure; and iv) they may induce regression of LVH. On the other hand, these beneficial effects may be partially mitigated since BB delay ventricular relaxation and reduce contractility16.

Although there are no clinical trials assessing BB efficacy in HFpEF, it is expected that these agents can be potentially beneficial, especially those with a vasodilator effect (e.g. carvedilol and nebivolol), because they can also reduce arterial stiffness.

Data from observational studies indicate that beta-blockers in HFPEF may reduce mortality51. Recently, a subanalysis derived from the SENIORS trial showed that in the subgroup of patients with EF > 35%, the benefits of this BB were similar, which suggests that the effectiveness of BB is not depend on ejection fraction52. With so many uncertainties, there is an urging need for a clinical trial to test the use of BB in HFpEF.

Aldosterone antagonists in HFpEFThe use of antagonists aldosterone in HFpEF can be

beneficial, at least from a theoretical standpoint. Aldosterone acts both on the myocardium and vessels, promoting myocyte hypertrophy, fibrosis and collagen deposition, all of which may contribute to increased myocardial and arterial stiffness, contributing HFpEF progression53. A small clinical trial demonstrated that spironolactone improved echocardiographic parameters of diastolic dysfunction54. A randomized clinical trial - the TOPCAT study - is currently in progress aimed at assessing the role of aldosterone antagonists in HFPEF patients.

Other therapeutic strategiesGiven so many uncertainties, only some general principles

are recommended for HFpEF treatment1: i) aggressive blood pressure control, to prevent the onset of HFpEF, to reduce the number of HF hospitalizations, to induce left ventricular hypertrophy regression and to improve ventricular-arterial coupling; ii) reduction of ventricular filling pressures, by restricting salt intake and administration of diuretics, which is particularly important since HFpEF patients are highly sensitive to changes in central volume and pre-load; iii) maintaining sinus rhythm, to preserve atrial contraction; iv) heart rate control, preventing tachycardia, which shortens diastole duration; and v) treatment of underlying comorbidities, using an integrated and multidisciplinary approach.

Potential new therapeutic targets in HFpEFThe future treatment for HFpEF is dependent on a

better understanding of its pathophysiology and on multiple interventions on the various underlying physiopathological mechanisms. Due to the heterogeneous mechanisms that cause HFpEF, its treatment will always be multifactorial and individualized to each patient.

Assuming that changes in relaxation and increased stiffness are the main pathophysiological alterations in HFpEF, it is necessary to develop new therapeutic strategies that specifically target these alterations. Alagebrium, or ALT-177, is a new drug that breaks the crosslinks that form between advanced glycosylation endproducts, thereby improving diastolic function (by reducing ventricular stiffness), vascular function (by improving arterial distensibility), and ventricular-arterial coupling. Small clinical trials have shown promising results in HFpEF55.

Given the importance of fibrosis in increasing ventricular stiffness, several studies are analyzing (with promising results) the antifibrotic effects of several growth factors, cytokines and signaling molecules56.

In recent years, our research group has also contributed to clarifying the determinants of left ventricular passive properties, demonstrating that ventricular stiffness is not just a passive property, but that it can be actively modulated (and reduced) using neuro-hormonal manipulation (e.g. renin-angiotensin system and endothelin, among others), opening new therapeutic targets for ventricular stiffness reduction57-60.

In HFpEF, ventricular relaxation should also be improved. As previously mentioned, relaxation is dependent on the uptake of calcium back into the sarcoplasmic reticulum by the action of SERCA2A, which in turn is regulated by phospholamban61. Animal studies have shown that genetic transfer of SERCA2A or modified phospholamban improves ventricular diastolic function62, 63.

Given the beneficial effects of nitric oxide (NO) on endothelial, vascular and myocardial functions, type 5 phosphodiesterase inhibitors (e.g. sildenafil) may have a role in HF treatment, including in HFpEF64. A clinical trial is currently in progress to assess this possibility.

Potential Conflict of InterestNo potential conflict of interest relevant to this article was

reported.

Sources of FundingThere were no external funding sources for this study.

Study AssociationThis study is not associated with any post-graduation

program.

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4. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007; 50 (8): 768-77.

5. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure. Part I. Diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002; 105 (11): 1387-93.

6. Owan TE, Hodge D, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006; 355 (3): 251-9.

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16. Fontes-Carvalho R, Leite-Moreira AF. The pathophysiology of heart failure with preserved ejection fraction and its therapeutic implications. Rev Port Cardiol. 2009; 28 (1): 63-82.

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18. Borbély A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, et al. Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009; 104 (6): 780-6.

19. Ahmed SH, Clark L, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease.Circulation. 2006; 113 (17): 2089-96.

20. Spinale FG, Coker M., Heung LJ, Bond BR, Gunasinghe HR, Etoht, et al. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation. 2000; 102 (16): 1944-9.

21. Periasamy M, Jansen P. Molecular basis of diastolic dysfunction. Heart Fail Clin. 2008; 4 (1): 13-21.

22. Hunt SA, Abraham W, Chin MH, Feldman AM, Francis S, Ganiats TG, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the ACC Foundation/AHA Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation.J Am Coll Cardiol, 2009; 53 (15): e1-e90.

23. Zile MR, Baicu C, Gaasch WH. Diastolic heart failure: abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 19 (19): 1953-9.

24. Paulus W, Tchoppe C, Sanderson J, Rusconi C, Flachskampf FE, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007; 28 (20): 2539-50.

25. Redfield MM, Jacobsen S, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003; 289 (2): 194-202.

26. Kuznetsova T, Herbotz L, Lopez B, Jin Y, Richart T, Thys L, et al. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail. 2009; 2 (2): 105-12.

27. Maurer MS, King D, El-Khoury R, Packer M, Burkhoff D. Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms. J Card Fail. 2005; 11 (3): 177-87.

28. Maeder M, Kaye D, Heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2009; 53 (11): 905-18.

29. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003; 107 (5): 714-20.

30. Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008; 4 (1): 23-36.

31. Borlaug BA, Melenovski V, Russell SD, Kessler K, Pacak K, Becker LC, et al. Impaired chronotropic and vasodilator reserves limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation. 2006; 114 (20): 2138-47.

32. Maurer MS, Burkhoff D, Fried LP, Gottdiener J, King DL, Kitzman DW. Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: the Cardiovascular Health Study. J Am Coll Cardiol. 2007; 49 (9): 972-81.

33. Wang J, Khoury D, Yue Y, Torre-Amione G, Nagueh SF. Preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation in patients with diastolic heart failure. Eur Heart J. 2008; 29 (10): 1283-9.

34. Tan YT, Wenzelburger F, Lee E, Heatlie G, Leyva F, Patel K, et al. The pathophysiology of heart failure with normal ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol. 2009; 54 (10): 36-46.

35. Westermann D, Kasner M, Steendijk P, Spillmann F, Riead A, Weitmann K, et al. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008; 117 (16): 2051-60.

36. Kitzman DW, Higginbotham M, Cobb FR, Sheikh KH, Sullivan MJ. Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism. J Am Coll Cardiol. 1991; 17 (5): 1065-72.

37. Bruch C, Gradaus R, Gunia S, Breithardt G, Wichter T. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr. 2003; 16 (10): 1031-6.

38. Yip G, Wang M, Zhang Y, Fung JW, Ho PY, Sanderson JE. Left ventricular long axis function in diastolic heart failure is reduced in both diastole and systole: time for a redefinition? Heart Fail Clin. 2002; 87 (2): 121-5.

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40. Mesquita E, Jorge A. Heart failure with normal ejection fraction: new diagnostic criteria and pathophysiological advances. Arq Bras Cardiol. 2009; 93 (2): 180-7.

41. Somaratne JB, Whalley G, Gamble GD, Doughty R. Restrictive filling pattern is a powerful predictor of heart failure events post acute myocardial infarction and in established heart failure: a literature-based meta-analysis. J Card Fail. 2007; 13 (5): 346-52.

42. Little WC, Oh J. Echocardiographic evaluation of diastolic function can be used to guide clinical care. Circulation. 2009; 120 (9): 802-9.

43. Lester SJ, Tajik A, Nishimura RA, Oh JK, Khanderia BK, Seward JB. Unlocking the misteries of diastolic function. J Am Coll Cardiol. 2008; 51 (7): 679-89.

44. Douglas P. The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol. 2003; 42 (7): 1206-7.

45. Dokainish H, Sengupta R, Pillai M, Bobek J, Lakkis N. Usefulness of new diastolic strain and strain rate indexes for the estimation of left ventricular filling pressure. Am J Cardiol. 2008; 101 (10): 1504-9.

46. Ha JW, Oh JK, Pellikka PA, Ommen SR, Stussy VL, Bailey KR, et al. Diastolic stress echocardiography: a novel noninvasive diagnostic test for diastolic dysfunction using supine bicycle exercise Doppler echocardiography. J Am Soc Echocardiogr. 2005; 18 (1): 63-8.

47. Tschöpe C, Paulus W. Is echocardiographic evaluation of diastolic function useful in determining clinical care? Doppler echocardiography yields dubious estimates of left ventricular diastolic pressures. Circulation. 2009; 120 (9): 810-20.

48. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor I. PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006; 27 (19): 2338-45.

49. Massie BM, Carson P, McMurray JJ, Komajda M, McKelvie R, Zile MR. I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008; 359 (23): 2456-67.

50. Yusuf S, Pfeffer M, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003; 362 (9386): 777-81.

51. Dobre D, van Veldhuisen D, DeJongste MJ, Lucas C, Cleuren G, Sanderman R, et al. Prescription of beta-blockers in patients with advanced heart failure and preserved left ventricular ejection fraction: clinical implications and survival. Eur J Heart Fail. 2007; 9 (3): 280-6.

52. van Veldhuisen DJ, Cohen-Solal A, Böhm M, Anker SD, Babalis D, Roughton M, et al. SENIORS Investigators. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: data from SENIORS. J Am Coll Cardiol. 2009; 53 (23): 2150-8.

53. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001; 345 (23): 1689-97.

54. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation. 2004; 110 (5): 558-65.

55. Little WC, Zile M, Kitzman DW, Hundley WG, O´Brien TX, Degroof RC. The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure. J Card Fail. 2005; 11 (3): 191-5.

56. Kaye DM, Krum H. Drug discovery for heart failure: a new era or the end of the pipeline? Nat Rev Drug Discov. 2007; 6 (2): 127-39.

57. Leite-Moreira AF, Castro-Chaves P, Pimentel-Nunes P, Lima-Carneiro A, Guerra MS, Soares JB, et al. Angiotensin II acutely decreases myocardial stiffness: a novel AT1, PKC and Na+/H+ exchanger-mediated effect. Br J Pharmacol. 2006; 147 (6): 690-7.

58. Leite-Moreira AF, Bras-Silva C, Pedrosa CA, Rocha-Sousa AA. ET-1 increases distensibility of acutely loaded myocardium: a novel ETA and Na+/H+ exchanger mediated effect. Am J Physiol Heart Circ Physiol. 2003; 284 (4): 1332-9.

59. Castro-Chaves P, Fontes-Carvalho R, Pintalhao M, Pimentel-Nunes P, Leite-Moreira AF. Angiotensin II-induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart. Exp Physiol. 2009; 94 (6): 665-74.

60. Ladeiras-Lopes R, Ferreira-Martins J, Leite-Moreira AF. Acute neurohumoral modulation of diastolic function. Peptides. 2009; 30 (2): 419-25.

61. Periasamy M, Jansen PM. Molecular basis of diastolic dysfunction. Heart. Fail Clin. 2008; 4 (1): 13-21.

62. Gupta D, Palma J, Molina E, Gaughan JP, Long W, Houser S, et al. Improved exercise capacity and reduced systemic inflammation after adenoviral-mediated SERCA-2a gene transfer. J Surg Res. 2008; 145 (2): 257-65.

63. Schmidt U, del Monte F, Miyamoto MI, Matsui T, Gwathmey JK, Rosenzweig A, et al. Restoration of diastolic function in senescent rat hearts through adenoviral gene transfer of sarcoplasmic reticulum Ca(2þ)-ATPase. Circulation. 2000; 101 (7): 790-6.

64. Goldsmith SR. Type 5 Phosphodiesterase inhibition in heart failure: the next step. J Am Coll Cardiol. 2007; 50 (22): 2145-7.

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7. REVIEW ARTICLE

“The Pathophysiology of Heart Failure Preserved Ejection Fraction and Its Therapeutic Implications”

Fisiopatologia da Insuficiência Cardíaca com FE Preservada e suas Implicações

Terapêuticas [6]RICARDO FONTES-CARVALHO (1,2); ADELINO LEITE-MOREIRA(1,3)

1 Serviço de Fisiologia da Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 2 Serviço de Cardiologia do Centro Hospitalar de Vila Nova de Gaia, Vila Nova de Gaia, Portugal; 3 Centro de Cirurgia Torácica do Hospital de São João, Porto, Portugal

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RESUMO

A insuficiência cardíaca com fracção deejecção preservada (ICFEP) é uma síndrome

muito frequente, representando cerca de 50%do total dos casos de IC. É uma doença

sobretudo do idoso, que está associada amúltiplas comorbilidades e que possui um

prognóstico sombrio, com elevadas taxas demortalidade e um profundo impacto na

qualidade de vida dos doentes.Surpreendentemente, apesar da sua crescente

relevância clínica, o tratamento da ICFEPpermanece, ainda hoje, largamente empírico e

não baseado na evidência. Talvez por isto, setenha observado que o tratamento

“convencional” desta entidade não se tenhatraduzido numa melhoria significativa do

prognóstico destes doentes.Pretende-se com esta revisão explorar

sucintamente as bases fisiopatológicas daICFEP e, em seguida, aplicá-las à práticaclínica do dia-a-dia, analisando quais as

melhores estratégias terapêuticas e quais asclasses de fármacos a utilizar nestes doentes.

Além disso, abordaremos como é que acompreensão da fisiopatologia desta doença

poderá ajudar a desenvolver novos tratamentospara a ICFEP, que possam demonstrar, pela

primeira vez, uma melhoria efectiva doprognóstico destes doentes.

Para já, o tratamento da ICFEP deve ser multi-factorial, multidisciplinar e individualizado a

cada doente.

Palavras-Chave

Insuficiência Cardíaca; Diástole; Fracção Ejecção

Preservada; Fisiopatologia; Tratamento

ABSTRACT

The Pathophysiology of Heart Failure withPreserved Ejection Fraction and ItsTherapeutic Implications

Heart failure with preserved ejection fraction(HFPEF) is a common syndrome, accountingfor nearly one half of all heart failure patients.It mostly affects the elderly, usually withmultiple comorbidities, and has a poorprognosis, with high mortality rates and asignificant impact on quality of life.Nevertheless, evidence-based therapeuticstrategies for the management of HFPEF arestill lacking, and so treatment remains largelyempirical. This is probably why currenttreatment of HFPEF has not led to a significantimprovement in prognosis.In this review article we will discuss thepathophysiology of HFPEF and its implicationsfor the best treatment strategies to apply inthese patients. We will also review theevidence supporting the use of each therapy inHFPEF. In addition, we will consider how anunderstanding of the pathophysiology ofHFPEF can help in developing newtherapeutic strategies that will improve theprognosis of this syndrome.Until new evidence-based clinical data areavailable, treatment of HFPEF should remainmultidisciplinary and individualized to eachpatient.

Key words

Heart failure; Diastole; Preserved ejection fraction;

Pathophysiology; Treatment

Recebido para publicação: Setembro de 2008 • Aceite para publicação: Outubro de 2008Received for publication: September 2008 • Accepted for publication: October 2008

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INTRODUÇÃO

Ainsuficiência cardíaca (IC) constitui umimportante e crescente problema de saúde

pública na sociedade actual, afectando 1-2 % dapopulação adulta dos países desenvolvidos.

Os doentes com IC são classicamente divididosem dois grupos: os que apresentam IC com fracçãode ejecção preservada (ICFEP), também chamadaIC diastólica, e aqueles com IC e redução dafracção de ejecção (ICFER), mais conhecida comoIC sistólica. Esta divisão, que é questionada poralguns, tem por base as diferenças entre estas duasentidades relativamente às suas característicasdemográficas e epidemiológicas, à estrutura efunção ventricular, e ainda, quanto às caracte-rísticas a nível histológico e molecular (1) (2).

Uma parte da polémica em torno da ICFEPresultava da ausência de consenso quanto aos seuscritérios de diagnóstico. Esta limitação foirecentemente ultrapassada após a publicação deum documento de consenso da SociedadeEuropeia de Cardiologia com a actualização doscritérios de diagnóstico da ICFEP (3).

Os doentes com ICFEP caracteristicamente sãoidosos, mais frequentemente do sexo feminino, eapresentam uma elevada prevalência dehipertensão, diabetes, obesidade, fibrilaçãoauricular e disfunção renal (4-7). Comparados com osdoentes com ICFER, apresentam menosfrequentemente doença coronária.

A ICFEP é uma entidade muito frequente,representando cerca de 50% de todos os doentescom IC (2,4,7). Esta proporção aumenta com a idade,podendo atingir mais de 60% dos doentes com ICe idade superior a 85 anos. Além disso, tem-severificado que a proporção de doentes com IC euma FE normal, tem vindo a aumentarsignificativamente nas últimas duas décadas,tendo passado de 38% para 54% do total de casosde IC(2). Espera-se que, nas próximas décadas, estaproporção continue a aumentar, devido aoprogressivo envelhecimento da população e aoexpectável aumento da prevalência da hiper-tensão, da obesidade e da diabetes.

Tradicionalmente a ICFEP era vista como umadoença essencialmente “benigna”, estandoassociada a um bom prognóstico. Contudo, osdados mais recentes têm demonstrado, de formaconsistente, que o prognóstico destes doentes é tãomau como o daqueles que apresentam uma fracçãode ejecção diminuída. Na verdade, os doentes com64

INTRODUCTION

Heart failure (HF) is a major and growingpublic health problem today, affecting 1-2%

of the adult population in developed countries.Patients with HF are conventionally divided

into two groups: those with preserved ejectionfraction (HFPEF), also known as diastolic HF,and those with reduced ejection fraction(HFREF), more commonly known as systolic HF.This distinction, which is questioned by some, isbased on differences between the two entities interms of demographic and epidemiologicalcharacteristics, ventricular structure andfunction, and histological and molecular features (1, 2).

One factor in the controversy surroundingHFPEF was the lack of consensus concerningdiagnostic criteria. This limitation has recentlybeen overcome with the publication of aconsensus statement by the European Society ofCardiology updating the diagnostic criteria forHFPEF (3).

HFPEF patients are typically elderly andmainly female, and have a high prevalence ofhypertension (HT), diabetes, obesity, atrialfibrillation and renal dysfunction (4-7). They alsohave a lower prevalence of coronary arterydisease than patients with HFREF.

HFPEF is a very common syndrome,accounting for around 50% of all HF patients (2, 4, 7). This percentage increases with age,and can be over 60% in patients aged over 85years. Furthermore, the proportion of HF patientswith normal EF has increased significantly in thelast twenty years, from 38% to 54% of all cases (2).This percentage is expected to increase further incoming decades, due to ageing populations andthe predicted rise in the prevalence ofhypertension, obesity and diabetes.

Traditionally, HFPEF was seen as anessentially ‘benign’ disease, associated with agood prognosis. However, more recent data haveconsistently shown that prognosis in thesepatients is as poor as in those with reducedejection fraction. Patients with HFPEF presentmortality rates at one year of 29% (compared to32% in those with HFREF), and 65% at fiveyears (versus 68%) (2). Morbidity is also high, withfrequent hospitalizations and a significantconsumption of resources. Once admitted for HF,patients have a 50% probability of being

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ICFEP apresentam taxas de mortalidade ao fim deum ano de 29% (versus 32% nos doentes comICFER), e de 65% ao fim de cinco anos (versus68%) (2). A morbilidade é igualmente muitoelevada, com necessidade de hospitalizaçõesfrequentes e de um consumo muito significativo derecursos. Uma vez hospitalizados por IC, estesdoentes têm uma probabilidade de 50% de seremre-hospitalizados nos 12 meses seguintes (8). Estesdados vêm demonstrar que a ICFEP é, não só, umacondição frequentemente letal, como tambémmuito incapacitante, causando uma deterioraçãomarcada na qualidade de vida destes doentes.Igualmente preocupantes são as evidências quedemonstram que a sobrevida dos doentes comICFEP não tem vindo a aumentar nos últimos anos,contrariamente aquilo que tem sido observado nosdoentes com ICFER (2). Isto leva a crer que,aparentemente, o tratamento e a abordagem destesdoentes não estão a ser os mais correctos.

Na verdade, apesar da sua relevância clínica eepidemiológica, sabemos que a abordagemterapêutica dos doentes com ICFEP permanecelargamente empírica e não baseada na evidência.Até à data, poucos têm sido os ensaios clínicosconduzidos nesta população de doentes.

Desta forma, urge inverter o estado actual daabordagem da ICFEP. São necessários maisensaios clínicos randomizados e de larga escalaenvolvendo doentes com ICFEP e é importante odesenvolvimento de alternativas terapêuticasinovadoras e especificamente dirigidas aotratamento desta entidade.

Até lá, e até ao aparecimento de novasevidências, os dados fisiopatológicos que actu-almente dispomos podem ser transpostos eaplicados à prática clínica do dia-a-dia, ajudandoa orientar a abordagem do doente com ICFEP.Além disso, só a compreensão detalhada dafisiopatologia desta entidade permitirá oaparecimento de novas terapêuticas que possamfinalmente inverter o prognóstico da ICFEP.

FISIOPATOLOGIA DA ICFEP

A disfunção diastólica desempenha um papelcentral na fisiopatologia da ICFEP, pelo que estaentidade é também designada por IC diastólica. Naverdade, praticamente todos os doentes com ICFEPapresentam anomalias na função diastólica (9).

Contudo, além das anomalias da função

rehospitalized within 12 months (8). These findingsdemonstrate that HFPEF is not only frequentlyfatal but also seriously disabling, resulting in amarked deterioration in quality of life. Equallyworrying is the fact that survival in HFPEFpatients has not improved in recent years, incontrast to what has been seen for patients withHFREF (2). This leads to the conclusion thattreatment and management of these patients maynot be the most appropriate.

Despite its clinical and epidemiologicalimportance, evidence-based therapeutic strate-gies for the management of HFPEF are stilllacking and treatment remains largely empirical.To date, few clinical trials have been conductedin this patient population.

There is thus a pressing need to change thecurrent approach to HFPEF. More large-scalerandomized clinical trials in HFPEF patients arerequired in order to develop innovativetherapeutic alternatives specifically aimed attreatment of this entity.

Until new evidence appears, thepathophysiological data currently available canbe applied to everyday clinical practice to helpguide the management of patients with HFPEF.In the meantime, only a thorough understandingof the pathophysiology of this entity can lead tothe development of new therapeutic strategiesthat will finally improve the prognosis of thissyndrome.

PATHOPHYSIOLOGY OF HFPEF

Diastolic dysfunction (DD) plays a central rolein the pathophysiology of HFPEF, which is why itis also known as diastolic HF; practically allHFPEF patients present abnormalities indiastolic function (9).

However, besides DD, other patho-physiological mechanisms have recently been putforward that may contribute to HFPEF. Theseinclude increased ventricular and arterialstiffness, poor ventricular-arterial coupling,increased central volume, neurohumoralactivation and impaired chronotropic andvasodilator reserve during exercise (10-12).These new discoveries have led to HFPEF beingseen as a more heterogeneous entity, and thereare probably different patient subgroups in whomthe relative importance of the various 65

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diastólica, têm surgido mais recentemente outrosmecanismos adicionais que são potenciaiscontribuidores para a fisiopatologia da ICFEP.Nestes incluem-se o aumento da rigidez ventri-cular e arterial, o mau acoplamento ventriculo--arterial, o aumento do volume dito “central”, aactivação neuro-humoral e a diminuição dasreservas cronotrópica e vasodilatadora durante oexercício físico (10-12). Estas novas descobertas, têmcontribuído para uma visão da ICFEP como umaentidade mais “heterogénea”, provavelmente comvários subgrupos de doentes em que as váriasalterações fisiopatológicas poderão representaruma importância relativa distinta, mas em que adisfunção diastólica permanece como a principalalteração subjacente.

Em seguida, serão abordados os principaismecanismos fisiopatológicos envolvidos na ICFEP,com um óbvio enfoque na disfunção diastólica.

Diástole e Disfunção DiastólicaA presença de uma função diastólica normal

permite que o ventrículo encha rápida ecompletamente, enquanto mantém pressõesdiastólicas normais, quer em repouso, querdurante o exercício. De um ponto de vista maisredutor, a função diastólica pode ser vista como acapacidade do ventrículo de relaxar e de encher.

A diástole é determinada por dois processos:pelo relaxamento activo do miocárdio e pelaspropriedades passivas do ventrículo. Deste modo,a disfunção diastólica resulta de alterações dorelaxamento ventricular e/ou do aumento darigidez ventricular.

Alterações do Relaxamento Ventricular eseus Determinantes

O relaxamento é o processo através do qual omiocárdio regressa ao seu comprimento e tensãode repouso. O relaxamento é modulado por trêsdeterminantes: pela carga, pela inactivação e pelanão-uniformidade (13).

Os efeitos da carga no relaxamento domiocárdio dependem do tipo de carga (pré ou pós-carga), da sua magnitude, duração e do momentono ciclo cardíaco em que é aplicada. A relevânciada carga como um importante modulador dorelaxamento do miocárdio pode ser observada nosdoentes com crise hipertensiva aguda, que é umfactor precipitante frequente de agudizações daICFEP (14). Neste contexto, o aumento súbito dapressão arterial impõe ao ventrículo esquerdo um

pathophysiological changes varies, but diastolicdysfunction remains the main underlyingalteration.

The main pathophysiological mechanismsinvolved in HFPEF are discussed below, focusingparticularly on diastolic dysfunction.

Diastole and diastolic dysfunctionNormal diastolic function enables rapid and

complete ventricular filling, while maintainingnormal diastolic pressures at rest and duringexercise. In essence, diastolic function can beseen as the ability of the ventricle to relax and fill.

Diastole is governed by two factors: the activerelaxation of the myocardium and the passiveproperties of the ventricle. Thus, diastolicdysfunction can result from abnormalities inventricular relaxation and/or from increasedventricular stiffness.

Abnormalities in ventricular relaxation andtheir causes

Relaxation is the process by which themyocardium regains its resting length and tensionand is determined by three factors: load,inactivation and non-uniformity (13).

The effects of load on myocardial relaxationdepend on its type (pre- or afterload), itsmagnitude and duration, and the point in thecardiac cycle at which it is applied. The effect ofload conditions on myocardial relaxation can beobserved in patients with acute hypertensivecrisis, which is a common trigger fordecompensated HFPEF (14). In this situation, thesudden increase in blood pressure increases leftventricular (LV) afterload, which in turn delaysventricular relaxation, leading to diastolicdysfunction, which contributes to worsening ofpulmonary congestion.

Inactivation refers to the processes by whichcalcium is removed from the cytosol andactin/myosin cross bridges are detached.Ventricular relaxation can be altered by changesin calcium homeostasis or in the proteinregulators of cross bridge cycling (15). Patients withdiastolic dysfunction frequently present reducedactivity of SERCA (the main protein responsiblefor extrusion of cytoplasmic calcium) or reducedphosphorylation of the proteins regulatingSERCA function, such as phospholamban,calmodulin and calsequestrin. Moreover,relaxation is an active process that requires66





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aumento da pós-carga que, por sua vez, induz umatraso no relaxamento ventricular promovendo,desta forma, disfunção diastólica, o que contribuipara o agravamento dos sintomas de congestãopulmonar.

Por sua vez, a inactivação diz respeito aosprocessos pelos quais o cálcio é removido docitoplasma e as pontes cruzadas de actina emiosina se dissociam. O relaxamento ventricularpode ser alterado por alterações na homeostasia docálcio ou por alterações das proteínas reguladorasdo ciclo das pontes cruzadas (15). Na verdade,doentes com disfunção diastólica apresentamfrequentemente diminuição da actividade daSERCA (a principal proteína responsável pelaextrusão de cálcio do citoplasma) ou do estado de fosforilação das proteínas que regulam aactividade da SERCA, como sejam o fosfolamban,a calmodulina e a calsequestrina. Além disso, orelaxamento é um processo activo, envolvendogasto de energia (ATP) pelo que, qualquer déficeenergético vai alterar o relaxamento do miocárdio.É por isso que as alterações do relaxamento e,consequentemente, do enchimento ventricular sãoas primeiras manifestações que ocorrem naisquemia do miocárdio, ainda antes de ocorrercompromisso da função sistólica (16).

Aumento da Rigidez VentricularA disfunção diastólica também pode ocorrer

devido a alterações das propriedades passivas doventrículo, nomeadamente da rigidez ventricular.Na verdade, o aumento da rigidez ventricular fazcom que pequenos aumentos do volume ven-tricular causem um aumento marcado das pressõesintraventriculares.

O aumento da rigidez do miocárdio pode sercausado por factores intrínsecos aos cardiomiócitos(por exemplo, alterações nas proteínas docitosqueleto) ou por alterações da matrizextracelular (nomeadamente alterações da rede decolagéneo) (15). Sabe-se que os doentes com ICFEPtêm ventrículos mais rígidos devido em parte ahipertrofia dos cardiomiócitos e/ou a alterações nasisoformas de titina (uma proteína do citosqueletoque é a principal determinante da tensão passiva do cardiomiócito). O aumento da rigidez tambémpode ser devido a factores extramiocárdicos,nomeadamente ao aumento da fibrose e daquantidade de colagéneo extra-celular (13).

energy expenditure (consumption of ATP), so anyenergy deficit will affect myocardial relaxation.This is why changes in relaxation, and henceventricular filling, are the first manifestations ofmyocardial ischemia, before any impairment insystolic function is observed (16).

Increased ventricular stiffnessDiastolic dysfunction can also occur due to

changes in the passive properties of the ventricle,particularly increased stiffness, as a result ofwhich small increases in ventricular volume leadto a marked increase in intraventricularpressures.

Increased myocardial stiffness may be causedby factors intrinsic to cardiomyocytes (forexample, alterations in cytoskeletal proteins) orby changes in the extracellular matrix(particularly alterations in the collagen network) (15). Patients with HFPEF have increasedventricular stiffness, due in part to cardiomyocytehypertrophy and/or changes in isoforms of titin (acytoskeletal protein that plays an important rolein determining the passive tension ofcardiomyocytes). Increased stiffness can also bedue to extramyocardial factors, particularlyworsening fibrosis and high levels of extracellularcollagen (13).

Hemodynamic changes in HFPEFAs a result of diastolic dysfunction, HFPEF

patients exhibit characteristic hemodynamicchanges. Increased ventricular stiffness shifts theend-diastolic pressure-volume relation leftwardand upward (Figure 1C). Thus, in a patient withincreased ventricular stiffness, a givenventricular volume is only attained with muchhigher filling pressures than those observed forthe same volume in a normal individual. Inaddition, in the presence of diastolic dysfunction,the slope of the end-diastolic pressure-volumerelation is steeper. This means that smallvariations in central volume lead to largevariations in intraventricular pressure andconsequently in ventricular filling pressures(Figure 1C)

Assessing degree of diastolic dysfunctionEchocardiography plays an essential role in

diagnosing HFPEF and characterizing the degreeof DD, which, as discussed below, is importantsince it can have major therapeutic implications. 67



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Alterações Hemodinâmicas na ICFEPDevido à disfunção diastólica que apresentam,

os doentes com ICFEP exibem alteraçõeshemodinâmicas características. O aumento darigidez ventricular promove um deslocamento paraa esquerda e para cima da relação pressão-volumetelediastólica (ver painel C, Figura 1). Destemodo, num ventrículo com rigidez aumentada, umdeterminado volume ventricular só é alcançado àcusta de pressões de enchimento muito superioresàquelas observadas para o mesmo volume, numindivíduo normal. Além disso, pode ser tambémobservado na Figura 1 que, na presença dedisfunção diastólica, o declive da relação pressão-volume telediastólica é mais acentuado. Isto fazcom que, nestas circunstâncias, pequenasvariações do volume dito “central” levem agrandes variações da pressão intraventricular e,

Based on echocardiographic findings,particularly transmitral Doppler flow and tissueDoppler, DD can be classified into four grades (17)

(Figure 2). In the normal individual (Figure 2A),there is a peak in transmitral flow velocity at thebeginning of diastole (E wave), followed by asecond peak during atrial contraction (A wave).In grade I DD (Figure 2B), there is delayedrelaxation, in which transmitral flow velocity islower at the beginning of diastole (reduced Ewave velocity), and so the flow is greater mainlyduring atrial contraction (increased A wavevelocity); this causes a reversal of the E/A ratioand an increase in diastolic deceleration time(DDT). In grade II DD (Figure 2C), most leftventricular filling once again takes place at thebeginning of diastole, since with worseningdiastolic dysfunction, LV pressure at the end of

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Figura 1. Ansas e Relações Pressão-Volume (P-V) Ventriculares Esquerdas na Disfunção Sistólica e Diastólica

Figure 1. Left ventricular pressure-volume loops and relations in systolic and diastolic dysfunction

Nos painéis A, B e C estão representadas a tracejado as ansas e relações P-V de um coração normal. A linha 1 corresponde à relação pressão-volumetelediastólica, a linha 2 à ansa P-V e a linha 3 à relação pressão-volume telessistólica. Na presença de disfunção sistólica (painel B, linha a cheio) observa-se uma diminuição da fracção de ejecção (traduzida pela menor largura da ansa P-V) e umaredução da contractilidade miocárdica, expressa pelo menor declive da relação P-V telessistólica (seta). Na disfunção sistólica há aumento das pressões deenchimento devido a um deslocamento da ansa P-V para a direita, ao longo da mesma relação P-V telediastólica.Pelo contrário, na disfunção diastólica (Painel C) a relação P-V telediastólica está deslocada para cima e para a esquerda (linha a cinzento). Isto faz com que umdeterminado volume de enchimento ventricular só seja alcançado à custa de pressões de enchimento muito superiores às observadas para o mesmo volume numindivíduo normal (ver pontos A e B do painel C). Além disso, na disfunção diastólica o próprio declive da linha da relação P-V telediastólica (declive da linhaa cinzento no painel C) também é maior em relação ao observado no indivíduo normal (linha 1, a tracejado, no painel C). Daqui resulta que, no indivíduo comdisfunção diastólica uma dada variação de volume ventricular provoca uma variação significativamente maior das pressões intraventriculares do que numindivíduo normal. No painel C as propriedades sistólicas estão normais, incluindo a fracção de ejecção e o declive e posição da relação pressão-volumetelessistólica.

The dotted lines in Figure 1A, B and C show the pressure-volume loops and relations in the normal heart. Line 1 corresponds to the end-diastolic pressure-volumerelation, line 2 to the pressure-volume loop, and line 3 to the end-systolic pressure-volume relation.In systolic dysfunction (Figure 1B, solid line), there is reduced ejection fraction (reflected in a narrower pressure-volume loop) and reduced myocardial contractility,expressed by the shallower slope of the end-systolic pressure-volume relation (arrow). There are also increased filling pressures due to the shift of the pressure-volumeloop to the right, along the same end-diastolic pressure-volume relation.By contrast, in diastolic dysfunction (Figure 1C), the end-diastolic pressure-volume relation is shifted upward and leftward (gray line). This means that any givenventricular filling volume will only be attained with far higher filling pressures than those observed for the same volume in a normal individual (points A and B inFigure 1C). In addition, the slope of the end-diastolic pressure-volume relation (gray line in Figure 1C) is also steeper than that observed in a normal individual(line 1, dotted, in Figure 1C). This means that, in diastolic dysfunction, a given change in ventricular volume produces a significantly greater variation inintraventricular pressures than in a normal individual. In Figure 1C, systolic properties are normal, including ejection fraction and the slope and position of the end-systolic pressure-volume relation.

Volume de LE

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consequentemente, das pressões de enchimentoventricular (ver painel C, Figura 1).

Avaliação do Grau de Disfunção DiastólicaA ecocardiografia desempenha um papel

essencial tanto no diagnóstico da ICFEP como naavaliação do grau de disfunção diastólica (DD). Acaracterização do grau de DD é relevante uma vezque, como será abordado posteriormente, poderáter importantes implicações terapêuticas.

Com base na avaliação ecocardiográfica,integrando sobretudo os dados do Doppler do fluxotransmitral e do Doppler Tecidular, podem serdefinidos quatro graus de disfunção diastólica(DD)(17) (ver Figura 2). No indivíduo normal (painelA, Figura 2), ocorre um pico na velocidade do fluxotransmitral no início da diástole (onda E), seguidoposteriormente de outro pico de velocidadedurante a contracção auricular (onda A). No grau Ide DD (painel B, Figura 2), ocorre um atraso dorelaxamento que faz com que a velocidade do fluxotransmitral seja menor no início da diástole (há

diastole is so high that the contribution of atrialcontraction is reduced once again. At this stage,transmitral flow is similar to that in the normalindividual (and hence is known as a pseudo-normal pattern), with the E wave again greaterthan the A wave. Differential diagnosis betweengrade II DD and normal function is mainly byanalyzing tissue Doppler velocities at the mitralannulus, and particularly the E/e’ ratio, which isincreased in all grades of diastolic dysfunction.Finally, increasing ventricular stiffness leads to arestrictive pattern (Figure 2D), which ischaracterized by a further increase in E wavevelocity, with a very high peak but rapiddeceleration (reduced DDT). This pattern isfound in grades III and IV diastolic dysfunction(depending on whether or not it is reversible) andis associated with poor prognosis.

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Figura 2. Velocidade do fluxo transmitral avaliada por Doppler (em cima) e velocidade do Doppler tecidular a nível do anel mitral (em baixo), nocoração normal e na presença de disfunção diastólica de gravidade crescente.

Figure 2. Transmitral flow velocity assessed by Doppler (top) and tissue Doppler velocity at the mitral annulus (bottom), in the normal heart and inthe presence of worsening diastolic dysfunction.

Legenda: DD - Disfunção diastólica; DDT - Tempo de desacelaração diastólica; E - velocidade de fluxo transmitral durante o enchimento ventricular precoce;A - velocidade de fluxo transmitral durante a contracção auricular; e’ - velocidade do Doppler tecidular a nível do anel mitral durante o enchimento ventricularprecoce; a’ - velocidade do Doppler tecidular a nível do anel mitral durante a contracção auricular.

DD: diastolic dysfunction; DDT: diastolic deceleration time; E: transmitral flow velocity during early ventricular filling; A: transmitral flow velocity during atrialcontraction; e’: tissue Doppler velocity at the mitral annulus during early ventricular filling; a’: tissue Doppler velocity at the mitral annulus during atrial contraction

A. Normal

A. Normal

B. Atraso Relaxamento(DD grau I)

B. Delayed relaxation(grade I DD)

C. Pseudonormal(DD GRAU)

C. Pseudonormal(grade II DD)

D. Padrão Restritivo(DD graus III e IV)

D. Restrictive pattern(grades III and IV DD)

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diminuição da velocidade da onda E), pelo que ofluxo é maior sobretudo durante a contracçãoauricular (aumento da onda A), o que causa umainversão da relação E/A e um aumento do tempode desaceleração diastólico (DDT). Com aprogressão da DD, surge o grau II (painel C,Figura 2). Nesta fase, a maior parte do enchimentodo VE passa a ocorrer novamente no início dadiástole uma vez que, com o agravar da disfunçãodiastólica, a pressão no VE no fim da diástole é tãoelevada que a contribuição da contracção daaurícula passa novamente a ser menor. Nesta faseo padrão do fluxo transmitral é semelhante ao doindivíduo normal (por isso é chamado padrão“pseudo-normal”), com uma onda E novamentesuperior à onda A. O diagnóstico diferencial entreeste grau II de DD e o normal faz-se sobretudorecorrendo à análise da velocidade do Dopplertecidular a nível do anel mitral, e, maisconcretamente, à relação E/e’, que está aumentadaem todos os graus de disfunção diastólica.Finalmente, com o agravamento da rigidezventricular surge o padrão restritivo (painel D,Figura 2). Este caracteriza-se por um novoaumento da velocidade da onda E, que se tornamuito elevada, mas com uma rápida desacelaraçãodeste fluxo (diminuição do DDT). Este padrãorestritivo está associado aos graus III e IV de DD(conforme este padrão seja ou não reversível,respectivamente) e está associado a um mauprognóstico.

Novos Mecanismos FisiopatológicosPotencialmente Envolvidos na ICFEP

Por tudo o que tem sido demonstrado, naICFEP as anomalias da função diastólicadesempenham um papel fundamental nafisiopatologia desta entidade (9). Além disso, pareceevidente que a progressão da disfunção diastólica- ou seja o agravamento progressivo das alteraçõesdo relaxamento e o aumento da rigidez ventricular- desempenha um papel fundamental noaparecimento dos sintomas. A título de exemplo, atransição da fase de doença cardíaca hiperten-siva assintomática para a ICFEP é causadapredominantemente pelo agravamento da DD (18).

Estes mecanismos não permitem, no entanto,compreender cabalmente a fisiopatologia destaentidade. Da investigação nesta área têm emergidooutros factores, incluindo factores extra-cardíacos,que se crê poderem também contribuir para oaparecimento da ICFEP (19). Assim, há evidências

New pathophysiological mechanismspotentially involved in HFPEF

As demonstrated above, abnormalities indiastolic function play a fundamental part in thepathophysiology of HFPEF (9). Furthermore, itappears that worsening diastolic dysfunction -progressive changes in relaxation and increasesin ventricular stiffness - plays an important rolein the appearance of symptoms. For example,progression from asymptomatic hypertensiveheart disease to HFPEF is mainly caused byworsening DD (18).

Such mechanisms do not, however, fullyexplain the pathophysiology of this entity. Otherfactors have emerged from research in this area,including extracardiac factors, that are alsobelieved to contribute to the development ofHFPEF (19). Evidence suggests that some HFPEFpatients have increased filling pressures due toan increase in effective circulating volume (20). Atthe same time, besides ventricular stiffness,increased arterial stiffness, endothelialdysfunction and changes in ventricular-arterialcoupling can exacerbate variations in bloodpressure and lead to the development of HFPEFin some patient subgroups (10-11). It has also beendemonstrated that exercise intolerance inpatients with HFPEF may be due to chronotropicincompetence, which results in the inability toincrease heart rate appropriately in response toexercise, and in reduced vasodilator reserve (12).More recently, based on echocardiographic dataobtained by speckle tracking, differences havebeen reported in ventricular stretching, radialdeformation and twisting between HF patientswith preserved and reduced ejection fraction (21).

TREATMENT OF HFPEF

Despite its high prevalence, poor prognosisand impact on public health, treatment of HFPEFremains largely empirical. Unlike HFREF, fewrandomized clinical trials have been conductedin these patients.

Thus, treatment of HFPEF consists ofrelieving symptoms and optimizing ventricularfilling parameters. The main therapeuticstrategies are blood pressure control, reduction ofventricular filling pressures (maintainingeuvolemia if possible), maintaining sinus rhythm to prevent tachycardia, neurohumoral70





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que sugerem que alguns doentes com ICFEPpossam ter um aumento das pressões deenchimento à custa de um aumento do volumecirculante efectivo (20). Por outro lado, além darigidez ventricular, o aumento da rigidez arterial, adisfunção endotelial e a alteração do acoplamentoventrículo-arterial podem exacerbar as variaçõesda pressão arterial e, dessa forma, causar odesenvolvimento de ICFEP em alguns subgruposde doentes (10-11). Foi ainda demonstrado que nosdoentes com ICFEP a intolerância ao esforço podeser também devida a uma incompetênciacronotrópica, que se traduz por uma incapacidadeem aumentar adequadamente a frequênciacardíaca em resposta ao exercício, e a umadiminuição da reserva vasodilatadora (12). Maisrecentemente, recorrendo a dados ecocardio-gráficos obtidos por speckle tracking foramdemostradas diferenças no estiramento, na rotaçãoe na torção ventriculares entre os doentes com ICcom FE preservada e com FE diminuída (21).

O TRATAMENTO DA ICFEP

Surpreendentemente, apesar da sua elevadaprevalência, do seu sombrio prognóstico e doimpacto na saúde pública, o tratamento da ICFEPpermanece largamente empírico. Contrariamenteao observado na ICFER, poucos são os ensaiosclínicos randomizados conduzidos nestes doentes.

Deste modo, a estratégia de tratamento destesdoentes passa pelo alívio sintomático e pelatentativa de optimização dos parâmetros deenchimento ventricular. Os princípios gerais dotratamento consistem no controlo da pressãoarterial, na redução das pressões de enchimentoventricular (tentando manter a euvolemia), namanutenção do ritmo sinusal evitando taquicardia,na modulação neuro-humoral, no tratamento dascomorbilidades subjacentes e no controlo dosfactores precipitantes de descompensação aguda.

Controlo da Pressão ArterialO controlo agressivo da pressão arterial é um

dos pontos fundamentais na abordagem dosdoentes com ICFEP, podendo desempenhar umimportante papel na prevenção da ICFEP, namelhoria da sintomatologia e na redução donúmero de descompensações agudas por IC.

É conhecida a forte associação epidemiológicaentre a HTA e a ICFEP pelo que, o tratamento

modulation, treatment of underlyingcomorbidities, and control of factors that maytrigger acute decompensation.

Blood pressure controlAggressive blood pressure control is crucial,

since it plays an important role in preventingHFPEF, improving symptoms and reducingepisodes of acute decompensation.

There is a strong epidemiological associationbetween hypertension and HFPEF, and so earlytreatment of HT helps prevent development ofsymptomatic diastolic dysfunction.

Treating HT in HFPEF patients can alsoreduce the incidence of decompensation for acuteHF. As stated above, a rapid rise in bloodpressure induces diastolic dysfunction throughdelayed ventricular relaxation. This explains whypatients with HFPEF present acute pulmonaryedema in the context of rapid and sharp rises inblood pressure (14).

Blood pressure control can also improvesymptoms in these patients. It has beendemonstrated that aggressive treatment of HTimproves diastolic function, particularlyventricular relaxation (22). In addition, it is knownthat HFPEF patients present not only increasedventricular stiffness but also arterial stiffness.This means that during exercise, these patientsshow a marked rise in blood pressure and hencedelayed ventricular relaxation and exerciseintolerance. Controlling this hypertensiveresponse during exertion would improve theirsymptoms.

Another advantage of antihypertensivetherapy in HFPEF is that it leads to regression ofleft ventricular hypertrophy (LVH) and improvedventricular-arterial coupling.

Importance of maintaining sinus rhythmIn normal diastolic function, most ventricular

filling takes place at the beginning of diastoleduring the rapid filling phase, with a relativelysmall contribution from atrial contraction. Inpatients with relaxation abnormalities,ventricular filling is reduced in the initial phaseof diastole and is more dependent on atrialfunction (see above). Thus, in these patients,atrial fibrillation (AF), with loss of atrialcontraction, can lead to hemodynamicdeterioration and hence decompensation. New-onset AF in these patients is one of the most 71



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precoce da HTA previne o desenvolvimento dedisfunção diastólica sintomática.

O tratamento da HTA na ICFEP pode tambémdiminuir o número de descompensações por ICaguda. Como foi dito previamente, uma elevaçãorápida da pressão arterial induz disfunçãodiastólica, porque causa atraso no relaxamentoventricular. Isto explica porque é que os doentescom ICFEP apresentam episódios de edema agudodo pulmão no contexto de aumentos rápidos emarcados da pressão arterial (14).

O controlo da pressão arterial pode aindamelhorar a sintomatologia destes doentes. Estádemonstrado que o tratamento agressivo da HTAmelhora a função diastólica, nomeadamente orelaxamento ventricular (22). Além disso, sabe-seque os doentes com ICFEP, apresentam aumentosnão só da rigidez ventricular como também darigidez arterial. Isto faz com que, durante o esforço,estes doentes tenham uma elevação exagerada dapressão arterial e consequentemente, um atraso dorelaxamento ventricular e intolerância ao esforço.O controlo desta resposta hipertensiva ao esforçopermitirá melhorar a sintomatologia destesdoentes.

Outros benefícios do tratamento anti-hiperten-sor na ICFEP são a indução de regressão da HVEe uma melhoria do acoplamento ventrículo-arterial.

Importância de Manter o Ritmo SinusalNo indivíduo com função diastólica normal a

maior parte do enchimento ventricular ocorre noinício da diástole, durante a fase de enchimentorápido, sendo relativamente pequena a contri-buição da contração auricular. Nos doentes comalteração do relaxamento, o enchimento doventrículo é menor na fase inicial da diástoleficando mais dependente da função auricular (verem cima). Deste modo, nestes doentes oaparecimento de fibrilação auricular (FA), com aperda da contracção da aurícula, pode levar a umadeterioração hemodinâmica e consequentemente adescompensação da IC. Nestes doentes, oaparecimento de FA de novo é um dos maisfrequentes factores precipitantes de descom-pensação e de hospitalização por IC aguda (6).

Quando a ICFEP está associada a FA, arealização de cardioversão farmacológica oueléctrica parece ajudar a manter um débitocardíaco adequado, através da manutenção dacontracção auricular.

common triggers for decompensation andhospitalization for acute HF (6).

When HFPEF is associated with AF,pharmacological or electrical cardioversionappears to help maintain adequate cardiac outputthrough maintaining atrial contraction.

Treatment of comorbidities and othertriggering factors

HFPEF patients frequently present multiplecomorbidities, including hypertension, diabetes,obesity, ischemic heart disease and renal failure.Besides uncontrolled hypertension and atrialarrhythmias (particularly AF), other commonfactors triggering episodes of decompensation arepoor adherence to therapy, increased salt andwater intake, ischemia (as mentioned above) andinfection. It is therefore essential to adopt anintegrated and multidisciplinary approach tosuch factors in HFPEF, so as to reduce not onlycardiovascular morbidity and mortality and thenumber of episodes of decompensated HF, butalso associated complications.

Use of specific drugs in HFPEF1. Diuretics

HFPEF patients are highly sensitive tochanges in volume and preload, since theypresent a steep slope in the end-diastolicpressure-volume relation (Figure 3). Thisexplains why increased salt and water intake is acommon trigger for acute decompensated HF andalso why these patients are extremely sensitive todiuretic therapy.

The use of diuretics in HFPEF reducespulmonary venous pressure, and consequentlypulmonary congestion, by shifting the LV end-diastolic pressure-volume relation to a morefavorable, less steep position (Figure 3).Hemodynamic changes induced by diureticsand/or salt restriction relieve these patients’symptoms, particularly exercise intolerance.However, merely changing the position of LVvolume on the end-diastolic pressure-volumerelation only improves symptoms; it has noimpact on long-term survival, since it has noeffect on the underlying cause. A truly effectivetherapy would shift the end-diastolic pressure-volume relation downward and rightward (Figure 3). Thus, diuretics in HFPEF can be seenas similar to paracetamol for fever: they improvesymptoms and quality of life but do not change72





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Tratamento das Comorbilidades e de OutrosFactores Precipitantes

Os doentes com ICFEP apresentamfrequentemente múltiplas comorbilidades, nomea-damente hipertensão, diabetes, obesidade, doençacardíaca isquémica e insuficiência renal. Entre osfactores precipitantes de descompensação de IC éfrequente encontrar não só a hipertensão nãocontrolada e as arritmias auriculares (nomea-damente a FA) como também, a má adesão àterapêutica, o aumento do aporte de sal e água, aisquemia (também já abordada anteriormente) e asinfecções. Deste modo, na ICFEP é fundamentaluma abordagem integrada e multidisciplinardestes vários factores, de modo a permitir reduzirnão só a morbi-mortalidade cardiovascular e onúmero de episódios de descompensação de IC,mas também as complicações inerentes aosmesmos.

Utilização de Agentes FarmacológicosEspecíficos na ICFEP

1. DiuréticosOs doentes com ICFEP são extremamente

sensíveis a variações do volume e da pré-carga,uma vez que apresentam um declive acentuado darelação pressão-volume telediastólica (ver Figura3). É por isso que um aumento da ingestão de sal eágua funciona como um factor precipitantefrequente de descompensação por IC aguda e étambém por isso, que estes doentes são bastantesensíveis à terapêutica diurética.

Na verdade, a utilização de diuréticos naICFEP permite reduzir a pressão venosa pulmonare consequentemente a congestão pulmonar, aoinduzir um deslocamento do volume telediastólicodo VE para uma posição mais favorável, e menosinclinada, na relação pressão-volume tele-diastólica (ver Figura 3). Estas alteraçõeshemodinâmicas induzidas pelos diuréticos e/oupela restrição do aporte de sal, permitem reduzir asintomatologia destes doentes, nomeadamente aintolerância ao esforço. Contudo, terapêuticas que,como os diuréticos, apenas levam alteração daposição do volume do VE na curva de pressão-volume telediastólica, apenas melhoram asintomatologia e não têm impacto na sobrevida alongo prazo, uma vez que não influenciam a causasubjacente. Um agente realmente terapêuticodeverá ser capaz de deslocar a relação pressão-volume telediastólica para baixo e para a direita

the natural history of the underlying disease. Thiswas confirmed in a recent randomized study onthe use of diuretics in HFPEF, which showed thatthese agents improve patients’ quality of life butdo not increase survival (23).

At the same time, the sensitivity of HFPEFpatients to changes in volume, particularlycentral volume, means diuretics must be usedwith caution, since due to these patients’increased ventricular stiffness, they need higherdiastolic ventricular pressures in order tomaintain ventricular filling and hence adequatecardiac output. High doses of these agents canresult in excessive reduction in preload andejection volume, leading to hypotension (15).

In conclusion, diuretics should be used inmost HFPEF patients, but initially at low doseswith progressive dose titration. In general, lowerdoses are required than in patients with systolicHF.

2. NitratesThe use of nitrates in these patients may be

beneficial since these agents reduce centralvolume, helping to shift diastolic volume to amore favorable position on the end-diastolic 73


LV volume

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In patients with HFPEF (curve A), the end-diastolic pressure-volume relationhas a steep slope, which means that small changes in left ventricular volumecause marked variations in intraventricular pressures. The use of diuretics inHFPEF patients reduces LV volume, along the same end-diastolic pressure-volume relation (shown in the above figure by a shift of point 1 to point 2).Thus, by reducing intraventricular volume, even slightly, diuretics markedlyreduce end-diastolic pressure and LV filling pressures, and hence improvesymptoms. On the other hand, these patients require higher filling pressures tomaintain end-diastolic volume and cardiac output, and so diuretic therapyshould be carefully monitored. A truly effective treatment for HFPEF mustshift the end-diastolic pressure-volume relation downward and rightward(from A to B ? arrow), similar to the curve observed in the normal heart.

Figure 3. Hemodynamic effects of possible therapeutic interventions onthe left ventricular end-diastolic pressure-volume relation


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(ver Figura 3). Sendo assim, a utilização dediuréticos na ICFEP poderá ser equiparada àutilização de paracetamol para a febre, ou seja,resulta numa melhoria da sintomatologia e daqualidade de vida, não alterando a história natural da doença subjacente. Estes dados foram confirmados recentemente num estudorandomizado, em que foi avaliada a utilização dediuréticos na ICFEP, tendo sido demonstrado queestes agentes melhoram a qualidade de vida dosdoentes, mas não aumentam a sua sobrevida (23).

Por outro lado, a grande sensibilidade que estesdoentes apresentam a variações do volume, eparticularmente do volume dito “central”, tambémobriga a uma utilização judiciosa dos diuréticosneste contexto, uma vez que, devido ao aumento darigidez ventricular, estes doentes necessitam de pressões ventriculares diastólicas mais altaspara manter um enchimento ventricular e,consequentemente, um débito cardíaco adequado.A administração de doses elevadas destesfármacos pode causar uma diminuição excessivada pré-carga, e uma diminuição do volume de

pressure-volume relation. Moreover, nitrates,unlike diuretics, have a direct effect on themyocardium, leading to release of nitric oxide(NO), which appears to improve ventriculardistensibility (24). However, the use of nitrates inthis context has yet to be assessed in clinicaltrials.

3. Beta-blockersIn theory, beta-blockers have various potential

benefits in the treatment of HFPEF: by reducingheart rate they increase the duration of diastoleand hence ventricular filling time; they decreasemyocardial oxygen requirements, lower bloodpressure, and can induce regression of LVH. Onthe other hand, these beneficial effects may beweakened to some extent since beta-blockersdelay ventricular relaxation and have negativeinotropic and lusitropic effects.

The benefits of reduced heart rate may not bethe same for all patients with diastolicdysfunction. In grade I or II DD, duration ofdiastole is extremely important for ventricularfilling, and so beta-blockers and other negativechronotropic agents have a favorable effect onsymptoms by increasing the time of diastole. Bycontrast, in those with grade III or IV DD(restrictive pattern), LV filling takes place almostentirely during the first half of diastole. Thus,negative chronotropic therapy will be lessbeneficial in these patients, since they have afixed ejection volume and decreasing heart ratewill reduce cardiac output and therefore worsensymptoms. This is yet another example of theimportance of an individualized approach inthese patients.

Beta-blockers are recommended in allpatients with systolic HF, based on the data fromvarious clinical trials (25). However, despite thetheoretical advantages of these agents in HFPEF,there have been few studies assessing theirefficacy in this context (26). Data fromobservational studies indicate that beta-blockersin HFPEF reduce mortality (27). The SENIORStrial (28), which tested nebivolol in heart failurepatients aged over 70, found that in the subgroupof patients with EF >35% there was a non-significant tendency for nebivolol to have abeneficial effect on the composite endpoint ofdeath and cardiovascular hospital admission.However, since due to the low cut-off point of35% for EF this subgroup with ‘preserved’74

Figura 3. Efeitos hemodinâmicos de potenciais intervençõesterapêuticas na relação pressão-volume telediastólica do VE.

Os doentes com ICFEP (curva A) apresentam um elevado declive darelação pressão-volume telediastólica, o faz com que pequenas variaçõesdo volume VE causem variações marcadas das pressões intraventriculares.A administração de diuréticos nos doentes com ICFEP permite diminuir ovolume do VE, ao longo da mesma linha de relação pressão-volumetelediastólica (visível na figura por um deslocamento do ponto 1 para oponto 2). Desta forma, os diuréticos ao causarem uma diminuição, mesmoque ligeira, do volume intraventricular levam a uma redução acentuada dapressão telediastólica e das pressões de enchimento do VE, induzindo umamelhoria da sintomatologia. Por outro lado, estes doentes necessitam depressões de enchimento mais elevadas para manter o volume telediastólicoe o débito cardíaco, pelo que o uso de diuréticos deve ser cuidadosamentemonitorizado. Um agente realmente terapêutico para a ICFEP deverá sercapaz de deslocar a relação pressão-volume telediastólica para baixo e paraa direita (de A para B, seta), ou seja, para a curva observada no oraçãonormal.

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ejecção com, consequentes episódios dehipotensão (15).

Em conclusão, nos doentes com ICFEP osdiuréticos devem ser utilizados na grande maioriados doentes, mas inicialmente em doses baixas,com posterior titulação progressiva da dose. Emgeral, são necessárias doses mais baixas que asutilizadas habitualmente no doente com ICsistólica.

2. NitratosA utilização de nitratos nestes doentes

poderá ser benéfica uma vez que estes fármacosdiminuem o volume “central”, ajudando adeslocar o volume diastólico para uma posiçãomais favorável na curva pressão-volumetelediastólica. Além disso, os nitratos, contra-riamente aos diuréticos, têm efeitos directossobre o miocárdio, levando à libertação de óxidonítrico, o que parece induzir uma melhoria dadistensibilidade ventricular (24). Contudo, autilização de nitratos neste contexto não foiainda objecto de análise em nenhum ensaioclínico.

3. Bloqueadores BetaDe um ponto de vista conceptual, os

bloqueadores beta (BB) têm vários benefíciospotenciais no tratamento da ICFEP: aoreduzirem a frequência cardíaca aumentam aduração da diástole e o tempo de enchimentoventricular; reduzem as necessidades deoxigénio do miocárdio; diminuem a pressãoarterial; podem induzir regressão da HVE. Poroutro lado, estes efeitos benéficos poderão serparcialmente atenuados porque os BB atrasam orelaxamento ventricular e têm efeitosinotrópicos e lusitrópicos negativos.

Os benefícios da diminuição da frequênciacardíaca podem não ser idênticos em todos osdoentes com disfunção diastólica. Nosindivíduos com disfunção diastólica (DD) dosgraus I e II, a duração da diástole é muitoimportante para o enchimento ventricular peloque, os BB ou outros agentes cronotrópicosnegativos providenciam uma respostasintomática favorável, ao induzirem um aumentodo tempo de diástole. Pelo contrário, em doentescom DD dos graus III ou IV (padrão restritivo),o enchimento do VE processa-se quaseinteiramente na primeira metade da diástole. Ouseja, nestes últimos graus de DD, a terapêutica

ejection fraction included patients with LVsystolic dysfunction, the clinical importance ofthese results for the population with HFPEFremains unclear. Nebivolol has three potentiallyuseful characteristics in HFPEF: it is a negativechronotropic agent, it has antihypertensive effectsand, due to its vasodilator properties linked to NOrelease, it increases arterial and possiblyventricular distensibility, thus improvingventricular-arterial coupling.

To summarize, the use of beta-blockers inclinical practice for patients with HFPEF appearsto be beneficial; they are generally well toleratedand gradual titration of the dose is unnecessary,unlike in systolic HF. The only exception is forpatients with grade III or IV diastolic dysfunction(restrictive pattern).

4. Other negative chronotropic agentsCalcium channel blockers, particularly

verapamil and diltiazem, are also theoreticallyattractive in HFPEF treatment due to theirnegative chronotropic and blood pressurelowering effects. Small prospective studies havedemonstrated that verapamil compared toplacebo improves these patients’ quality of life byrelieving symptoms and increasing exercisecapacity (29, 30).

Ivabradine, a selective sinus node If currentinhibitor, selectively reduces heart rate with theadvantage that, unlike beta-blockers, it does notdelay relaxation or reduce contractility. In animalmodels of HF, ivabradine was shown to havebeneficial effects on myocardial function and toreduce LV collagen density (31). The possiblebenefits of this agent in HFPEF are for nowpurely theoretical, in the absence of experimentalevidence.

Recent evidence suggests that HFPEFpatients present chronotropic incompetence andthat this may be partly responsible for theirexercise intolerance (12). Thus, heart rate controlshould be approached with caution since if it istoo aggressive, it may be poorly tolerated bycertain patients, particularly those with grade IIIor IV diastolic dysfunction.

5. Renin-angiotensin system modulatorsActivation of the renin-angiotensin-

aldosterone system raises blood pressure,stimulates salt and water retention in the kidneys,and promotes myocardial fibrosis and ventricular 75



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cronotrópica negativa não será tão benéfica,uma vez que estes doentes têm já um volume deejecção fixo pelo que, a diminuição dafrequência cardíaca irá causar uma diminuiçãodo débito cardíaco, com consequenteagravamento da sintomatologia. Este é mais umaspecto que sublinha a importância de umaabordagem terapêutica individualizada destesdoentes.

É sabido que a utilização dos BB estárecomendada em todos os doentes com ICsistólica, com base nos dados de vários ensaiosclínicos (25). Apesar das supracitadas vantagensteóricas destes agentes na ICFEP, poucos têmsido os estudos a avaliar a sua eficácia nestecontexto (26). Dados extraídos de estudosobservacionais apontam para que a utilização deBB na ICFEP leve a uma diminuição damortalidade (27). No estudo SENIORS (28), em quefoi testado o nebivolol numa população dedoentes com insuficiência cardíaca e mais de 70anos de idade, observou-se que no subgrupo dedoentes com uma FE>35% houve umatendência, não significativa, para o benefício donebivolol em termos do endpoint composto demorte e hospitalização cardiovascular. Contudo,uma vez que este subgrupo com fracção deejecção “preservada” se encontra contaminadopor doentes com disfunção sistólica ventricularesquerda, devido ao cut-off baixo de 35% para aFE, permanece por esclarecer a relevânciaclínica destes resultados na população comICFEP. O nebivolol tem três característicaspotencialmente úteis na ICFEP: é um agentecronotrópico negativo, é um anti-hipertensor e,dadas as suas propriedades vasodilatadorasrelacionadas com a libertação de NO, aumenta adistensibilidade arterial (e potencialmentetambém a distensibilidade ventricular), melho-rando o acopolamento ventrículo-arterial.

Em resumo, a utilização na prática clínicados BB em doentes com ICFEP parece serbenéfica e sabe-se que estes agentes sãogeralmente bem tolerados, não sendo necessáriauma titulação lenta e progressiva da dose,contrariamente ao que ocorre na IC sistólica. Aúnica excepção parece ser nos doentes comdisfunção diastólica dos graus III e IV (padrãorestritivo).

4. Outros Agentes Cronotrópicos NegativosOs antagonistas dos canais de cálcio,

hypertrophy, all of which, in isolation or incombination, contribute to the development andprogression of diastolic dysfunction.

Thus, neurohumoral modulation of this systemis theoretically of benefit in patients with HFPEF.Various experimental studies in animals andhumans have in fact shown that inhibiting thissystem with angiotensin-converting enzymeinhibitors (ACEIs) or angiotensin receptorblockers (ARBs) improves diastolic function,induces regression of myocardial fibrosis anddecreases left ventricular mass (32, 33).

It is also known that left atrial (LA) dilatation,in the absence of an underlying cause, can beseen as a morphological expression of prolongeddiastolic dysfunction and that increased LAvolume is a marker of its chronicity (17). In patientswith LA dilatation, treatment with ACEIs orARBs leads to favorable remodeling of theatrium, an effect that is independent of bloodpressure reduction (34). Thus, particularly inpatients with LA enlargement, inhibiting therenin-angiotensin system reduces the risk of new-onset AF (35) and hence the number ofdecompensations for acute HF.

Moreover, ACEIs and ARBs have otherbeneficial effects in patients with multiplecomorbidities, such as diabetes, coronary diseaseand chronic renal failure. Among other effects,inhibition of the renin-angiotensin system in suchpatients reduces cardiovascular events (36) anddelays progression to renal failure.

On the available evidence, particularly ontheir neurohumoral effects, ACEIs and ARBs areprobably the antihypertensives of choice inHFPEF, since it has also been demonstrated thatlowering blood pressure with ARBs improvesdiastolic function (22).

Somewhat surprisingly, all these potentialbenefits have yet to be reflected in significantreductions in clinical events. In one of the fewrandomized clinical trials conducted specificallyin HFPEF patients - the CHARM-Preserved Trial- candesartan, compared to placebo, reduced thenumber of hospitalizations for heart failure, butdid not significantly reduce mortality (37).Similarly, the PEP-CHF study, which comparedperindopril to placebo in a similar population,showed that one year’s treatment with perindoprilimproved certain secondary endpoints,particularly symptom relief, increased exercisecapacity and reduced hospital admissions for HF,76





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particularmente o verapamil e o diltiazem, pelosseus efeitos cronotrópico negativo e de reduçãoda pressão arterial, são igualmente teoricamenteatractivos no tratamento da ICFEP. Estudosprospectivos de pequena dimensão demons-traram que o verapamil, em comparação com oplacebo, melhora a qualidade de vida destesdoentes, induzindo melhoria sintomática e dacapacidade de exercício (29) (30).

A ivabradina, um inibidor específico dacorrente If no nó sinusal, causa uma reduçãoselectiva da frequência cardíaca com avantagem de, contrariamente aos BB, nãoinduzir um atraso no relaxamento e não causaruma diminuição da contractilidade. Em modelosanimais de IC a ivabradina demonstrou efeitosbenéficos sobre a função do miocárdio e reduziua densidade de colagéneo no ventrículoesquerdo (31). Os potenciais benefícios desteagente no âmbito da ICFEP são, para já, apenasconceptuais carecendo de evidênciaexperimental.

Por outro lado, evidências recentes sugeremque os doentes com ICFEP apresentam in-competência cronotrópica, e que esta pode serparcialmente responsável pelos sintomas deintolerância ao esforço (12). Deste modo, ocontrolo da frequência cardíaca deve ser feitocom precaução uma vez que, se for muitoagressivo, pode ser mal tolerado por algunsdoentes, particularmente naqueles comdisfunção diastólica dos graus III e IV.

5. Moduladores do Eixo Renina-AngiotensinaA activação do eixo renina-angiotensina-

aldosterona contribui para a elevação da pressãoarterial, estimula a retenção renal de sódio eágua, promove a fibrose do miocárdio e ahipertrofia ventricular. Estes aspectos,isoladamente ou em conjunto, contribuem para oaparecimento e para a progressão da disfunçãodiastólica.

Desta forma, a modulação neuro-humoraldeste eixo é teoricamente benéfica nos doentescom ICFEP. Na verdade, vários estudosexperimentais realizados, quer em animais querem humanos, mostraram que a inibição desteeixo, com IECAs ou com ARAS, melhora afunção diastólica, induz a regressão da fibrosedo miocárdio e diminui a massa ventricularesquerda (32) (33).

Sabemos ainda que a dilatação da aurícula

but did not significantly improve survival (38). Boththese studies appear to indicate that inhibition ofthe renin-angiotensin system, while not affectingmortality, does at least lead to improved quality oflife for these patients, an important factor in anelderly population with multiple comorbidities.In contrast to the above findings, a recentprospective study demonstrated that in patientswith HFPEF the use of ACEIs after a firsthospitalization for decompensated HF wasassociated with a significant reduction (up to40%) in mortality at five years (39). Results fromthe I-PRESERVE study on irbesartan are to bepublished shortly.

6. Aldosterone antagonistsAldosterone has known effects on the

myocardium and blood vessels, promotingmyocyte hypertrophy, fibrosis and collagendeposition, all of which may contribute toincreased myocardial and arterial stiffness,leading to diastolic dysfunction (40).

To date, the use of aldosterone antagonists inthe context of HFPEF has been evaluated in onlyone small study involving around 30 patients,which demonstrated that spironolactoneimproved echocardiographic indices of diastolicdysfunction (41).

Based on their theoretical benefit, arandomized clinical trial - the TOPCAT study - iscurrently in progress aimed at assessing the roleof aldosterone antagonists in HFPEF patients.

7. DigoxinIn theory, digoxin would appear inappropriate

for patients with HFPEF, since by increasingintracytoplasmic calcium concentrations, itdelays myocardial relaxation. Moreover, as apositive inotropic agent, it would not bringsignificant benefits to patients with preservedsystolic function.

The DIG-PEF trial (42) found that the use ofdigoxin in HFPEF, while having no effect onmortality, was associated with a non-significanttendency for fewer hospital admissions for HF.However, digoxin did not reduce totalhospitalizations for cardiovascular cause, sinceits use was associated with more admissions forunstable angina. The mechanisms behind thepartial benefit of digoxin in reducing hospitaladmissions for HF remain to be determined, butmay be due to its negative chronotropic effect in 77



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esquerda (AE), na ausência de uma causaprecipitante subjacente, pode ser visto comouma expressão morfológica de disfunçãodiastólica prolongada e que o aumento dovolume da AE é um marcador de “cronicidade”da disfunção diastólica (17). Nos doentes comdilatação da AE, o tratamento com IECA ouARA induz uma remodelagem favorável daaurícula, efeito que é independente da reduçãoda pressão arterial (34). Desta forma, sobretudonestes doentes já com aumento da AE, ainibição do eixo renina-angiotensina reduz orisco de aparecimento de FA de novo (35),reduzindo-se assim número de descompen-sações por IC aguda.

Além disto, os IECAs e os ARAs apresentamoutros efeitos benéficos numa população queapresenta simultaneamente múltiplas comor-bilidades como, a diabetes, a doença coronáriaou a insuficiência renal crónica. Nestes doentesa inibição do eixo renina-angiotensina permite,entre outras coisas, uma redução dos eventoscardiovasculares (36) ou o atraso na progressão dainsuficiência renal.

Pelas evidências que têm sido apresentadas,e particularmente pelas suas acções neuro-humorais, os IECAs e os ARAS perfilam-seprovavelmente como os anti-hipertensores deeleição a utilizar na ICFEP, tendo sido in-clusivamente demonstrado que a redução dapressão arterial com ARAs melhora a funçãocardíaca diastólica (22).

Algo surpreendentemente, todos estesbenefícios potenciais não se traduziram aindanuma diminuição marcada dos eventos clínicos.Na verdade, num dos poucos ensaios clínicosrandomizados conduzidos especificamente napopulação de doentes com ICFEP - no estudoCHARM-Preserved - foi comparada a utilizaçãode candesartan versus placebo. A utilização decandesartan reduziu o número de hospita-lizações por insuficiência cardíaca, nãocausando uma diminuição significativa damortalidade (37). De igual forma, o estudo PEP-CHF, em que se comparou perindopril versusplacebo numa população semelhante,evidenciou que ao fim de um ano de tratamentoo perindopril melhorou alguns endpointssecundários, levando nomeadamente a umamelhoria da sintomatologia, a um aumento dacapacidade de exercício e uma diminuição dashospitalizações por IC. Não foi contudo

patients with AF, or its inhibition of thesympathetic system, stimulation of theparasympathetic system, and suppression of therenin-angiotensin-aldosterone system (43).

In conclusion, the role of digoxin in thetreatment of HFPEF has yet to be clarified (25). Itis therefore not recommended in all patients withHFPEF, and its use should be restricted tocontrolling heart rate in patients withconcomitant AF. Furthermore, in the elderly, thepopulation mainly affected by HFPEF, the risk ofdigitalis intoxication is greater, and so half theusual dose of digoxin should be used initially,with subsequent close monitoring of serum levels.

8. StatinsThe potential benefits of statins in HFPEF

patients are multiple, but can be divided into twogeneral categories. Firstly, due to their effect onlipid profile, statins reduce cardiovascular eventsin patients who, as mentioned above, havemultiple comorbidities and high cardiovascularmorbidity and mortality. Secondly, independentlyof changes in lipid profile, statins havepleiotropic effects that improve diastolic functionsuch as reducing myocardial hypertrophy andfibrosis, and enhancing endothelial function andarterial distensibility (44).

A small observational study confirmed thebenefits of statin therapy in HFPEF patients bydemonstrating that adding statins to conventionaltreatment appeared to reduce both morbidity andmortality in these patients (45). Controversyremains, however, since two recently publishedclinical trials on statins found no significantbenefits in populations with HF, although themajority of the patients had systolic HF (46, 47).

FUTURE PROSPECTS FOR THETREATMENT OF HFPEF

Alagebrium, also known as ALT-177, isamong the new drugs being investigated for thetreatment of HFPEF. It breaks the crosslinks thatform between advanced glycosylation end-products and proteins such as collagen. In theelderly, increased ventricular and arterialstiffness is partly due to the formation of thesecrosslinks, and in experimental modelsalagebrium improves ventricular distensibility,arterial compliance and ventricular-arterial78





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observado um aumento significativo dasobrevida com perindopril (38). Sendo assim,ambos os estudos apontam para que a inibiçãodeste eixo, parecendo não alterar a mortalidade,induz pelo menos uma melhoria da qualidade devida destes doentes, factor que é sem dúvidarelevante numa população envelhecida e commúltiplas comorbilidades. Contrariando estesdados, muito recentemente, um estudoprospectivo demonstrou que a utilização deIECA em doentes com ICFEP após umaprimeira hospitalização por IC descompensada,está associada a uma redução significativa, deaté 40%, da mortalidade ao fim de cinco anos (39).Aguardam-se os resultados do estudo I-PRESERVE, com irbesartan, a publicarbrevemente.

6. Antagonistas da AldosteronaSão conhecidos os efeitos da aldosterona

sobre o miocárdio e sobre os vasos promovendoa hipertrofia miocitária, a fibrose e a deposiçãode colagéneo. Estas acções, podem contribuirpara o aumento da rigidez miocárdica e arterial,levando a disfunção diastólica (40).

Até à data, a utilização dos antagonistas daaldosterona no contexto da ICFEP foi avaliadaapenas num pequeno ensaio, envolvendo cercade 30 doentes, em que se demonstrou que aespironolactona, melhorou os índices ecocar-diográficos de disfunção diastólica (41).

Partindo destes pressupostos teóricos, estáactualmente em curso um ensaio clínicorandomizado, o estudo TOPCAT, que tem comoobjectivo avaliar o papel do antagonismo daaldosterona nos doentes com ICFEP.

7. DigoxinaEm teoria, a digoxina parece ser um agente

pouco adequado para os doentes com ICFEP.Isto porque, ao aumentar as concentrações decálcio intra-citoplasmático causa um atraso norelaxamento do miocárdio. Além disso, adigoxina é um agente inotrópico positivo que,como tal, não beneficiaria significativamentedoentes já com uma função sistólica preservada.

No estudo DIG-PEF (42) foi observado que autilização de digoxina na ICFEP, apesar de nãoalterar a mortalidade, estava associada a umatendência, não significativa, para uma reduçãodas hospitalizações por IC. Contudo, a digoxinanão reduziu as hospitalizações totais devidas a

coupling. In a small clinical trial, treatingHFPEF patients with alagebrium for 16 weeksled to a decrease in LV mass and improvementsin LV diastolic filling patterns and quality of life(48). All the studies conducted so far with this newdrug have shown positive results, although theimpact has been less than expected. Data fromlarger, randomized clinical trials are awaited.

Given the role of nitric oxide in stimulatingcGMP production and its beneficial effects onendothelial function, vascular function, and, asrecently reported, on myocardial function, it hasbeen speculated that NO donors would be ofbenefit in heart failure, particularly HFPEF (49).Drugs such as type 5 phosphodiesteraseinhibitors, for example sildenafil, may have a rolein HF treatment, including HFPEF (49, 50). Aclinical trial is currently in progress to assess thispossibility.

Ideally, any new treatment for HFPEF wouldalter the various underlying pathophysiologicalmechanisms. The future of HFPEF treatment istherefore dependent on a deeper understanding ofits pathophysiology. Even so, in view of thediverse nature of the underlying mechanisms,treatment will always have to be multidisciplinaryand individualized to each patient. This includesenhancing diastolic function by reducingmyocardial stiffness and/or improving ventricularrelaxation, while treating concomitant extra-cardiac factors, such as improving arterialdistensibility, ventricular-arterial coupling andendothelial function, as well as controlling bloodpressure, diabetes and renal dysfunction.

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em que predominavam os doentes com ICsistólica (46) (47).

Futuras Direcções para o Tratamento daICFEP

Entre as novas perspectivas para otratamento da ICFEP encontra-se o alagebrium.O alagebrium, ou ALT-177, é um fármaco queinduz a quebra das ligações cruzadas que se formam entre os produtos de glicosilaçãoavançada e proteínas como o colagéneo. Sabe-seque, sobretudo no idoso, o aumento da rigidezventricular e arterial se deve parcialmente àformação destas ligações cruzadas e que, emmodelos experimentais, o alagebrium melhora adistensibilidade ventricular, a complacênciaarterial e o acoplamento ventriculo-arterial.Num estudo clínico de pequena dimensão, otratamento de doentes com ICFEP comalagebrium durante 16 semanas induziu umadiminuição da massa do VE e uma melhoria dopadrão de enchimento diastólico do VE e daqualidade de vida (48). Todos os estudosconduzidos até à data com este novo fármacotêm sido positivos, embora com um menorimpacto que aquilo que seria esperado.Aguardam-se dados de ensaios clínicos,randomizados, de maior dimensão.

Dado o papel do óxido nítrico (NO) comoestimulador da produção do GMPc e, atendendoaos seus efeitos benéficos sobre a funçãoendotelial, sobre a função vascular e maisrecentemente sobre a função miocárdica, tem-seespeculado sobre os benefícios dos dadores deNO na insuficiência cardíaca, e particularmentena ICFEP (49). Neste contexto, fármacos como osinibidores da fosfodiesterase tipo 5, exemplo dosildenafil, poderão desempenhar um papel notratamento da IC, incluindo na ICFEP (49) (50).Encontra-se em curso um ensaio clínico paraavaliar esta possibilidade.

O(s) agente(s) ideal(ais) para o tratamento daICFEP será aquele capaz de alterar os váriosmecanismos fisiopatológicos subjacentes. Destemodo, o futuro do tratamento da ICFEP estarádependente de um aprofundamento dosconhecimentos sobre a fisiopatologia destaentidade. Ainda assim, dada a heterogeneidadedos mecanismos causadores da ICFEP, o seutratamento será sempre multifactorial e indi-vidualizado a cada doente. Passará pela induçãode uma melhoria da função diastólica, através

uma causa cardiovascular, uma vez que a suautilização esteve associada a um aumento dasadmissões por angina instável. Permanece poresclarecer qual o mecanismo potencialmenteresponsável por este benefício parcial dadigoxina sobre a redução das hospitalizaçõespor IC, que pode dever-se ao seu efeitocronotrópico negativo nos doentes com FA, ou àssuas propriedades de inibição do simpático,potenciação do parassimpático e de supressãodo eixo renina-angiotensina-aldosterona (43).

Em conclusão, não está estabelecido qual opapel dos digitálicos no tratamento da ICFEP (25).Desta forma, a digoxina não pode serrecomendada a todos os doentes com ICFEP,ficando a sua utilização restrita ao controlo dafrequência cardíaca nos doentes com FAconcomitante. De notar ainda que numapopulação idosa, como é a população comICFEP, o risco de intoxicação digitálica é maior,devendo ser utilizada inicialmente metade dadose de digoxina e posteriormente umamonitorização mais apertada dos seus níveisséricos.

8. EstatinasOs efeitos benéficos potenciais das estatinas

em doentes com ICFEP são multifactoriais, maspodem ser divididos genericamente em doisgrupos. Por um lado, as estatinas, pelos seusefeitos no perfil lipídico, diminuem os eventoscardiovasculares numa população de doentesque, como foi dito anteriormente, apresentamúltiplas comorbilidades e uma elevadafrequência de morbi-mortalidade cardiovas-cular. Por outro lado, as estatinas possuemefeitos pleotrópicos, independentes da alteraçãodo perfil lipídico, onde se incluem efeitosbenéficos sobre a função diastólica como sejam,a redução da hipertrofia e da fibrose domiocárdio, a melhoria da função do endotélio eda distensibilidade arterial (44).

Comprovando estes efeitos benéficos poten-ciais das estatinas, um pequeno estudoobservacional em doentes com ICFEP, demons-trou que a adição de estatinas ao tratamentoconvencional parece reduzir tanto a morbilidadecomo a mortalidade destes doentes (45). Tambémneste aspecto subsiste a controvérsia, uma vezque em dois ensaios clínicos recentementepublicados as estatinas não mostraram bene-fícios relevantes numa população com IC, mas80





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19.Maurer MS, King DL, El-Khoury Rumbarger L, et al. Left heartfailure with a normal ejection fraction: identification of differentpathophysiologic mechanisms. J Card Fail, 2005. 11: 177-187.

20.Maurer MS, Burkhoff D, Fried LP, et al. Ventricular structureand function in hypertensive participants with heart failure and anormal ejection fraction: the Cardiovascular Health Study. J AmColl Cardiol, 2007. 49: 972-981.

21.Wang J, Khoury DS, Yue Y, Torre-Amione G, Nagueh SF.Preserved left ventricular twist and circumferential deformation,but depressed longitudinal and radial deformation in patients withdiastolic heart failure. Eur Heart J, 2008. 29: 1283-1289.

22.Solomon SD, Janardhanan R, Verma A, et al. Effect ofangiotensin receptor blockade and antihypertensive drugs ondiastolic function in patients with hypertension and diastolicdysfunction: a randomised trial. Lancet, 2007. 369: 2079-2087.

23.W K Yip, M Wang, T Wang, et al. The Hong Kong diastolic heartfailure study: a randomised controlled trial of diuretics, irbesartanand ramipril on quality of life, exercise capacity, left ventricularglobal and regional function in heart failure with a normal ejectionfraction. Heart, 2008. 94: 573-580.

24.Paulus W. Beneficial effects of nitric oxide on cardiac diastolicfunction: 'the flip side of the coin'. Heart Fail Rev, 2000. 5: 337-44.

25.Hunt S.A., Abraham W.T, Marshall H, et al. ACC/AHA 2005Guideline Update for the Diagnosis and Management of ChronicHeart Failure in the Adult. Circulation, 2005. 112: 154-235.

da diminuição da rigidez do miocárdio e/ou pelamelhoria do relaxamento ventricular, semcontudo esquecer uma abordagem dos factoresextracardíacos concomitantes, como a induçãode uma melhoria da distensibilidade arterial, doacopolamento ventriculo-arterial, da funçãoendotelial e do controlo da pressão arterial, dadiabetes ou da disfunção renal.

Pedidos de separatas para:

Address for reprints:

ADELINO LEITE-MOREIRAServiço de FisiologiaFac. de Medicina da Universidade do PortoAlameda Prof. Hernâni Monteiro4200-319 Porto, PORTUGALTel. +351225508452;Fax. +351225519194;E-mail: [email protected]

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in patients with chronic heart failure and preserved left-ventricularejection fraction: the CHARM-Preserved Trial. Lancet, 2003. 362:777–781.

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“The important thing is to never stop questioning “

Albert Einstein (1879-1955)

Purpose

CHAPTER II | PURPOSE

71

In this project we aimed to evaluate the role of left ventricular diastolic function in several phases of the

cardiovascular continuum, assessing the determinants, its evaluation, the impact on exercise performance

and possible modulation by a program of exercise training, as structured in figure 5.

DIASTOLIC

(DYS)FUNCTION

DETERMINANTS

IMPACT ON EXERCISE CAPACITY

ADIPOSE TISSU

E

EPICARDIAL ADIPOSE TISSUE

INSULIN RESISTANCE, METABOLIC SYNDROME,

TYPE 2 DIABETES

MODULATION BY

EXERCISE TRAINING

EVALUATION OUTCOMES

ADIPOKYNES

VISCERAL vs SUBCUTANEOUS FAT

LEFT ATRIUM FUNCTION AND VOLUMES

DIASTOLIC FUNCTION GRADES

-‐ GRADE IA -‐

Figure 5. Schematic depiction of the main objectives

Specific aims were:

1. To evaluate the association between increased adiposity and diastolic dysfunction and the role of

the direct and indirect pathophysiological mechanisms involved;

2. To evaluate the role of adipose tissue distribution on diastolic function, especially the relative role

of total, subcutaneous and visceral adiposity parameters;

3. To detail the local/paracrine effect of epicardial adipose tissue on left ventricular diastolic function;

4. To determine if an endocrine effect, mediated by the secretion of adipokines (leptin and adiponectin),

can be involved in the association between obesity and diastolic dysfunction;

5. To evaluate the relative contribution of insulin resistance, metabolic syndrome and diabetes as

determinants of diastolic function;

6. To evaluate in the general population the prevalence and clinical characteristics of patients with the

new grade IA of diastolic dysfunction;

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7. To determine the impact of diastolic function on exercise capacity after myocardial infarction;

8. To evaluate the relation between left atrium volumes and function with left ventricular diastolic

function (atrium-ventricular coupling) and their role as predictors of exercise capacity after

myocardial infarction;

9. To evaluate if a structured exercise training program can improve diastolic function after myocardial

infarction.

Results/ Publications

CHAPTER III | RESULTS/ PUBLICATIONS

75

The results will be presented in the form of published and submitted articles. These articles have been

organized in 4 sub-chapters:

A) DETERMINANTS OF DIASTOLIC DYSFUNCTION

1. Association Between Increased Adiposity and Diastolic Function in the General Population Ricardo Fontes-Carvalho, Alexandra Gonçalves, Milton Severo, Patrícia Lourenço, Francisco Rocha Gonçalves,

Paulo Bettencourt, Adelino Leite-Moreira, Ana Azevedo. Direct, inflammation-mediated and blood-pressure-

mediated effects of total and abdominal adiposity on diastolic function: EPIPorto study. Int J Cardiol 2015, in

press.

2. Effect of Adipokines Levels on Diastolic Function in the General PopulationRicardo Fontes-Carvalho, Joana Pimenta, Paulo Bettencourt, Adelino Leite-Moreira, Ana Azevedo. Plasma

leptin and adiponectin levels and diastolic function in the general population: data from the EPIPorto study.

Expert Opin Ther Targets. 2015 Mar 18:1-9.

3. Role of Epicardial Fat and Adipose Tissue Distribution on Diastolic Function in Patients After

Myocardial InfarctionRicardo Fontes-Carvalho, Marta Fontes-Oliveira, Francisco Sampaio, Jennifer Mancio, Nuno Bettencourt,

Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama, Adelino Leite-Moreira. Influence of Epicardial

and Visceral Fat on Left Ventricular Diastolic and Systolic Function in Patients After Myocardial Infarction. Am

J Cardiol 2014, 114(11): 1663-9.

4. Role of Insulin Resistance, Metabolic Syndrome and Diabetes on Diastolic Function in the General

PopulationRicardo Fontes-Carvalho, Ricardo Ladeiras-Lopes, Paulo Bettencourt, Adelino Leite-Moreira, Ana Azevedo.

Diastolic Dysfunction in the Diabetic Continuum: Association with Insulin Resistance, Metabolic Syndrome and

Type 2 Diabetes. Cardiovasc Diabetol. 2015 Jan 13;14(1):4.

B) THE EVALUATION OF DIASTOLIC DYSFUNCTION

5. Characterization of Diastolic Dysfunction Grades in the General Population: the New Grade IA of

Diastolic DysfunctionFontes-Carvalho R, Azevedo A, Leite-Moreira A. The new grade IA of diastolic dysfunction: is it relevant at the

population level? JACC Cardiovasc Imaging. 2015 (2): 229-30.

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C) THE IMPACT OF DIASTOLIC FUNCTION ON EXERCISE CAPACITY

6. The Role of Diastolic Function as Predictor of Exercise Capacity after Myocardial InfarctionRicardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama,

Ana Azevedo, Adelino Leite-Moreira. Left Ventricular Diastolic Dysfunction and E/E’ ratio as the Strongest

Echocardiographic Predictors of Reduced Exercise Capacity After Acute Myocardial Infarction. Clin Cardiol.

2015;38(4):222-9.

7. The Role of Left Atrium Volumes, Function and Atrium-Ventricular Coupling on Exercise Capacity

After Myocardial InfarctionRicardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama,

Ana Azevedo, Adelino Leite-Moreira. Left atrial deformation analysis by speckle tracking echocardiography to

predict exercise capacity after myocardial infarction. [Under review, J Am Soc Echocardiog 2015].

D) THE MODULATION OF DIASTOLIC FUNCTION BY EXERCISE TRAINING

8. The Effect of an Exercise Training Program on Diastolic Function after Myocardial Infarction: study

protocolRicardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Vasco Gama, Adelino Leite-Moreira. The role

of a structured exercise-training program on cardiac structure and function after acute myocardial infarction:

study protocol for a randomized controlled trial. Trials. 2015 Mar 12;16(1):90.

9. The Effect of Exercise Training on Diastolic Function after Myocardial Infarction: study resultsRicardo Fontes-Carvalho, Francisco Sampaio, Madalena Teixeira, Francisco Rocha Gonçalves, Vasco Gama, Ana

Azevedo, Adelino Leite-Moreira. The effect of exercise training on diastolic and systolic function after acute

myocardial infarction: a randomized study. [Under Review, Medicine 2015].


A) Determinants of Diastolic Dysfunction

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ARTICLE 2

1. Introduction

2. Methods

3. Results

4. Discussion

5. Conclusion

Original Research

Association between plasmaleptin and adiponectin levelsand diastolic function in thegeneral populationRicardo Fontes-Carvalho†, Joana Pimenta, Paulo Bettencourt,Adelino Leite-Moreira & Ana Azevedo†Faculty of Medicine, University of Porto, Al. Prof Hernani Monteiro, Porto, Portugal and Gaia

Hospital Center, Cardiology Department, Rua Conceicao Fernandes, Vila Nova Gaia, Portugal

Background: Total and visceral obesity are associated with subclinical diastolic

dysfunction (DD) and heart failure. Adipose tissue is an endocrine organ able

to secrete adipokines involved in several obesity-associated diseases. We

aimed to evaluate the association between leptin and adiponectin levels

and diastolic function.

Methods and results:Within a population-based study (EPIPorto), 556 individ-

uals were evaluated. DD was assessed by echocardiography, using tissue

Doppler analysis (early diastolic E’ velocity and E/E’, the ratio between

E wave velocity of transmitral flow and E’ velocity), according to consensus

recommendations. Patients with DD had significantly higher leptin, but simi-

lar adiponectin levels. Patients in the highest leptin tertile had lower E’ veloc-

ity and an increased E/E’ ratio (p < 0.01). The association between leptin and

DD was sex-specific. After multivariate adjustment, women in the highest lep-

tin tertile had an increased risk of DD (adjusted odds ratio: 3.06; 95%

CI: 1.44 -- 6.49). Adiponectin levels were not significantly associated with

increased risk of DD in both men and women.

Conclusions: Higher leptin levels were independently associated with DD,

especially in women. Secretion of leptin can be involved in the association

between obesity, DD and heart failure risk. Future studies will determine if

the inhibition of leptin can improve diastolic function.

Keywords: adiponectin, diastole, leptin, obesity

Expert Opin. Ther. Targets [Early Online]

1. Introduction

Recent studies have shown that obesity, especially visceral adiposity, inducessubclinical diastolic dysfunction (DD) [1-4], suggesting that DD is involved as anintermediate step in the association between obesity and heart failure [5-7]. Giventhe high prevalence of obesity worldwide and the increased risk of heart failure inthe obese, there is considerable interest in understanding the mechanisms involvedin the association between obesity and DD [8].

Increased adiposity can impair diastolic function by several potential pathophysio-logical mechanisms [9]. First, the effect could be indirect because obesity is associatedwith other cardiovascular risk factors, namely with hypertension [10], that can induceDD. However, previous studies have shown that this association is independent ofthese traditional risk factors [1]. Alternatively, obesity can directly affect myocardialstructure and function by inducing increased circulating volume and cardiacoutput [11], by a local effect [12] or through the secretion of several adipokines [13,14].The adipose tissue is an endocrine organ that produces several substances (such as

10.1517/14728222.2015.1019468 © 2015 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 1All rights reserved: reproduction in whole or in part not permitted

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leptin, adiponectin, resistin and others), some of which havebeen shown to directly induce left ventricle (LV) remodelingand myocardial dysfunction [15,16]. Low adiponectin levels areassociated with several obesity-related disorders [17,18] anddecreased adiponectin levels are associated with changes in leftventricular structure and function [19,20]. On the other hand,high leptin levels have a mitogenic effect [21], increasecardiomyocyte fatty acid loading [22] and reduce cardiomyocytecontraction [23]. No data are available on the effect of adipokinesas determinants of diastolic function. However, a recent largeprospective study showed that the association between obesityand heart failure was partially mediated by plasma leptinlevels [24]. Understanding the link between obesity, adipokinesand diastolic function can be important in the prevention ofdiastolic heart failure, a disease in which no therapy or interven-tion has been shown to significantly change its prognosis.In this study, our aim was to evaluate the effect of leptin

and adiponectin levels on diastolic function parameters atthe population level. Because leptin and adiponectin levelsvary significantly between men and women, a sex-specificanalysis was performed.

2. Methods

2.1 Study sampleParticipants were selected within the first follow-up of a cohortrepresentative, at baseline, of the adult population of Porto,Portugal -- the EPIPorto cohort study. In 1999 -- 2003, thecohort assembly was made by random-digit dialing, usinghouseholds as the sampling frame, followed by random selec-tion of one person aged 18 years or older in each household.Refusals were not substituted within the same household.The proportion of participation was 70% as previouslystated [25]. At baseline, 2485 participants were recruited.Between October 2006 and July 2008, participants aged45 years or over were submitted to a systematic evaluation ofparameters of cardiac structure and function, which includeda cardiovascular clinical history, physical examination, detailedanthropometric evaluation, collection of fasting blood sampleand a transthoracic echocardiogram. Among 2048 cohortmembers in the eligible age range at this time, 134 (6.5%)had died, 198 (9.7%) refused to be re-evaluated and580 (28.3%) were lost to follow-up (unreachable by telephoneor post). For this study, we excluded 73 patients with previousmyocardial infarction, percutaneous or surgical revasculariza-tion, prior cardiac surgery or significant (moderate to severe)valvular heart disease. Complete data, with both leptin andadiponectin levels, was available from 556 patients. Writteninformed consent was obtained from all the individuals andthe local university’s ethics committee approved the study.

2.2 Clinical variables definitionsHypertension was defined as systolic blood pressure ‡ 140mmHg or diastolic blood pressure ‡ 90 mmHg at the timeof the visit (mean of two readings) or use of antihypertensive

medication [26]. Diabetes was defined as fasting bloodglucose ‡ 126 mg/dl or the patient’s self-reported history ofdiabetes or use of diabetes medications [26]. Hypercholesterol-emia was defined as total serum cholesterol ‡ 220 mg/dl orthe use of lipid-lowering drug treatment.

2.3 Anthropometric evaluationMeasurements included height, weight, waist circumferenceand hip circumference. Body mass index (BMI;weight/height2 in kg/m2) was calculated for each subject.Waist circumference was measured at the midpoint betweenthe iliac crest and the lower rib margins measured in themidaxillary line. Overweight was defined as BMI ‡ 25 andbelow 30 kg/m2, and obesity as BMI ‡ 30 kg/m2. Hip-to-height and waist-to-height ratios were calculated as the ratiobetween hip circumference (cm) or waist circumference(cm), respectively, and height (cm). Body composition wasassessed by bioelectrical impedance analysis (Tanita Corp,Arlington Heights, IL) to determine body fat percentage (%).

2.4 Analytical dataA fasting venous blood sample was obtained in the morningfor measurement of glucose, total cholesterol, LDL-choles-terol, HDL-cholesterol, triglycerides and high-sensitivityC-reactive protein (hs-CRP) by immunonephelometry.Leptin and adiponectin levels were measured byradioimmunoassay.

2.5 Echocardiography dataAll echocardiography studies were acquired by one of fourcardiologists, using the same equipment (Hewlett-PackardSonos 5500). Images were stored on videotape for posterioroffline analysis by two experienced cardiologists, blinded toclinical data.

Cardiac chambers dimensions, volumes and left ventricularmass were measured according to current recommenda-tions [27], and indexed to body surface area. Diastolic functionwas assessed according to the latest consensus guidelines ondiastolic function evaluation [28] measuring mitral inflowvelocities (E-wave, A wave, E/A ratio) and E-wave decelera-tion time (DT) and isovolumetric relaxation time usingpulsed-wave (PW) Doppler in the apical four-chamber view.Velocities were recorded at end expiration and averaged overthree consecutive cardiac cycles. PW tissue-Doppler velocitieswere acquired at end expiration, in the apical four-chamberview, at the lateral side of the mitral annulus, measuring earlydiastolic (E¢) and late diastolic (A¢) velocities and estimatingthe E/E¢ ratio accordingly. Following the recommendationsin the consensus document [28], patients were categorized bytwo independent cardiologists in DD grades: grade I (mildDD) if E¢ lateral < 10 cm/s and E/A < 0.8, DT > 200 ms,E/E £ 8; grade II (moderate DD) if E¢ lateral < 10 cm/s andE/A between 0.8 and 1.5, DT 160 -- 200 ms, E/E¢ 9 -- 12;and grade III (severe DD), if E¢ lateral < 10 cm/s andE/A ‡ 2, DT < 160, E/E¢ ‡ 13.

R. Fontes-Carvalho et al.

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2.6 Statistical analysisStatistical analyses were performed using SPSS statistics20 (IBM Corp, Armonk, NY). All p values are two-tailed anda significance level of 5% was used. Data are expressed asmean and standard deviation for quantitative variables withnormal distribution, as median and 25th and 75th percentiles(P25 -- P75) for variables with non-normal distribution or asnumber (n) and percentage (%) for categorical variables.

Bivariate correlations were assessed by Pearson’s (r) andSpearman’s (r) correlation coefficient, as appropriate.Patients were categorized in tertiles of leptin and adiponectinlevels according to sex-specific cutoffs. E¢ velocity and E/E¢ratio were compared between tertiles using ANOVA. Logisticregression analysis was performed to analyze the associationbetween adipokines tertiles (independent variables) and DD(dependent variable), defined as any grade of DD. A separatelogistic multivariate regression analysis was performed adjust-ing for age and systolic blood pressure (in model 1) and forage, systolic blood pressure and BMI (in model 2).

3. Results

Table 1 shows the clinical, anthropometric, analytical andechocardiographic characteristics of the study sample(n = 556). In summary, most were women (67.8%), withmean age of 59.9 ± 7.5 years, with high prevalence of cardio-vascular risk factors, especially hypertension (71.0%), dyslipi-demia (55.9%), obesity (28.8%) and diabetes (10.1%). Theoverall prevalence of DD was 19.4%: 10.3% (n = 57) hadmild DD (grade I DD), 8.0% (n = 44) had moderate DD(grade II DD) and one patient had restrictive pattern (gradeIII DD). In six patients (1.1%) it was not possible to deter-mine DD grade due to atrial fibrillation or fusion of theE/A mitral flow pattern. Regarding medication use, 26.1%were doing renin--angiotensin axis blockers, 7.7% were takingcalcium channel blockers, 12.9% were on diuretics and24.3% were taking statins.

Leptin levels were significantly higher in women comparedto men, as shown in Table 1 (p < 0.01). There was a significantcorrelation between plasma leptin levels with several adiposityparameters, namely with BMI (r = 0.57, p < 0.01), waist-to-height ratio (r = 0.49, p < 0.01) hip-to-height ratio (r = 0.69,p < 0.01) and fat mass percentage (r = 0.76; p < 0.01).

On the contrary, adiponectin plasma levels were onlyweakly and inversely correlated with BMI (r = -0.13;p < 0.01) and waist-to-height ratio (r = -0.13, p = 0.02).Obese patients had slightly lower adiponectin levelsthan nonobese: median 5800.7 ng/ml (P25 -- 75:3284.7 -- 9489.6 ng/ml) versus 7039.0 ng/ml (P25 -- 75:3509.4 -- 11529.3 ng/ml); p = 0.02. Adiponectin levelswere inversely correlated with triglycerides (r = -0.17;p < 0.01) and blood glucose (r = -0.18; p < 0.01). Adiponectinwas also higher in women compared tomen (p < 0.01), as shownin Table 1.

3.1 Association between leptin levels and diastolic

function parametersPatients with normal diastolic function had significantly lowerleptin plasma levels compared to patients with mild or mod-erate/severe DD: 13.7 ng/ml (P25 -- 75: 7.4 -- 22.8 ng/ml)versus 15.8 ng/ml (P25 -- 75: 9.5 -- 25.3 ng/ml) in mildDD and 20.4 ng/ml (P25 -- 75: 13.9 -- 31.7 ng/ml) inmoderate/severe DD (p < 0.01), as also shown in Figure 1.There was also a modest, but significant, correlation betweenhigher leptin levels with lower E¢ velocity (r = -0.10, p = 0.02)and higher E/E¢ ratio (r = 0.19, p < 0.01).

As shown in Table 2, there was a progressive decrease in E¢velocity and a stepwise increase in E/E¢ ratio, according to thedistribution in leptin tertiles. However, the associationbetween leptin levels and DD was more significant in womenthan in men. In men, the association between plasma leptinand DD was largely explained by age and blood pressure(Table 3). On the contrary, in women, even after multivariateadjustment the highest leptin tertile had a threefold higherodds of DD (Table 3). The adjustment for waist-perimeter/height or waist-to-hip instead of BMI did not significantlychange the logistic regression results shown in Table 3, model2 (data not shown).

3.2 Association between adiponectin levels and

diastolic function parametersOverall, there was no significant difference in adiponectinmedian (P25 -- P75) levels between individuals with normaldiastolic function (6533.4 ng/ml [3552.3 -- 10746.8 ng/ml])and patients with DD (7016.1 ng/ml [3265.8 -- 10511.0ng/ml]), p = 0.89, as detailed in Figure 1.

In men, we did not find a significant difference in E¢ veloc-ities or E/E¢ ratio according to adiponectin tertiles (Table 2)and there was no significant increase in the risk of havingDD (Table 3). Also, in women, although tertile 1 had a lowerE¢ velocity compared to tertiles 2 and 3 (Table 2), there was noincreased risk of DD after multivariate adjustment (Table 3).

4. Discussion

Adipose tissue is an active endocrine organ able to secreteseveral adipokines that have been increasingly recognized asinvolved in the pathophysiology of several obesity-associateddiseases, including in heart failure and myocardial remodel-ing. In this population-based study, we showed that higherleptin levels were independently associated with increasedrisk of DD, especially in women. On the contrary, adiponec-tin did not correlate with diastolic function parameters.

4.1 The association between the secretion of

adipokines and diastolic functionSeveral adipokines, such as leptin, adiponectin, resistin, angio-tensinogen, IL-6 and plasminogen activator inhibitor-1, havebeen shown to play a role in cardiovascular homeostasis,

Association between plasma leptin and adiponectin levels and diastolic function in the general population

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especially in the risk of coronary artery disease [16,29]. However,

less clinical data is available on the influence of these substan-

ces on myocardial structure and function. The association with

diastolic function can be particularly relevant, because visceral

adiposity is independently associated with an increased risk of

DD [4].Leptin regulates energy expenditure and metabolism, hav-

ing an inhibitory effect on appetite [14,30,31]. Higher plasma

leptin levels are associated with increased BMI and the major-

ity of obese individuals are hyperleptinemic, due to a state of

leptin resistance. Leptin can also influence the cardiovascular

system by exerting pro-thrombotic, pro-inflammatory and

pro-atherogenic effects [14,30]. However, it remains contro-

versial whether hyperleptinemia is independently associated

with increased risk of atherosclerotic cardiovascular events [32].

Although some studies have found a positive correlation

between circulating leptin levels and coronary artery dis-

ease [33], others have failed to demonstrate this association [34].

Beyond coronary artery disease, long-term increased levels of

leptin can potentially induce structural, functional and

Table 1. Characterization of the study sample according to gender.

Total (n = 556) Women (n = 377) Men (n = 179) p value

Age, years 59.9 ± 7.5 59.5 ± 7.4 60.9 ± 7.3 0.05Cardiovascular risk factorsHypertension (%) 395 (71.0%) 263 (69.8%) 132 (73.7%) 0.37Diabetes (%) 56 (10.1%) 38 (10.1%) 18 (10.1%) 0.86Dyslipidemia (%) 311 (55.9%) 214 (56.8%) 97 (54.2%) 0.58Obesity (%) 160 (28.8%) 131 (34.7%) 29 (16.2%) < 0.01

Systolic blood pressure, mmHg 134.2 ± 19.8 133.9 ± 21.1 134.8 ± 17.0 0.63Diastolic blood pressure, mmHg 82.5 ± 10.6 82.2 ± 11.0 83.3 ± 9.7 0.23Adiposity parametersBMI, kg/m2 27.8 ± 5.0 28.3 ± 5.4 26.9 ± 3.7 < 0.01Waist circumference/height, cm/m 0.59 ± 0.08 0.59 ± 0.08 0.58 ± 0.06 0.01Hip circumference/height, cm/m 0.64 ± 0.07 0.66 ± 0.07 0.59 ± 0.04 < 0.01Waist-to-hip ratio 0.91 ± 0.08 0.88 ± 0.06 0.97 ± 0.07 < 0.01Fat mass percentage, % 32.2 ± 8.3 35.8 ± 7.0 24.8 ± 5.4 < 0.01Analytical dataTotal cholesterol, mg/dl 222.7 ± 51.3 227.1 ± 54.0 211.2 ± 42.4 < 0.01HDL, mg/dl 62.1 ± 42.7 65.7 ± 50.2 54.4 ± 10.7 < 0.01LDL, mg/dl 136.0 ± 51.0 139.8 ± 55.1 127.1 ± 38.3 0.02Triglycerides, mg/dl 114.0 (85.0 -- 156.0) 111.0 (85.0 -- 153.0) 122.0 (86.0 -- 176.0) 0.05Glucose, mg/dl 105.7 ± 47.2 103.6 ± 52.8 111.0 ± 32.8 0.04Leptin, ng/ml 14.5 (8.3 -- 24.4) 19.0 (8.3 -- 24.4) 7.6 (5.2 -- 11.6) < 0.01Adiponectin, ng/ml 6533.4

(3434.7 -- 10746.8)7000.9(4121.8 -- 11926.9)

5444.3(3063.6 -- 8987.7)

< 0.01

EchocardiographySeptum, mm 8.6 ± 1.5 8.4 ± 1.5 9.3 ± 1.3 < 0.01Posterior wall, mm 7.9 ± 1.3 7.7 ± 1.3 8.4 ± 1.3 < 0.01LV mass index, g/m2 79.1 ± 19.1 75.8 ± 18.3 87.5 ± 21.7 < 0.01Left atrium volume index, ml/m2 29.0 ± 9.7 28.8 ± 9.3 29.3 ± 10.8 0.60LV end-diastolic volume, ml/m2 66.2 ± 16.4 63.7 ± 15.5 71.5 ± 17.6 < 0.01LV end-systolic volume, ml/m2 26.9 ± 9.5 25.4 ± 8.8 29.9 ± 10.4 < 0.01Ejection fraction, % 60.5 ± 6.4 61.2 ± 6.2 59.0 ± 6.7 < 0.01E wave, cm/s 72.4 ± 15.9 74.4 ± 15.6 67.7 ± 15.8 < 0.01A wave, cm/s 78.2 ± 18.6 80.1 ± 18.6 74.5 ± 17.8 0.01E/A ratio 0.97 ± 0.28 0.97 ± 0.28 0.94 ± 0.28 0.25Deceleration time, ms 231.9 ± 50.1 230.0 ± 47.0 237.9 ± 57.2 0.13IVRT, ms 91.1 ± 15.6 90.6 ± 16.0 91.9 ± 15.7 0.70E’ velocity, cm/s 10.8 ± 3.0 10.7 ± 3.1 10.6 ± 3.1 0.47E/E’ ratio 7.1 ± 2.3 7.4 ± 2.4 6.7 ± 2.3 < 0.01DD gradeNormal diastolic function, n (%) 448 (80.6%) 298 (79.0%) 150 (84.3%) 0.29Mild DD, n (%) 57 (10.3%) 36 (9.5%) 21 (11.7%)Moderate/severe DD, n (%) 45 (8.1%) 38 (10.1%) 7 (3.9%)Undetermined, n (%) 6 (1.1%) 5 (1.3%) 1 (0.6%)

Data are presented as mean (standard deviation) or median (percentile 25 -- 75) for continuous variables and count (percentage) for categorical variables.

BMI: Body mass index; DD: Diastolic dysfunction; hs-CRP: High-sensitivity C-reactive protein; IVRT: Isovolumetric relaxation time; LV: Left ventricle.



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metabolic changes in the heart. Experimental data suggested

that leptin has mitogenic effects [21], can induce myocardial

hypertrophy [35], can increase cardiomyocyte fatty acid load-

ing [22] and reduce cardiomyocyte contraction [23]. In this

population study, we did not find a significant association

with systolic function (data not shown), whereas higher leptin

levels were associated with worse diastolic function. Indeed,

individuals with DD had significantly higher leptin levels,

and higher leptin levels were associated with lower early dia-

stolic filling velocities (E¢ velocity), higher filling pressures

(higher E/E¢ ratio) and an increased risk of DD, which was

independent of age and hypertension. Few other studies

have looked into this association. In a smaller study, that

included only patients undergoing cardiac catheterization for

suspected coronary artery disease, no significant association

was found between leptin and diastolic function [36].Adiponectin is another adipokine that is involved in the

regulation of energy metabolism and insulin resistance [17].

Decreased adiponectin levels have been associated with several

obesity-related disorders, including diabetes, endothelial dys-

function, atherosclerosis, hypertension and coronary artery

disease [17,18]. Some experimental studies suggested that

decreased adiponectin can change LV structure and function,

by promoting hypertrophy, fibrosis and LV remodeling [19,20].

However, contrary to what we have observed with leptin, we

did not find a significant relation between decreased adipo-

nectin levels and diastolic function parameters. The effect of

adiponectin on DD can eventually differ according to disease

30000.00

25000.00

20000.00

15000.00

10000.00

5000.00

0.00

Ad

ipo

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(n

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l)

Women Men

p = 0.52

p = 0.13

Normal diastolic function

Diastolic dysfunction

Lep

tin

(n

g/m

l)

50.00

40.00

30.00

20.00

10.00

0.00

Women Men

p = 0.05

Normal diastolic function


p = 0.02

Figure 1. Comparison of leptin and adiponectin levels between patients with normal diastolic function (left) and diastolic

dysfunction (right), separated by gender.



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state and study populations, because in two small studies ofpatients undergoing coronary angiography [36] and with heartfailure [37], decreased adiponectin levels were associated withworse diastolic function.

4.2 Sex-specificities in the association between

adiposity, adipokines and diastolic functionIt is known that women have higher total fat mass and adifferent pattern of adiposity distribution, as we also observedin this study (Table 1). Therefore, it is plausible that the effectof adiposity, and the role of adipokines, on changes in myo-cardial structure and function could be sex-specific [36,38,39].First, it is known that women have significantly higher lep-tin [40] and adiponectin [17] levels, as also shown in our study.Second, few previous studies have assessed the differencesbetween men and women in the association between obesityand diastolic function. However, in the study fromCanepa et al., the association between waist circumferenceand diastolic function was more pronounced in women thanin men. Also in a hypertension study, the adverse effect ofabdominal obesity on cardiac function was more pronouncedin female hypertensives [38]. It is known that central adiposityand visceral fat are the metabolically most active fat depositsand the major source of adipokines production. This canpartly explain our results showing a stronger associationbetween leptin levels and DD in women. Finally, in our studywe only included individuals older than 45 years. Therefore,

Table 2. Diastolic function parameters (E’ velocity and

E/E’ ratio) according to leptin and adiponectin tertiles,

separated by gender.

E’ velocity E/E’ ratio

LeptinMenTertile 1 11.2 ± 2.7 6.2 ± 1.7Tertile 2 10.3 ± 3.1 6.8 ± 2.0Tertile 3 10.5 ± 3.3 7.3 ± 3.0

(p = 0.18) (p = 0.04)WomenTertile 1 11.4 ± 3.2 6.9 ± 2.1Tertile 2 10.6 ± 2.9 7.5 ± 2.3Tertile 3 10.2 ± 3.0 7.8 ± 2.7

(p = 0.01) (p = 0.01)AdiponectinMenTertile 1 10.1 ± 2.9 7.1 ± 2.1Tertile 2 11.2 ± 3.5 6.6 ± 2.4Tertile 3 10.7 ± 2.7 6.7 ± 2.6

(p = 0.12) (p = 0.50)WomenTertile 1 10.2 ± 2.9 7.7 ± 2.5Tertile 2 11.2 ± 3.3 7.1 ± 2.1Tertile 3 10.9 ± 2.9 7.4 ± 2.6

(p = 0.02) (p = 0.12)

Data are shown as mean ± SD of E’ velocity and E/E’ ratio by leptin and

adiponectin tertiles, stratified by gender.

Table 3. Diastolic function (dependent variable) parameters according to leptin and adiponectin tertiles

(independent variables), separated by gender.


n (%) Adjusted OR (95% CI)

Model 1*Adjusted OR (95% CI)

Model 2‡

LeptinMenTertile 1 4 (6.9%) 1.00 1.00Tertile 2 13 (21.0%) 3.49 (1.04 -- 11.7) 2.89 (0.85 -- 9.82)Tertile 3 11 (18.6%) 3.18 (0.92 -- 10.9) 1.38 (0.32 -- 5.90)WomenTertile 1 14 (11.2%) 1.00 1.00Tertile 2 26 (20.6%) 2.00 (0.93 -- 4.27) 2.08 (0.94 -- 4.60)Tertile 3 34 (27.0%) 3.06 (1.44 -- 6.49) 3.24 (1.34 -- 7.87)AdiponectinMenTertile 1 13 (22.8%) 2.45 (0.86 -- 7.00) 2.68 (0.90 -- 7.95)Tertile 2 8 (13.1%) 1.47 (0.47 -- 4.56) 1.59 (0.50 -- 5.07)Tertile 3 7 (12.1%) 1.00 1.00WomenTertile 1 29 (23.2%) 1.31 (0.67 -- 2.55) 1.24 (0.63 -- 2.44)Tertile 2 23 (18.1%) 1.10 (0.55 -- 2.22) 1.06 (0.53 -- 2.14)Tertile 3 22 (17.7%) 1.00 1.00

Adjusted odds ratio was estimated by logistic regression analysis, including the presence of any grade of diastolic dysfunction as the dependent variable.

In model 1* multivariate logistic regression analysis was performed adjusting for age and blood pressure.

In model 2‡ adjustment for age, blood pressure and body mass index was performed.



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most included women were likely post-menopausal. This canbe important because the association between adiposity anddiastolic function can be modulated by a hormonal effect,since estrogens have been shown to have beneficial effects ondiastolic function by promoting nitric oxide secretion [41],inhibiting smooth muscle proliferation [42] and inducingperipheral vasodilation [43].

4.3 The association between adiposity, DD and heart

failureObesity is established as an independent risk factor for thedevelopment of heart failure in the general population [5-7,24].However, the mechanisms leading to this obesity cardiomy-opathy are not entirely understood [8]. Recent studies haveshown that increased adiposity is associated with subclinicalDD [1,2], which is an important predictor of symptomaticheart failure, especially of heart failure with preserved ejectionfraction [44,45]. Therefore, DD is postulated to be an impor-tant pathophysiological mechanism linking obesity, heartfailure and mortality risk [6]. Of interest, abdominal adiposity,which is the major source of adipokines secretion [46] is astronger determinant of heart failure risk, cardiovascularmortality [47,48] and DD [4], compared to BMI. Also, in tworecent studies, waist circumference [4] and increased abdomi-nal visceral fat mass [49] were important determinants ofDD, independently of BMI and subcutaneous fat, respec-tively. All these observations reinforce the hypothesis thatthe link between adiposity, DD and heart failure can bepartially mediated by the secretion of adipokines [24]. Severalauthors have proposed leptin as one of the most promisingmechanisms in this association [24,31,40,50]. Our data reinforcethis hypothesis showing, for the first time, an associationbetween leptin and diastolic function in the general popula-tion. More interestingly, long-term prospective studies haveshown that in individuals without coronary artery disease,higher leptin levels at baseline are associated with increasedrisk of incident HF, after adjustment for multiple risk factors,including BMI [24].

These observations have potential clinical implications.First, the early identification and correction of the main deter-minants of subclinical DD can be important to reduce the riskof heart failure [8]. This can be especially important in theprevention of heart failure with preserved ejection fraction, adisease in which no therapy has been shown to change theprognosis. Future research will determine if the reduction ofcirculating leptin and/or blockade of its peripheral actions [51]

can improve diastolic function or confer favorable myocardialremodeling in hiperleptinemic patients.

4.4 Strengths and limitationsStrengths of this study include the relatively large sample ofindividuals from the general population without other cardiacdiseases and the contemporaneous assessment of cardiacdiastolic function using tissue Doppler and the consensuscriteria.

The main limitation is the cross-sectional design, whichpartially limits comments on causality, as this would bemore robust in a prospective design. This population hadsignificantly more women than men, which reduced the statis-tical power in this latter group and limited the additionaladjustment for other possible confounders. Other adipokines,besides leptin and adiponectin, were not measured in thisstudy. We did not evaluate the intraobserver and interobservervariability. However, all four cardiologists had extensive expe-rience in echocardiography, worked in the same institutionand a detailed procedure protocol was discussed between theteam, prior to study beginning, to harmonize the methodol-ogy and the measurements. Moreover, several previous studieshave shown a good reproducibility and a low interobservermean error for diastolic parameters [52].

5. Conclusion

In this population-based study, higher leptin levels were inde-pendently associated with DD, particularly in women. On thecontrary, adiponectin did not correlate with diastolic functionparameters. Secretion of adipokines, especially leptin, can beone of the pathophysiological mechanisms linking increasedadiposity, diastolic dysfunction and heart failure risk.

Declaration of interest

The authors were supported by Portuguese Foundation for Sci-ence and Technology Grants POCI/SAU-ESP/61492/2004,PEST-C/SAU/UI0051/2011, EXCL/BIM-MEC/0055/2012(partially funded by FEDER through COMPETE) andEuropean-Commission Grant FP7-Health-2010; MEDIA-261409. The authors have no other relevant affiliations orfinancial involvement with any organization or entity with afinancial interest in or financial conflict with the subject matteror materials discussed in the manuscript apart from thosedisclosed.



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Circ Cardiovasc Imaging 2010;3:614-22

AffiliationRicardo Fontes-Carvalho†1,2,3 MD,

Joana Pimenta4 MD PhD,

Paulo Bettencourt4 MD PhD,

Adelino Leite-Moreira3,5 MD PhD &

Ana Azevedo1,6 MD PhD†Author for correspondence1University of Porto, EPIUnit - Institute of

Public Health, Porto, Portugal2Gaia Hospital Center, Cardiology Department,

Gaia, Portugal

Tel: +351 227 865 100;

Fax: +351 225 519 194;

E-mail: [email protected] of Porto, Department of Physiology

and Cardiothoracic Surgery, Faculty of Medicine,

Porto, Portugal4University of Porto, Department of Medicine,

Faculty of Medicine, Porto, Portugal5Centro Hospitalar Sao Joao, Department of

Cardiothoracic Surgery, Porto, Portugal6University of Porto, Department of Clinical

Epidemiology, Predictive Medicine and Public

Health, Faculty of Medicine, Porto, Portugal



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Influence of Epicardial and Visceral Fat on Left VentricularDiastolic and Systolic Functions in Patients After

Myocardial Infarction

Ricardo Fontes-Carvalho, MDa,b,*, Marta Fontes-Oliveira, MDb, Francisco Sampaio, MDa,Jennifer Mancio, MDa, Nuno Bettencourt, PhDa, Madalena Teixeira, MDa,

Francisco Rocha Gonçalves, MD, PhDc, Vasco Gama, MDa, and Adelino Leite-Moreira, MD, PhDb

Obesity has been associated with subclinical left ventricular (LV) diastolic dysfunction andincreased risk of heart failure. Few data are available on the relative contribution ofadiposity distribution and changes in myocardial structure and function. We evaluated theinfluence of visceral versus subcutaneous abdominal adipose tissue and epicardial fat on LVdiastolic function after acute myocardial infarction. One month after acute myocardialinfarction, 225 consecutive patients were prospectively enrolled and underwent anthropo-metric evaluation, bioimpedance analysis, detailed echocardiography, and multidetector64-slice computed tomography scan for quantification of epicardial fat volume (EFV) andof total, subcutaneous and visceral abdominal fat areas. We found a significant associationbetween LV diastolic dysfunction parameters and body mass index, fat-mass percentage,and waist-to-height ratio. E0 velocity and E/E0 ratio were correlated with total and visceralabdominal fat (r [ L0.27, p <0.001 and r [ 0.21, p <0.01, respectively), but not withsubcutaneous fat. After multivariate analysis, increasing EFV was associated withdecreased E0 velocity (adjusted b L0.11, 95% confidence intervalL0.19 toL0.03; p <0.01)and increased E/E0 ratio (adjusted b 0.19, 95% confidence interval 0.07 to 0.31, p <0.01).Patients with diastolic dysfunction showed higher EFV (116.7 – 67.9 ml vs 93.0 – 52.3 ml,p [ 0.01), and there was a progressive increase in EFV according to diastolic dysfunctiongrades (p [ 0.001). None of the adiposity parameters correlated with ejection fraction or S0velocities. In conclusion, in patients after myocardial infarction, impaired LV diastolicfunction was associated with increased adiposity, especially with visceral and central fatparameters. Increasing EFV was independently associated with worse LV diastolicfunction. � 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;114:1663e1669)

Few previous studies have assessed the relative importanceof visceral versus subcutaneous adiposity as determinants ofleft ventricular (LV) diastolic dysfunction. The few dataavailable suggest that visceral fat, themostmetabolically activefat depot, can be a more important determinant of diastolicdysfunction.1 Moreover, the heart itself is covered by fat, theepicardial adipose tissue (EAT). Because EAT secretesproinflammatory, proatherogenic, and prothrombotic adipo-kines,2,3 and there is no physical barrier separating it from theadjacent myocardium and coronary arteries, EAT can have a

local metabolic role by a paracrine effect.4 In fact, severalstudies have demonstrated that EAT is associated with thedevelopment and progression of coronary artery disease,5e7

independently of other cardiovascular risk factors or other fatdeposits and also with changes in myocardial structure andfunction.8e11 In this study we aimed to assess: (1) the role oftotal versus central adiposity parameters as determinants ofdiastolic dysfunction after myocardial infarction, (2) the rela-tive importance of total, subcutaneous, and visceral abdominalfat mass in this association, (3) the influence of EAT onmyocardial systolic and diastolic functions.

Methods

The present study included 225 consecutive patientsreferred to a cardiac rehabilitation program, 1 month after anacute myocardial infarction. Exclusion criteria were age>75 years, inability to exercise, severe valvular heart dis-ease, moderate or severe chronic lung disease, atrial fibril-lation, or exercise-induced myocardial ischemia. All patientswere prospectively enrolled and were submitted on the sameday to clinical evaluation (performed by a cardiologist),anthropometric evaluation, detailed transthoracic echocar-diography, computed tomography (CT) scan, and bloodsample collection. The investigation conforms to the

aCardiology Department, Gaia Hospital Center, Gaia, Portugal andDepartments of bPhysiology and Cardiothoracic Surgery and cMedicine,Faculty of Medicine, University of Porto, Porto, Portugal. Manuscriptreceived June 18, 2014; revised manuscript received and accepted August15, 2014.

This work was supported by the European Commission grant FP7-Health-2010: MEDIA-261409 and by the Portuguese-Foundation-for-Science-and-Technology grants PEst-C/SAU/UI0051/2011 and EXCL/BIM-MEC/0055/2012 (partially funded by Fundo Europeu Desenvolvimento Regional throughCOMPETE).

See page 1669 for disclosure information.*Corresponding author: Tel: (þ351) 22 786 51 00; fax: (þ351) 22

551 9194.E-mail address: [email protected] (R. Fontes-Carvalho).

0002-9149/14/$ - see front matter � 2014 Elsevier Inc. All rights reserved. www.ajconline.orghttp://dx.doi.org/10.1016/j.amjcard.2014.08.037

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principles outlined in the Declaration of Helsinki and wasapproved by the institution’s ethical committee. All patientsgave their written informed consent.

Measurements included height, weight, and waistcircumference. Body mass index (BMI) was calculated foreach subject. Waist circumference was measured at themidpoint between the iliac crest and the lower rib margins,in the midaxillary line. According to World Health Orga-nization criteria, overweight was defined as BMI between25 and 30 kg/m2 and obesity as BMI >30 kg/m2. Abdom-inal obesity was defined as waist circumference >102 cm inmen and >88 cm in women. Hip-to-height and waist-to-height ratios were calculated as the ratio between hipcircumference (cm) or waist circumference (cm), respec-tively, and height (m). Body composition was assessed bybioelectrical impedance analysis (Tanita Corporation,Arlington Heights, Illinois) to determine body fat percentage(%).

All echocardiographic studies were acquired by a singleexperienced cardiologist using an ultrasound system (iE33,Philips Medical Systems, Best, The Netherlands) equippedwith an S5-1 transducer. Images were digitally stored forposterior offline analysis. Cardiac chambers dimensions;volumes, and LV mass were measured according to currentrecommendations.12 Mitral inflow velocities were assessedusing pulse-wave Doppler in the apical 4-chamber view, witha 3 mm sample placed between the tips of the mitral leaflets;velocities were recorded at end expiration and averaged over3 consecutive cardiac cycles. Pulse-wave tissue-Dopplervelocities were acquired at end expiration, in the apical4-chamber view, with the sample positioned at the septal andlateral mitral annulus. Pulse-wave Doppler velocities at theupper right pulmonary vein were also recorded. For all

parameters the average of 3 consecutive heartbeats wasrecorded.

Diastolic function was assessed according to the recentconsensus guidelines on diastolic function evaluation13 bydetermining peak early (E) and late (A) diastolic mitral inflowvelocities; deceleration time of early LV filling (DT); the E/Aratio; the septal, lateral and average myocardial annular tissuevelocities (E0 sep, E0 lat, and E0 mean, respectively); the E/E0ratio (septal, lateral, and mean E/E0); pulmonary vein flowanalysis (to calculate the Ard-Ad difference: the time differ-ence between the duration of the atrial reversal wave of thepulmonary floweArdeand themitral A-wave durationeAd);and isovolumic relaxation time. Using the recent EuropeanAssociation of Echocardiography/American Society ofEchocardiography guidelines on diastolic function evalua-tion,13 patients were categorized in diastolic dysfunctiongrades normal, grade I (mild diastolic dysfunction), grade II(moderate diastolic dysfunction), and grade III (severe dia-stolic dysfunction) by 2 independent cardiologists who wereblinded for the study data. In case of discordance, each casewas discussed individually, and if doubt persisted no gradewas endorsed, which happened in 20 patients (8.9%).

Multidetector CT scans were performed in all patientsusing a 64-slice CT scanner (SOMATOM Sensation 64,Siemens Medical Solutions, Forchheim, Germany) with 2different acquisitions: 1 for abdominal fat quantification andthe other for epicardial adipose tissue quantification. Toassess abdominal fat, a single-slice abdominal CT scan wasperformed between L4 and L5, according to the methoddescribed byBorkan et al.14 The scan parameterswere 120 kVand 216 mA with 5 mm thickness. This resulted in an esti-mated radiation exposure of 0.06mSv.On the scan obtained, acursor pointer was used to trace the abdominal visceral fat

Figure 1. Measurement of EFV by CT. The level of the axial slices used for pericardial delineation is shown in a coronal projection. EAT was identified withinthe limits of pericardium sac using the adipose tissue attenuation references (�50 to �150 Hounsfield units). Pericardium contour was traced for every 10 mm,starting from the lower visible level of pulmonary artery bifurcation until the top level of the pulmonary valve; for every 20 mm from there until the first slicewhere the diaphragm becomes visible; and for every 10 mm from this point until the last slice where pericardium is still visible. Final EAT volume quan-tification was calculated as the sum of all slices fat values.

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area, and the data were processed using a histogram-basedstatistical program according to the previously describedmethod.15 One expert, unaware of the patient’s details,measured abdominal fat distribution. Fat tissue was defined inthe range between �150 and �50 Hounsfield units. Totalabdominal fat area was measured and subcutaneous fat areawas obtained by subtracting abdominal visceral fat from thetotal abdominal fat area.

An experienced radiographer, blinded for the purpose ofthe study and the patient’s anthropometric data, quantifiedepicardial fat volume (EFV). A cursor pointer was used to

manually trace the pericardial contour using 1 mm-thickreconstructed axial slices. Pericardium contour was tracedfor every 10 mm, starting from the lower visible level ofpulmonary artery bifurcation until the top level of the pul-monary valve, for every 20 mm from there until the firstslice where the diaphragm becomes visible and again forevery 10 mm from this point until the last slice wherepericardium is still visible,15 as illustrated in Figure 1. Thepericardium contour was extrapolated by the software,syngo Volume (Siemens Medical Solutions, Inc) for thenontraced slices and rechecked by the operator. Within theseanatomical limits, EAT was identified using the adiposetissue attenuation references (from �150 to �50 Hounsfieldunits) and a final EFV resulted from the sum of all slices offat values.

Statistical analysis was performed with SPSS programversion 20 (IBM Corp, Armonk, NY). All continuous vari-ables are shown as a mean � SD for normally distributedvariables or as a median and interquartile range for non-normally distributed variables. Categorical variables areexpressed as a number (n) and percentage (%). Statisticalsignificance was defined as p <0.05. Pearson and spearmancorrelation coefficients (r), as appropriate, were analyzed toaccess the correlations between cardiac function and structureechocardiographic and adiposity parameters obtained byanthropometry and CT scan. To compare median values ofseveral adiposity parameters according to diastolic functiongrades, nonparametric tests were used (Mann-Whitney andKruskal-Wallis tests, accordingly). Linear regression analysiswas performed for univariate and multivariate analyses of fatdistribution variables that predict worse diastolic function.Multivariate analysis was performed accordingly withadjustment for age, hypertension, gender, and several fatdepots.

Results

The clinical, anthropometric and analytical characteris-tics of the study population are listed in Table 1. Most pa-tients were men (84%), with a mean age of 55.1 �10.9 years, 47.6% were overweight and 20.9% were obese.The mean ejection fraction was 53.6 � 9.3% and most pa-tients (64.4%) had some degree of diastolic dysfunction. Aslisted in Table 2, there was a significant correlation betweenBMI and decreased early diastolic velocity (E0 lateral) andincreased LV filling pressures (E/E0 mean). Fat-mass per-centage, assessed by bioelectric impedance analysis, wasalso inversely correlated with E0 septal velocity, E0 lateralvelocity (as shown in Figure 2), and E/E0 mean ratio. Incontrast, as listed in Table 3, there was a significant increasein fat-mass percentage, according to the classification indiastolic dysfunction grades (p for trend <0.01). Aftermultivariate analysis, with adjustment for age, gender, andhypertension history, the association between fat-mass per-centage and early diastolic velocities (E0 septal and lateral)remained significant, as listed in Table 4.

The correlation between diastolic function and adiposityparameters was better with central obesity (assessed by waist-to-height ratio) than with total fat parameters, such as BMI(Table 2). Also, the association between waist-to-height ratioand E0 lateral velocity was independent of BMI or fat-mass

Table 1Characterization of the study population (n¼ 225)

Age, years 55.1 � 10.9Male 189 (84.0%)Cardiovascular risk factorsHypertension 35 (15.6%)Type 2 Diabetes Mellitus 35 (15.6%)Dyslipidemia 119 (52.9%)Smoker 117 (52.0%)Familial history 22 (9.8%)

ST-elevation myocardial infarction 85 (37.8%)Non ST-elevation myocardial infarction 140 (62.2%)Percutaneous coronary intervention 191 (84.9%)Overweight 107 (47.6%)Obese 47 (20.9%)Body mass index (Kg/m2) 26.9 � 4.5Weight (kg) 76.0 � 12.9Waist perimeter (cm) 96.8 � 10.0Bioimpedance fat mass (%) 26.0 � 7.3Total abdominal fat (cm2) 343.1 � 163.8Subcutaneous fat (cm2) 182.5 � 82.6Visceral fat (cm2) 148.7 � 70.5Epicardial fat (cm3) 113.6 � 43.2Total cholesterol (mg/dL) 137.5 � 32.3HDL (mg/dL) 39.9 � 10.3LDL (mg/dL) 75.4 � 35.5Triglycerides (mg/dL) 123.3 � 56.7Glucose (mg/dL) 97.1 � 18.8Hemoglobin (g/L) 14.1 � 1.4A1c hemoglobin (%) 5.9 � 0.9NT-ProBNP (ng/L) 357.0 � 531.0EchocardiographySeptum (mm) 9.6 � 1.6Posterior wall (mm) 9.3 � 1.5Left ventricle mass index (g/m2) 105.3 � 25.0Relative wall thickness 0.35 � 0.07Left atrium volume (ml/m2) 34.8 � 9.3Left ventricle end-diastolic volume (ml/m2) 111.3 � 30.6Left ventricle end-systolic volume (ml/m2) 52.4 � 22.4Left ventricular ejection fraction (%) 53.6 � 9.3E wave velocity (cm/s) 78.1 � 19.4A wave velocity (cm/s) 68.1 � 17.6E/A ratio 1.22 � 0.50Deceleration time (ms) 221.8 � 49.8Isovolumic relaxation time (ms) 98.7 � 24.4E’ lateral velocity (cm/s) 9.8 � 2.3E’ septal velocity (cm/s) 6.9 � 1.8E/E’ mean ratio 10.4 � 3.9Normal diastolic function 80 (39.0%)Grade 1 diastolic dysfunction 57 (27.8%)Grade 2 diastolic dysfunction 58 (28.3%)Grade 3 diastolic dysfunction 10 (4.9%)

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percentage (p <0.01). As listed in Table 4, after multivariateadjustment, for each unit increase in waist-to-heightratio there was a decrease of �0.09 (95% confidenceinterval �0.15 to �0.03, p <0.01) in E0 lateral velocity.

When analyzing the association between diastolic func-tion and abdominal fat distribution assessed by CT scan,increased total abdominal fat mass significantly correlatedwith decreased E0 velocities and increased E/E0 ratios (aslisted in Table 2 and Figure 2). Patients with diastolicdysfunction had increased total abdominal fat mass, as listedin Table 3.

There was a significant correlation between E0 lateral andE0 septal velocities with visceral abdominal fat mass, but notwith subcutaneous fat, as listed in Table 2 and in Figure 2.

According to the classification in diastolic dysfunctiongrades, we observed an increase in visceral abdominal fat(p for trend ¼ 0.01) but not in subcutaneous abdominal fatmass, with worse diastolic function (Table 3).

EFV was significantly correlated with all echocardio-graphic diastolic dysfunction parameters, namely withreduced lateral and septal E0 velocities and with higher septal,lateral, and mean E/E0 ratios (Table 2 and Figure 2). Also,across diastolic dysfunction grades there was a progressiveincrease in EFV (p for trend 0.001), as shown in Figure 3.Patients with any degree of diastolic dysfunction had signif-icantly higher EFVs (116.7� 67.9ml) than those with normaldiastolic function (93.0 � 52.3 ml). The association betweenEFV and E0 lateral velocity was independent of other

Table 2Correlation coefficients between several adiposity parameters and diastolic function

E’ septal E’ lateral E/E’ lateral E/E’septal E/E’ mean

BMI -0.11(p¼0.11)

-0.16(p¼0.02)

0.21(p¼0.001)

0.18(p¼0.01)

0.18(p<0.01)

Fat mass percentage -0.26(p<0.001)

-0.25(p<0.001)

0.29(p<0.001)

0.31(p<0.001)

0.28(p<0.001)

Waist perimeter/height -0.27(p<0.001)

-0.27(p<0.001)

0.28(p<0.001)

0.30(p<0.001)

0.28(p<0.001)

Total abdominal fat -0.19(p<0.01)

-0.20(p<0.01)

0.26(p<0.001)

0.23(p¼0.001)

0.22(p<0.01)

Subcutaneous abdominal fat -0.10(p¼0.15)

-0.09(p¼0.20)

0.20(p<0.01)

0.20(p<0.01)

0.17(p¼0.02)

Visceral abdominal fat -0.23(p¼0.001)

-0.27(p<0.001)

0.25(p<0.001)

0.21(p<0.01)

0.21(p<0.01)

Epicardial fat -0.26(p<0.001)

-0.28(p<0.001)

0.28(p<0.001)

0.24(p<0.001)

0.25(p<0.001)

Figure 2. Scatter plots showing the association between several adiposity parameters and diastolic function, assessed by E0 lateral velocity. r ¼ correlationcoefficient between the 2 variables.




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adiposity parameters (p <0.01 after adjustment for total fat-mass percentage, p <0.01 after adjustment for total abdom-inal fat, and p ¼ 0.03 after adjustment for visceral fat). Aftermultivariate regression analysis with adjustment for age,gender, and hypertension, increased epicardial fat is associ-ated with a decreased lateral E0 and septal E0 velocities andincreased E/E0 mean ratio, as listed in Table 4.

No significant association was found between total bodyfat parameters such as BMI, waist-to-height ratio, andfat-mass percentage with systolic function, namely withejection fraction or with systolic mitral annulus velocities (S0septal and S0 lateral). Also, neither abdominal fat mass (eithertotal fat, subcutaneous, or visceral fat) nor EFVwas correlatedwith any systolic function parameter.

Discussion

In this study, we analyzed the effect of several adiposityparameters on diastolic function after myocardial infarction

and observed the following: (1) overall, there was a sig-nificant association between increased total adiposity andimpaired diastolic function, (2) this association was strongerwith central and/or visceral adiposity than with subcutane-ous or total fat parameters, and (3) the association of EFVwith diastolic dysfunction was independent of other car-diovascular risk factors (namely aging and hypertension),gender, and other adiposity parameters. On the contrary, wedid not find any association between increased adiposity andsystolic function parameters.

The present study is, to the best of our knowledge, thefirst analyzing in detail the association between severaladiposity parameters, including epicardial fat and changes inmyocardial function. Fat distribution was analyzed not onlywith classical anthropometry parameters but also using CTscan data for determination of total, visceral, and subcu-taneous abdominal fat mass and EFV. CT scan is consideredto be the best method to assess epicardial fat.16 Diastolicfunction was assessed according to the most recent

Table 3Distribution of adiposity parameters according to diastolic function grades

Normal Diastolic function(n¼80)

Grade 1Diastolic Dysfunction

(n¼ 57)


(n¼ 58)


(n¼ 10)

p value(for trend)

BMI 25.8 � 4.23 26.9 � 5.6 26.8 � 3.7* 25.7 � 10.9 0.17Fat mass % 22.1 � 7.9 25.5 � 11.7† 25.9 � 9.2† 24.8 � 16.1 <0.01Waist perimeter/height 55.4 � 7.0 58.3.0 � 7.1† 58.5 � 7.9† 56.2 � 15.4 <0.01Total abdominalfat

270.0 � 151.6 331.1 � 149.3* 321.0 � 170.5† 308.8 �300.6 0.02

Subcutaneous abdominalfat

155.32 � 90.5 165.4 � 99.6 175.3 �74.7 194.4 � 135.9 0.13

Visceral abdominal fat 111.6 � 103.7 141.0 � 75.9† 160.0 � 88.8† 134.0 � 155.6 0.01Epicardial fat 93.0 � 52.3 111.15 � 60.2* 117.15 � 64.3† 136.4 � 83.1† 0.001

* p <0.05 compared to patients with normal diastolic function.† p <0.01 compared to patients with normal diastolic function.

Table 4Univariate and multivariate linear regression analyses for the association of diastolic function parameters (E’ velocity and E/E’ ratio) with adiposity parameters

E’ septal velocity E’ lateral velocity E/E’ ratio

Crude b(95% CI)

Adjusted b*(95% CI*)

p value* Crude b(95% CI)


p value* Crude b(95% CI)


p value*

BMI -0.05(-0.10 to 0.00)

-0.05(-0.09 to -0.01)

0.02 -0.08(-0.16 to -0,01)

-0.09(-0.16 to -0,02)

<0.01 0.09(-0.03 to 0.20)

0.10(-0.01 to 0.22)

0.08

Fat mass % -0.06(-0.09 to -0.03)

-0.04(-0.07 to 0.00)

0.04 -0.09(-0.14 to -0.04)

-0.08(-0.13 to -0.02)

<0.01 0.09(0.01 to 0.16)

0.08(-0.02 to 0.17)

0.11

WP/height -0.09(-0.13 to -0.05)

-0.05(-0.09 to -0.01)

0.02 -0.13(-0.19 to -0.07)

-0.09(-0.15 to -0.03)

<0.01 0.11(0.02 to 0.21)

0.09(-0.01 to 0.19)

0.07

Total abdominalFat (x10)

-0.03(-0.05 to -0.01)

0.02(-0.04 to 0.00)

0.07 -0.05(-0.07 to -0.02)

-0.03(-0.06 to 0.00)

0.03 0.04(0.00 to 0.09)

0.04(-0.01 to 0.08)

0.09

Subcutaneousabdominal fat(x10)

-0.02(-0.05 to 0.01)

-0.02(-0.05 to 0.00)

0.23 -0.03(-0,08 to 0.01)

-0.04(-0.08 to 0.00)

0.07 0.04(-0.03 to 0.11)

0.04(-0.03 to 0.11)

0.25

Visceralabdominal fat(x10)

-0.06(-0.09 to -0.03)

-0.03(-0.06 to 0.01)

0.15 -0.10(-0.15 to -0.05)

-0.05(-0.10 to 0.00)

0.04 0.08(0.001to 0.16)

0.08(0.00 to 0.16)

0.06

Epicardial fat(x10)

-0.11(-0.17 to -0.06)

-0.06(-0.12 to -0.01)

0.02 -0.17(-0.25 to -0.09)

-0.11(-0.19 to -0.03)

<0.01 0.19(0.07 to 0.31)

0.19(0.06 to 0.32)

<0.01

b ¼ regression coefficient; 95% CI ¼ 95% confidence interval.* Adjusted for age, hypertension history, sex.


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consensus document for the evaluation of LV diastolicfunction.13

Our results are in accordance with very recent studies thathave shown an association between increased total adiposityand diastolic dysfunction.17,18 In a general population sample,Russo et al 18 found an association between increased BMI andreduced early diastolic mitral annulus velocity (E0), increasedfilling pressures (E/E0 ratio), and the presence of diastolicdysfunction. However, it is known that BMI is not a goodmarker of fat accumulation because it is influenced by severalother factors.19 In our study, we have shown that worse dia-stolic function is associated not only with increased BMI, butalso with increased fat-mass percentage (assessed by bioelec-tric impedance), which reinforces the association between totalfat accumulation and diastolic dysfunction. This associationbetween obesity and diastolic function was independent oftraditional cardiovascular risk factors, suggesting that otherpathophysiological mechanisms are responsible for this asso-ciation.Adipose tissue canmodulate the cardiovascular systemby several metabolic and neuroendocrine pathways, whichinclude abnormalities in sodium balance, neuroendocrineactivation of the renin-angiotensin-aldosterone axis and sym-pathetic system,20 secretion of adipokines,21 or increasedmyocardial oxidative stress.22

Visceral adipose tissue is inherently different from sub-cutaneous fat in several processes. Visceral fat is the meta-bolically most active organ, secreting several adipokines andbeing the main contributor to a systemic proinflammatorystate that can affect cardiovascular system and diastolicfunction.21,23 In our study, diastolic dysfunction correlatedmore strongly with central and visceral adiposity parametersthan with measures of total and subcutaneous obesity. Asimilar finding, showing an association between waist-to-height ratio and diastolic dysfunction, independent of BMI,has also been recently demonstrated in the general popula-tion.17 Another study from the Baltimore Longitudinal Studyof Aging, in which abdominal visceral and subcutaneous fatwere measured using CT scan, showed that although both

visceral and subcutaneous fat were associated with LV dia-stolic dysfunction, only visceral fat was significantly associ-ated with LV diastolic dysfunction when both were includedin the samemodel.1 Our data are also in accordancewith thesefindings.

In this study we have also shown that increased EFV wassignificantly associated with worse diastolic function. Thisassociation was independent of other diastolic dysfunctiondeterminants, such as aging, gender, and hypertension his-tory. A similar finding has been recently reported showingan association between epicardial fat thickness (determinedby echocardiography), but not visceral adipose tissue, withsubclinical diastolic in peritoneal dialyzed patients.9

Epicardial fat has special properties that distinguish it fromother visceral fat components. It directly covers the heartand the coronary arteries without any mechanical barrier tothe cardiomyocytes and vessels and also shares the sameblood supply.24 Therefore, because EAT is an importantsource of several proinflammatory and proatherogenic cy-tokines, EAT can have a direct effect on coronary athero-sclerosis and/or cardiac structure and function.4,25 Recently,several studies have recognized increased EAT as an inde-pendent determinant of the development and progression ofcoronary artery disease,5,15 presence of myocardial perfu-sion abnormalities,26 and vulnerable coronary atheroscle-rotic plaques.7 EAT is a stronger determinant of coronaryartery disease than visceral adiposity located in other bodycompartments.5

In contrast, EAT can also directly influence myocardialstructure and function by mechanical, systemic, and paracrinepathways. The systemic effects of obesity on cardiac functionwere described previously. Our data are in accordance withother studies9e11 suggesting a direct influence of EAT ondiastolic function, possibly mediated by local mechanical orparacrine effects. First, EFV can range from 50 g to >250 gand, therefore, can induce an outside compression of the heart,which can pose a mechanical limitation to cardiac expansion,further deteriorating diastolic function.8 However, local para-crine inflammatory pathways can also play an important role inthis association. In an interesting study, using biopsies of pa-tientswhounderwent electiveCABG, itwas shown thatEAT isa local source of several inflammatory mediators (such asinterleukin-1 beta, interleukin-6, monocyte chemoattractantprotein-1, and tumor necrosis factor-alpha) independent ofplasma inflammatory biomarkers.2 As stated previously,inflammation can induce stiffer cardiomyocytes and increasedinterstitial fibrosis deposition and diastolic dysfunction.23

Moreover, EAT can also secrete locally several adipokines(such as adiponectin, resistin, leptin, and others)2 that caninduce changes inmyocardial structure and function.24 Finally,EAT is a source of free fatty acids, leading to the accumulationof myocardial triglycerides, cardiomyocyte apoptosis, oxida-tive stress, and impaired cardiac function.27,28

Regarding the study limitations, we followed a cross-sectional design, and therefore, we cannot infer about cau-sality relation between adiposity parameters and diastolicdysfunction. Longitudinal studies are now required to furtherassess this association. Also, we have only included patientsafter myocardial infarction, and therefore, we cannot extrap-olate these conclusions to the general population or to othercardiac diseases.

Figure 3. Distribution of EFV according to diastolic dysfunction grades. *p<0.05 compared with patients with normal diastolic function, †p <0.01compared with patients with normal diastolic function.




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Disclosures

The authors have no conflicts of interest to disclose.

1. Canepa M, Strait JB, Milaneschi Y, Alghatrif M, Ramachandran R,Makrogiannis S, Moni M, David M, Brunelli C, Lakatta EG, FerrucciL. The relationship between visceral adiposity and left ventriculardiastolic function: results from the Baltimore Longitudinal Study ofAging. Nutr Metab Cardiovasc Dis 2013;23:1263e1270.

2. Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H,Sarov-Blat L, O’Brien S, Keiper EA, Johnson AG, Martin J, GoldsteinBJ, Shi Y. Human epicardial adipose tissue is a source of inflammatorymediators. Circulation 2003;108:2460e2466.

3. Dutour A, Achard V, Sell H, Naour N, Collart F, Gaborit B, Silaghi A,Eckel J, Alessi MC, Henegar C, Clement K. Secretory type II phos-pholipase A2 is produced and secreted by epicardial adipose tissue andoverexpressed in patients with coronary artery disease. J Clin Endo-crinol Metab 2010;95:963e967.

4. Sacks HS, Fain JN. Human epicardial adipose tissue: a review. AmHeart J 2007;153:907e917.

5. Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA,Vasan RS, O’Donnell CJ, Fox CS. Pericardial fat, visceral abdominalfat, cardiovascular disease risk factors, and vascular calcification in acommunity-based sample: the Framingham Heart Study. Circulation2008;117:605e613.

6. Mahabadi AA, Reinsch N, Lehmann N, Altenbernd J, Kalsch H, SeibelRM, Erbel R, Mohlenkamp S. Association of pericoronary fat volumewith atherosclerotic plaque burden in the underlying coronary artery: asegment analysis. Atherosclerosis 2010;211:195e199.

7. Alexopoulos N, McLean DS, Janik M, Arepalli CD, Stillman AE,Raggi P. Epicardial adipose tissue and coronary artery plaque charac-teristics. Atherosclerosis 2010;210:150e154.

8. Fox CS, Gona P, Hoffmann U, Porter SA, Salton CJ, Massaro JM,Levy D, Larson MG, D’Agostino RB Sr, O’Donnell CJ, Manning WJ.Pericardial fat, intrathoracic fat, and measures of left ventricularstructure and function: the Framingham Heart Study. Circulation2009;119:1586e1591.

9. Lin HH, Lee JK, Yang CY, Lien YC, Huang JW, Wu CK. Accumu-lation of epicardial fat rather than visceral fat is an independent riskfactor for left ventricular diastolic dysfunction in patients undergoingperitoneal dialysis. Cardiovasc Diabetol 2013;12:127.

10. Konishi M, Sugiyama S, Sugamura K, Nozaki T, Matsubara J,Akiyama E, Utsunomiya D, Matsuzawa Y, Yamashita Y, Kimura K,Umemura S, Ogawa H. Accumulation of pericardial fat correlates withleft ventricular diastolic dysfunction in patients with normal ejectionfraction. J Cardiol 2012;59:344e351.

11. Iacobellis G, Leonetti F, Singh N, A MS. Relationship of epicardialadipose tissue with atrial dimensions and diastolic function in morbidlyobese subjects. Int J Cardiol 2007;115:272e273.

12. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, PellikkaPA, Picard MH, RomanMJ, Seward J, Shanewise J, Solomon S, SpencerKT, St John Sutton M, Stewart W; American Society of Echocardiog-raphy’s Nomenclature and Standards Committee; Task Force onChamberQuantification; American College of Cardiology EchocardiographyCommittee; American Heart Association; European Association ofEchocardiography, European Society of Cardiology. Recommendationsfor chamber quantification. Eur J Echocardiogr 2006;7:79e108.

13. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, SmisethOA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A.Recommendations for the evaluation of left ventricular diastolicfunction by echocardiography. Eur J Echocardiogr 2009;10:165e193.

14. Borkan GA, Gerzof SG, Robbins AH, Hults DE, Silbert CK, Silbert JE.Assessment of abdominal fat content by computed tomography. Am JClin Nutr 1982;36:172e177.

15. Bettencourt N, Toschke AM, Leite D, Rocha J, Carvalho M, SampaioF, Xara S, Leite-Moreira A, Nagel E, Gama V. Epicardial adiposetissue is an independent predictor of coronary atherosclerotic burden.Int J Cardiol 2012;158:26e32.

16. Marwan M, Achenbach S. Quantification of epicardial fat by computedtomography: why, when and how? J Cardiovasc Comput Tomogr2013;7:3e10.

17. Canepa M, Strait JB, Abramov D, Milaneschi Y, AlGhatrif M, MoniM, Ramachandran R, Najjar SS, Brunelli C, Abraham TP, Lakatta EG,Ferrucci L. Contribution of central adiposity to left ventricular diastolicfunction (from the Baltimore Longitudinal Study of Aging). Am JCardiol 2012;109:1171e1178.

18. Russo C, Jin Z, Homma S, Rundek T, Elkind MS, Sacco RL, Di TullioMR. Effect of obesity and overweight on left ventricular diastolicfunction: a community-based study in an elderly cohort. J Am CollCardiol 2011;57:1368e1374.

19. Cornier MA, Despres JP, Davis N, Grossniklaus DA, Klein S,Lamarche B, Lopez-Jimenez F, Rao G, St-Onge MP, Towfighi A,Poirier P; American Heart Association Obesity Committee of theCouncil on Nutrition; Physical Activity and Metabolism; Council onArteriosclerosis; Thrombosis and Vascular Biology; Council onCardiovascular Disease in the Young; Council on CardiovascularRadiology and Intervention; Council on Cardiovascular Nursing,Council on Epidemiology and Prevention; Council on the Kidney inCardiovascular Disease, and Stroke Council. Assessing adiposity: ascientific statement from the American Heart Association. Circulation2011;124:1996e2019.

20. Gorzelniak K, Engeli S, Janke J, Luft FC, Sharma AM. Hormonalregulation of the human adipose-tissue renin-angiotensin system: rela-tionship to obesity and hypertension. J Hypertens 2002;20:965e973.

21. Falcao-Pires I, Castro-Chaves P, Miranda-Silva D, Lourenco AP,Leite-Moreira AF. Physiological, pathological and potential therapeuticroles of adipokines. Drug Discov Today 2012;17:880e889.

22. Vincent HK, Powers SK, Stewart DJ, Shanely RA, Demirel H, NaitoH. Obesity is associated with increased myocardial oxidative stress. IntJ Obes Relat Metab Disord 1999;23:67e74.

23. Paulus WJ, Tschope C. A novel paradigm for heart failure with pre-served ejection fraction: comorbidities drive myocardial dysfunctionand remodeling through coronary microvascular endothelial inflam-mation. J Am Coll Cardiol 2013;62:263e271.

24. Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue:anatomic, biomolecular and clinical relationships with the heart. NatClin Pract Cardiovasc Med 2005;2:536e543.

25. Iozzo P. Myocardial, perivascular, and epicardial fat. Diabetes Care2011;34(Suppl 2):S371eS379.

26. Janik M, Hartlage G, Alexopoulos N, Mirzoyev Z, McLean DS, Are-palli CD, Chen Z, Stillman AE, Raggi P. Epicardial adipose tissuevolume and coronary artery calcium to predict myocardial ischemia onpositron emission tomography-computed tomography studies. J NuclCardiol 2010;17:841e847.

27. Malavazos AE, Di Leo G, Secchi F, Lupo EN, Dogliotti G, Coman C,Morricone L, Corsi MM, Sardanelli F, Iacobellis G. Relation ofechocardiographic epicardial fat thickness and myocardial fat. Am JCardiol 2010;105:1831e1835.

28. van der Meer RW, Rijzewijk LJ, Diamant M, Hammer S, Schar M, BaxJJ, Smit JW, Romijn JA, de Roos A, Lamb HJ. The ageing male heart:myocardial triglyceride content as independent predictor of diastolicfunction. Eur Heart J 2008;29:1516e1522.


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ORIGINAL INVESTIGATION Open Access

Diastolic dysfunction in the diabetic continuum:association with insulin resistance, metabolicsyndrome and type 2 diabetesRicardo Fontes-Carvalho1,2,3*, Ricardo Ladeiras-Lopes2,3, Paulo Bettencourt4,5, Adelino Leite-Moreira3,6

and Ana Azevedo1,7

Abstract

Background: Diabetes increases the risk of heart failure but the underlying mechanisms leading to diabeticcardiomyopathy are poorly understood. Left ventricle diastolic dysfunction (LVDD) is one of the earliest cardiacchanges in these patients. We aimed to evaluate the association between LVDD with insulin resistance, metabolicsyndrome (MS) and diabetes, across the diabetic continuum.

Methods: Within a population-based study (EPIPorto), a total of 1063 individuals aged ≥45 years (38% male,61.2 ± 9.6 years) were evaluated. Diastolic function was assessed by echocardiography, using tissue Doppleranalysis (E’ velocity and E/E’ ratio) according to the latest consensus guidelines. Insulin resistance was assessedusing the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score.

Results: The HOMA-IR score correlated to E’ velocity (ρ = −0.20;p < 0.0001) and E/E’ ratio (ρ = 0.20; p < 0.0001).There was a progressive worsening in E’ velocity (p for trend < 0.001) and in E/E’ ratio across HOMA-IR quartiles(p for trend <0.001). Individuals in the highest HOMA-IR quartile were more likely to have LVDD, even afteradjustment for age, sex, blood pressure and body mass index (adjusted OR: 1.82; 95% CI: 1.09-3.03). From individualswith no MS, to patients with MS and no diabetes, to patients with diabetes, there was a progressive decrease in E’velocity (11.2 ± 3.3 vs 9.7 ± 3.1 vs 9.2 ± 2.8 cm/s; p < 0.0001), higher E/E’ (6.9 ± 2.3 vs 7.8 ± 2.7 vs 9.0 ± 3.6; p < 0.0001) andmore diastolic dysfunction (adjusted OR: 1.62; 95% CI: 1.12-2.36 and 1.78; 95% CI: 1.09-2.91, respectively).

Conclusions: HOMA-IR score and metabolic syndrome were independently associated with LVDD. Changes in diastolicfunction are already present before the onset of diabetes, being mainly associated with the state of insulin resistance.

Keywords: Insulin resistance, Diabetes, Diastole, Diabetic cardiomyopathy

BackgroundSubclinical left ventricle diastolic dysfunction (LVDD) iscommon in the community [1] and is recognized as animportant predictor of heart failure [2] and long-termmortality [3]. Current heart failure guidelines [4] givespecial emphasis to the early detection of these asymp-tomatic changes of left ventricle function and the identi-fication of its main risk factors.

Epidemiological studies have associated diastolic func-tion with aging, hypertension and myocardial ischemia[1]. Besides, more recent data have also demonstrated anindependent association between diastolic function andobesity [5], especially with abdominal obesity [6] and vis-ceral fat mass [7]. Insulin resistance can be one of theimportant pathophysiological links involved in this asso-ciation [8,9]. Several studies have suggested that LVDDis one of the earliest signs of myocardial involvement intype 2 diabetes mellitus (T2DM) [10], being a key com-ponent of diabetic cardiomyopathy [11].More recently, it was suggested that changes in dia-

stolic function precede the onset of diabetes, beingalready present in pre-diabetic patients [12,13], which

* Correspondence: [email protected] - Institute of Public Health, University of Porto, Porto, Portugal2Cardiology Department, Gaia Hospital Center, Vila Nova Gaia, PortugalFull list of author information is available at the end of the article

CARDIOVASCULAR DIABETOLOGY

© 2015 Fontes-Carvalho et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in thisarticle, unless otherwise stated.

Fontes-Carvalho et al. Cardiovascular Diabetology (2015) 14:4 DOI 10.1186/s12933-014-0168-x

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could be associated with the state of insulin resistance.Metabolic syndrome (MS), or insulin resistance syn-drome, is a cluster of cardiovascular risk factors shownto act synergistically to increase the risk of adverse car-diovascular events [14], but also inducing subclinicalchanges in cardiac structure and function. Indeed, pa-tients with metabolic syndrome also have an increasedprevalence of LVDD [15,16], frequently with a subclin-ical course [17].In this study, our aim was to evaluate, at the popula-

tion level, the association between insulin resistance andLVDD in different stages of the diabetic continuum.

MethodsStudy populationParticipants were selected within the first follow-up of acohort, representative at baseline of the adult populationof Porto, Portugal — the EPIPorto cohort study. In1999–2003, the cohort assembly was made by random-digit dialing, using households as the sampling frame,followed by random selection of one person aged 18years or older in each household. Refusals were notsubstituted within the same household. The proportionof participation was 70%. At baseline, 2485 participantswere recruited. Between October 2006 and July 2008,participants aged 45 years or over were eligible to a sys-tematic evaluation of parameters of cardiac structureand function, which included a cardiovascular clinicalhistory, physical examination, detailed anthropometricevaluation, collection of fasting blood sample and atransthoracic echocardiogram. Among 2048 cohortmembers in the eligible age range at this time, 134(6.5%) had died, 198 (9.7%) refused to be re-evaluatedand 580 (28.3%) were lost to follow-up (unreachable bytelephone or post). From this analysis we excluded 73patients with previous myocardial infarction, percutan-eous or surgical revascularization, prior cardiac surgeryor significant (moderate to severe) valvular heart disease.Patients with type 1 diabetes (n = 6) were excluded fromthe analysis.Written informed consent was obtained from all the

individuals and the local ethics committee (ComissãoÉtica Centro Hospitalar S. João) approved the study. Theinvestigation conforms to the principles outlined in theDeclaration of Helsinki.

Clinical variables definitionsHypertension was defined as systolic blood pressure(SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg at the time of the visit (mean of 3 readings)or use of antihypertensive medication. T2DM was de-fined as fasting blood glucose ≥126 mg/dl or the pa-tient’s self-reported history of diabetes or use of diabetesmedications. Hypercholesterolemia was defined as total

serum cholesterol ≥220 mg/dl or the use of lipid- lower-ing treatment. Obesity was defined as body mass index(BMI) ≥ 30 kg/m2 and central obesity as waist circumfer-ence >102 cm in men and >88 cm in women. Metabolicsyndrome was defined according to the American HeartAssociation updated National Cholesterol EducationProgram Adult Treatment Panel III (AHA/NCEP) criteria[18]. Although there are several definitions for metabolicsyndrome, we used this definition because it showed thestrongest association with cardiovascular disease in thePortuguese population [19].MS was diagnosed if any 3 of the following were

present: central obesity (WC 102 cm in men and 88 cmin women), raised triglycerides (≥150 mg/dL or fibratesintake), reduced HDL-C (< 40 mg/dL in males and 50mg/dL in females), raised blood pressure (SBP ≥ 130mmHg or DBP ≥ 85 mmHg or anti-hypertensive treat-ment) or raised fasting plasma glucose (FPG ≥ 100 mg/dL or previously diagnosed T2DM). We defined 3 popu-lations of interest in the diabetic continuum: individualswith no MS, patients with MS without T2DM and pa-tients with T2DM.

Analytical dataA fasting venous blood sample was obtained in themorning for measurement of glucose, total cholesterol,LDL, HDL, triglycerides and high-sensitivity C-reactiveprotein (by immunonephelometry). For insulin measure-ment the blood was immediately centrifuged and theplasma stored at −20°C, for later measurement. Insulinresistance was assessed using the Homeostasis ModelAssessment of Insulin Resistance (HOMA-IR) score insubjects without a history of T2DM before inclusioninto the study. The HOMA score was calculated fromthe formula [20]: HOMA-IR = fasting glucose (mg/dl) ×insulin (μU/ml)/405.

Echocardiography dataAll echocardiographic studies were acquired using thesame equipment (Hewlett-Packard Sonos 5500). Imageswere stored on videotape for posterior offline analysis bytwo experienced cardiologists, blinded to clinical data.Cardiac chambers dimensions, volumes and left ven-

tricular mass were measured according to current rec-ommendations [21], and indexed to body surface area.Diastolic function was assessed according to the recentconsensus guidelines on diastolic function evaluation[22] measuring mitral inflow velocities (E-wave, A wave,E/A ratio) and deceleration time (DT) using pulsed-wave (PW) Doppler in the apical four-chamber view.Velocities were recorded at end-expiration and averagedover three consecutive cardiac cycles. Isovolumetric relax-ation time (IVRT) was also assessed accordingly. PWtissue-Doppler velocities were acquired at end-expiration,

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in the apical four-chamber view, with the sample posi-tioned at the lateral mitral annulus, measuring early dia-stolic (E’) and late diastolic (A’) velocities and calculatingthe E/E’ ratio. Patients were categorized into normal dia-stolic function or LVDD grades I (mild LVDD), II (moder-ate LVDD) and III (severe LVDD), by two independentcardiologists according to the criteria in the consensusguidelines [22]. In case of discordance, each case wasdiscussed individually, and if doubt persisted no grade wasendorsed. LV systolic function was evaluated by determin-ation of LV ejection fraction using the modified Simpson’srule from biplane 4-chamber.

Statistical analysisStatistical analyses were performed using STATA version12 (STATA Corp, TX, USA). Data are expressed as mean± standard deviation for quantitative variables with normaldistribution, as median and 25th and 75th percentiles(P25-P75) for variables with non-normal distribution or asnumber (n) and percentage (%) for categorical variables.Pearson coefficient (r) was calculated to assess the correl-ation of two normally distributed continuous variables andthe Spearman correlation (ρ) was used when the variableswere non-normally distributed. The trend across categor-ical variables was tested with the nptrend command,which is an extension of the Wilcoxon rank-sum test. Uni-variate and multivariate logistic regression analysis wasperformed to predict the presence of LVDD. The variablesincluded in the multivariate model based on previousknowledge were age, gender, systolic blood pressure andBMI. An interaction term was added to the model to as-sess effect modification by sex, which was not confirmed.

ResultsPatient characteristicsIn this study, 1063 individuals were included, 38% weremale, with a mean age of 62.4 ± 10.6 years. The preva-lence of MS according to the AHA/NCEP criteria was41.8% and 11.9% had diabetes. Only 16 patients hadT2DM without fulfilling the criteria of MS. Table 1shows the clinical, anthropometric, analytical and echo-cardiographic characteristics of the study sample. The

Table 1 Characteristics of the study participants

Total

n = 1063

Age, years 62.2 ± 10.6

Male sex, n (%) 394 (37.1)

Cardiovascular risk factors

Hypertension, n (%) 361 (34.8)

Diabetes, n (%) 123 (11.8)

Dyslipidemia, n (%) 570 (54.9)

Obesity, n (%) 258 (24.3)

Systolic blood pressure,mmHg

133 ± 20

Diastolic blood pressure,mmHg

78 ± 11

BMI, Kg/m2 27.5 ± 4.6

Waist perimeter/height,cm/cm

0.58 ± 0.07

Hip perimeter/height,cm/cm

0.64 ± 0.07

Waist-to-hip ratio 0.92 ± 0.08

Analytical data

Total cholesterol, mg/dL 220 ± 52

HDL, mg/dL 62 ± 44

LDL, mg/dL 134 ± 52

Triglycerides, mg/dL 152 ± 443

Glucose, mg/dL 104 ± 47

C-reactive protein, mg/dL 0.19 (0.09-0.4)

HOMA-IR score 1.09 (0.62-1.86)

Echocardiography

Septum, mm 8.7 ± 1.5

Posterior wall, mm 7.9 ± 1.3

LV mass index, g/m2 80.2 ± 21.0

Left atrium volume index,ml/m2

29.2 ± 10.4

LV end-diastolic volume,ml/m2

66.5 ± 16.9

LV end-systolic volume,ml/m2

27.3 ± 10.2

Ejection fraction, % 60.2 ± 6.8

E wave, cm/s 71.4 ± 15.8

A wave, cm/s 78.6 ± 19.9

E/A ratio 0.96 ± 0.32

Deceleration time, ms 238.1 ± 56.9

IVRT, ms 92.0 ± 16.1

E’ velocity, cm/s 10.5 ± 3.3

E/E’ ratio 7.4 ± 2.7

LVDD grade

Normal, n (%) 792 (76.3)

Mild, n (%) 151 (14.5)

Table 1 Characteristics of the study participants(Continued)

Moderate, n (%) 92 (8.9)

Severe, n (%) 3 (0.3)

Undetermined 25

Data are presented as mean ± standard deviation for continuous variables withnormal distribution, median and 25th and 75th percentiles (P25-P75) for variableswith non-normal distribution and count (percentage) for categorical variables.(BMI – body mass index; s – seconds; DD – diastolic dysfunction; IVRT –isovolumetric relaxation time; LV – left ventricle; LVDD – left ventriclediastolic dysfunction).


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total prevalence of LVDD in this study population was23.7%: 14.5% had mild diastolic dysfunction and 9.2%had moderate or severe diastolic dysfunction. In 25 pa-tients (2.4%) it was not possible to determine LVDDgrade due to atrial fibrillation or fusion of the E/A mitralflow pattern. Regarding medication use, 24.6% weredoing renin-angiotensin axis blockers, 7.1% were takingcalcium channel blockers, 12.1% were on diuretics and22.8% were taking statins.

Insulin resistance and LVDDThe HOMA-IR score was inversely correlated to lateral E’velocity (Spearman’s ρ = −0.20; p < 0.001) and positivelycorrelated to E/E’ ratio (Spearman’s ρ = 0.20; p < 0.001).According to HOMA-IR quartiles, higher insulin resist-ance was associated with lower E’ velocity and higher E/E’ratio, as shown in Table 2 and Figures 1 and 2.We observed a stepwise increase in HOMA-IR score

according to the grades of diastolic function. HOMA-IRscore increased from 0.95 (P25-75: 0.56-1.69) in individ-uals with normal diastolic function, to 1.30 (P25-75:0.70-2.03) in patients with grade I diastolic dysfunctionand to 1.59 (P25-75: 0.83-2.41) in patients with moder-ate/severe diastolic dysfunction (p < 0.001).Table 2 shows the association of diastolic function pa-

rameters with insulin resistance (HOMA-IR) and dia-betes status. We observed a significant trend for lower E’velocity and higher E/E’ ratio across HOMA-IR quar-tiles. Compared to the first quartile, individuals in thehighest HOMA-IR quartile showed a 1.82-fold increasedodds of LVDD (95% CI: 1.09-3.03), as detailed inTable 3.

Metabolic syndrome, T2DM and LVDDFirst, we observed a significant increase in HOMA-IRscore from patients without MS (0.80; P25-75: 0.44-1.28)

to patients with MS without T2DM (1.60; P25-75: 0.91-2.25) and to patients with MS and T2DM (2.56; P25-75:1.55-4.64), p < 0.001.Patients with MS or T2DM showed lower E’ velocity

and increased E/E’ ratio. Furthermore, as shown inTable 2, there was a significant trend for progressivelylower E’ velocity and E/A ratio and higher E/E’ ratio andDT when comparing individuals without MS, to patientswith MS not including T2DM and to patients with MSand T2DM.The prevalence of diastolic dysfunction was 16.3% in

the patients without MS, 32.6% in patients with MS andno T2DM and 36.6% in patients with MS and T2DM (pfor trend < 0.001; Table 3). After adjusting for age, sex,SBP and BMI, patients with MS and no T2DM showed a1.62 (95% CI: 1.12-2.36) increased odds of having LVDDand patients with T2DM showed an OR of 1.78 (95% CI:1.09-2.91). There was no statistically significant differ-ence in the odds of LVDD between patients with MSand no T2DM compared to patients with T2DM (p =0.696). Also, T2DM was not associated with an increasedodds of LVDD (adjusted OR: 1.38; 95% CI: 0.88-2.16)after including in the comparator group both patientswith and without MS. We did not find any significantinteraction according to gender for the association be-tween diastolic dysfunction with insulin resistance,metabolic syndrome or T2DM.

DiscussionIn this population-based study, we showed that insulinresistance is associated with left ventricular diastolicdysfunction. There was also a progressive worsening ofdiastolic function parameters (E’ velocity and E/E’ ratio)from individuals without MS, to patient with MS with-out T2DM and to patients with fully established T2DM.Metabolic syndrome was significantly associated with

Table 2 Diastolic dysfunction parameters according to quartiles of insulin resistance and metabolic syndrome status

Diastolic function parameters

E’ velocity E/E’ ratio E/A ratio DT

Insulin resistance

(HOMA-IR score)

Quartile 1 11.3 ± 3.3 6.8 ± 2.6 1.03 ± 0.37 232.8 ± 52.8

Quartile 2 10.7 ± 2.9 7.1 ± 2.3 0.97 ± 0.28 233.2 ± 50.4

Quartile 3 10.1 ± 3.6 7.6 ± 2.7 0.92 ± 0.27 240.8 ± 69.5

Quartile 4 9.8 ± 3.0 8.1 ± 3.1 0.92 ± 0.35 245.5 ± 54.3

No Metabolic Syndrome (n = 571) 11.2 ± 3.3 6.9 ± 2.3 1.01 ± 0.32 232.3 ± 56.9

Metabolic Syndrome without T2DM (n = 331) 9.7 ± 3.1 7.8 ± 2.7 0.88 ± 0.25 248.4 ± 57.2

Metabolic Syndrome with T2DM (n = 123) 9.2 ± 2.8 9.0 ± 3.6 0.95 ± 0.46 237.9 ± 52.7

p for trend p < 0.001 p < 0.001 p < 0.001 p = 0.002

DT - deceleration time; T2DM - type 2 diabetes mellitus; HOMA-IR - Homeostasis Model Assessment of Insulin Resistance.Results are presented as mean ± standard deviation.




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increased risk of diastolic dysfunction, independently ofage, blood pressure and body mass index.

The association between diastolic dysfunction and insulinresistanceIn most patients with glucose metabolism disturbances,insulin resistance is the key pathophysiological mechan-ism. In this study we found that individuals with higherinsulin resistance had worse diastolic function parame-ters and a significantly increased risk of LVDD, whichwas independent of other determinants of diastolic func-tion. Until now, few other studies have analyzed the

association between insulin resistance and changes incardiac function, namely with diastolic dysfunction. In agroup of selected non-diabetic patients undergoingelective coronary angiography, Dinh et al. also foundthat insulin resistance was independently associated withLVDD [23] and the same has been observed in a smallstudy of patients with aortic valve sclerosis [24]. Twoother studies have demonstrated changes in diastolicfunction across the diabetic continuum, including in pre-diabetic patients [12,13]. Altogether these data suggestthat subclinical changes in myocardial diastolic functionare already present before the onset of T2DM, being

Figure 1 E’ velocity according to insulin resistance quartiles.

Figure 2 E/E’ ratio according to insulin resistance quartiles.


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associated mainly with the state of insulin resistance andnot only to sustained hyperglycemia.Metabolic syndrome, also known as insulin resistance

syndrome, is common, affecting more than 20% of theadult population of United States and Europe [25]. Insulinresistance is central to the pathophysiology of MS, beingassociated with a pro-inflammatory, pro-thrombotic andoxidative state and increased risk of atherosclerotic cardio-vascular disease [14]. In this study we showed that MS isalso independently associated with subclinical changes inmyocardial function, namely with LVDD. Compared toindividuals without MS, patients with MS had worsediastolic function parameters, including reduced E’velocity, which is a marker of LV relaxation, andhigher E/E’ ratio, which reflects increased LV fillingpressures. Moreover, MS was associated with a 1.62-increased odd of LVDD independently of age, sex,blood pressure and body mass index. These data are inaccordance with the observations of other smallerstudies [15,16,26,27], that also showed a progressiveworsening of diastolic function parameters accordingto the number of criteria for metabolic syndrome[15,16]. Several pathophysiologic mechanisms can beinvolved in the association between insulin resistanceand LVDD [28]. In the heart, insulin stimulates glu-cose uptake and oxidation and, although it increasesfatty acid uptake, it inhibits fatty acid utilization forenergy. Therefore insulin resistance results in a reduc-tion of myocardial energy supply due to changes insubstrate utilization from glucose to free fatty acids[11,29]. Other involved mechanisms include increasedmyocardial interstitial fibrosis [30], activation of sym-pathetic nervous system [31], increased afterload andimpaired ventricular-vascular coupling due to arterial stiff-ness [32,33], endothelial dysfunction [34], increasedmyocardial oxidative stress [35] or secretion of fattyacid-binding protein 4 [36].

Diastolic dysfunction and type 2 diabetes mellitusAt the other end of the diabetic continuum, it is sug-gested that diabetes can affect cardiac structure andfunction in the absence of changes in blood pressure orcoronary artery disease, a condition called diabetic car-diomyopathy [11,37]. In humans, LVDD is consideredthe earliest manifestation of diabetic cardiomyopathy,preceding the development of systolic dysfunction [11].In our study, we observed that the greatest difference indiastolic function parameters occurs between individualswithout MS and patients with metabolic syndrome.However, patients with T2DM had an additional worsen-ing in diastolic function parameters, such as E’ velocityand E/E’ ratio, and a further increased prevalence ofLVDD. It is known that the pathogenesis of diabeticcardiomyopathy is multifactorial [11] and beyond thechanges associated with insulin resistance, sustainedhyperglycemia also increases glycation of interstitialproteins such as collagen by deposition of advancednonenzymatic glycation end products (AGE) in theextracellular matrix [38], resulting in a further increasein myocardial stiffness. Reinforcing the possibility of anadditional “glucotoxic” effect of hyperglycemia on car-diac function, a large study of patients with type 1 dia-betes – where insulin resistance is not an importantpathophysiological mechanism – showed that incidentheart failure was associated with HbA1c and the rate ofglycemic control [39].

Future research and implications to clinical practiceSubclinical LVDD is recognized as an important pre-dictor of heart failure [40] and long-term mortality[1,41]. Therefore, the early identification and correctionof the main determinants of subclinical diastolic dys-function, such as insulin resistance, can be important toreduce morbidity and mortality in these individuals [4].This can be especially important in the prevention of

Table 3 Crude and adjusted odds ratios for the presence of any grade of diastolic dysfunction according to quartilesof insulin resistance and metabolic syndrome status

Prevalence of LVDD n (%) Crude OR (95% CI) Adjusted OR* (95% CI)

Insulin resistance

(HOMA-IR score)

Quartile 1 35 (14.9%) Reference Reference

Quartile 2 42 (18.6%) 1.30 (0.80-2.13) 1.08 (0.63-1.86)

Quartile 3 70 (29.3%) 2.37 (1.50-3.73) 1.88 (1.12-3.14)

Quartile 4 89 (30.6%) 2.52 (1.63-3.90) 1.82 (1.09-3.03)

No Metabolic Syndrome (n = 571) 93 (16.3%) Reference Reference

Metabolic Syndrome without T2DM (n = 331) 108 (32.6%) 2.54 (1.85-3.50) 1.62 (1.12-2.36)

Metabolic Syndrome with T2DM (n = 123) 45 (36.6%) 3.04 (1.98-4.67) 1.78 (1.09-2.91)

T2DM: type 2 diabetes mellitus; LVDD: left ventricular diastolic dysfunction; HOMA-IR - Homeostasis Model Assessment of Insulin Resistance;OR (95% CI) – odds ratio with 95% confidence interval.*Variables included in the model: age (continuous), sex, systolic blood pressure (continuous) and body mass index (continuous).




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heart failure with preserved ejection fraction (alsoknown as diastolic heart failure), a disease where notherapy has been shown to significantly improve theprognosis [42].All these data suggest that the deterioration of dia-

stolic function is already present in an early phase ofglucose disturbance metabolism, before the onset of dia-betes, being mainly associated with insulin resistanceand not only with sustained hyperglycemia. Interestingly,several studies have shown that insulin resistance, withor without diabetes mellitus, predicted incident heartfailure independently of other established risk factors[8,43,44]. On the contrary, only few studies [45] haveclearly demonstrated an independent association be-tween diabetes and incident heart failure, especially be-cause this association is confounded by the simultaneouspresence of other risk factors. Most of these studies havecompared diabetic versus non-diabetic individuals, in-cluding in the comparator group individuals with insulinresistance and metabolic syndrome, which can partlyattenuate the differences in heart failure risk.Future research will determine if the administration of

drugs that increase insulin sensitivity can improvemyocardial structure and function, particularly dia-stolic function. Recently, in animal models of insulinresistance, metformin reduced myocardial fibrosis, at-tenuated cardiac remodeling and the progression toheart failure [46,47]. This “cardioprotective” effect of met-formin can be due to the interference with TGF-beta sig-naling pathway and activation of the AMP-kinasesignaling cascade [48,49]. A new phase II clinical trial isnow evaluating if the administration of metformin im-proves diastolic function in patients with metabolic syn-drome and LVDD [50].Finally, both insulin resistance and metabolic syn-

drome are closely associated with obesity. Recent datahave demonstrated an independent association be-tween LVDD and obesity [5], especially with abdom-inal obesity [6] and visceral fat mass [7]. Therefore, ithas been proposed that insulin resistance was one ofthe important pathophysiological links involved in this as-sociation between obesity and LVDD [8,9]. Our data alsoshow that the association between insulin resistance andLVDD is independent of body mass index, which is in ac-cordance with the study by Ayalon et al. [27].

Strengths and limitationsStrengths of this study include the relatively large sampleof individuals from the general population without othercardiac diseases and the contemporaneous assessment ofcardiac diastolic function using tissue Doppler and usingthe integrated consensus criteria for diastolic dysfunc-tion evaluation [22]. The latest consensus recommenda-tions on LV diastolic function assessment strongly advise

in favor of the systematic use of tissue Doppler-derivedearly mitral annulus velocity (E’ wave) and E/E’ ratios, asthe main echocardiographic parameters for diastolicfunction evaluation. It is known that the E’ wave is apreload-independent index of LV relaxation, beingclosely related with invasively determined tau (the timeconstant of isovolumic pressure decline). Moreover, anE/E’ ratio > 15 strongly correlates with invasively deter-mined increased LV filling pressures [22]. On the con-trary, E/A ratio and DT, which are derived from theevaluation of mitral inflow velocities, have several limita-tions in the evaluation of diastolic function, especiallybecause they are dependent on loading conditions and onheart rate. Moreover, these two variables have a U-shapedrelation with the severity of diastolic dysfunction, whichexplains why E/A ratio does not decrease stepwise accord-ing to the groups of insulin resistance.The main limitation is the cross-sectional design,

which partially limits comments on causality, as thiswould be more robust in a prospective design. Althoughwe have excluded patients with clinical signs of coronaryartery disease, we did not perform any stress test to ex-clude myocardial ischemia, which is one determinant ofdiastolic dysfunction. In this study, patients were notsubmitted to oral glucose tolerance test. Finally, detailedanalysis of left ventricle function using new strain andstrain rates techniques was not performed in this study.

ConclusionInsulin resistance and metabolic syndrome are associ-ated with diastolic dysfunction independently of age,blood pressure and body mass index. These data suggestthat subclinical changes in myocardial diastolic functionare already present before the onset of diabetes, beingassociated mainly with the state of insulin resistanceand not only to sustained hyperglycemia. Future re-search will determine if improving insulin resistanceusing insulin-sensitizers or lifestyle changes can im-prove diastolic function.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsRFC participated in the conception of the study, analysis and interpretation of thedata, statistical analysis and writing the manuscript. RLL participated in the analysisand interpretation of the data and statistical analysis. PB contributed in the designof the study, collection of clinical data, funding and revision of the manuscript.ALM was involved in the conception of the study, interpretation of the data andrevision of the manuscript providing important intellectual content. AAparticipated in the conception of the study, analysis and interpretation of thedata, statistical revision of the data, funding and revision of the manuscript. Allauthors read and approved the final manuscript.

AcknowledgmentsThis work was supported by Portuguese Foundation for Science andTechnology Grants POCI/SAU-ESP/61492/2004, PEST-C/SAU/UI0051/2014,EXCL/BIM-MEC/0055/2012 (partially funded by FEDER through COMPETE)and European-Commission Grant FP7-Health-2010; MEDIA-261409.


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Author details1EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal.2Cardiology Department, Gaia Hospital Center, Vila Nova Gaia, Portugal.3Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine,University of Porto, Porto, Portugal. 4Department of Medicine, Faculty ofMedicine, University of Porto, Porto, Portugal. 5Department of InternalMedicine, Centro Hospitalar São João, Porto, Portugal. 6Department ofCardiothoracic Surgery, Centro Hospitalar São João, Porto, Portugal.7Department of Clinical Epidemiology, Predictive Medicine and Public Health,Faculty of Medicine, University of Porto, Porto, Portugal.

Received: 29 October 2014 Accepted: 27 December 2014

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B) The Evaluation of Diastolic Dysfunction

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LETTER TO THE EDITOR

The New Grade IA of Diastolic Dysfunction

Is It Relevant at the Population Level?

We read with great interest the article by Kuwakiet al. (1) describing a new grade of diastolic functionand its association with major adverse cardiovascularevents. The study is also noteworthy because theauthors performed speckle-tracking analysis of theleft atrium, giving an additional emphasis on theinterrelation between diastolic function and leftatrium mechanics. In their study, Kuwaki et al. (1)determined diastolic dysfunction grades in patientsreferred for echocardiography in a tertiary care cen-ter. We sought to evaluate the prevalence of this newgrade of diastolic function at the general-populationlevel.

In this study, we analyzed data from individualswithin the first follow-up of a cohort representative,at baseline, of a European adult population fromPorto, Portugal—the EPIPorto cohort study. All pa-tients were prospectively evaluated with a clinicalinterview, detailed echocardiography, and bloodtesting. Patients with coronary artery disease, percu-taneous or surgical revascularization, prior cardiacsurgery, or significant valvular heart disease wereexcluded from this analysis. A total of 1,038 in-dividuals aged $45 years (62% female; mean age:62.4 � 10.6 years) were evaluated for the determina-tion of diastolic dysfunction grades, applying thesame criteria used by Kuwaki et al.

In this sample from the general population, wefound that the new IA grade of diastolic dysfunctionwas present in only 53 individuals (5.1%), whichis three times less frequent than the prevalenceobserved by Kuwaki et al. (17.9%). In our population,most of the patients had normal diastolic function(56.3%) compared with only 35.5% in the study byKuwaki et al. Grade I diastolic dysfunction wasfound in 21.1% (n ¼ 219); grade II, in 9.5% (n ¼ 99);and grade III, in 0.2% (n ¼ 2). In 67 patients (6.4%),no grade was endorsed. The main differences inthe prevalence of diastolic dysfunction may beattributable to the high prevalences of cardiovas-cular disease (21%) and of cancer (25%) in the studyby Kuwaki et al. A limitation of their study was

the high prevalence (19.3%) of mitral annular calcifi-cation in the group with grade IA, because in thesepatients the annular velocity measurements andthe E/ε0 ratio should be interpreted with extremecaution (2).

In our population we observed that compared withindividuals with grade I diastolic dysfunction, in-dividuals with the new grade IA diastolic dysfunctionwere older (72.7 � 8.1 years vs. 67.9 � 9.1 years; p ¼0.001), had higher systolic blood pressure (150.2 �25.6 mm Hg vs. 142.1 � 20.2 mm Hg; p ¼ 0.01),and had a greater left ventricular mass (p ¼ 0.004).On the other hand, when we compared patientswith the new grade IA diastolic dysfunction withthose with grade II diastolic dysfunction, we found asignificant difference only in age (72.7 � 8.1 years vs.68.3 � 8.5 years; p ¼ 0.002).

These data also emphasize the difficulty in theclassification of diastolic grades in some patients.Sometimes parameters are conflicting and thereis variation between observers and according tothe population studied. Nonetheless, in everydayclinical practice, the determination of the E/ε0 ratioshould be routine. It has some limitations but itis easy to calculate, is reproducible, and providesprognostic information on several cardiovasculardiseases (2). Finally, in the same way that theevaluation of systolic function should go far be-yond the calculation of ejection fraction, the E/ε0ratio should not be “the be-all and end-all ofdiastology” Q1(3).

Q3Ricardo Fontes-Carvalho, MD*Ana Azevedo, MD, PhDAdelino Leite-Moreira, MD, PhD

*Department of CardiologyGaia Hospital CenterRua Conceicao Fernandes4434-502 Vila Nova Gaia, Portugal Q2

E-mail: [email protected]://dx.doi.org/10.1016/j.jcmg.2014.09.022

RE F E RENCE S

1. Kuwaki H, Takeuchi M, Wu VC, et al. Redefining diastolic dysfunctiongrading: combination of E/A #0.75 and deceleration time >140 ms andE/ε’ $10. J Am Coll Cardiol Img 2014;7:749–58.

2. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for theevaluation of left ventricular diastolic function by echocardiography. EurJ Echocardiogr 2009;10:165–93.

3. Tajik AJ, Jan MF. The heart of the matter: prime time E/ε’ prime! J AmColl Cardiol Img 2014;7:759–61.

J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . - , N O . - , 2 0 1 4

ª 2 0 1 4 B Y T H E A M E R I C A N CO L L E G E O F C A R D I O L O G Y F O U N DA T I O N I S S N 1 9 3 6 - 8 7 8 X / $ 3 6 . 0 0

P U B L I S H E D B Y E L S E V I E R I N C .

COR 5.2.0 DTD � JCMG1538_proof � 16 December 2014 � 4:49 pm � ce

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C) The Impact of Diastolic Function on Exercise Capacity

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Address for correspondence:Ricardo Fontes-Carvalho, MD,Physiology and CardiothoracicSurgery Department,Faculty of Medicine,University of Porto,Alameda Professor Hernani Monteiro,4200–319 Porto,Portugal,[email protected]

Clinical Investigations

Left Ventricular Diastolic Dysfunction andE/E� Ratio as the Strongest EchocardiographicPredictors of Reduced Exercise Capacity AfterAcute Myocardial InfarctionRicardo Fontes-Carvalho, MD; Francisco Sampaio, MD, PhD; Madalena Teixeira, MD;Francisco Rocha-Goncalves, MD, PhD; Vasco Gama, MD; Ana Azevedo, MD, PhD;Adelino Leite-Moreira, MD, PhDCardiology Department (Fontes-Carvalho, Sampaio, Teixeira, Gama), Gaia Hospital Center, Gaia,Portugal; Department of Physiology and Cardiothoracic Surgery (Fontes-Carvalho,Leite-Moreira), Faculty of Medicine, University of Porto, Porto, Portugal; Department of Medicine(Rocha-Goncalves), Faculty of Medicine, University of Porto, Porto, Portugal; Department ofClinical Epidemiology (Azevedo), Predictive Medicine and Public Health, Faculty of Medicine,University of Porto, Porto, Portugal; EPIUnit–Institute of Public Health (Azevedo), University ofPorto, Porto, Portugal

Background: The mechanisms that determine reduced exercise capacity after acute myocardial infarction(AMI) are not fully understood, especially the relative role of left ventricular diastolic and systolic function.Hypothesis: To evaluate the role of different diastolic and systolic function echocardiographic parameters aspredictors of reduced functional capacity in patients after AMI.Methods: One month after AMI, 225 patients (84% male; mean age, 55.1± 10.9 years) were enrolled andunderwent detailed echocardiography and cardiopulmonary exercise test on the same day. Systolic anddiastolic function was evaluated by echocardiography according to the latest consensus recommendations,including tissue Doppler evaluation. Exercise capacity was evaluated with peak oxygen consumption (VO2).Results: Peak VO2 was significantly correlated with early diastolic tissue Doppler velocity (E�) septal (r = 0.42,P< 0.001), E� lateral (r = 0.35, P< 0.001), septal E/E� ratio (r = −0.35, P= 0.001), and lateral E/E� (r = −0.27,P< 0.001). These diastolic function parameters predicted impaired exercise capacity (VO2 <19 mL/kg/min),with an area under the receiver operating characteristic curve of 0.77 (95% confidence interval [CI]: 0.68–0.86,P< 0.001) for septal E/E�. On multivariate analysis, for each unit increase in septal E/E� ratio there was a−0.35 (95% CI:−0.54 to−0.15) mL/kg/min decrease in peak VO2 independently of age, sex, bodymass index,hypertension, and diabetes. There was a mild correlation between peak VO2 and systolic function parameters(r = 0.17, P= 0.01 with ejection fraction; and r = 0.23, P= 0.02 with lateral systolic tissue Doppler velocity)that persisted after multivariate adjustment.Conclusions: After AMI, resting diastolic function parameters were the strongest correlates of exercisetolerance. Septal E/E� ratio was the best echocardiographic predictor of reduced functional capacity.

IntroductionReduced exercise capacity frequently occurs after acutemyocardial infarction (AMI) and is an important predictorof cardiovascular outcomes, decreased quality of life, anddisability.1 However, the mechanisms that underlie poorfunctional capacity after AMI are not fully understood,

This work was supported by the Portuguese Foundation for Science and Technology grants PEst-C/SAU/UI0051/2014 andEXCL/BIM-MEC/0055/2012 through the Cardiovascular Research and Development Unit and by European Commission grantFP7-Health-2010, MEDIA-261409.The authors have no other funding, financial relationships, or conflicts of interest to disclose.Additional Supporting Information may be found in the online version of this article.

especially the relative role of left ventricular (LV) systolicand diastolic functions.

Traditional parameters of LV systolic function evaluationare poor predictors of reduced exercise capacity.2 Onthe other hand, diastolic dysfunction can be an importantdeterminant of functional capacity in patients with systolic

222 Clin. Cardiol. 38, 4, 222–229 (2015)Published online in Wiley Online Library (wileyonlinelibrary.com)DOI:10.1002/clc.22378 © 2015 Wiley Periodicals, Inc.

Received: October 1, 2014Accepted with revision: November 22, 2014

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heart failure.3,4 Information is sparse for patients after AMI,especially using modern and integrated echocardiographicparameters for diastolic function assessment. It is nowrecognized that tissue Doppler imaging parameters allow amore accurate assessment of cardiac function.5

Objective assessment of exercise capacity can be doneby cardiopulmonary exercise testing (CPX), comprisingsimultaneous measurement of oxygen consumption (VO2),carbon dioxide production, and ventilatory response, whichprovides the most accurate, reliable, and reproduciblemeasurements of exercise tolerance.1

The aim of this study was to assess the role of differentLV systolic and diastolic function echocardiographicparameters as predictors of reduced functional capacityin patients after AMI.

MethodsStudy Sample

We prospectively enrolled 225 patients 1 month followingAMI, both with ST-elevation and non–ST-elevation myocar-dial infarction. The diagnosis was established using therecommendations from the universal definition of AMI.6

Exclusion criteria were age >75 years, inability to exercise,hemodynamically significant valvular disease, atrial fib-rillation, uncontrolled tachyarrhythmias, exercise-inducedischemia, pericardial disease, moderate to severe chroniclung disease, anemia (hemoglobin <12 g/dL), severe renaldisease (creatinine clearance <30 mL/min calculated by theCockcroft-Gault formula).

On the same day, patients received clinical evaluation,detailed transthoracic echocardiography, blood sample col-lection, anthropometric evaluation, and a cardiopulmonaryexercise test.

The study protocol conforms to the principles outlined inthe Declaration of Helsinki. Informed consent was obtainedfrom all patients and the local institution ethics committeeapproved the study protocol.

Echocardiographic Evaluation

All echocardiography studies were acquired by a singleexperienced operator using an ultrasound system (iE33;Philips Medical Systems, Best, the Netherlands). Cardiacchambers dimensions, volumes, and left ventricular masswere measured according to current recommendations.7

Mitral inflow velocities were assessed using pulsed-wave(PW) Doppler in the apical 4-chamber view. Tissue Dopplervelocities were acquired in the apical 4-chamber view, withthe sample positioned at the septal and lateral mitral annulusfor determination of systolic (S�), early diastolic (E�), andlate diastolic (A�) velocities. PW Doppler velocities at theupper right pulmonary vein were also recorded. For allparameters, the average of 3 consecutive heartbeats wasrecorded, and velocities were recorded at end-expiration.

Left ventricle diastolic function was assessed accordingto the latest consensus guidelines on diastolic functionevaluation,5 which included determination of peak early (E)and late (A) diastolic mitral inflow velocities, decelerationtime of early LV filling (DT), E/A ratio, E� septal and lateralvelocities, ratio between the E wave velocity of the diastolic

mitral inflow and the E� velocity of tissue Doppler (E/E�

ratio) E/E� ratio, isovolumetric relaxation time (IVRT),and pulmonary vein flow analysis (to calculate the Ard-Ad relation: the time difference between the duration ofthe atrial reverse wave of the pulmonary flow [Ard] and themitral A-wave duration [Ad]). Patients were also categorizedin diastolic dysfunction (DD) grades: normal, grade I (mildDD), grade II (moderate DD), and grade III (severe DD), by2 blinded independent cardiologists. In case of discordance,each case was discussed individually, and if doubt persistedno grade was endorsed, which occurred in 20 patients.

Systolic function was evaluated by ejection fraction (EF)using the modified Simpson’s rule from biplane 4-chamberand long-axis views and by analyzing systolic myocardialannular tissue velocity (S� septal and S� lateral).

Cardiopulmonary Exercise Testing

Patients underwent a symptom-limited CPX on a treadmillusing the modified Bruce protocol. Expired gases were col-lected continuously throughout exercise and analyzed forventilatory volume and for oxygen (O2) and carbon dioxide(CO2) content using dedicated analyzers. Standard spirome-try was also undertaken before the exercise test. Equipmentcalibration and all measurements were done according tothe recommendations of the American Thoracic Society andAmerican College of Chest Physicians.8

The following variables were calculated: peak VO2, mea-sured in milliliters per kilogram per minute (mL/kg/min);peak respiratory exchange ratio, defined by the ratio ofCO2 production to O2 consumption at peak effort; anaerobicthreshold, defined as the point at which carbon dioxideproduction increased disproportionately in relation to oxy-gen consumption obtained from a graph plotting oxygenconsumption against carbon dioxide production; and totalexercise duration (in minutes). Patients were not asked todiscontinue β-blockers before the test.

Statistical Analysis

Statistical analysis was performed using SPSS Statistics22 (IBM Corp, Armonk, NY). All continuous variableswere expressed as mean ± standard deviation or asmedian (percentile 25–75, interquartile range [IQR]) forvariables with skewed distribution. Categorical variablesare expressed as number and percentage.

The bivariate correlations between left ventricular func-tion variables and CPX parameters were assessed by Pear-son correlation coefficient (r). Univariate and multivariatelinear regression analyses were performed to identify base-line clinical and echocardiographic parameters associatedwith functional capacity. Multivariate regression analysiswas performed with adjustment for other determinantsof reduced exercise capacity, namely age, sex, hyperten-sion, diabetes, and body mass index. Receiver operatingcharacteristic (ROC) curve analysis was used to evaluatethe performance of different systolic and diastolic functionparameters to identify reduced exercise capacity, defined asa peak VO2 below the 10th percentile of the distribution inour sample (peak VO2 < 19 mL/kg/min). In the SupportingFigure in the online supplement, the linear regression line

Clin. Cardiol. 38, 4, 222–229 (2015) 223R. Fontes-Carvalho et al: Reduced functional capacity after AMI

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Table 1. Characteristics of the Study Sample (N= 225)

Value

Clinical Data

Age, y 55.1± 10.9

Sex, male, % 84.0%

BMI, kg/m2 27.2± 3.9

Waist perimeter, cm 96.8± 10.0

Cardiovascular risk factors, %

Hypertension 44.9

Diabetes 15.6

Dyslipidemia 52.9

Smoker 52.0

Familial history 9.8

Type of MI, %

ST-elevation MI 37.8

Non–ST-elevation MI 62.2

Culprit artery, %

Left anterior descending 42.7

Circumflex 18.2

Right coronary 34.2

Other 4.8

Angioplasty 76.0

NT-ProBNP, ng/L 350.0 (170.0–722.0)

Cardiopulmonary exercise test

Peak VO2, mL/kg/min 28.5± 7.7

Anaerobic threshold, mL/kg/min 17.4± 3.9

Exercise duration, s 556.3± 138.0

VE/VCO2 slope 25.7± 4.6

Echocardiography

Septum, mm 9.6± 1.6

Posterior wall, mm 9.3± 1.5

LV mass index, g/m2 105.3± 25.0

Left atrium volume index, mL/m2 34.8± 9.3

LV end-diastolic volume, mL/m2 58.6± 15.1

LV end-systolic volume, mL/m2 27.4± 11.7

Ejection fraction, % 53.6± 9.6

E wave, cm/s 77.9± 19.1

A wave, cm/s 67.6± 17.0

E/A ratio 1.2± 0.5

Table 1. Conitnued

Value

Deceleration time, ms 222.2± 49.6

Ard-Ad, s 29.5± 39.2

E� septal, cm/s 6.9± 1.8

E� lateral, cm/s 9.8± 2.6

E/E� septal 12.0± 4.4

E/E� lateral 8.5± 3.3

E/E� mean 10.3± 3.5

Diastolic dysfunction, grade

Normal 80 (35.6)

Grade 1: mild DD, n (%) 57 (25.3)

Grade 2: moderate DD, n (%) 58 (25.8)

Grade 3: severe DD, n (%) 10 (4.4)

Undetermined 20 (8.9)

S� septal, cm/s 6.7± 1.2

S� lateral, cm/s 7.5± 1.8

Abbreviations: A, peak late diastolic mitral inflow velocity; A�, latediastolic velocity; ARd-Ad, time difference between the duration ofthe atrial reversal wave of the pulmonary flow and the mitral A-wave duration; BMI, body mass index; DD, diastolic dysfunction; E,peak early diastolic mitral inflow velocity; E�, early diastolic velocity;E/A, ratio between E and A waves velocities; E/E�, ratio between Evelocity of transmitral flow and E� velocity from tissue Doppler; LV,left ventricular; MI, myocardial infarction; NT-ProBNP, N-terminal pro-brain type natriuretic peptide; PCI, percutaneous coronary intervention;S�, systolic velocity; VE/VCO2 slope, relationship between minuteventilation and carbon dioxide production; VO2, oxygen consumption.Data are presented as mean± standard deviation for continuousvariables with normal distribution, asmedian (percentile 25th–75th) forvariables with non-normal distribution, and as number and percentagefor categorical variables.

is shown except for E/E� lateral and E/E� mean, where thequadratic term was significant (P < 0.05).

ResultsThe clinical, demographic, echocardiographic, and CPXvariables of the study sample are presented in Table 1. Thestudy population included mostly men (84.0%), with a meanage of 55.1 ± 10.9 years, a mean EF of 53.6% ± 9.6%, andan overall prevalence of DD of 55.5%. Patients receivedoptimized medical therapy: dual antiplatelet therapy andstatin in 100%, renin-angiotensin system inhibitor in 97.7%,β-blocker in 94.6%, and aldosterone antagonist in 16.4%.

Diastolic Function Parameters and Exercise Capacity

As shown in Table 2, there was a significant correlationbetween E� velocities and exercise capacity, namely withpeak VO2 (see Supporting Figure in the online versionof this article), VO2 at anaerobic threshold, and exercisecapacity. LV filling pressures (assessed by E/E� ratio)

224 Clin. Cardiol. 38, 4, 222–229 (2015)R. Fontes-Carvalho et al: Reduced functional capacity after AMIPublished online in Wiley Online Library (wileyonlinelibrary.com)DOI:10.1002/clc.22378 © 2015 Wiley Periodicals, Inc.

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Table 2. Correlations Between Left Ventricle Diastolic and Systolic Function With Several Exercise Capacity Parameters

Peak VO2, mL/kg/minVO2 at Anaerobic

Threshold, mL/kg /min Exercise Duration, min

r P Value r P Value r P Value

Diastolic function parameters

E� septal 0.42 <0.001 0.29 <0.001 0.36 <0.001

E� lateral 0.35 <0.001 0.31 <0.001 0.33 <0.001

E/E� septal −0.35 <0.001 −0.24 <0.001 −0.29 <0.001

E/E� lateral −0.27 <0.001 −0.26 <0.001 −0.24 <0.001

E/E� mean −0.35 <0.01 −0.27 <0.001 −0.29 <0.001

E/A 0.05 0.50 0.01 0.88 0.11 0.10

DT 0.07 0.30 −0.06 0.43 −0.05 0.45

IVRT 0.08 0.41 0.02 0.89 0.13 0.09

Ard-Ad −0.09 0.22 −0.13 0.09 −0.04 0.58

LA volume index −0.11 0.14 −0.02 0.81 −0.15 0.04

Systolic function parameters

Ejection fraction 0.17 0.01 0.11 0.13 0.16 0.02

S� septal 0.31 <0.01 0.24 0.03 0.25 0.01

S� lateral 0.23 0.02 0.20 0.08 0.16 0.10

Abbreviations: A, peak late diastolic mitral inflow velocity; Ard-Ad, time difference between the duration of the atrial reversal wave of the pulmonary flowand the mitral A-wave duration; DT, E-wave deceleration time; E, peak early diastolic mitral inflow velocity; E� early diastolic velocity from tissue Doppler;E/A, ratio between E and A wave velocities from mitral inflow; E/E�, ratio between E velocity of mitral flow and E� velocity from tissue Doppler; IVRT,isovolumic relaxation time; LA, left atrium; S�, systolic velocity from tissue Doppler; VO2, oxygen consumption.

were also associated with decreased peak VO2, VO2 atanaerobic threshold, and exercise duration. The E/A ratio,DT, and the Ard-Ad had no significant correlation withpeak VO2, anaerobic threshold, or exercise time duration(Table 2).

On ROC curve analysis, septal E/E� ratio was the bestpredictor of reduced functional capacity, with an area underthe curve (AUC) of 0.77 (95% confidence interval [CI]:0.68-0.86, P < 0.001), as shown in the Figure 1. A septal E/E�

ratio of 11.9 predicted a peak VO2 < 19 mL/kg/min, witha sensitivity of 81.8% and a specificity of 63.2%. Otherpredictors of reduced exercise capacity were mean E/E�

ratio, E� septal velocity (as shown in Figure 1), lateralE/E� ratio (AUC: 0.71; 95% CI: 0.60-0.82; P = 0.001),and E� lateral velocity (AUC: 0.67: 95% CI: 0.60-0.82;P = 0.008). (See the Supporting Table in the onlineversion of this article for the comparison of clinical andechocardiographic characteristics between patients withpreserved and reduced exercise capacity.)

For each unit increase in septal E/E� ratio, there wasa decrease of 0.62 mL/kg/min in peak VO2 as shown inTable 3. After multivariate regression analysis, adjusting forother determinants of reduced exercise capacity, namelyage, sex, body mass index, hypertension, and diabetes, E�

septal and lateral velocities, and septal, lateral, and meanE/E� ratios remained as independent predictors of peakVO2, as detailed in Table 3.

According to the analysis in diastolic function grades, weobserved that patients with DD had a significantly reducedpeak VO2 (26.7 ± 6.5 vs 32.0 plusmn; 8.1 mL/kg/mincompared to patients with normal diastolic function;P < 0.001), VO2 at anaerobic threshold (16.7 ± 3.9 vs18.5 ± 3.5 mL/kg/min; P = 0.01), and reduced exerciseduration (527.0 ± 134.9 vs 602.9 ± 138.3 seconds; P < 0.001).Figure 2 displays the peak VO2 according to the classifica-tion in diastolic function grades (P value for trend < 0.001).

Systolic Function and Exercise Capacity

We found a modest, but significant, correlation betweenEF and peak VO2 as shown in Table 2 (see the SupportingFigure in the online version of this article). Patients withEF < 50% had slightly reduced peak VO2 (25.5 ± 7.0 vs26.7 ± 28.3 mL/kg/min; P = 0.01) and exercise duration(8.73 ± 2.61 vs 9.51 ± 2.16 minutes; P = 0.03), compared topatients with EF ≥ 50%. Reduced tissue Doppler systolicannular velocity (S� velocity), either at the septal or lateralside of the mitral annulus, was modestly correlated with peakVO2, VO2 at anaerobic threshold, and exercise duration, asdetailed in Table 2. On the ROC curve analysis, S� septaland S� lateral predicted reduced functional capacity, withan AUC of 0.73 (95% CI: 0.58-0.88, P = 0.002) and 0.65 (95%CI: 0.53-0.78, P = 0.04), respectively, but the same was notobserved for EF, with an AUC of 0.64 (95% CI: 0.58-0.88,P = 0.06).





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Figure 1. Receiver operating characteristic curve analysis for the prediction of <19mL/kg/min using different diastolic function parameters. Abbreviations:AUC, area under the curve; CI, confidence interval; E′, early diastolic velocity; E/E′, ratio between E velocity of mitral flow and E′ velocity from tissue Doppler.

As shown in Table 3, after multivariate regression analysiswith adjustment for age, sex, body mass index, hyperten-sion, and diabetes, for each centimeter per second decreasein S′ velocity, there is a 0.72 (95% CI: 0.10-1.35) mL/kg/min reduction in peak VO2.

DiscussionIn patients after AMI, without significant valve diseaseor exercise-induced residual ischemia, we found thatresting diastolic function parameters, particularly E/E′ ratioand E′ velocities, were the strongest echocardiographiccorrelates of exercise capacity, assessed by peak VO2.This association was independent of other determinantsof exercise capacity such as age, sex, obesity, hypertension,and diabetes. Among the studied parameters, the septalE/E′ ratio was the best predictor of reduced functionalcapacity.

Diastolic dysfunction is caused by impaired myocardialrelaxation and/or increased ventricular stiffness and ischaracterized by elevated LV filling pressures.5,9 Untilrecently, noninvasive evaluation of diastolic function hasbeen difficult, due to several limitations of traditionalechocardiographic parameters, especially those derived

from mitral inflow velocities analysis.5 The latest consensusrecommendations on LV diastolic function assessmentstrongly advise the systematic use of tissue Doppler-derivedearly mitral annulus velocity (E′ wave) and E/E′ ratios. Itis known that early mitral annulus velocity (E′ wave) is apreload-independent index of LV relaxation, being closelyrelated with invasively determined tau (the time constantof isovolumic pressure decline).10,11 Moreover, an E/E′ratio >15 strongly correlates with invasively determinedincreased LV filling pressures.5,12,13

In our study, diastolic function parameters based onmitral inflow velocities, such as E/A ratio, DT, or Ard-Ad, did not predict exercise capacity. Several studies haveshown that these measurements are markedly influencedby loading conditions, by LV compliance, and by left atriumfunction,5,14 showing a poor correlation with global cardiachemodynamics in several clinical settings, including inpatients with coronary artery disease.15

Our data are in accordance with previous observationsin other patient populations. In selected groups of patientswith systolic heart failure, E′ velocities and E/E′ ratio wereimportant predictors of functional capacity, compared toEF.3,16,17 More recently, in patients with systolic heartfailure, endurance exercise training improved E/E′ ratio,


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Figure 2. Box plots with peak oxygen consumption (VO2) according to diastolic dysfunction grades. *P< 0.001, compared to patients with normal diastolicfunction. Abbreviations: DD, diastolic dysfunction.

Table 3. Univariate and Multivariate Linear Regression Analyses for theAssociation of Left Ventricle Diastolic and Systolic Function ParametersWith Exercise Capacity (Assessed by Peak Oxygen Consumption)

Crude β 95% CI Adjusted βa 95% CI

E� septal 1.84 1.30 to 2.39 0.93 0.41 to 1.45

E� lateral 1.03 0.65 to 0.42 0.42 0.06 to 0.77

E/E� septal −0.62 −0.85 to −0.39 −0.35 −0.54 to −0.15

E/E� lateral −0.63 −0.93 to −0.33 −0.33 −0.58 to −0.07

E/E� mean −0.74 −1.02 to −0.47 −0.41 −0.65 to −0.17

S� septal 1.84 0.76 to 2.92 0.86 −0.08 to 1.80

S� lateral 0.92 0.18 to 1.66 0.72 0.10 to 1.35

Ejection fraction 0.14 0.03 to 0.25 0.2 0.11 to 0.28

Abbreviations: CI, confidence interval; E� early diastolic velocity fromtissue Doppler; E/E�, ratio between E velocity of mitral flow and E�

velocity from tissue Doppler; S�, systolic velocity from tissue Doppler.aAdjusted for age, sex, hypertension, diabetes, and body mass index.

which was responsible for the observed increase in peakVO2.18 Likewise, in patients with heart failure preservedEF, Edelmann et al demonstrated that E/E� ratio wasstrongly related with peak VO2, and that improving diastolicfunction by exercise training could significantly enhance

exercise capacity.19 In other patient groups, namely aftermyocardial infarction, the association between diastolicfunction and functional capacity has not been extensivelyanalyzed. In a retrospective analysis of an unselectedpopulation of individuals with preserved EF referred forexercise echocardiography, exercise capacity (assessedonly with metabolic equivalent estimation) was mainlydetermined by diastolic function parameters.2 The role ofdiastolic dysfunction as a determinant of reduced functionalcapacity can be explained because impaired relaxation andincreased filling pressures can reduce diastolic LV filling,thus decreasing the stroke volume response to exercise.9

Moreover, it is known that increased LV filling pressuresand increased pulmonary capillary wedge pressure leads toventilation-perfusion abnormalities, which negatively affectthe gas-exchange response during exercise, causing thesensation of exertion dyspnea.1

After myocardial infarction, diastolic dysfunction isfrequent, affecting more than 50% of patients. Accordingto our study, diastolic dysfunction determines reducedfunctional capacity, and expectedly, decreased quality oflife. Other studies have also found that diastolic dysfunctionis an independent predictor of future cardiovascularevents after AMI.20,21 These observations suggest thatthe echocardiographic evaluation after AMI should alwaysinclude an integrated evaluation of diastolic function,with calculation of E� velocities and E/E� ratios, and the





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determination of diastolic dysfunction grades, using theconsensus recommendations.5

In this study, we also demonstrated a modest, butindependent, association between peak VO2 and EF. It iswell known that EF is preload and afterload dependentand has several limitations in global systolic functionassessment. This can probably explain why some, butnot all, studies have found a correlation between exerciseperformance and ejection fraction.4,17,22 The evaluationof systolic mitral annulus velocity by tissue Doppler (S�velocities) can be more accurate to assess global andregional systolic function especially after AMI.23 In ourstudy, we also showed that reduced S� velocity was mildlyassociated with reduced functional capacity.

Finally, the pathophysiology of functional impairmentafter AMI is complex. It depends on alterations in both car-diac (systolic and diastolic dysfunction24) and noncardiacfactors. Among these are age, gender, body mass index,hypertension history, and diabetes, but also abnormali-ties in pulmonary function, blood hemoglobin, endothelialfunction, blood flow regulation, and skeletal muscle functionand substrate utilization.1,2,25 Therefore, cardiac functionand diastolic dysfunction alone could never be isolatedpredictors of exercise capacity, which explains the modestcorrelation coefficients between oxygen consumption and E�septal and E/E� septal (r = 0.42 and r = −0.35, respectively).In this study we excluded patients with anemia, signif-icant pulmonary disease, and exercise-induced ischemiathat are well-known determinants of reduced functionalcapacity.

Regarding the study’s strengths, diastolic function wasevaluated according to the latest consensus recommenda-tions. Exercise capacity was evaluated by cardiopulmonaryexercise testing, with determination of peak O2 consump-tion, which is the gold standard parameter to evaluateexercise tolerance.1 There were also some limitations.Cardiac function was assessed only at rest, just beforecardiopulmonary exercise testing, and therefore we did notevaluate cardiac function during exercise. This could havebeen interesting because Podolec et al found that in patientswith systolic heart failure, E/E� ratio at peak exercise wasa better predictor of decreased exercise capacity than thesame parameter at rest.3 Nevertheless, it has been shownthat the great majority of patients with exercise-induceddiastolic dysfunction already have significant changes indiastolic function at rest.2 As recommended in the consen-sus document on diastolic function evaluation, we measuredE� velocities and E/E� ratios at both the septal and lateralside of the mitral annulus plus the average of the 2 mea-surements. The evaluation of these 3 measurements can beparticularly important in patients after AMI, which usuallyhave regional wall motion abnormalities and can explain theminor differences between them as predictors of reducedexercise capacity.

ConclusionIn patients after myocardial infarction, LV diastolic functionwas an independent predictor of reduced functional capacity.Among the studied echocardiographic parameters, theseptal E/E� ratio was the best predictor of reduced functionalcapacity.

References1. Kitzman DW, Groban L. Exercise intolerance. Heart Fail Clin.

2008;4:99–115.2. Grewal J, McCully RB, Kane GC, et al. Left ventricular function

and exercise capacity. JAMA. 2009;301:286–294.3. Podolec P, Rubis P, Tomkiewicz-Pajak L, et al. Usefulness of

the evaluation of left ventricular diastolic function changesduring stress echocardiography in predicting exercise capacityin patients with ischemic heart failure. J Am Soc Echocardiogr.2008;21:834–840.

4. Gardin JM, Leifer ES, Fleg JL, et al. Relationship of Doppler-echocardiographic left ventricular diastolic function to exerciseperformance in systolic heart failure: the HF-ACTION study. AmHeart J. 2009;158(4 suppl):S45–S52.

5. Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendationsfor the evaluation of left ventricular diastolic function byechocardiography. Eur J Echocardiogr. 2009;10:165–193.

6. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition ofmyocardial infarction. Eur Heart J. 2012;33:2551–2567.

7. Lang RM, Bierig M, Devereux RB, et al. Recommenda-tions for chamber quantification. Eur J Echocardiogr. 2006;7:79–108.

8. Ross RM. ATS/ACCP statement on cardiopulmonary exercisetesting [author reply]. Am J Respir Crit Care Med. 2003;167:1451.

9. Leite-Moreira AF. Current perspectives in diastolic dysfunctionand diastolic heart failure. Heart. 2006;92:712–718.

10. Nagueh SF, Sun H, Kopelen HA, et al. Hemodynamic determinantsof the mitral annulus diastolic velocities by tissue Doppler. J AmColl Cardiol. 2001;37:278–285.

11. Oki T, Tabata T, Yamada H, et al. Clinical application of pulsedDoppler tissue imaging for assessing abnormal left ventricularrelaxation. Am J Cardiol. 1997;79:921–928.

12. Ommen SR, Nishimura RA, Appleton CP, et al. Clinical util-ity of Doppler echocardiography and tissue Doppler imagingin the estimation of left ventricular filling pressures: a com-parative simultaneous Doppler-catheterization study. Circulation.2000;102:1788–1794.

13. Burgess MI, Jenkins C, Sharman JE, et al. Diastolic stress echocar-diography: hemodynamic validation and clinical significance ofestimation of ventricular filling pressure with exercise. J Am CollCardiol. 2006;47:1891–1900.

14. Appleton CP, Hatle LK, Popp RL. Relation of transmitral flowvelocity patterns to left ventricular diastolic function: new insightsfrom a combined hemodynamic and Doppler echocardiographicstudy. J Am Coll Cardiol. 1988;12:426–440.

15. Yamamoto K, Nishimura RA, Chaliki HP, et al. Determinationof left ventricular filling pressure by Doppler echocardiographyin patients with coronary artery disease: critical role ofleft ventricular systolic function. J Am Coll Cardiol. 1997;30:1819–1826.

16. Hadano Y, Murata K, Yamamoto T, et al. Usefulness of mitralannular velocity in predicting exercise tolerance in patientswith impaired left ventricular systolic function. Am J Cardiol.2006;97:1025–1028.

17. Hummel YM, Bugatti S, Damman K, et al. Functional andhemodynamic cardiac determinants of exercise capacity inpatients with systolic heart failure. Am J Cardiol. 2012;110:1336–1341.

18. Sandri M, Kozarez I, Adams V, et al. Age-related effects of exercisetraining on diastolic function in heart failure with reduced ejectionfraction: the Leipzig Exercise Intervention in Chronic HeartFailure and Aging (LEICA) Diastolic Dysfunction Study. EurHeart J. 2012;33:1758–1768.

19. Edelmann F, Gelbrich G, Dungen HD, et al. Exercise train-ing improves exercise capacity and diastolic function inpatients with heart failure with preserved ejection frac-tion: results of the Ex-DHF (Exercise training in Dias-tolic Heart Failure) pilot study. J Am Coll Cardiol. 2011;58:1780–1791.

20. Moller JE, Whalley GA, Dini FL, et al. Independent prognosticimportance of a restrictive left ventricular filling pattern aftermyocardial infarction: an individual patient meta-analysis: Meta-Analysis Research Group in Echocardiography acute myocardialinfarction. Circulation. 2008;117:2591–2598.


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21. Iwahashi N, Kimura K, Kosuge M, et al. E/e′ two weeks afteronset is a powerful predictor of cardiac death and heart failure inpatients with a first-time ST elevation acute myocardial infarction.J Am Soc Echocardiogr. 2012;25:1290–1298.

22. Hillis GS, Moller JE, Pellikka PA, et al. Noninvasive estimationof left ventricular filling pressure by E/e’ is a powerful predictorof survival after acute myocardial infarction. J Am Coll Cardiol.2004;43:360–367.

23. Alam M, Witt N, Nordlander R, et al. Detection of abnormalleft ventricular function by Doppler tissue imaging in patientswith a first myocardial infarction and showing normal function

assessed by conventional echocardiography. Eur J Echocardiogr.2007;8:37–41.

24. Wang YC, Yu CC, Chiu FC, et al. Impacts of mitralE/e′ on myocardial contractile motion and synchronicityin heart failure patients with reduced ejection fraction:an exercise-echocardiography study. Clin Cardiol. 2013;36:462–467.

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TITLE

Left atrial deformation analysis by speckle tracking echocardiography to predict exercise capacity after myocardial

infarction

SHORT TITLE

Left atrium and exercise capacity after AMI

AUTHORS

Ricardo Fontes-Carvalho1,2 (MD), Francisco Sampaio1 (MD, PhD), Madalena Teixeira1 (MD), Francisco Rocha Gonçalves3

(MD, PhD), Vasco Gama Ribeiro1(MD), Ana Azevedo4,5 (MD, PhD), Adelino Leite-Moreira2 (MD, PhD)

INSTITUTIONS

1 Cardiology Department, Gaia Hospital Center, Gaia, Portugal;2 Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal;3 Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal; 4 Department of Clinical Epidemiology, Predictive Medicine and Public Health, Faculty of Medicine, University of

Porto, Porto, Portugal;5 EPIUnit - Institute of Public Health, University of Porto, Porto, Portugal.

CORRESPONDING AUTHOR


Address:

Physiology and Cardiothoracic Surgery Department, Faculty of Medicine, University of Porto

Alameda Professor Hernani Monteiro; 4200-319 Porto, Portugal

Tel: +351964661091

Fax: +351 225519194

[email protected]

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ABSTRACT

Background: Strain and strain rate analysis by speckle tracking is a novel tool to evaluate the different phases of left

atrium (LA) function. LA size and function are associated with adverse outcome after myocardial infarction (AMI) but

few data are available regarding its role on exercise capacity.

Methods: One month after AMI, 94 patients (mean age 54.8±11.0; 82% male) were enrolled. We evaluated LA

volumes and several indexes of LA conduit, contraction and reservoir function (passive ejection fraction, active

ejection fraction and expansion index, respectively). LA deformation was assessed by 2D speckle tracking to calculate

strain and strain rate at different phases of the cardiac cycle. Exercise capacity was evaluated by cardiopulmonary

exercise test with O2 consumption (VO2).

Results: Increased LA volumes, especially LA volume before atrial contraction, were correlated with reduced peak

VO2 and reduced VO2 at anaerobic threshold. Decreased peak VO2 was associated with reduced LA passive ejection

fraction (ρ=0.24;p=0.02), but not with LA active ejection fraction (ρ= -0.07;p=0.53). Lower peak atrial longitudinal

strain, passive emptying strain and early diastole strain rate were associated with worse exercise capacity. LA

volumes, LA conduit and reservoir function and LA strain parameters were strongly correlated with left ventricle (LV)

diastolic function.

Conclusions: After myocardial infarction, increased LA volumes were markers of decreased functional capacity, that

was associated with decreased LA conduit function, but not with LA contractile function. LA size, function and strain

parameters were interdependent with LV diastolic function, reinforcing the role of correct atrioventricular coupling

in these patients.

KEY WORDS

Left atrium; Left atrial function; Speckle-tracking imaging; Velocity Vector Imaging



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INTRODUCTION

Decreased exercise capacity frequently occurs after acute myocardial infarction (AMI) and is an important predictor

of cardiovascular outcomes and decreased quality of life [1]. However, the cardiac and non-cardiac mechanisms that

underlies poor functional capacity after AMI are not fully understood.

Left atrium (LA) size and function are now important prognostic markers in several cardiovascular diseases, particularly

in patients after myocardial infarction [2] [3]. It is known that the LA plays an important role in the regulation of

global cardiac function, acting as a blood reservoir during systole, as a conduit during early diastole and as an active

pump during late diastole [4]. However, beyond its prognostic value, few data are available regarding the impact of

LA volume and function on exercise capacity. The evaluation of strain and strain rate by two-dimensional speckle

tracking analysis is a novel echocardiographic tool that tracks the speckle pattern, frame by frame, in standard

B-mode images. Several studies have shown good feasibility and reproducibility for the evaluation of the different

phases of LA function [5,6] [7] [8].

Exercise capacity can be objectively assessed by cardiopulmonary exercise testing (CPX), which involves the

simultaneous measurement of oxygen consumption (VO2), carbon dioxide production, and ventilatory response.

Indeed, CPX provides the most accurate, reliable and reproducible measurements of exercise tolerance [1].

The aim of this study was to assess the role of LA volumes and different indexes of LA conduit, contraction and

reservoir function - derived both from standard volumetric and novel speckle tracking LA analysis – as determinants

of exercise capacity in patients after myocardial infarction.

PATIENTS AND METHODS

Study sample

One month after an acute myocardial infarction, 94 consecutive patients were prospectively enrolled. Clinical

evaluation, anthropometric evaluation, detailed transthoracic echocardiography, blood sample collection, and

cardiopulmonary exercise test were performed in all patients, on the same day. Exclusion criteria were age above 75

years, inability to exercise, severe valvular disease, moderate to severe chronic lung disease, anemia (hemoglobin <

12 g/L), atrial fibrillation and exercise induced myocardial ischaemia.

Baseline demographic, clinical and echocardiographic variables were acquired and their independent associations

with exercise performance parameters were analyzed.

The study protocol conforms to the principles outlined in the Declaration of Helsinki. Informed consent was obtained

from all patients and the local institution review board approved the study protocol.

Echocardiography data

All echocardiography studies were acquired by a single experienced operator using an ultrasound system (iE33,

Philips Medical Systems, Best, The Netherlands) equipped with a S5-1 transducer. Images were digitally stored for

posterior offline analysis.

Cardiac chambers dimensions, volumes and left ventricular mass were measured according to current

recommendations [9,10]. Mitral inflow velocities were assessed using pulsed-wave (PW) Doppler in the apical four-

chamber view, with the sample placed at the tips of the mitral leaflets; velocities were recorded at end-expiration

and averaged over three consecutive cardiac cycles. PW tissue-Doppler velocities were acquired at end expiration, in

the apical four-chamber view, with the sample positioned at the septal and lateral mitral annulus: systolic (S’), early

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diastolic (E’) and late diastolic (A’) velocities were measured. PW Doppler velocities at the upper right pulmonary vein

were also recorded. For all parameters the average of three consecutive heartbeats was recorded.

Systolic function was evaluated by ejection fraction calculation using the modified Simpson’s rule from biplane 4- and

2-chamber views and by analyzing systolic myocardial annular tissue velocity (S’ sep, S’ lat and S’ mean). Diastolic

function was assessed according to the latest consensus guidelines on diastolic function evaluation [11] by determining

peak early (E) and late (A) diastolic mitral inflow velocities, deceleration time of early left ventricular filling (DT), the

E/A ratio, the septal, lateral and average myocardial annular tissue velocity (E'sep, E’lat, E´mean, respectively), the E/E'

ratio (also at the septal, lateral and mean E/E’), pulmonary vein flow analysis (to calculate the Ard-Ad relation: the time

difference between the duration of the atrial reversal wave of the pulmonary flow, Ard, and the mitral A-wave duration,

Ad) and isovolumic relaxation time (IVRT). Using the EAE/ESC guidelines on diastolic function evaluation[11], patients

were categorized in diastolic dysfunction (DD) grades – normal, grade I (mild DD), grade II (moderate DD) and grade III

(severe DD), by two independent cardiologists who were blinded for the exercise capacity data. In case of discordance,

each case was discussed individually, and if doubt persisted no grade was endorsed.

Analysis of LA dimensions, function and deformation parameters

Two-dimensional grey-scale images were acquired in the apical four- and two-chamber views, with a frame rate

between 70 and 100 frames/sec. Three cardiac cycles were digitally stored. The LA endocardial border was manually

traced and analysis was performed using the Velocity Vector Imaging (VVI) software (Syngo VVI 2.0, Siemens Medical

Solutions USA Inc), by one observer blinded to the clinical data, as previously described [10] [12] [13]. As shown

in figure 1, the software divides the LA in six segments and tracking quality was visually checked in all segments.

The operator manually adjusted segments that the software failed to track. Patients with inadequate tracking in

more than 2 segments were excluded from the study. From the displacement of the LA endocardial pixels time–

volume curves we extracted the data of maximum LA volume (LA max), minimum LA volume (LA min) and LA volume

before atrial contraction (LA preA), as previously described [14]. All LA volumes were indexed to body surface as

recommended [10].

LA function was assessed from LA volumes using several validated formulas tested in previous studies [4] [15] [13].

LA reservoir volume (also known as LA stroke volume) was calculated as LA max – LA min, LA passive emptying

volume as LA max – LA preA and LA contractile volume as LA preA – LA min. LA ejection fraction was calculated

as (LA max – LA min) / LA max x 100. We also determined LA active ejection fraction, which known as an index of

LA active contraction, as (LA preA –LA min) / LA preA x100 and LA passive ejection fraction, an index of LA conduit

function, as (LA max – LA preA) / LA max x 100. Finally, LA expansion index, which is an index of reservoir function,

was determined as (LA max – LA min) / LA min x 100.

LA strain and strain rate was assessed using the same software, by tracking and comparing the relative position

of speckles throughout the cardiac cycle. Strain curves were displayed for each of the six segments automatically

generated by the software. Zero strain was set at the QRS onset. As shown in figure 1, 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, after a plateau, by a second decrease that corresponds to atrial contraction.

From the average of the strain curves of all segments we evaluated peak LA strain at the end of ventricular systole

(PALS) – which is a measure of LA reservoir function [13] – and peak atrial strain before atrial contraction (PACS) - that

can be considered marker of LA pump, as previously described [13, 16] . Passive emptying strain was calculated as

the difference between PALS and PACS . Using strain rate analysis we measured peak LA strain rate during ventricular

systole (SRs), peak LA strain rate during early LV filling (SRe) and peak LA strain rate during atrial contraction (SRa), as



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shown in figure 2.

Figure 1 . Two-dimensional left atrium speckle tracking analysis for the determination of left atrial strain.Four-chamber view depicting the corresponding LA strain curves for each of 6 segments analyzed in each view. Peak LA strain at the end of

ventricular systole (PALS), is a measure of LA reservoir function and peak atrial strain before atrial contraction (PACS) is considered a marker of

LA pump. Passive emptying strain was calculated as the difference between PALS and PACS.

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Figure 2 . Two-dimensional left atrium speckle tracking analysis for the determination of left atrial strain rate.Four-chamber view showing the LA strain rate curves for the 6 segments analyzed, with determination of peak LA strain rate during ventricular

systole (SRs), peak LA strain rate during early LV filling (SRe) and peak LA strain rate during atrial contraction (SRa).

Cardiopulmonary Exercise testing

Each patient underwent a symptom-limited cardiopulmonary exercise test on a treadmill, using the modified Bruce

protocol. Expired gases were collected continuously throughout exercise and analyzed for ventilatory volume and

for oxygen (O2) and carbon dioxide (CO2) content using dedicated analyzers. Standard spirometry (forced expiratory

volume in one second (FEV1) and forced vital capacity (FVC)) was also undertaken before the exercise test. Equipment

calibration and all measurements were done according to the recommendations of the American Thoracic Society

and American College of Chest Physicians[17]. The following variables were calculated: peak oxygen consumption

(pVO2) measured in milliliter per kilogram per minute (ml/Kg/min); peak respiratory exchange ratio, defined by the

ratio of CO2 production to O2 consumption at peak effort; VE/VCO2 slope defined as the slope of the increase in

peak ventilation/increase in CO2 production throughout exercise; anaerobic threshold (defined as the point at which

carbon dioxide production increased disproportionately in relation to oxygen consumption obtained from a graph

plotting oxygen consumption against carbon dioxide production); and total exercise duration (seconds). Patients

were not asked to discontinue beta-blockers before the test.



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Statistical analysis

Statistical analyses were performed using SPSS statistics 20 (SPSS Inc., Chicago, IL, USA). All P values are 2-tailed and a

significance level of 5% was used. Data are expressed as mean and standard deviation for quantitative variables with

normal distribution or as median (25th-75th percentile) for variables with non-normal distribution. Categorical variables

are expressed as a number (n) and percentage (%). The bivariate correlations between left atrium parameters and

CPX parameters were assessed by Pearson's (r) and Spearman’s correlation coefficient (ρ), as appropriate. Differences

between groups were assessed using T-Student and Mann-Whitney U Tests for quantitative variables comparisons,

and Chi-square tests were performed for discrete variables comparisons. The bivariate correlations between left

atrium parameters and CPX parameters were assessed by Pearson's (r) or Spearman’s correlation coefficient (ρ), as

appropriate.

To test the intraobserver and interobserver reproducibility of LA measurements, ten patients were randomly

selected. For intraobserver variability, the same operator performed a second measurement, more than a month

after the initial analysis. For interobserver variability, a second operator analyzed the same loops. Bland-Altman

analyses were performed, and the intraclass correlation coefficient and coefficient of variation were calculated. The

software showed good intra- and interobserver agreement, as detailed in previous studies by our group[18].

RESULTS

The baseline characteristics of the study population are outlined in table 1. A total of 94 patients – predominantly

male (n=77, 81.9%), with a mean age of 54.8± 11.0, with both ST and non-ST elevation myocardial infarction (57.4%

and 42.6%, respectively) - were evaluated. The left anterior descending artery was the culprit artery in 40.4% and the

majority were submitted to percutaneous coronary intervention (71.3%). Patients received optimized medical therapy:

dual anti-platelet therapy and statin in 100%, renin-angiotensin system inhibitor in 96.8%, beta-blocker in 95.7% and

aldosterone antagonist in 15.0%. The echocardiographic characteristics, one month after myocardial infarction, are

also shown in table 1: mean ejection fraction was 54.2±9.2% and there was a high prevalence of diastolic dysfunction

(61.7%). Left atrial volumes as well as function and deformation parameters are displayed in table 2.

We found a significant association between VO2/Kg and the classical determinants of exercise capacity, namely age

(r= -0.41;p<0.001), body mass index (r= -0.27; p=0.01) and NT-proBNP (ρ= -0.42; p<0.001). Lower VO2/Kg was also

associated with previous history of hypertension (p=0.02) and female gender (p<0.001). There was a significant

correlation between VO2/Kg and diastolic function parameters, namely E’ septal (r= 0.36; p=0.001), E’ lateral (r= 0.37;

p<0.001), E/E’ septal (r= -0.42; p<0.001), E/E’ lateral (r= -0.33; p<0.01) and E/E’ mean (r= -0.42; p<0.001). Patients

with diastolic dysfunction had significantly lower VO2/Kg (25.7±7.0ml/kg/min versus 29.7±7.4 ml/kg/min in patients

with normal diastolic function; p=0.02).

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Table 1 . Characteristics of the study population

Clinical Data Echocardiography

Age (years) 54.8 ± 11.0 Septum (mm) 9.4 ± 1.5

Sex, male (%) 81.9% Posterior wall (mm) 9.1 ± 1.4

BMI (Kg/m2) 26.9 ± 3.2 LV mass index (g/m2) 100.5 ± 22.6

Cardiovascular Risk Factors LV end-diastolic volume (ml/m2) 59.9 ± 15.1

Hypertension (n, %) 59.6% LV end-systolic volume (ml/m2) 27.8 ± 11.5

Diabetes (n, %) 14.9% Ejection fraction (%) 54.2 ± 9.2

Dyslipidemia (n, %) 52.1% E wave (cm/s) 77.3 ± 17.2

Smoker (n, %) 42.6% A wave (cm/s) 68.9 ± 15.5

Familial history (n, %) 9.6 % E/A ratio 1.2 (0.9-1.5)

Type of myocardial infarction Deceleration time (ms) 211.3 ± 40.5

ST elevation MI (n, %) 57.4% E’ septal (cm/s) 6.7 ± 1.9

Non-ST elevation MI (n, %) 42.6% E’ lateral (cm/s) 9.5 ± 2.6

Culprit artery E/E’ septal 12.3 ± 4.1

Left anterior descending (n, %) 40.4% E/E’ lateral 8.7 ± 2.8

Circumflex (n, %) 21.3% E/E’ mean 10.5 ± 3.2

Right coronary (n, %) 33.0 % Diastolic dysfunction (DD) grade

Other (n, %) 4.3% Normal 31 (33.0%)

Angioplasty (n, %) 71.3% Grade 1: mild DD (n, %) 24 (25.5%)

NT-ProBNP (ng/L)336.0

(169.0-621.5) Grade 2: moderate DD (n, %) 31 (33.0%)

Grade 3: severe DD (n, %) 3 (3.2%)

Cardiopulmonary Exercise Test Undetermined (n, %) 5 (5.3%)

Peak VO2 (ml/kg/min) 28.4 ± 6.8 S’ septal (cm/s) 7.7 ± 0.2

Anaerobic threshold (ml/kg/min) 16.7 ± 3.7 S’ lateral (cm/s) 7.7 ± 1.9

Exercise duration (s) 549.2 ± 138.9

Data are presented as mean and standard deviation, or as median (percentile 25-75)

for continuous variables and count and percentage for categorical variables.

(BMI – body mass index; MI – myocardial infarction; PCI – percutaneous coronary intervention; s – seconds; LV – left ventricle)



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Table 2. Characterization of left atrium size, function and deformation parameters

Left Atrium Volumes

LA maximum volume, mL/m2 43.9 ± 11.7

LA volume pre-A, mL/m2 30.8 ± 9.2

LA minimum volume, mL/m2 19.9 ± 8.0

LA Function Indexes

LA stroke volume (max-min), mL 44.7 ± 12.8

LA Passive emptying volume (max-preA), mL 24.5 ± 10.1

LA Contractile volume (preA-min), mL 20.2 ± 7.1

LA ejection fraction, % 55.9 (48.9 - 63.2)

LA passive ejection fraction, % 30.3 (22.5-36.1)

LA active ejection fraction, % 36.9 (28.9 – 43.8)

LA expansion index, % 126.8 (96.3 – 165.2)

LA Strain Analysis

Peak LA systolic strain (PALS), % 29.3 (21.4 – 34.6)

Peak LA contraction strain (PACS), % 12.3 (9.2 – 16.5)

Passive emptying strain (PALS-PACS), % 15.8 (11.2 – 20.8)

LA Strain Rate Analysis

SR systole, s-1 1.2 (1.0 – 1.5)

SR early diastole, s-1 -1.1 (-1.4 to -0.8)

SR atrial contraction, s-1 -1.3 (-1.8 to -0.9)

LA- left atrium; SR- strain rate

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Association between LA volumes and functional parameters with exercise capacity

As shown in table 3, increased LA volumes were correlated with reduced exercise capacity, particularly with reduced

peak VO2, reduced VO2 at anaerobic threshold and decreased exercise duration in seconds. Among volume parameters,

LA volume immediately before atrial contraction (LA preA) showed the better correlation with exercise capacity.

We found a positive correlation between LA passive ejection fraction, an index of conduit function, with exercise

capacity (table 3). On the contrary, LA active ejection fraction, an index of LA active contraction, did not correlate

with any exercise performance parameter.

Table 3 . Correlations (r) between left atrium volumes, function and deformation parameters with exercise capacity

Peak VO2

(ml/Kg/min)

VO2 at Anaerobic Threshold

(ml/min/kg)

Exercise Duration(seconds)

ρ p value ρ p value ρ p value

Left Atrium Volumes

LA maximum volume -0.25 0.02 -0.24 0.05 -0.27 0.01

LA volume pre-A -0.31 <0.01 -0.32 0.01 -0.37 <0.01

LA minimum volume -0.20 0.06 -0.28 0.02 -0.30 <0.01

LA Function Indexes

LA passive ejection fraction 0.24 0.02 0.28 0.02 0.30 <0.01

LA active ejection fraction -0.07 0.53 0.10 0.42 0.10 0.35

LA expansion index 0.08 0.46 0.25 0.04 0.25 0.02

LA Strain Analysis

Peak LA systolic strain (PALS) 0.24 0.02 0.30 0.01 0.35 <0.01

Peak LA contraction strain (PACS) 0.00 0.97 0.19 0.12 0.18 0.09

Passive emptying strain (PALS-PACS) 0.30 <0.01 0.23 0.06 0.31 <0.01


Strain rate systole (SRs) 0.07 0.54 0.18 0.17 0.21 0.05

Strain rate early diastole (SRe) -0.21 0.05 -0.31 0.01 -0.29 <0.01

Strain rate atrial contraction (SRa) -0.05 0.65 -0.21 0.10 -0.17 0.10

LA- left atrium; ρ – spearman’s correlation coefficient

Association between LA strain and strain rate with exercise capacity

There was a significant and positive correlation between peak LA systolic strain (PALS) with peak VO2, VO2 at anaerobic

threshold and exercise duration (table 3). Passive emptying strain (the difference between PALS and PACS) was also

significantly correlated with exercise capacity but no association was found between strain during atrial contraction

(PACS) and exercise capacity.

We found an inverse correlation between exercise capacity parameters and LA strain rate at early diastole, but not

with LA strain rate during ventricular systole or atrial contraction.



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The relation between LA size and function with left ventricle diastolic and systolic function

As shown in table 4, worse left ventricular diastolic function, assessed by E’ velocity and E/E’ ratio, was associated with

increased LA volumes, especially with LA volume before atrial contraction. We also observed a direct and significant

correlation between E’ velocity with LA passive ejection fraction and with LA expansion index, but not with active

ejection fraction. LA deformation parameters, namely peak atrial longitudinal strain (PALS), passive emptying strain and

strain rate during early diastole (SRe) showed a strong correlation with E’ velocity and E/E’ ratio. There was a modest

correlation between peak atrial longitudinal strain (PALS) and strain rate during systole (SRs) with ejection fraction.

Table 4 . Correlations (r) between left atrium parameters and diastolic and systolic function

E’ velocity E/E’ ratio Ejection Fraction

ρ p value ρ p value ρ p value

Left Atrium Volumes

LA maximum volume -0.32 <0.01 0.45 <0.001 -0.16 0.13

LA volume pre-A -0.49 <0.001 0.51 <0.001 -0.21 0.05

LA minimum volume -0.38 <0.001 0.49 <0.001 -0.26 0.01

LA Function Indexes

LA passive ejection fraction 0.55 <0.001 -0.35 <0.001 0.11 0.29

LA active ejection fraction 0.07 0.47 -0.25 0.02 0.19 0.06

LA expansion index 0.36 <0.001 -0.37 <0.001 0.20 0.05

LA Strain Analysis

Peak LA systolic strain (PALS) 0.37 <0.001 -0.27 0.01 0.29 <0.01

Peak LA contraction strain (PACS) -0.04 0.71 -0.08 0.43 0.20 0.06

Passive emptying strain (PALS-PACS) 0.60 <0.001 -0.32 <0.01 0.23 0.03


Strain rate systole (SRs) 0.27 0.01 -0.20 0.06 0.20 0.06

Strain rate early diastole (SRe) -0.64 <0.001 0.43 <0.001 -0.19 0.08

Strain rate atrial contraction (SRa) -0.04 0.73 0.21 0.05 -0.23 0.03

LA- left atrium; ρ – spearman’s correlation coefficient

DISCUSSION

In this study, we have shown that increased LA volumes are associated with decreased functional capacity, in patients

after myocardial infarction. We found a significant correlation between exercise capacity and LA conduit function, but

not with contractile function. Lower peak atrial longitudinal strain and reduced early diastolic strain rate correlated

with worse exercise capacity parameters, suggesting that LA longitudinal strain analysis may also be useful to predict

reduced exercise capacity.

The role of left atrium evaluation in cardiovascular disease

Several studies have shown that LA enlargement is a strong predictor of cardiovascular outcomes in patients after

myocardial infarction [2] [3], in heart failure [19] and in atrial fibrillation [20]. Beyond the prognostic value, in this

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study we observed that increased LA volumes, especially LA volume before atrial contraction, were also associated

with reduced exercise capacity. This observation is in accordance with another study, showing the same association

between poor exercise performance and increased maximum LA volume in patients with heart failure with preserved

ejection fraction (HFPEF) [21].

The left atrium plays an important role in the regulation of global cardiac function. It acts as a reservoir during systole,

as a conduit during early diastole, and as an active blood pump during late diastole. More recent studies have shown

that not only LA size, but also reduced LA function, is associated with adverse outcome. In patients after myocardial

infarction, LA ejection fraction was an independent predictor of mortality, providing prognostic value incremental to

that of maximum LA volume [22]. Few data are available on the role of LA function in exercise capacity. In two small

studies LA function, assessed only by LA ejection fraction, was associated with reduced exercise capacity in HFPEF [23]

and in patients with dilated cardiomyopathy [24]. In our study, we evaluated LA function using several parameters

and indexes that allow a more complete evaluation of the different phases of LA function. We found that decreased

exercise capacity was associated with reduced LA passive ejection fraction, which is an index of LA conduit function

[4], but not with LA active ejection fraction, which is an index of LA active contraction [4]. Finally, we observed that LA

reservoir function was a less important marker of reduced functional capacity, because LA expansion index was not

significantly related with peak VO2, but showed a modest association with VO2 at anaerobic threshold and reduced

exercise duration. However, to assess LA reservoir function, the analysis of parameters derived from strain analysis

can be more accurate, especially the evaluation of peak atrial longitudinal strain (PALS).

The evaluation of LA function by strain and strain rate using 2D speckle tracking

Two-dimensional speckle tracking is a new echocardiographic tool that tracks the speckle pattern, frame by frame, to

calculate strain and strain rate. Strain represents myocardial deformation, whereas strain rate represents the speed

at which myocardial deformation occurs [25]. Several studies have demonstrated good feasibility and reproducibility

of LA strain analysis by speckle tracking [5] [7] [8]. Interestingly, Cameli et al [26] have now demonstrated that LA

strain analysis is a predictor of cardiovascular events, showing that LA strain can be more sensitive for the evaluation

of LA function. Indeed, longitudinal studies have also suggested that LA myocardial deformation parameters are

reduced before atrial volume is increased [27].

In our study, LA longitudinal strain parameters, such as peak atrial systolic strain (PALS) were well correlated with

reduced exercise capacity. This observation is consistent with another recent study, performed in patients referred

for exercise echocardiography, showing a strong correlation between total LA longitudinal strain and maximal

exercise tolerance, evaluated only by estimated metabolic equivalents [16]. It is known that PALS reflects the passive

stretching of the left atrium during LV systole and is considered as a measure of LA reservoir function [5] [13] [27].

After AMI, the LA reservoir function can be particularly important because it can withstand the impact of the

increased LA pressure due to LV dysfunction, helping to maintain an adequate LV filling. However, on the long term,

the sustained increase in LA pressure will induce LA dysfunction and LA dilatation. Indeed, it has been shown that

reduced PALS after myocardial infarction was an independent predictor of LA remodeling and reduced LA function

at 1-year follow-up[27].

We did not find a significant relation between exercise capacity and LA contraction strain, a marker of LA pump

function [13] [16]. Consistent with this finding, in our study we did not observe an association between exercise

parameters and other measures of LA contraction function, such as the LA active ejection fraction or the LA strain rate

during atrial contraction. This reinforces the observation that LA pump function is not a very significant determinant

of functional capacity, even after myocardial infarction. Indeed, in atrial fibrillation, although peak VO2 is reduced, the



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degree of reduction is associated with the underlying cardiac pathologic conditions and not to the atrial fibrillation

per se [28]. Also, in these patients, cardioversion to sinus rhythm only increases exercise capacity by about 5% [29].

The interaction between left atrium and left ventricle diastolic function: the role of atrioventricular coupling

With its reservoir, conduit and active contraction phases, the LA actively modulates left ventricle (LV) function [30]. The LA

reservoir phase is important for LV filling because the energy stored in the LA during ventricular systole is released after mitral

valve opening, contributing to early diastolic function. In fact, LA reservoir function is impaired in several cardiac diseases

that are associated with impaired cardiac filling [27] [31]. Besides, the LA conduit phase spans early LV filling and diastasis

and the LA contractile phase depends on preload, afterload, intrinsic LA contractility and electromechanical coupling. To

maintain LV filling at an optimum level during exercise, the LA reservoir, conduit, and pumping function should work in

harmony. Therefore, it is known that the interaction between the LA and the LV functions – the atrioventricular coupling

– can directly influence global cardiac function, cardiac output and exercise capacity [16]. In the study from Kusunose et

al, analyzing patients with preserved LV ejection fraction referred for exercise echocardiography, the association between

reduced LA function and impaired exercise capacity was similar to that of elevated left ventricle filling pressures (E/E’ ratio),

emphasizing the importance of correct atrioventricular coupling [16].

On the other hand, since the LA is directly exposed to left ventricular diastolic pressure, LV diastolic dysfunction can

lead to an increase in LA size and to changes in several phases of LA function. It is known that LA volume is a sensitive

biomarker of the severity and duration of LV filling pressures and an indicator of chronic LV diastolic dysfunction [32]

[33]. In this study we have also observed a significant correlation between diastolic function parameters (such as E’

velocity and E/E’ ratio) and LA volumes. This observation can possibly explain the association between LA volumes

and exercise capacity in our study. Interestingly, we found that increased LA volume before atrial contraction, which

is more dependent on early LV diastolic function and on LA conduit function [34], was the LA volume parameter that

showed the best correlation with exercise parameters. We also observed a strong correlation between LV diastolic

parameters with LA passive ejection fraction (an index of LA conduit function) and with LA expansion index (that

reflects reservoir function) but not with LA active ejection fraction. Moreover, as another example of the importance

of atrioventricular coupling, recent data have shown that different grades of diastolic dysfunction can influence

the different phases of LA function [34] [35]. In patients with mild diastolic dysfunction the LA passive emptying is

decreased which is compensated by an increase in active contraction but, as the severity of diastolic dysfunction

advances, this mechanism no longer operates resulting in a reduction of LV filling volume [35].

LA strain and strain rate parameters evaluated by speckle tracking imaging are also significantly correlated with left

ventricular diastolic function [6] [13] [36]. Our data are consistent with these observations showing a significant

correlation between E’ velocity and E/E’ ratio with peak LA systolic strain and with LA passive emptying strain. As

expected, we also found a significant association between diastolic function and LA strain rate, especially LA strain

rate during early diastole.

Finally, regarding the association between LA function parameters and systolic function the available data are

controversial [13] [36]. However, in the study from Wakami et al, that performed invasive measurements in patients

undergoing cardiac catheterization, LA systolic strain was mainly correlated with LV end-diastolic pressures but also

with LV ejection fraction[36]. In our study we have also found a modest, but significant, association between LA

reservoir function (assessed either with LA peak systolic strain and LA expansion index) and ejection fraction.

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Study’s strengths and limitations

The present study extends previous results emphasizing the clinical relevance of analyzing left atrium size and

function in several clinical settings. Beyond the classical parameters we also evaluated LA function by novel speckle

tracking imaging parameters. In this study exercise capacity was evaluated using data from cardiopulmonary exercise

testing with O2 consumption measurement, which is the most accurate, reliable and reproducible measurements of

exercise tolerance [1]. The evaluation of exercise capacity using peak VO2, is considered the gold standard parameter

for functional capacity assessment [17]. We have also assessed submaximal exercise capacity by determination

of ventilatory anaerobic threshold, using the V-slope method, which has the advantage of being relatively effort

independent [1].

In this study, LA function was assessed at rest. It is possible that measurements obtained during exercise might have

been more predictive of exercise intolerance. Although speckle strain has been widely used for LA evaluation [5]

[7] [8] [27], and appears to predict cardiovascular outcomes [26], no dedicated software has been validated for the

assessment of LA strain.

CONCLUSION

Beyond its prognostic value, increased left atrium volumes can be useful to predict reduced exercise capacity in

patients after myocardial infarction. Reduced exercise capacity was associated with reduced LA conduit function,

but not with LA contractile function. Lower peak atrial longitudinal strain and reduced early diastolic strain rate also

correlated with worse exercise parameters. Left atrium size and function parameters were interdependent on left

ventricle diastolic function reinforcing the importance of correct atrioventricular coupling in these patients.

ACKNOWLEDGMENTS

This work was supported by the Portuguese Foundation for Science and Technology Grants PEst-C/SAU/UI0051/2011

and EXCL/BIM-MEC/0055/2012 through the Cardiovascular R&D Unit and by European Commission Grant FP7-

Health-2010; MEDIA-261409.

DISCLOSURES

None of the authors have disclosures to report.



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36. Wakami K, Ohte N, Asada K, Fukuta H, Goto T, Mukai S, et al. Correlation between left ventricular end-diastolic pressure and peak left atrial wall strain during left ventricular systole. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography. 2009;22:847-51.


D) Modulation of Diastolic Function by Exercise Training

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STUDY PROTOCOL Open Access

The role of a structured exercise training programon cardiac structure and function after acutemyocardial infarction: study protocol for arandomized controlled trialRicardo Fontes-Carvalho1,2*, Francisco Sampaio1, Madalena Teixeira1, Vasco Gama1 and Adelino F Leite-Moreira2,3

Abstract

Background: Exercise training is effective in improving functional capacity and quality of life in patients withcoronary artery disease, but its effects on left ventricular systolic and diastolic function are controversial. Diastolicdysfunction is a major determinant of adverse outcome after myocardial infarction and, contrary to systolicfunction, no therapy or intervention has proved to significantly improve diastolic function. Data from animal studiesand from patients with diastolic heart failure has suggested that exercise training can have a positive effect ondiastolic function parameters.This trial aims to evaluate if a structured exercise training program can improve resting left ventricular diastolic andsystolic function in patients who have had an acute myocardial infarction.

Methods/Design: This is a phase II, prospective, randomized, open-label, blinded-endpoint trial that will include atleast 96 consecutive patients who have had an acute myocardial infarction one month previously. Patients will berandomized (1:1) to an exercise training program or a control group, receiving standard of care. At enrolment, andat the end of the follow-up period, patients will be submitted to an echocardiography (with detailed assessment ofdiastolic and systolic function using recent consensus guidelines), cardiopulmonary exercise testing, an anthropometricassessment, blood testing, and clinical evaluation. Patients randomized to the intervention group will be submitted toan eight-week outpatient exercise program, combining endurance and resistance training, for three sessions per week.The primary endpoint will be the change in lateral E’ velocity immediately after the eight-week exercise trainingprogram. Secondary endpoints will include other echocardiographic parameters of left ventricular diastolic andsystolic function, cardiac structure, metabolic and inflammation biomarkers (high-sensitivity C-reactive protein andpro-BNP), functional capacity (peak oxygen consumption and anaerobic threshold) and anthropometric measurements.

Discussion: New strategies that can improve left ventricular diastolic function are clinically needed. This will be the firsttrial to evaluate, in patients who have had an acute myocardial infarction, the effects of a structured program of exercisetraining on diastolic and systolic function, assessed by novel echocardiographic parameters.

Trial registration: Registered with ClinicalTrials.gov (reference: NCT02224495) on 21 August 2014.

Keywords: Diastole, Systole, Exercise therapy, Myocardial infarction

* Correspondence: [email protected] Department, Gaia Hospital Centre, Rua Conceicao Fernandes,4434-502 Vila Nova Gaia, Portugal2Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine,University of Porto, Al. Prof. Hernâni Monteiro, 4200 - 319 Porto, PortugalFull list of author information is available at the end of the article

TRIALS

© 2015 Fontes-Carvalho et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons PublicDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in thisarticle, unless otherwise stated.

Fontes-Carvalho et al. Trials (2015) 16:90 DOI 10.1186/s13063-015-0612-6

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BackgroundExercise training is effective in improving functional cap-acity and quality of life in patients with coronary arterydisease [1,2]. It is known that exercise can improve severalcardiovascular and non-cardiovascular parameters, suchas glucose metabolism, skeletal muscle function, oxidativestress, vascular function, pulmonary circulation, ischemia-reperfusion lesion, and ventricular remodelling [3].However, the effect of exercise training on left ven-

tricle systolic and diastolic function is still controversial[4-6], especially after acute myocardial infarction (AMI),where no longitudinal study has evaluated cardiac func-tion using modern echocardiographic parameters, such asthose derived from tissue Doppler analysis. After AMI, theeffect of exercise training on diastolic function can be clin-ically relevant because the majority of these patients havediastolic dysfunction (DD) [4,7,8] and, most importantly,because no therapy or intervention has been shown to sig-nificantly improve diastolic function [9]. Data from animalstudies are encouraging, showing that endurance trainingcan improve myocardial relaxation and calcium homeosta-sis by increasing the myocardial expression of SERCA2aand phospholamban (PLB) [10,11]. Also, a recent studyevaluating patients with heart failure with preserved ejec-tion fraction (also known as diastolic heart failure) hasshown that the combination of endurance and resistancetraining can improve diastolic function parameters [12].Finally, it is also still controversial whether systolic function

can be improved by exercise training [4,13,14]. Most ofthese studies were small, lacked control groups, and evalu-ated systolic function only by ejection fraction, which hasseveral limitations in the evaluation of global left ventriclesystolic function [15].In this trial our aim is to assess, in patients who have

had an AMI, if a structured exercise training programcan improve resting left ventricular systolic and diastolicfunction.

Methods/DesignTrial designIn this prospective, randomized, open-label, blinded-endpoint (“The Effect of Exercise Training on Car-diac Structure and Function”) trial, patients who havehad an AMI one month previously will be randomized(1:1) to be included in an eight-week duration exercisetraining program or a control group, receiving standard ofcare. Immediately before enrolment and at the end of thefollow-up period, patients will be submitted to a clinicalevaluation, detailed echocardiography, cardiopulmonaryexercise testing, and an anthropometric assessment, ac-cording to the study design outlined in Figure 1. Becausethe intervention is a structured exercise training program,it is not possible to perform patient blinding. However, themedical staff performing all the measurements will beblinded to the type of intervention.

Figure 1 Design of the trial. In this prospective, randomized, open-label, blinded-endpoint trial consecutive patients who have had an acutemyocardial infarction one month previously will be randomized (1:1) to an eight-week outpatient exercise training program or standard of care.The primary endpoint will be the change in lateral E’ velocity between baseline and follow-up.

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Randomization by blocks will be used with an alloca-tion sequence based on a fixed block size of eight, gener-ated with a computer random number generator.

ParticipantsEligible patients will be consecutive individuals admittedto Gaia Hospital Centre (a tertiary care hospital with areference population of 700,000 patients) after AMI,including both ST-elevation and non-ST elevationmyocardial infarction. For inclusion in the study, we willuse the criteria in the universal definition of myocardialinfarction [16]. Table 1 details the study’s inclusion andexclusion criteria.

Intervention: the exercise training programPatients randomized to the exercise training group will beincluded in an eight-week outpatient program, encompass-ing three sessions per week, combining endurance and re-sistance training. Each session will consist of 10 minutes ofwarm up, 50 minutes of aerobic and resistance training,and 10 minutes of cool down. During the eight weeks, en-durance training (cycling in the first four weeks and tread-mill in the remaining four weeks) of increasing intensitywill be performed. Training intensity will be individualizedto a target heart rate of 70 to 85% of the maximal heartrate achieved in the baseline cardiopulmonary exercise test.Resistance training will also be included in each sessionconsisting of arm, leg, and thoracic exercises, includingdumbbell or weight training depending, on the patient’scondition and exercise capacity. Clinical and training

parameters will be monitored throughout the exerciseincluding arterial blood pressure, heart rate, glycaemia(in diabetic patients), and training level intensity. Fa-tigue will be monitored using the Borg scale.Patients randomized to the control group will receive

standard of care, with regular appointments with the car-diologist, optimized medication, and recommendations onhealthy lifestyle.

Measurements: the echocardiographic evaluation protocolA single experienced cardiologist, blinded to the patientassignment group, will perform all echocardiographicstudies using an ultrasound system (iE33, Philips Med-ical Solutions, Best, The Netherlands) equipped with anS5-1 and X5-1 transducer. Cardiac chamber dimensions,volumes, and left ventricular mass will be measured ac-cording to current recommendations and indexed to bodysurface area [17]. Mitral inflow velocities will be accessedusing pulsed-wave Doppler in the apical four-chamberview, placed between the tips of the mitral leaflets and vel-ocities recorded at end-expiration. Tissue Doppler veloci-ties will also be acquired at end-expiration, in the apicalfour-chamber view, with the sample positioned at the sep-tal and lateral mitral annulus for determination of systolic(S’), early diastolic (E’), and late diastolic (A’) velocities.Pulsed wave Doppler velocities at the upper right pulmon-ary vein will also be recorded to calculate the Ard-Ad rela-tion: the time difference between the duration of the atrialreverse wave of the pulmonary flow (Ard) and the mitralA-wave duration. For all parameters, the average of threeconsecutive heart beats will be recorded.Left ventricle diastolic function will be evaluated accord-

ing to the EAE/ASE consensus guidelines on diastolic func-tion evaluation [18], which include the determination ofpeak early (E) and late (A) diastolic mitral inflow velocities,deceleration time of early left ventricular filling (DT), E/Aratio, isovolumetric relaxation time (IVRT), myocardialearly diastolic velocities at the septal and lateral side of mi-tral annulus (E’ septal, E’ lateral, and E’ mean), E/E’ ratio(including septal, lateral, and mean E/E’) and Ard-Ad rela-tion. Moreover, using the consensus criteria [18], patientswill be categorized in DD grades: normal diastolic func-tion, grade I (mild DD), grade II (moderate DD), andgrade III (severe DD), by two blinded independent cardiol-ogists. In case of discordance, each case will be discussedindividually.Left ventricle systolic function will be evaluated by cal-

culation of biplane ejection fraction (Simpson’s rule) anddetermination of systolic velocities at the septal and lateralside of mitral annulus by tissue Doppler (S’ septal and S’lateral). It is known that, compared to ejection fraction, S’velocities are more sensitive parameters for global andregional systolic function evaluation after myocardialinfarction [19].

Table 1 Study population: inclusion and exclusion criteria

Inclusion criteria:

Between 18 and 75-years-old

Acute myocardial infarction (according to the universal definitionof myocardial infarction [16])

Both ST elevation and non-ST elevation myocardial infarction

One month since discharge

Left ventricular ejection fraction >30%

Able to exercise

Exclusion criteria

Moderate or severe valvular disease

Atrial fibrillation

Uncontrolled atrial or ventricular tachyarrhythmias

Exercise-induced myocardial ischemia

Pericardial disease

Moderate or severe chronic lung disease (vital capacity and/or forcedexpiratory volume in 1 second <80% of age-dependent predicted value)

Severe renal disease or dysfunction (creatinine clearance<30 mL/min, calculated by the Cockcroft-Gault formula)

Anaemia (hemoglobin <12 g/dL)


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Measurements: cardiopulmonary exercise testingAt the beginning and end of the study protocol, patientswill be submitted to symptom-limited cardiopulmonaryexercise testing on a treadmill, using the modified Bruceprotocol (Cardiovit CS-200 Ergo Spiro; Schiller, Baar,Switzerland). Expired gases will be continuously collectedthroughout exercise and analyzed for ventilatory volume(VE) and for oxygen (O2) and carbon dioxide (CO2) con-tent, using dedicated analyzers. Standard spirometry (forcedexpiratory volume in one second (FEV1) and forced vitalcapacity (FVC)) will also be performed before the exercisetest. Equipment calibration and all measurements will bedone according to the recommendations of the AmericanThoracic Society and American College of Chest Physicians[20]. The following variables will be calculated: peak oxygenconsumption (pVO2), measured in milliliter per kilogramper minute (mL/Kg/min); peak respiratory exchange ratio,defined by the ratio of CO2 production to O2 consumptionat peak effort; oxygen consumption at anaerobic threshold(AT), defined as the point at which CO2 production in-creases disproportionately in relation to O2 consumption,obtained from a graph plotting O2 consumption againstCO2 production; and total exercise duration (seconds). Itis known that cardiopulmonary exercise testing with O2

consumption measurement provides the most accurate,reliable, and reproducible measurements of exercise cap-acity [21]. We will assess exercise capacity mainly bymeasuring pVO2, which is considered the gold standardparameter for functional capacity assessment [22]. How-ever, we will also evaluate submaximal exercise capacityby determination of the ventilatory AT that has the advan-tage of being relatively effort independent [21].

Measurements: clinical, analytical, and anthropometric dataAt baseline and at the end of the study protocol all pa-tients will be submitted to a clinical evaluation performedby a cardiologist, a blood sample, and detailed anthropo-metric evaluation. The clinical evaluation will include aninterview, review of medical registries, and a physicalexamination to collect data on cardiovascular risk factors,previous medical history, medication use or change sincelast evaluation, symptoms of angina, and New York HeartAssociation functional status (NYHA class).The anthropometric evaluation will include the measure-

ment of height, weight, waist circumference, and hip cir-cumference. Body mass index ((BMI) weight/height2 inkg/m2) will be calculated for each subject. Waist circumfer-ence will be measured at the midpoint between the iliaccrest and the lower rib margins, measured in the midaxil-lary line. Body composition will be assessed by bioelectricalimpedance analysis (Tanita Inner Scan BC-522; Tanita,Tokyo, Japan) to determine body fat percentage (%).A fasting venous blood sample will be obtained immedi-

ately before and after the study for measurement of glucose,

total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyc-erides, high-sensitivity C-reactive protein, and N-terminalpro-BNP. Insulin resistance will be assessed using theHomeostasis Model Assessment of Insulin Resistance(HOMA-IR) score.

Study endpointsThe primary endpoint will be the change in E’ lateralvelocity after the eight-week exercise training program.Secondary endpoints will be other echocardiographic pa-rameters of left ventricular diastolic and systolic func-tion, metabolic and inflammation biomarkers, functionalcapacity, and anthropometric measurements, as detailedin Study primary and secondary endpoints:

Primary endpointE’ lateral velocity: change between baseline and follow-upSecondary endpoints– Left ventricular diastolic function parameters:E’ septal velocity; E/E’ septal, lateral and mean ratio;E/A ratio; E-wave deceleration time; isovolumetricrelaxation time; diastolic dysfunction grades according tothe ASE/ESE consensus– Systolic function parameters:Ejection fraction, S’ lateral and septal velocities– Functional capacity parameters:Peak VO2; VO2 at anaerobic threshold; exerciseduration– Metabolic biomarkers:Insulin and glucose plasma levels; insulin resistance(Homeostasis Model Assessment);– Cardiovascular biomarkers:N-terminal pro-BNP and high sensitivity C-reactiveprotein– Anthropometric parameters:Weight, body mass index, waist and hip perimeter, fatmass percentage by bioimpedance analysis

Statistical analysis and sample size calculationThe analysis of the primary endpoint will be performed onan intention-to-treat basis by repeated-measures analysisof covariance (ANCOVA), including the following vari-ables: baseline E′ velocity, age, mean arterial pressure,treatment group, gender, and baseline degree of DD.To calculate the sample size we used as a reference the

data from the study of Edelman et al., which tested the ef-fect of exercise training in patients with heart failure withpreserved ejection fraction [12]. Assuming a standard de-viation of the change in E’ velocity from baseline tofollow-up of 1.5 cm/s in each group, we estimated that, todetect a difference of 1 cm/s in the change of E’ velocitybetween treatment groups, a minimum of 48 patients




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would be required in each group. A significance level of5% and a statistical power of 90% will be defined.

Ethical and legal issuesInformed consent will be obtained from all patients priorto study beginning. The ethics review board (Comissãode Ética do Centro Hospitalar de Vila Nova de Gaia) ap-proved the study protocol (reference: 627/10). The studyconforms to the principles outlined in the Declaration ofHelsinki (1975) and has been registered at ClinicalTrials.gov (reference: NCT02224495).

DiscussionUntil now no therapy or intervention has proved to sig-nificantly improve diastolic function and to change theprognosis of diastolic heart failure [9,23]. Structured pro-grams of exercise training can have several benefits inmetabolic, muscular, pulmonary, and cardiovascular pa-rameters. Data from experimental studies also suggestthat exercise training can improve systolic and diastolicfunction and promote favorable myocardial remodelling[10,11]. In this study, we aim to evaluate the impact ofa structured program of endurance plus resistancetraining on cardiac function in patients who have hadan AMI. Theoretically, the benefits of exercise trainingcan depend on clinical context and on the type, intensity,and duration of exercise [24,25]. In this study, we will testa combination of endurance plus resistance training dur-ing eight-weeks, encompassing three sessions per week.The combination of endurance and strength training isimportant because strength training is useful to acceleratethe improvements in skeletal muscle bulk and function.The protocol that will be used is similar to the one appliedby Edelmann et al., that also tested the effect of exercisetraining on diastolic function in patients with heart failurewith preserved ejection fraction [12].Cardiac function will be assessed by echocardiography

using both traditional parameters and those derived fromtissue Doppler imaging. Diastolic function will be evalu-ated according to the latest consensus criteria between theAmerican Society of Echocardiography and the EuropeanAssociation of Echocardiography. For the evaluation of leftventricular diastolic function it is known that traditionalparameters, based on mitral inflow and pulmonary veinflow velocities (such as the E/A ratio, DT, or Ard-Ad), aremarkedly influenced by loading conditions, left ventricularcompliance, and left atrium function [18,23,26,27]. There-fore the primary endpoint in this study will be the E’velocity, determined by tissue Doppler analysis. Severalstudies have shown that E’ velocity is closely related withleft ventricular relaxation assessed invasively by tau (thetime constant of isovolumic pressure decline) [28,29]. Wewill also evaluate the E/E’ ratio, which is a diastolic func-tion parameter derived from tissue Doppler that closely

reflects left ventricular filling pressures determined inva-sively [18,30]. Systolic function will be evaluated by ejec-tion fraction and by systolic mitral annulus velocities(S’ velocity) from tissue Doppler. It is known that ejectionfraction is both preload- and afterload-dependent, and hasseveral limitations in the assessment of global left ventriclesystolic function. On the contrary, the evaluation of S’velocities is more sensitive in the evaluation of global andregional systolic function after myocardial infarction [19].

Trial statusRecruitment for the study has finished; 188 patients havebeen included as of February 2015.

AbbreviationsAMI: Acute myocardial infarction; ASE: American Society of Echocardiography;AT: Anaerobic threshold; BMI: Body mass index; BNP: Brain Natriuretic Peptide;DD: Diastolic dysfunction; DT: Deceleration time; EAE: European Association ofEchocardiography; IVRT: Isovolumetric relaxation time; HOMA-IR: HomeostasisModel Assessment of Insulin Resistance; pVO2: Peak oxygen consumption.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsRFC participated in the conception and design of the research, statisticalanalysis, fund raising, drafting and revision of the manuscript. FS participatedin the design of the research, drafting and revision of the manuscript. MTparticipated in the conception of the research, fund raising and revision ofthe manuscript. VG participated in the coordination of the research, fundraising and revision of the manuscript. ALM participated in the conceptionand design of the research, coordination, supervision, fund raising, draftingand revision of the manuscript. All authors read and approved the finalmanuscript.

AcknowledgementsThis work is supported and funded by Portuguese Foundation for Scienceand Technology Grants within the project PTDC/DES/113753/2009, and alsopartly by the projects POCI/SAU-ESP/61492/2004, PEST-C/SAU/UI0051/2011,PEst-OE/SAU/UI0617/2011, and EXCL/BIM-MEC/0055/2012, and by EuropeanCommission Grant FP7-Health-2010 (MEDIA-261409).

Author details1Cardiology Department, Gaia Hospital Centre, Rua Conceicao Fernandes,4434-502 Vila Nova Gaia, Portugal. 2Department of Physiology andCardiothoracic Surgery, Faculty of Medicine, University of Porto, Al. Prof.Hernâni Monteiro, 4200 - 319 Porto, Portugal. 3Department of CardiothoracicSurgery, Centro Hospitalar São João, Al. Prof. Hernâni Monteiro, 4200 - 319Porto, Portugal.

Received: 4 September 2014 Accepted: 18 February 2015

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TITLE

The effect of exercise training on diastolic and systolic function after acute myocardial infarction:

a randomized study

AUTHORS

Ricardo Fontes-Carvalho (MD)1,2, Ana Isabel Azevedo (MD)1, Francisco Sampaio (MD, PhD)1, Madalena Teixeira (MD)1,

Nuno Bettencourt (MD, PhD)1, Lilibeth Campos (MD)1, Francisco Rocha Gonçalves (MD, PhD)3, Vasco Gama Ribeiro

(MD)1, Ana Azevedo (MD, PhD)4,5Adelino Leite-Moreira (MD, PhD)2,6

INSTITUTIONS

1 Cardiology Department, Gaia Hospital Centre, Gaia, Portugal;2 Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal;3 Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal; 4 Department of Clinical Epidemiology, Predictive Medicine and Public Health, Faculty of Medicine, University of

Porto, Porto, Portugal; 5 EPIUnit - Institute of Public Health, University of Porto (ISPUP), Porto, Portugal;6 Department of Cardiothoracic Surgery, Centro Hospitalar São João, Porto, Portugal.

CORRESPONDING AUTHOR


Cardiology Department, Gaia Hospital Center

Rua Conceição Fernandes,

4434-502 Vila Nova Gaia, Portugal

Tel: +351 22 786 51 00

Fax: +351 225519194

[email protected]

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ABSTRACT

Background: After acute myocardial infarction (AMI), diastolic dysfunction is frequent and an important determinant

of adverse outcome. However, few interventions have proven to be effective in improving diastolic function. We

aimed to determine the effect of exercise training on diastolic and systolic function after AMI.

Methods: One month after AMI, 188 patients were prospectively randomized (1:1) to an 8-week supervised program

of endurance and resistance exercise training (n=86; 55.9±10.8 years) versus standard of care (n=89; 55.4±10.3

years). All patients were submitted to detailed echocardiography and cardiopulmonary exercise test, at baseline and

immediately after the study.

Results: At follow-up, there was no significant change in E’ septal velocity or E/E’ septal ratio in the exercise group. We

observed a small, although non-significant, improvement in E’ lateral (mean change 0.1±2.0 cm/s;p=0.40) and E/E’

lateral ratio (mean change of -0.3±2.5;p=0.24), while patients in the control group had a non-significant reduction in

E’ lateral (mean change -0.4±1.9 cm/s; p=0.09) and an increase in E/E’ lateral ratio (mean change +0.3±3.3;p=0.34).

No relevant changes occurred in other diastolic parameters. The exercise-training program also did not improve

systolic function (S’ velocities or ejection fraction).

Exercise capacity improved only in the exercise-training group, with an increase of 1.6mL/Kg/min in pVO2 (p=0.001)

and of 1.9mL/Kg/min in VO2 at anaerobic threshold (p<0.001).

Conclusions: After AMI, an eight-week endurance plus resistance exercise-training program did not significantly

improve diastolic or systolic function, although it was associated with an improvement in exercise capacity parameters.

KEY WORDS

Diastole; systole; exercise therapy; myocardial infarction



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INTRODUCTION

Diastolic dysfunction is prevalent in the community (1) and is recognized as an important predictor of heart failure

(2) and long-term mortality (1) (3). After acute myocardial infarction (AMI), both systolic and diastolic functions are

significantly impaired, and the majority of patients have diastolic dysfunction (4) (5) (6). In these patients diastolic

dysfunction is also a major determinant of adverse clinical outcome (4) and decreased functional capacity (5).

However, contrary to systolic function, no therapy or intervention has been shown to significantly improve diastolic

function after AMI (7).

Exercise training, as part of cardiac rehabilitation, is effective in improving functional capacity and quality of life

in patients with coronary artery disease (8) (9). Other cardiovascular and non-cardiovascular benefits have been

reported, namely in glucose metabolism, skeletal muscle function, oxidative stress, vascular function, pulmonary

circulation, ischaemia-reperfusion lesion and ventricular remodelling (10). However, the benefit of exercise training

on diastolic function is controversial (6) (11) (12), especially after AMI where no longitudinal study has evaluated

diastolic function using modern echocardiographic parameters.

We conducted a prospective, randomized, controlled study to determine the effect of exercise training on resting

diastolic and systolic function in patients after acute myocardial infarction.

METHODS

Participants and study design

We prospectively enrolled patients one month after AMI, with both ST elevation and non-ST elevation AMI, defined

according to the universal definition consensus document (13). Exclusion criteria were age below 18 or above 75

years, inability to exercise, hemodinamically significant valvular disease, moderate to severe chronic lung disease

(vital capacity and/or forced expiratory volume in 1 s below 80% of age-dependent predicted value), atrial fibrillation,

uncontrolled atrial or ventricular tachyarrhythmias, exercise induced myocardial ischemi, severe renal disease or

dysfunction (creatinine clearance <30 mL/min, calculated by the Cockcroft-Gault formula) and anaemia (haemoglobin

<12 g/dl). Patients were randomized (1:1) to be included in a structured exercise-training program versus a control

group, receiving standard of care. Randomization by blocks was used, and an allocation sequence based on a fixed

block size of 8 was generated with a computer random number generator.

Immediately before enrolment and at the end of the follow-up, all patients were submitted to clinical evaluation,

detailed transthoracic echocardiography and cardiopulmonary exercise test. Both groups had regular appointments

with a cardiologist and received optimal medical therapy. Informed consent was obtained from all patients and the

local institution review board (“Comissão de Ética do Centro Hospitalar de Vila Nova de Gaia”) approved the study

protocol (reference 627/10). The study protocol conforms to the principles outlined in the Declaration of Helsinki

(1975) and the study has been registered at ClinicalTrials.gov (reference NCT02224495).

Echocardiographic evaluation

A single experienced cardiologist, blinded to the patient assignment group, will perform all echocardiographic

studies using an ultrasound system (iE33, Philips Medical Solutions, Best, The Netherlands) equipped with S5-1

and X5-1 transducer. Cardiac chamber dimensions, volumes and left ventricular mass were measured according

to current recommendations (14). Mitral inflow velocities were assessed using pulsed-wave Doppler in the apical

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four-chamber view, with a 3mm sample placed between the tips of the mitral leaflets; velocities were recorded at

end-expiration. Tissue Doppler velocities were acquired at end-expiration, in the apical four-chamber view, with the

sample positioned at the septal and lateral mitral annulus for determination of systolic (S’), early diastolic (E’) and

late diastolic (A’) velocities. Pulsed wave Doppler velocities at the upper right pulmonary vein were also recorded.

For all parameters, the average of three consecutive heart beats was recorded.

Left ventricle diastolic function was assessed according to the EAE/ASE consensus guidelines on diastolic function

evaluation (15) which included determination of peak early (E) and late (A) diastolic mitral inflow velocities,

deceleration time of early left ventricular filling (DT), E/A ratio, myocardial early diastolic velocities at the septal

and lateral side of mitral annulus (E’septal, E’lateral, E’mean), E/E’ ratio (including septal, lateral and mean E/E’),

pulmonary vein flow analysis (to calculate the Ard-Ad relation: the time difference between the duration of the atrial

reverse wave of the pulmonary flow - Ard – and the mitral A-wave duration) and isovolumetric time relaxation (IVRT).

Using the consensus criteria (15) patients were categorized in diastolic dysfunction (DD) grades: normal, grade I

(mild DD), grade II (moderate DD) and grade III (severe DD), by two blinded independent cardiologists. In case of

discordance, each case was discussed individually.

Left ventricle systolic function was evaluated by calculation of biplane ejection fraction (Simpson’s method) and

determination of systolic velocities at the septal and lateral side of mitral annulus by tissue Doppler (S’septal and

S’lateral).

Cardiopulmonary exercise testing

At the beginning and at the end of the study, each patient underwent a symptom-limited cardiopulmonary

exercise testing (CPX) on a treadmill, using the modified Bruce protocol (Cardiovit CS-200 Ergo Spiro; Schiller, Baar,

Switzerland). Expired gases were continuously collected throughout exercise and analysed for ventilatory volume

(VE) and for oxygen (O2) and carbon dioxide (CO2) content, using dedicated analysers. Standard spirometry (forced

expiratory volume in one second (FEV1) and forced vital capacity (FVC)) were also undertaken before exercise

test. Equipment calibration and all measurements were done according to the recommendations of the American

Thoracic Society and American College of Chest Physicians (16). The following variables were calculated: peak oxygen

consumption (pVO2) measured in millilitre per kilogram per minute (mL/Kg/min); peak respiratory exchange ratio,

defined by the ratio of CO2 production to O2 consumption at peak effort; anaerobic threshold (AT) defined as the

point at which CO2 production increases disproportionately in relation to O2 consumption, obtained from a graph

plotting O2 consumption against CO2 production; and total exercise duration (seconds). Patients were not asked to

discontinue beta-blockers before the test.

Intervention: the exercise-training program

The exercise-training group participated in an 8-week outpatient exercise-training program, encompassing 3 sessions

per week, including endurance and resistance training. Each session consisted of 10 minutes of warm up, 50 minutes

of aerobic and resistance training and 10 minutes of cool down. During the 8 weeks, endurance training (cycling on

the first 4 weeks and treadmill on the remaining 4 weeks) of increasing intensity was performed. Training intensity

was individualized to a target heart rate of 70-85% of the maximal heart rate achieved in baseline CPX. Resistance

training was also included in each session, including arms, legs and thoracic exercises including dumbbell or weight

training depending on the patient’s condition and exercise capacity. Clinical and training parameters were monitored

including arterial blood pressure, heart rate (by telemetry or wrist device), glycaemia (in diabetic patients) and



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training level intensity. Borg scale was used to monitor fatigue. Patients randomized to the control group received

standard of care, with regular appointments with the cardiologist, optimized medication and recommendations on

healthy lifestyle.

The primary endpoint was the change in E’ lateral velocity. Secondary endpoints were other echocardiographic

parameters of left ventricular diastolic (E’ septal velocity and E/E’ septal, lateral and mean ratio, E/A ratio,) and

systolic function (S’ septal and lateral velocities and ejection fraction) and parameters of exercise capacity (peak VO2,

VO2 at anaerobic threshold and exercise duration).

Statistical analysis

Statistical analysis was performed using SPSS Statistics 22.0 (IBM Corp, Armonk, NY, USA). All continuous variables

were expressed as mean ± standard deviation or as median (percentile 25-75) (IQR) for variables with non-normal

distribution. Categorical variables are expressed as number (n) and percentage (%). A significance level of 0.05 was

used. Differences between clinical and echocardiographic baseline characteristics of the two groups were assessed

by an independent-samples t-test, chi-square or Mann-Whitney test, as appropriate. Changes in echocardiographic

and cardiopulmonary test within groups during follow-up were determined by paired-sample t-test (if normally

distributed) or Wilcoxon test (if not normally distributed).

To calculate the sample size we used as reference the data from the study of Edelman et al, which tested the effect

of exercise training (17). Assuming a standard deviation of the change in E’ velocity from baseline to follow up of

1.5 cm/s in each group, we estimated that, to detect a difference of 1 cm/s in the change of E’ velocity between

treatment groups, a minimum of 48 patients would be required in each group. A significance level of 5% and a

statistical power of 90% were defined.

RESULTS

From 313 patients assessed for eligibility, 175 completed the protocol according to the study’s flow chart outlined in

figure 1. The characterization of the study population is presented in table 1. The study sample included mostly men

(82.3%), with a mean age of 55.6±10.5 years, an ejection fraction of 54.0±9.5% and an overall prevalence of DD of

61.1%: 26.9% had grade I DD; 29.3% had grade II and 4.8% had grade III DD. Baseline demographic characteristics,

cardiovascular risk factors and echocardiographic parameters did not significantly differ between groups, as shown in

table 1. Patients were doing optimized medical therapy, with dual anti-platelet therapy in all patients, beta-blockers

in 95.2%, renin-angiotensin axis inhibitor in 97.8%, aldosterone antagonist in 37.2% and statins in 97.3%. There were

no significant differences between the two groups in cardiovascular medical therapy.

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Figure 1 . Flow chart of the study



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Table 1 . Baseline characteristics of the study sample

Control Group (n= 86)

Exercise Training (n= 89)

p value

Age (years) 55.9±10.8 55.4±10.3 0.73

Sex, male (%) 79.1% 85.4% 0.19

Hypertension (%) 45.3% 49.4% 0.35

Diabetes (%) 9.3% 14.6% 0.20

Dyslipidemia (%) 48.8% 57.3% 0.17

Smoker (%) 55.8% 51.7% 0.35

Obesity (%) 16.3 % 20.2% 0.30

ST elevation Myocardial Infarction (%) 34.9% 39.3% 0.81

Angioplasty (%) 75.6% 76.4% 0.57

NT-ProBNP (ng/L)348.0

(138.0-736.0)366.0

(198.3-729.5)0.45

Echocardiography

Septum (mm) 9.6±1.7 9.7±1.5 0.46

Posterior wall (mm) 9.2±1.5 9.5±1.5 0.23

LV mass index (g/m2) 104.2±24.5 106.0±25.9 0.66

LA volume index (ml/m2) 34.8±9.6 34.6±8.9 0.90

LV end-diastolic volume (ml) 107.0±29.3 109.9±27.6 0.44

LV end-systolic volume (ml) 49.2±21.4 52.6±22.4 0.61

E wave (cm/s) 78.5±17.6 77.8±19.4 0.80

A wave (cm/s) 67.9±16.0 67.8±19.4 0.95

E/A ratio 1.2±0.4 1.2±0.5 0.94

Deceleration time (ms) 211.5±43.1 227.7±52.6 0.03

E’ septal (cm/s) 6.8±1.6 6.9±1.8 0.82

E’ lateral (cm/s) 9.6±2.4 9.7±2.7 0.56

E/E’ septal 12.0±3.3 11.9±4.7 0.95

E/E’ lateral 8.6±3.1 8.6±3.5 0.98

E/E’ mean 10.3±3.0 10.3±3.8 0.96

IVRT (s) 124.7±27.0 126.6±27.1 0.73

Ard-Ad (s) 33.1±40.9 26.7±41.6 0.33

Ejection Fraction (%) 54.2±9.4 53.9±9.8 0.83

S’ septal (cm/s) 6.7±1.1 6.7±1.5 0.98

S’ lateral (cm/s) 7.6±1.7 7.3±1.8 0.56

Data are presented as mean and standard deviation or as median (percentile 25-75)

for continuous variables and percentage for categorical variables.(LV – left ventricle; LA – left atrium; ARd-Ad - time difference between the duration of the atrial reversal wave of the pulmonary flow and the mitral A-wave duration;

IVRT – isovolumetric relaxation time )

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The effect of exercise training on diastolic and systolic cardiac function

As shown in table 2, there was no significant improvement in E’ septal or E/E’ septal neither in the exercise training

group nor in controls. At follow-up, patients in the control group showed a non-significant reduction in E’ lateral

(mean change of -0.4±1.9 cm/s) and an increase in E/E’ lateral ratio (mean change of +0.3±3.3) and in E/E’ mean ratio

(change of +0.2±2.8), whereas in the exercise training group there was a slight, but also non-significant, improvement

in E’ lateral (mean change of 0.1±2.0 cm/s), E/E’ lateral ratio (mean change of -0.3±2.5) and in E/E’ mean ratio (mean

change -0.3±2.8).

Table 2. Comparison of diastolic function parameters at baseline and follow-up between control and exercise training groups

Control Exercise Training p valueτ

E’ lateral, cm/s

Baseline 9.6±2.4 9.7±2.7

Follow-up 9.3±2.5 9.9±2.7

Change -0.4±1.9 0.1±2.0 0.10

p value* 0.09 0.40

E’ septal, cm/s

Baseline 6.8±1.6 6.9±1.8

Follow-up 6.8±1.8 6.9±1.8

Change 0.0±1.2 0.0±1.2 0.97

p value* 0.88 0.84

E/E’ lateral ratio

Baseline 8.6±3.1 8.6±3.5

Follow-up 8.9±4.0 8.3±3.5

Change 0.3±3.3 -0.3±2.5 0.14

p value* 0.34 0.24

E/E’ septal ratio

Baseline 12.0±3.3 11.9±4.7

Follow-up 12.1±4.4 11.7±3.8

Change 0.0±2.9 -0.2±3.7 0.60

p value* 0.88 0.58

E/E’ mean ratio

Baseline 10.3±3.0 10.3±3.8

Follow-up 10.5±4.0 10.0±3.4

Change 0.2±2.8 -0.3±2.8 0.29

p value* 0.53 0.38

E/A ratio

Baseline 1.2±0.4 1.2±0.4

Follow-up 1.2±0.4 1.1±0.4

Change 0.0±0.4 -0.1±0.5 0.28

p value* 0.58 0.07

* p value for the comparison between baseline and follow-up values of each individual (paired T test)τ p value for the difference between groups in the change of each parameter from baseline to follow-up (independent-samples T test)



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Exercise training did not significantly improve other diastolic function parameters, such as E/A ratio, deceleration

time, isovolumic relaxation time or the Ard-Ad relation derived from pulmonary vein flow analysis. Between baseline

and follow-up, we did not observe a significant change in left atrium volume index in neither group (34.7±8.9 ml/m2

at baseline to 34.7±10.9 ml/m2 at follow up, in the exercise-training group; p=0.97).

Patients in the exercise-training and in the control groups did not significantly improved left ventricle ejection

fraction, as outlined in table 3. Regarding the evaluation of systolic function by tissue Doppler parameters there

wasn’t a significant change in S’ septal or S’ lateral in patients submitted to exercise training.

Table 3 . Comparison of systolic function parameters at baseline and follow-up between control and exercise training groups

Control Exercise Training Difference between groups

S’ septal, cm/s

Baseline 6.7±1.1 6.7±1.5

Follow-up 6.7±1.1 6.6±1.3

Change 0.0±0.9 0.1±1.0 0.52

p value 0.82 0.31

S’ lateral, cm/s

Baseline 7.6±1.7 7.3±1.8

Follow-up 7.5±1.8 7.4±1.7

Change 0.0±1.2 0.0±1.0 0.78

p value 0.94 0.50

Ejection Fraction, %

Baseline 54.5±9.4 54.1±9.7

Follow-up 54.5±8.9 53.7±8.4

Change 0.0±9.1 -0.3±7.5 0.85

p value 0.98 0.74

The effect of exercise training on functional capacity

Exercise training significantly improved exercise capacity parameters, as shown in table 4. At follow-up, patients in

the exercise-training group had an increase in peak VO2 (mean increase of +1.9±5.26 mL/min/kg; p<0.01), in VO2 at

anaerobic threshold (+1.4±3.8 mL/min/kg; p<0.01) and in exercise duration (+74.5±76.9 seconds; p<0.01), compared

to baseline. Patients in the control group slightly improved exercise duration (+34.0±73.6 s compared to baseline;

p<0.01) but there was no increase in peak VO2 or in VO2 at anaerobic threshold.

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Table 4 . Comparison of capacity parameters at baseline and follow-up between control and exercise training groups.

Control (n=86)

Exercise Training (n=89)

p value** (difference between groups)

VO2 peak, ml/min/kg

Baseline 29.6±6.9 29.1±7.6

Follow-up 29.4±7.7 31.0±9.5

Change 0.2±3.6 1.9±5.2 <0.01

p value* 0.70 <0.01

VO2 at Anaerobic Threshold, kg/ml/min/Kg

Baseline 17.9±4.0 16.7±3.8

Follow-up 18.2±5.3 18.2±5.0

Change 0.2±3.9 1.4±3.8 0.06

p value* 0.62 <0.01

Exercise Duration, s

Baseline 577.2±132.0 553.0±136.1

Follow-up 611.2±138.1 625.7±147.5

Change 34.0±73.6 74.5±76.9 <0.01

p value* <0.01 <0.01

* p value for the comparison between baseline and follow-up values of each individual (paired T test)

** p value for the difference between groups in the change of each parameter from baseline to follow-up (independent-samples T test)

DISCUSSION

In this prospective, randomized, controlled study an eight-week exercise-training program after myocardial infaction

did not significantly improve diastolic or systolic function parameters, although it was associated with a significant

improvement in exercise capacity.

In patients after myocardial infarction, left ventricle diastolic dysfunction is frequent (4) (5) (6) and an important

determinant of adverse clinical outcome (4). In our study, using the most recent consensus definition for diastolic

function evaluation (15), we confirmed a high prevalence (61.1%) of diastolic dysfunction in this population. It is also

known that diastolic dysfunction is also an important determinant of exercise intolerance(5), but no interventions

have proven to significantly improve diastolic function (7).

The impact of exercise on left ventricular diastolic function

Data from animal studies suggested that endurance training could improve myocardial relaxation and calcium

homeostasis, by increasing the myocardial expression of SERCA2a and phospholamban (18) (19). In patients with

systolic heart failure, the benefit of exercise on diastolic function is controversial (11) (20), but in patients with

heart failure with preserved ejection fraction, recent studies have shown that exercise can improve diastolic function

parameters (17). However, after AMI few longitudinal studies have evaluated the impact of exercise training on left

ventricular diastolic function(6) and none of them have used modern and integrated echocardiographic parameters

for diastolic function assessment. In our study, we observed that this eight-week structured exercise-training

program, consisting of endurance plus resistance training, did not significantly improve diastolic function because



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there was no significant change in lateral or septal E’ velocities and no reduction in left ventricle filling pressures

estimated by E/E’ ratio.

The potential benefits of exercise training on myocardial structure and function can be influenced by several factors,

such as the underlying cardiovascular disease, the baseline systolic and diastolic function, the criteria used for diastolic

function evaluation, and the timing, type (endurance versus resistance) and duration of exercise. In this study we

tested a combination of endurance plus resistance training during a relatively short period of time. First, it is possible

that an 8-week duration exercise program was too short to induce changes in myocardial function. However, in the

study from Edelmann et al, including patients with heart failure preserved ejection fraction, there was a significant

improvement in E/E’ ratio already at 12 weeks (17). On the contrary, another study consisting of 16-week exercise

training failed to improve cardiac function in patients with diastolic dysfunction (11). Second, the type of exercise

could be responsible for these results (21). The present study incorporated traditional endurance training, which was

complemented with a strength-training component and was very similar to the training protocol used by Edelman

(17). In this setting, strength training can be useful to accelerate improvements in skeletal muscle bulk and function.

Newer training modalities using high intensity aerobic interval training (reaching 95% of peak heart rate) seem to

be superior to moderate continuous endurance training, for improving ejection fraction, endothelial function and

skeletal muscle function in patients with systolic heart failure (22). Third, the timing of initiation of exercise can also

influence the effect of exercise training. Previous studies have suggested that the largest improvements in ventricular

volumes and ejection fraction can be obtained when exercise is began just one week after AMI (23). This latter study

did not evaluate the effect on diastolic function.

Effect of exercise training on left ventricular systolic function

It is also controversial if resting left ventricle systolic function can be improved by exercise training (6) (24) (25).

Most of the studies were small, lacked control groups and evaluated systolic function only using ejection fraction. It

is known that ejection fraction is preload and afterload dependent and has several limitations in the assessment of

global left ventricle systolic function. In this study we evaluated systolic function also using tissue Doppler derived

systolic mitral annulus velocities (S’ lateral and septal velocities) that is known to be more sensitive in the evaluation

of global and regional systolic function after myocardial infarction (26). However, in our study, neither ejection

fraction nor S’ velocities significantly improved after the implementation of this exercise training program.

The effect of exercise training on functional capacity

Contrary to cardiac function, the exercise training protocol significantly improved functional capacity, as determined

by a peak VO2. These observations suggest that the improvement in functional capacity was caused mainly by non-

cardiac mechanisms, similar to what has been observed in heart failure patients (22) (27). These mechanisms may

include improved oxidative capacity or anaerobic glycolysis of skeletal muscle, improved arteriovenous difference

(with better oxygen uptake by the peripheral tissues) and/or improved vascular function (11, 22). In another study,

Smart et al also showed that in patients with diastolic dysfunction the improvement in functional capacity parameters

after 16 weeks of training was related to improvements in non-cardiac parameters [10].

Strengths and limitations

This was a prospective, randomized, single-blinded, controlled trial that evaluated the effect of a supervised

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exercise-training program on diastolic and systolic function. For the assessment of cardiac function, we used recent

echocardiographic parameters derived from tissue Doppler analysis, which provide a more accurate evaluation of left

ventricular function in comparison with classical parameters. Also, we compared exercise capacity before and after

the program by evaluating peak VO2 that is considered the gold-standard method to evaluate exercise tolerance.

Regarding the limitations of this study we investigated mostly middle-aged men and, therefore, no assumptions can

be made regarding older individuals or women. We evaluated cardiac function only at rest, and therefore potential

benefits of exercise training on cardiac function during exercise could not be evaluated. We tested the effect of

an exercise-training protocol that was of relatively short duration and consisting of both endurance plus strength

training protocol. However, in patients after AMI the optimal type, duration, frequency and intensity of exercise

training still needs to be addressed in the future. Finally, the contribution of non-cardiac factors (peripheral and

muscular) in the improvement of exercise capacity should be addressed in forthcoming studies.

CONCLUSION

In patients one month after acute myocardial infarction, an eight-week structured exercise-training program,

consisting of endurance plus resistance training, improved exercise capacity, but was not associated with a significant

change in both diastolic and systolic left ventricular function.

ACKNOWLEDGMENTS

This work is supported and funded by Portuguese Foundation for Science and Technology Grants within the project

PTDC/DES/113753/2009 and also, partly, by the projects POCI/SAU-ESP/61492/2004, PEST-C/SAU/UI0051/2011,

PEst-OE/SAU/UI0617/2011, EXCL/BIM-MEC/0055/2012 and by European-Commission Grant FP7-Health-2010

(MEDIA-261409).

CONFLICT OF INTEREST

None of the authors have conflicts of interest to declare.



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“Research is to see what everybody else has seen, and to think what nobody else has thought.”

Albert Szent-Györgi (1893-1986)

Discussion

CHAPTER IV | DISCUSSION

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Diastolic dysfunction: a prevalent condition across the cardiovascular continuum

In this research project we uncovered several features on the importance of evaluating diastolic function

in different phases of the cardiovascular continuum. First, we observed that LVDD was frequent across the

cardiovascular continuum, showing an increasing prevalence from individuals with no cardiovascular risk

factors to patients after myocardial infarction. We observed that the overall prevalence of LVDD in the general

population was high (23%), even after excluding patients with known cardiovascular disease. The prevalence

of diastolic dysfunction is influenced by the presence of several risk factors, mainly by hypertension, obesity

and insulin resistance/diabetes. Whereas in individuals without cardiovascular risk factors the prevalence of

diastolic dysfunction was only 16.3%, it doubled to 33% in patients with metabolic syndrome. Myocardial

ischemia is another well-known determinant of LVDD (9). In our cohort of patients after myocardial infarction

– which represent a more advanced stage of the cardiovascular continuum – the prevalence of LVDD increased

to 56%. Although not analyzed in this project, at the other end of the cardiovascular continuum, LVDD is

reported to affect almost all patients with HFpEF (23).

Unraveling the determinants of subclinical diastolic dysfunction to stop the progression to heart failure

According to the ACCF/AHA classification, an individual with subclinical LVDD is classified has having

stage B of heart failure (16) because LVDD, even when asymptomatic, is associated with the development of

symptomatic heart failure and with long-term mortality (13). Although the progression from subclinical LVDD

to symptomatic HFpEF is dependent on several other cardiac and extracardiac conditions (20), as detailed in

figure 2, the identification and correction of the main determinants of diastolic function can be of paramount

importance to stop the progression to overt heart failure. This can be especially relevant for the management

of heart failure with preserved ejection fraction (98), a disease where no therapy or intervention has shown

to significantly change the prognosis. Our research unveiled the role of some new determinants of diastolic

dysfunction, especially the role of obesity (visceral versus subcutaneous adiposity), epicardial fat, adipokines

secretion and insulin resistance.

Obesity cardiomyopathy: a novel entity contributing to subclinical diastolic dysfunction

Obesity is independently associated with heart failure risk (60). Therefore, the latest heart failure

guidelines have recognized obesity cardiomyopathy as a new and distinct clinical entity (16). The precise

mechanisms leading to this obesity-related cardiomyopathy are not known, but diastolic dysfunction seems

to be an intermediate step between obesity and heart failure (99). Furthermore, the comprehension of this

obesity cardiomyopathy can be also useful to understand the pathophysiology of HFpEF because several

epidemiological studies have shown that these patients have more obesity, compared to patients with

systolic heart failure (21).

The results of this research provided several new insights to the comprehension of the mechanisms

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underlying this obesity cardiomyopathy. First, we observed that total adiposity parameters were independent

determinants of subclinical diastolic function. We observed an association with body mass index, but also

with fat mass percentage (determined by bioimpedance analysis), which is a more accurate measure of total

adiposity. Moreover, we have validated the association between increased fat mass and diastolic dysfunction

in two different populations: one from the general community and the other from a relatively large sample

of patients after myocardial infarction. These observations are also in accordance with recently published

studies (58) (100).

Secondly, the association between diastolic function and fat mass was especially relevant with the

adiposity parameters that measure visceral fat, such as the waist perimeter and the abdominal visceral

fat area (determined by CT scan). It is known that visceral fat is the metabolically most active fat depot

(62), secreting adipokines, causing insulin resistance and inducing a systemic pro-inflammatory effect. The

combination of all our results suggests that this association is partially mediated by an endocrine effect,

as will be discussed latter. In the literature, two other studies have confirmed that waist circumference

(101), and increased abdominal visceral fat mass assessed by CT scan (102), were determinants of LVDD,

independently of BMI and subcutaneous fat, respectively. It is known that the total amount of fat, and its

distribution, is influenced by age and sex. Thus, not surprisingly, we observed that the effect of adiposity on

left ventricle diastolic function was sex- and age-specific, being more important in men than in women, and

especially in the younger population.

The secretion of adipokines is another mechanism that could be involved in the association between

adiposity and LVDD. Previous experimental studies found that the secretion of leptin and adiponectin can

have mitogenic effects (103), induce myocardial hypertrophy (104), increase cardiomyocyte fatty acid loading

(105) and change cardiac systolic function (106). In a sample of 556 individuals from the general population

we observed that higher leptin levels – but not of adiponectin – were independently associated with LVDD.

Recently, a long-term prospective study has shown that higher leptin levels were independently associated

with incident heart failure, even after adjustment for multiple risk factors, including body mass index (107).

Altogether, these data suggest that the secretion of adipokines, especially of leptin, can be involved in the

established association between obesity, diastolic dysfunction and heart failure risk. Therefore, if these

observations are confirmed in other studies, it will be possible to use leptin as a new therapeutic target for

diastolic dysfunction. Future research will determine if the inhibition of leptin activity in the cardiovascular

system – using recently developed superactive leptin muteins or leptin-blocking peptides, proteins,

monoclonal antibodies, and nanobodies(108) – can improve diastolic function or confer favorable myocardial

remodeling in hiperleptinemic patients.

Several other direct and indirect pathophysiological mechanisms can be involved in the association

between increased adiposity and LVDD. The effect can be indirect because obesity is associated with

hypertension, diabetes, coronary artery disease and sleep apnea (57), conditions that can influence diastolic

function (20). To evaluate the relative role of these direct and indirect mechanisms on LVDD we performed


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a path analysis in our sample from the general population. In women we observed that adiposity induced

diastolic dysfunction mainly by an indirect effect, especially through hypertension. On the contrary, in men the

mechanism involved was mainly direct. Although not evaluated in this project, obesity can modulate cardiac

function by other mechanisms, such as by inducing myocardial fat acid infiltration, increasing peripheral

resistance and ventricular afterload and causing chronic volume overload (109) (110).

In recent years, considerable interest has risen on the local/paracrine effect of epicardial fat. Several

studies have demonstrated an independent association with the development and progression of coronary

artery disease (68, 70-72, 111). In order to evaluate if epicardial fat was also associated with changes in

myocardial function, we measured epicardial fat volume by CT scan and found that increased epicardial

fat was associated with impaired diastolic function, independently of body mass index. It is known that

epicardial adipose tissue can influence myocardial structure and function by “systemic” (obesity mediated),

“mechanical” and “paracrine” pathways. The systemic effects of increased adiposity on LVDD have been

previously discussed. Furthermore, epicardial fat volume can range from 50 g to >250 g, which can directly

influence diastolic function by posing a mechanical limitation to cardiac expansion(73). Finally, at a local

level, epicardial adipose tissue produces several inflammatory mediators and adipokines that can directly

induce changes in the myocardium by a paracrine effect (66) (112), and/or producing free fatty acids which

can accumulate in the myocardium and induce cardiomyocyte apoptosis (113) (109). In this study we

only evaluated the role of epicardial fat in patients after myocardial infarction and, therefore, we cannot

extrapolate these conclusions to the general population or to other cardiac diseases.

The association between obesity, diastolic function and HFpEF can have several clinical implications. First,

the increasing obesity epidemic worldwide will likely contribute to the expected increase in the incidence

of heart failure. Interestingly, epidemiological studies have shown that the proportion of patients with the

HFpEF have increased over time from 38% to 54% of cases of heart failure (21), which is related to the ageing

of the population but also to increased rates of hypertension and obesity. Data from a recent longitudinal

follow-up of the CARDIAC study suggested that strategies for promoting weight loss, and reduce central

adiposity may be effective for the prevention of HFpEF (114). Also, two studies with significant weight loss

after bariatric surgery showed a significant improvement in diastolic function (115) (116). Future studies

will determine the efficacy and safety of weight loss (with diet, exercise and/or bariatric surgery) to prevent

the onset and progression of subclinical diastolic dysfunction and to stop the progression to heart failure in

obese patients. These interventions should probably be applied from early ages because recent studies have

shown subclinical changes in diastolic function already in obese children (117).

Subclinical diastolic dysfunction as a cardiometabolic disease: the role of insulin resistance, metabolic

syndrome and diabetes

LVDD is one of the earliest manifestations of myocardial involvement in type 2 diabetes mellitus (85)

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and a key component of diabetic cardiomyopathy (83). Nevertheless, few studies have clearly demonstrated

an independent association between diabetes and incident heart failure (118), especially because this

association is confounded by the simultaneous presence of other heart failure risk factors.

In our sample from the general population we observed that changes in diastolic function precede the

onset of diabetes, being mainly associated with the state of insulin resistance. These data are in accordance

with previous studies also showing that in early phases of the diabetic continuum – such as in patients with

impaired glucose tolerance – changes in diastolic function are already apparent (86) (87). Therefore, insulin

resistance can be the main pathophysiologic mechanism involved in this “diabetic cardiomyopathy”. Insulin

resistance can cause LVDD by inducing changes in myocardial substrate utilization (88) (83), increasing

myocardial interstitial fibrosis (89), activation of the sympathetic nervous system (90) and impaired

ventricular-vascular coupling (91) (92). Furthermore, insulin resistance, with or without diabetes mellitus, is

established as an independent risk factor for incident HF (119) (120) (121).

In our study, we also showed a progressive worsening of diastolic function parameters from normal

individuals to patients with metabolic syndrome, and then to patients with fully established type 2 diabetes.

In our population, metabolic syndrome was associated with LVDD, independently of age, sex, blood pressure

and body mass index. These data are in accordance with the observations of other smaller studies (95) (122)

(123) (96), which have also demonstrated a progressive worsening of diastolic function parameters according

to the number of criteria for metabolic syndrome (95) (96).

Altogether these data suggest that subclinical changes in left ventricular diastolic function are already

present in an early phase of glucose disturbance metabolism, before the onset of diabetes, being mainly

associated with the state of insulin resistance and not only to sustained hyperglycemia. However, it is known

that sustained hyperglycemia increases glycation of interstitial proteins, such as collagen and the deposition

of advanced nonenzymatic glycation end products (AGE) in the extracellular matrix (38), resulting in a further

increase in myocardial stiffness. This “glucotoxic” effect can partially explain the additional deterioration

of diastolic function from patients with metabolic syndrome but without diabetes, to patients with fully

established diabetes. Reinforcing this possibility, a large study of patients with type 1 diabetes (where

insulin resistance is not an important pathophysiological mechanism) showed that incident heart failure was

associated with HbA1c and the rate of glycemic control (124). Consequently, current guidelines advocate

glycemic control in all stages of the ACCF/AHA stages of heart failure, although no trial has demonstrated that

such control can reduce subsequent risk of heart failure. On the contrary, clinical trials with thiazolidinediones

(125) and, more recently, with the dipeptidyl peptidase-4 (DPP-4) inhibitors (126) have shown an increased

risk of heart failure.

Future research will determine if the administration of drugs acting in an earlier phase of the diabetic

continuum can improve myocardial structure and function, especially diastolic dysfunction. Indeed, in animal

models of insulin resistance, metformin had a “cardioprotective” effect by reducing myocardial fibrosis,

improving cardiac remodeling and preventing the progression to heart failure (127) (128). Therefore, we


173

are now conducting a single center, phase II clinical trial (MET-DIME), to evaluate if the administration of

metformin can improve diastolic function in patients with metabolic syndrome and left ventricular diastolic

dysfunction. The study protocol is detailed elsewhere (129) and is published in clinicaltrials.gov (reference

NCT02017561).

The role of diastolic function on functional capacity and its modulation by exercise training

LVDD is an important prognostic marker of adverse clinical outcome in patients at different stages of

the cardiovascular continuum (9) (18) (19). Beyond its prognostic role, we showed that resting diastolic

function parameters, particularly E/E’ ratios and E’ velocities, were the strongest echocardiographic

correlates of exercise capacity, after myocardial infarction. Diastolic function correlated with functional

capacity independently of other determinants of exercise capacity such as age, sex, obesity, hypertension

and diabetes.

Furthermore, it is known that sustained LVDD induces left atrium remodeling (41). Thus, increased LA

volume (in the absence of other causes of LA enlargement) can be considered a biomarker of the severity

and duration of LV filling pressures and an indicator of chronic LV diastolic dysfunction (3) (35) (41). In this

project we have also evaluated left atrium volumes and function, by speckle tracking analysis, in a subgroup

of patients after myocardial infarction. As expected, we found a significant relation between increased

LA volumes and E’ velocity and E/E’ ratio. This can explain the observed association between increased

LA volumes and reduced exercise capacity. The LA volume parameter that best correlated with exercise

performance was the LA volume immediately before atrial contraction, which is more dependent on early LV

diastolic function and on LA conduit function (130).

LA function also plays an important role in the regulation of global cardiac function, especially of diastolic

function (42). A recent study showed that LA ejection fraction is an independent predictor of mortality,

providing prognostic value incremental to that of maximum LA volume (131). In our study we found that

decreased exercise capacity was associated with LA function, especially with reduced LA conduit function,

but not with LA contractile function. Finally, we observed that lower peak atrial longitudinal strain (PALS) was

well correlated with exercise capacity parameters, suggesting that the LA longitudinal strain analysis can also

be useful to predict reduced exercise capacity after myocardial infarction.

The association between diastolic function and functional capacity has been observed in other studies

evaluating patients in different stages of the cardiovascular continuum. In selected groups of patients with

systolic heart failure, E’ velocities and E/E’ ratios were important predictors of functional capacity and

significantly better than ejection fraction(29, 132, 133). Likewise, in patients with heart failure preserved

ejection fraction, Edelmann et al demonstrated that E/E’ ratio was strongly related with peak oxygen

consumption and that the improvement of diastolic function could increase exercise capacity (134).

Therefore, in this project we also wanted to evaluate if a structured program of exercise training could

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174

improve diastolic function in patients after myocardial infarction. This can be clinically relevant because no

therapy or intervention has proven to significantly improve diastolic function in these patients. However,

in our prospective, randomized, controlled study, we did not observe a significant change in diastolic

function parameters, after an eight-week program combining resistance and endurance exercise training.

Future research will determine if exercise training programs of longer duration and/or using newer training

modalities of high intensity aerobic interval training (22) can provide additional benefits to cardiac structure

and function in these patients.

Finally, although we have not shown a significant improvement in diastolic function after myocardial

infarction, exercise can be a new intervention target for the prevention of HFPeF in individuals with

subclinical diastolic dysfunction (135). A recent large study showed that low fitness was associated with a

higher prevalence of concentric remodeling and diastolic dysfunction, suggesting that long-term exercise

can lower heart failure risk by inducing favorable cardiac remodeling and improving diastolic function (136).

Conclusions

CHAPTER V | CONCLUSIONS

177

“Now this is not the end. It is not even the beginning of the end.

But it is, perhaps, the end of the beginning”.

Winston Churchill (1874-1965)

Left ventricular diastolic dysfunction is a frequent condition, with increasing prevalence across the

cardiovascular continuum. Subclinical diastolic dysfunction is an intermediate step in the progression to

HFpEF, a disease where no therapy or intervention significantly improved the prognosis. Therefore, the

management of HFpEF should focus on its prevention, which highlights the importance of identifying - and

correcting - the determinants of diastolic dysfunction.

Obesity is an important new determinant of diastolic function. Increased adiposity, especially of

visceral adiposity, is associated with impaired diastolic dysfunction. The mechanisms involved in this

“obesity cardiomyopathy” are multifactorial, including both direct and indirect effects, which probably

are sex and age-specific. Among the several pathophysiological pathways involved, an endocrine effect

through the secretion of adipokines – especially of leptin – seems to play a role, which can represent a new

therapeutic target. Moreover, a local or paracrine pathway can also be responsible for this association,

because increased epicardial fat volume was independently related with impaired diastolic function.

Future research will determine if weight loss can prevent the onset or progression from subclinical diastolic

dysfunction to heart failure.

Insulin resistance and metabolic syndrome are also associated with subclinical diastolic dysfunction,

independently of other determinants of diastolic function. More interestingly, changes in diastolic function

were already present before the onset of diabetes, which reinforces the hypothesis that diastolic dysfunction

is mainly associated with the state of insulin resistance and not only to sustained hyperglycemia. We are

now conducting a phase II clinical trial (MET-DIME) to determine if an insulin-sensitizer, such as metformin,

can improve diastolic function and provide cardioprotection.

Diastolic dysfunction is an important prognostic marker in several phases of the cardiovascular

continuum. Beyond this prognostic information, diastolic dysfunction is associated with significant

morbidity, being an important determinant of reduced exercise capacity, especially after myocardial

infarction. Therefore, the evaluation of diastolic function can provide important clinical and prognostic

information and should be an integral part of a routine echocardiography examination. Sometimes the

echocardiographic evaluation of diastolic function can be challenging, but at least the measurement of

E’ velocities and E/E’ ratio and the determination of the diastolic dysfunction grade, should be routine.

The new grade IA of diastolic dysfunction was found to be infrequent in the general population and future

studies will determine if it will be clinically useful. Because left ventricle diastolic function and left atrium

function and volumes are interdependent events, the analysis of the left atrium by new speckle tracking

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CHAPTER V | CONCLUSIONS

178

techniques is a new technique giving further insight into the evaluation of diastolic function.

New therapies and therapeutic interventions are eagerly needed to improve diastolic function.

Although promising, the implementation of a structured program combining endurance and resistance

exercise training failed to improve diastolic function in patients after myocardial infarction. Nevertheless,

it is still conceivable that chronic exposure to exercise, especially when applied in earlier phases of the

cardiovascular continuum (such as in patients with subclinical diastolic dysfunction) can improve myocardial

function and modify the progression to HFpEF.

The quest for understanding the determinants, mechanisms, implications and management of LVDD

across the cardiovascular continuum “is not at the end”, but just at the end of a new beginning.

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CHAPTER VI | BIBLIOGRAPHY

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