A gordura epicárdica (GE) é um depósito de gordura visceral, localizado entre o coração e o pericárdio, que compartilha muitas das propriedades fisiopatológicas dos demais depósitos de gordura visceral, mas com potenciais efeitos locais diretos no processo inflamatório e aterosclerótico coronariano. Ecocardiografia, tomografia computadorizada e ressonância magnética têm sido utilizadas para avaliar a GE, mas variações entre as metodologias limitam a comparabilidade entre elas. Realizamos uma revisão sistemática da literatura e encontramos associações de GE com síndrome metabólica e doença arterial coronariana. A quantificação dessas associações é limitada pela grande heterogeneidade dos métodos utilizados e das populações estudadas, sendo a maior parte dos sujeitos com alto risco para doença cardiovascular. A GE também está associada com outros fatores conhecidos, tais como, obesidade, diabetes mellitus, idade e hipertensão, o que dificulta interpretar seu papel independente como marcador de risco. Baseado nesses dados, concluímos que a GE é um depósito de gordura visceral com potencial implicação na doença arterial coronariana. Descrevemos os valores de referência da GE nos diferentes métodos de imagem, ainda que os mesmos não estejam validados para emprego clínico. Ainda é necessário melhor definir os valores de referência normais e o risco associado à GE, para então definir sua utilidade na avaliação de risco cardiovascular e metabólico em relação aos outros critérios atualmente empregados.
Angela Gallina Bertaso
IPrograma de Pós-Graduação em Ciências da Saúde: Cardiologia e Ciências Cardiovasculares - Universidade Federal do Rio Grande do Sul
IIPrograma de Pós-Graduação em Epidemiologia - Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil
A gordura epicárdica (GE) é um depósito de gordura visceral, localizado entre o coração e o pericárdio, que compartilha muitas das propriedades fisiopatológicas dos demais depósitos de gordura visceral, mas com potenciais efeitos locais diretos no processo inflamatório e aterosclerótico coronariano. Ecocardiografia, tomografia computadorizada e ressonância magnética têm sido utilizadas para avaliar a GE, mas variações entre as metodologias limitam a comparabilidade entre elas. Realizamos uma revisão sistemática da literatura e encontramos associações de GE com síndrome metabólica e doença arterial coronariana. A quantificação dessas associações é limitada pela grande heterogeneidade dos métodos utilizados e das populações estudadas, sendo a maior parte dos sujeitos com alto risco para doença cardiovascular. A GE também está associada com outros fatores conhecidos, tais como, obesidade,
A gordura epicárdica (GE) tem sido proposta como marcador de risco cardiovascular. Nesta revisão apresentamos as características anatômicas e fisiopatológicas da GE, os métodos de mensuração, principais determinantes e associações clínicas. Realizamos uma revisão sistemática da literatura em busca de artigos descrevendo as associações entre GE e os principais desfechos relacionados: síndrome metabólica (SM) e doença arterial coronariana (DAC).
Frequentemente encontramos depósitos de gordura ao redor do coração. Esta gordura pode ser separada em diferentes compartimentos. Chamamos de gordura epicárdica o tecido adiposo acumulado entre o pericárdio seroso visceral e o miocárdio, sem uma estrutura ou fáscia que a separe do miocárdio e dos vasos epicárdicos. A gordura epicárdica é distribuída de forma variável, sendo mais proeminente nos sulcos atrioventricular, interventricular e na parede lateral do ventrículo direito1, podendo ocorrer infiltração de adipócitos no miocárdio e de triglicerídeos nos miócitos.
Já a gordura localizada na parte externa do pericárdio fibroso difere da GE em suas propriedades bioquímicas, moleculares e na nutrição vascular. Ela é nutrida pela artéria pericárdica frênica, um ramo da artéria torácica interna2, enquanto a GE é nutrida pelas artérias coronárias. A estrutura que delimita estas camadas é o pericárdio, visto nos exames de imagem como uma fina lâmina entre 1,0 e 4,0 mm em volta do coração, cuja visibilização é, às vezes, difícil3. Este depósito de gordura extrapericárdica é denominado de forma diversa pelos autores, sendo chamado de intratorácica4,5, paracárdica6, mediastinal7 ou pericárdica8. Alguns grupos tratam estes diferentes depósitos de gordura como um depósito único, chamando-o de gordura paracárdica ou pericárdica9. Devido às discrepâncias e ambiguidades na definição e nomenclatura dos depósitos de gordura entre os diversos autores, empregamos uma denominação comum nos artigos revisados, de acordo com a
Pequenos depósitos de gordura são naturalmente encontrados fora do tecido adiposo subcutâneo, entre eles a gordura epicárdica. A GE tem a mesma origem embriológica dos tecidos adiposos omental e mesentérico e produz citocinas com um padrão comparável ao tecido adiposo visceral abdominal2,10.
Dentre os diversos papéis fisiológicos da GE estão: regulação e distribuição local do fluxo vascular por mecanismos vasócrinos11; barreira imunológica, protegendo o miocárdio e as artérias coronárias de substâncias inflamatórias e patogênicas12; proteção mecânica das artérias coronárias; prover espaço para a expansão da parede arterial nas fases iniciais da aterosclerose; ser fonte local de ácidos graxos para o miocárdio em momentos de alta demanda13; e efeitos termogênicos relacionados ao tecido adiposo marrom14.
A GE aumenta nos estados de balanço energético positivo, quando os ácidos graxos livres no sangue são convertidos em triglicerídeos e acumulados inicialmente em adipócitos e depois em células não adiposas15. Já foi demonstrada por ressonância magnética e espectroscopia a forte correlação (r = 0,79; p < 0,01) entre o volume de GE e a concentração de triglicerídeos no miocárdio16. Não só o acúmulo de triglicerídeos mas também os distúrbios do metabolismo da glicose-insulina e inflamação crônica de baixo grau, com produção de citocinas pró- e anti-inflamatórias pelos adipócitos10, estão relacionados à síndrome metabólica17,18 e são fenômenos identificados na GE19.
As adipocinas são as citocinas produzidas predominantemente pelo tecido adiposo, com papel na regulação de outras citocinas, no metabolismo da glicose-insulina e dos lipídios. Leptina e resistina estão associadas com maior risco cardiovascular10,20 e têm maior concentração na GE21.
Já a adiponectina é uma citocina anti-inflamatória que aumenta a sensibilidade à insulina, diminuindo os ácidos graxos livres circulantes e o conteúdo de triglicerídeo intracelular no fígado e no músculo. Os níveis de adiponectina são menores em indivíduos obesos10 ou com risco cardiovascular aumentado22-24 e estão inversamente relacionados com depósitos de gordura visceral abdominal, epicárdica e intratorácica25.
Além desses efeitos sistêmicos compartilhados com os demais depósitos de gordura visceral, é possível que a GE tenha efeitos parácrinos. Devido à proximidade anatômica, as citocinas e ácidos graxos ficam em contato direto, ou são difundidas localmente através da microcirculação e da
A ecocardiografia permite a adequada avaliação do espaço pericárdico na maior parte das situações clínicas, sendo utilizada para a medida da GE, principalmente por Iacobellis e cols.30, a partir de 2003. A tomografia computadorizada (TC) e a ressonância magnética (RM) têm sido tradicionalmente usadas como adjuvantes da ecocardiografia, mas vêm aumentando seu papel devido à resolução espacial e à possibilidade de avaliação volumétrica.
Ainda não há consenso quanto à sua utilização na prática clínica, mas algumas recomendações são sugeridas para a medida da GE por ecocardiografia1. Sua espessura deve ser medida na parede livre do ventrículo direito em pelo menos dois locais, sendo recomendada a medida na janela paraesternal longitudinal e na janela transversal basal (Figura 1), utilizando a média de três batimentos consecutivos. Essas medidas demonstram boa correlação com os valores encontrados na RM (r = 0,91; p = 0,001)31. A GE é visibilizada como um espaço hipoecoico anterior à parede do ventrículo direito, sendo sua espessura medida entre a superfície epicárdica e o pericárdio parietal, identificado pelo deslizamento entre essas camadas, porém tomando-se o cuidado para não confundir com o líquido pericárdico. Já a gordura paracárdica é de difícil delimitação pela ecocardiografia. Um ponto crítico na medida da GE é a inconsistência no local da medida por variações da janela ecocardiográfica, particularmente junto aos vasos da base e o ventrículo direito. Deve-se sempre utilizar referências anatômicas nas medidas, como a posição do septo interventricular e do anel aórtico32. Outra controvérsia é qual o momento do ciclo cardíaco mais adequado para medir a espessura da GE na ecocardiografia. Alguns defendem a medida na sístole para evitar uma possível deformação por compressão da GE durante a diástole1 e outros na diástole, por coincidir com os outros exames de imagem (TC e RM)6,33. Os valores médios descritos para a espessura da GE na sístole por Iacobellis e cols.34 foram de 6,8 mm (1,1-22,6 mm) na investigação de risco cardiovascular e de 9,5 mm (7,0-20,0 mm) para homens e de 7,5 mm (6,0-15,0 mm) para mulheres em uma amostra de pacientes obesos e com sobrepeso35. Quando medida na diástole, Jeong e cols.36 encontraram um valor médio de 6,4 mm (1,1-16,6 mm) em mais de 200 indivíduos que se submeteram à angiografia coronariana e Nelson e cols.37 encontraram uma média de 4,7 ± 1,5 mm em 356 pacientes assintomáticos. Mesmo que alguns desses estudos tenham sugerido pontos de corte maiores, medidas acima de 5 mm devem representar um ponto de corte relevante para definição de GE aumentada, especialmente em populações de baixo risco.
A ressonância magnética é considerada o padrão-ouro para avaliação de gordura corporal total e referência para análise de volumes e massa ventricular38,39, tornando-se assim uma escolha natural para detecção e quantificação da GE31.
A avaliação da GE por ressonância magnética usualmente inclui avaliação estrutural com sequências que permitam a caracterização da gordura (
A avaliação do volume total pode ser realizada utilizando o método dos discos modificados de Simpson, no qual o tecido epicárdico é contornado em cada eixo curto ao final da diástole. A reprodutibilidade interobservador da medida do volume de GE parece ser superior à mensuração da espessura de GE (coeficiente de variabilidade 5,9% para o método volumétrico e 13,6% para a espessura da GE no eixo-longo), entretanto é tecnicamente mais trabalhoso. A medida da espessura máxima da GE é mais factível, sem comprometimento significativo da acurácia. Flutcher e cols.42 avaliaram a espessura da GE por ressonância magnética utilizando a média da espessura máxima em diversos pontos da parede livre do ventrículo direito e encontraram valores médios comparáveis aos encontrados por Schejbal e cols.43 em 200 autópsias (espessura média 4,12 ± 1,4 mm).
Os estudos de ressonância magnética e GE publicados até o momento avaliaram pequenas amostras de pacientes, cuja representatividade populacional é discutível para a definição de valores de referência.
É possível medir a GE com tomógrafos de 16 ou mais detectores e as mesmas aquisições empregadas na investigação de DAC, tanto na avaliação de escore de cálcio coronariano como na angiotomografia coronariana44. Em exames de escore de cálcio coronariano, as imagens são coletadas prospectivamente utilizando o traçado eletrocardiográfico. A exposição à radiação ocorre em fase predeterminada do ciclo cardíaco (65-85% do intervalo R-R). Não há necessidade do uso de contraste. As imagens adquiridas são reconstruídas em cortes de espessura de 2-3 mm45 (Figura 3).
Os exames de angiotomografia permitem a reconstrução de imagens com maior detalhe, com cortes menores que 1,0 mm, mas demandam emprego de contraste e maiores cuidados técnicos na aquisição das imagens para minimizar o uso de radiação46.
Pode-se medir de forma acurada a espessura, o volume e a área total da gordura epicárdica, individualizando-se os depósitos de gordura epicárdica e de gordura paracárdica/intratorácica por meio da delimitação do pericárdio parietal. Já foi demonstrada a associação independente da gordura pericárdica com fatores de risco cardiovascular, calcificação coronariana e presença de DAC. No entanto, muitos destes estudos não diferenciam a gordura epicárdica da pericárdica, gerando dúvidas sobre a relevância da medida da gordura paracárdica neste contexto. Mesmo com propriedades diferentes, a medida da gordura pericárdica como marcador substituto da GE seria operacionalmente mais rápida e simples por dispensar a delimitação do pericárdio, tendo como justificativa a forte correlação entre as duas medidas (coeficiente de correlação de Spearman = 0,92; p < 0,001)9.
A espessura da GE pode ser aferida na parede livre do ventrículo direito e ao redor das principais artérias coronárias21,47, estas limitadas pela espessura dos cortes, usualmente maiores nos exames de avaliação de escore de cálcio coronariano. A medida da gordura pericoronariana é realizada em cortes axiais perpendiculares à superfície do coração, ao nível das três principais artérias coronarianas (direita, descendente anterior e circunflexa). A espessura da gordura também pode ser aferida em diferentes regiões da superfície cardíaca, como a parede livre do ventrículo direito e dos sulcos inter e átrio-ventriculares. A dificuldade de padronização dos locais de medida limita a determinação de valores de referência para a espessura medida por TC.
Assim como a ecocardiografia, a avaliação da espessura por TC parece estar mais suscetível à variabilidade interobservador, fato que parece ser minimizado ao realizar-se a medida do volume total de GE (coeficiente de correlação interclasse 0,95)4,47. Diversos estudos foram publicados utilizando a técnica de mensuração semiautomática do volume de GE44,47-50. Esta técnica necessita de ferramenta própria na estação de trabalho para determinação do volume de gordura. A região do tórax onde é visualizada a GE deve ser delimitada pelo operador, incluindo cortes 1 cm acima da emergência do tronco da coronária esquerda até o ápice cardíaco. O pericárdio deve ser contornado manualmente pelo operador em cada corte transversal, determinando-se assim a área de interesse. Em indivíduos magros, pode existir dificuldade na visualização do pericárdio9. Os estudos que avaliam a gordura pericárdica (epicárdica e paracárdica) consideram como limite anterior a parede torácica e como limite posterior a aorta e os brônquios, sem delimitação do pericárdio. Ao final, o software reconhece na área delimitada o conteúdo com densidade entre -30 a -200 HU, característico do tecido gorduroso. A soma do volume de todos os cortes fornece o volume de GE total. Mais recentemente, programas proprietários vêm sendo utilizados visando a automatização da medida da GE51.
O volume médio de GE encontrado em estudos de base populacional varia entre 68 ± 34 mL e 124 ± 50 mL5,52. Em estudo incluindo pacientes da coorte de Framingham, o volume médio de GE foi de 110 ± 41 mL em mulheres e de 137 ± 53 mL em homens8. Em 2011, Shmilovich e cols.53 publicaram estudo que objetivava determinar o limite superior da normalidade de volume de GE por tomografia em uma população de baixo risco cardiovascular. Nesta coorte de 226 pacientes, o percentil 95 de volume de GE indexada para superfície corporal foi 68,1 mL/m2.
Além de fatores metodológicos, ocorre uma grande variação individual na quantidade e distribuição da GE, atribuíveis às suas características clínicas e demográficas.
É descrita a associação entre GE e obesidade34,49, além disso, diminuição do peso corporal (redução média de 40 ± 14kg) em pacientes submetidos a cirurgia bariátrica reflete em diminuição da espessura da GE de 5,3 ± 2,4 mm para 4,0 ± 1,6 mm (p < 0,001)54.
A gordura epicárdica parece aumentar com a idade4,50,55, sendo 22% mais espessa em pessoas com mais de 65 anos de idade44. No processo de envelhecimento ocorre diminuição da massa magra e aumento da massa gorda, com redistribuição do tecido adiposo para o tronco e as vísceras56. Estas alterações parecem ocorrer em ritmo e intensidade diferentes entre homens e mulheres, havendo uma maior redistribuição nas mulheres idosas57.
Na literatura não há uniformidade de opiniões sobre o impacto do sexo na quantidade de gordura epicárdica. A partir dos dados da coorte de Framingham, Rosito e cols.8 sugerem que a GE está mais associada com fatores de risco em mulheres do que em homens, porém, outros dois estudos da mesma coorte não encontraram esta associação5,53. Tendo estes aspectos em consideração, não é possível afirmar se as diferenças descritas entre homens e mulheres estão relacionadas propriamente ao sexo ou a outras características simultaneamente presentes.
A etnia também pode ter uma contribuição na quantidade de GE. De forma geral, pessoas com cor de pele preta possuem menor distribuição central de gordura do que as brancas, apesar de serem mais insulinorresistentes58, sugerindo que naqueles com cor de pele preta a adiposidade tem natureza mais diabetogênica do que aterogênica, por mecanismos ainda não bem compreendidos59.
Existem poucos dados sobre etnia e GE, mas estes são consistentes com os encontrados para a gordura visceral, ou seja, menor em pessoas com a cor de pele preta do que branca60.
Já foram observadas associações de GE com diversos desfechos cardiovasculares clínicos e intermediários, sendo mais investigadas as associações com síndrome metabólica e doença arterial coronariana. Para isto, realizamos uma revisão sistemática da literatura (detalhes no Apêndice). Os resultados mostram uma heterogeneidade dos métodos empregados e das populações estudadas, o que impediu a sumarização dos resultados na forma de metanálise. A descrição dos achados está nas
Grande parte dos estudos8,21,31,34,61-64 encontrou maior quantidade de GE em pessoas com síndrome metabólica (SM), apesar das diferentes características clínicas dos pacientes e prevalências de SM nos estudos (
Alterações inflamatórias21,22,24,28, da sensibilidade insulínica31,65 e hipertensão arterial50,63,66, que caracterizam a SM, já foram relacionadas com a GE. De uma maneira geral, observa-se uma associação moderada entre GE e SM, mas grande parte desses efeitos pode ser explicada pela obesidade.
Também é descrita uma associação moderada de GE com a glicemia67 e a prevalência de DM68.
De modo geral, os estudos observacionais em pacientes submetidos a cineangiocoronariografia identificaram uma relação direta entre a quantidade de GE e a presença/gravidade de coronariopatia. A dimensão da associação é bastante variável, sendo até inexistente em alguns estudos37,69, fenômeno que pode ser atribuído às diferenças na gravidade da doença coronariana entre os indivíduos e aos métodos de investigação utilizados.
Dois estudos encontraram uma associação moderada entre GE e desfechos clínicos. Cheng e cols.70, em um estudo de caso-controle de casos incidentes, compararam 58 pacientes com eventos cardíacos adversos maiores que ocorreram no período de 4 anos com 174 controles livres de eventos pareados por sexo e por um escore de propensão de risco que incluiu idade, fatores de risco e escore de cálcio coronariano. Os pesquisadores encontraram maior risco de eventos (OR = 1,74; Intervalo de confiança 95% [IC95%]: 1,03-2,95) com a duplicação do volume de GE. Ding e cols.9 conduziram um estudo de caso-coorte na coorte do MESA (
A calcificação arterial coronariana (CAC) tem sido utilizada como marcador de aterosclerose subclínica em amostras representativas da população. Associações entre GE e CAC foram evidenciadas tanto no estudo de Framingham8 como no MESA52.
Especula-se que o aumento da gordura epicárdica e a infiltração de gordura no miocárdio podem acarretar outros efeitos deletérios, tais como, interferir no relaxamento diastólico, afetar o sistema de condução cardíaco e predispor à fibrilação atrial71,72. A GE está inversamente associada com fração de ejeção e massa ventricular esquerda33,73. Além disso, a GE pode ser uma manifestação de lipodistrofia associada a aterosclerose subclínica nos pacientes com HIV, principalmente após a introdução da terapia antirretroviral de alta atividade74.
A gordura epicárdica é um depósito de gordura visceral sistêmica que compartilha seus efeitos metabólicos e inflamatórios sistêmicos. Além disso, há justificativa teórica para o papel da GE no processo aterosclerótico pelo efeito local na parede das artérias coronarianas. A GE está associada de forma consistente com síndrome metabólica e doença arterial coronariana, apesar de a magnitude das associações ser provavelmente menor do que a previamente esperada. Limitações para seu emprego são as inconsistências na nomenclatura e nos métodos de mensuração. De acordo com o conhecimento atual, podem ser considerados valores anormais de GE a espessura maior que 5 mm ou o volume maior que 125 mL ou 68 mL/m2. Apesar da disponibilidade de diferentes métodos para avaliar sua espessura e volume, não há justificativa para a indicação primária de exames para a sua mensuração. Entretanto, a identificação dos pacientes com quantidade abundante de GE durante a realização de exames de imagem por outras indicações pode servir como critério auxiliar no julgamento das condições cardiometabólicas.
Estratégia de busca: Realizada por dois revisores na base de dados
Seleção de artigos: Inicialmente foram encontrados 771 artigos. Foram excluídas revisões (51), editoriais e correspondências (31), metanálises (1) e consensos de sociedades (1), além de artigos em modelos experimentais ou que avaliavam exclusivamente variáveis laboratoriais. O critério de seleção dos desfechos foi limitado aos unitermos
Extração e sumarização dos dados: Os dois revisores extraíram os seguintes dados dos artigos: tamanho da amostra, características demográficas da população (sexo, idade, índice de massa corporal, risco cardiovascular) critério de inclusão no estudo (amostra de conveniência ou estudo populacional), fator em exposição com método empregado (TC, RM, ecocardiografia), medida avaliada (espessura ou volume), desfecho de interesse (SM, DAC, escore de cálcio) e valores médios e medidas de associação entre os grupos. Devido à heterogeneidade dos métodos empregados e populações estudadas consideramos inapropriada a sumarização dos resultados na forma de metanálise. Os resultados da revisão sistemática estão descritos nas
Concepção e desenho da pesquisa, Análise e interpretação dos dados, Redação do manuscrito e Revisão crítica do manuscrito quanto ao conteúdo intelectual: Bertaso AG, Bertol D, Duncan BB, Foppa M; Obtenção de dados: Bertaso AG, Bertol D, Foppa M; Análise estatística: Bertaso AG, Bertol D.
Declaro não haver conflito de interesses pertinentes.
O presente estudo não teve fontes de financiamento externas.
Este artigo é composto por conteúdo parcial das Dissertações de Mestrado de Angela Gallina Bertaso e Daniela Bertol, pela Universidade Federal do Rio Grande do Sul.
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61. Ahn SG, Lim H-S, Joe DY, Kang SJ, Choi BJ, Choi SY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart. 2008;94(3):e7.
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63. Eroglu S, Sade LE, Yildirir A, Bal U, Ozbicer S, Ozgul AS, et al. Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease. Nutr Metab Cardiovasc Dis. 2009;19(3):211-7.
64. Yorgun H, Canpolat U, Hazırolan T, Ateş AH, Sunman H, Dural M, et al. Increased epicardial fat tissue is a marker of metabolic syndrome in adult patients. Int J Cardiol. 2011 Sep 16. [Epub ahead of print].
65. Sironi AM, Pingitore A, Ghione S, De Marchi D, Scattini B, Positano V, et al. Early hypertension is associated with reduced regional cardiac function, insulin resistance, epicardial, and visceral fat. Hypertension. 2008;51(2):282-8.
66. Nakazato R, Rajani R, Cheng VY, Shmilovich H, Nakanishi R, Otaki Y, et al. Weight change modulates epicardial fat burden: A 4-year serial study with non-contrast computed tomography. Atherosclerosis. 2012;220(1):139-44.
67. Iacobellis G, Barbaro G, Gerstein HC. Relationship of epicardial fat thickness and fasting glucose. In J Cardiol. 2008;128(3):424-6.
68. Bettencourt N, Toschke AM, Leite D, Rocha J, Carvalho M, Sampaio F, et al. Epicardial adipose tissue is an independent predictor of coronary atherosclerotic burden. Int J Cardiol. 2012;158(1):26-32.
69. Chaowalit N, Somers VK, Pellikka PA, Rihal CS, Lopez-Jimenez F. Subepicardial adipose tissue and the presence and severity of coronary artery disease. Atherosclerosis. 2006;186(2):354-9.
70. Cheng VY, Dey D, Tamarappoo B, Nakazato R, Gransar H, Miranda-Peats R, et al. Pericardial fat burden on ECG-gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. JACC Cardiovasc Imaging. 2010;3(4):352-60.
71. Thanassoulis G, Massaro JM, O'Donnell CJ, Hoffmann U, Levy D, Ellinor PT, et al. Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study. Circ Arrhythm Electrophysiol. 2010;3(4):345-50.
72. Wong CX, Abed HS, Molaee P, Nelson AJ, Brooks AG, Sharma G, et al. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol. 2011;57(17):1745-51.
73. Liu J, Fox CS, Hickson DA, May WL, Ding J, Carr JJ, et al. Pericardial fat and echocardiographic measures of cardiac abnormalities: the Jackson Heart Study. Diabetes Care. 2011;34(2):341-6.
74. Guaraldi G, Scaglioni R, Zona S, Orlando G, Carli F, Ligabue G, et al. Epicardial adipose tissue is an independent marker of cardiovascular risk in HIV-infected patients. AIDS. 2011;25(9):1199-205.
75. Lai YH, Yun CH, Yang FS, Liu CC, Wu YJ, Kuo JY, et al. Epicardial adipose tissue relating to anthropometrics, metabolic derangements and fatty liver disease independently contributes to serum high-sensitivity c-reactive protein beyond body fat composition: a study validated with computed tomography. J Am Echocardiogr. 2012;25(2):234-41.
76. Momesso DP, Bussade I, Epifanio MA, Schettino CD, Russo LA, Kupfer R. Increased epicardial adipose tissue in type 1 diabetes is associated with central obesity and metabolic syndrome. Diabetes Res Clin Pract. 2011;91(1):47-53.
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Murilo Foppa Hospital de Clinicas de Porto Alegre - Unidade de Metodos Nao Invasivos Rua Ramiro Barcelos, 2350 Sala 2061 CEP 90035-903 - Porto Alegre, RS - Brasil E-mail:
Artigo recebido em 15/09/12, revisado em 05/01/13, aceito em 17/01/13.
Angela Gallina Bertaso e Daniela Bertol contribuiram igualmente como primeiro autores
Epicardial fat (EF) is a visceral fat deposit, located between the heart and the pericardium, which shares many of the pathophysiological properties of other visceral fat deposits, It also potentially causes local inflammation and likely has direct effects on coronary atherosclerosis. Echocardiography, computed tomography and magnetic resonance imaging have been used to evaluate EF, but variations between methodologies limit the comparability between these modalities. We performed a systematic review of the literature finding associations of EF with metabolic syndrome and coronary artery disease. The summarization of these associations is limited by the heterogeneity of the methods used and the populations studied, where most of the subjects were at high cardiovascular disease risk. EF is also associated with other known factors, such as obesity, diabetes mellitus, age and hypertension, which makes the interpretation of its role as an independent risk marker intricate. Based on these data, we conclude that EF is a visceral fat deposit with potential implications in coronary artery disease. We describe the reference values of EF for the different imaging modalities, even though these have not yet been validated for clinical use. It is still necessary to better define normal reference values and the risk associated with EF to further evaluate its role in cardiovascular and metabolic risk assessment in relation to other criteria currently used.
Angela Gallina Bertaso
IPrograma de Pós-Graduação em Ciências da Saúde: Cardiologia e Ciências Cardiovasculares - Universidade Federal do Rio Grande do Sul
IIPrograma de Pós-Graduação em Epidemiologia - Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Epicardial fat (EF) is a visceral fat deposit, located between the heart and the pericardium, which shares many of the pathophysiological properties of other visceral fat deposits, It also potentially causes local inflammation and likely has direct effects on coronary atherosclerosis. Echocardiography, computed tomography and magnetic resonance imaging have been used to evaluate EF, but variations between methodologies limit the comparability between these modalities.
We performed a systematic review of the literature finding associations of EF with metabolic syndrome and coronary artery disease. The summarization of these associations is limited by the heterogeneity of the methods used and the populations studied, where most of the subjects were at high cardiovascular disease risk.
EF is also associated with other known factors, such as obesity, diabetes mellitus, age and hypertension, which makes the interpretation of its role as an independent risk marker intricate. Based on these data, we conclude that EF is a visceral fat deposit with potential implications in coronary artery disease. We describe the reference values of EF for the different imaging modalities, even though these have not yet been validated for clinical use. It is still necessary to better define normal reference values and the risk associated with EF to further evaluate its role in cardiovascular and metabolic risk assessment in relation to other criteria currently used.
Epicardial fat (EF) has been proposed as a marker of cardiovascular risk. This review shows the anatomical and pathophysiological characteristics of EF, its measurement methods, its main determinants and clinical associations. We systematically reviewed the literature for articles describing the associations between EF and the major related outcomes: Metabolic Syndrome (MS) and coronary artery disease (CAD).
Fat deposits are often found around the heart. This fat can be separated into different compartments. Epicardial fat is the adipose tissue accumulated between the visceral pericardium and the myocardium, without a structure or fascia separating it from the myocardium and the epicardial vessels. EF has a variable distribution, being more prominent in the atrioventricular and interventricular grooves and right ventricular lateral wall1. Adipocyte infiltration into the myocardium wall as well as triglyceride infiltration into myocytes may also occur.
The fat located on the outer surface of the fibrous pericardium differs from EF in their biochemical, molecular and vascular nutrition properties. It is nourished by the pericardiophrenic artery, a branch of the internal thoracic artery2, while EF is nourished by the coronary arteries. The structure that delimitates these layers is the pericardium, seen on imaging tests as a thin layer around the heart, between 1.0 and 4.0 mm, of which visualization is sometimes difficult3. This extrapericardial fat deposit nomenclature varies according to different authors, being called intrathoracic4,5, paracardial6, mediastinal7 or pericardial8. Some groups treat these different fat deposits as a single compartment, calling it paracardial or pericardial fat9. Due to discrepancies and ambiguities in the definition and nomenclature of fatty deposits among several authors, we used a common name in the reviewed articles, according to
Small fat deposits are naturally found outside the subcutaneous adipose tissue, including epicardial fat. EF has the same embryological origin of omental and mesenteric adipose tissues and produces cytokines with a standard comparable to abdominal visceral adipose tissue2,10.
Among the several physiological roles of EF are: local distribution and regulation of vascular flow by vasocrine mechanisms11; immune barrier, protecting the myocardium and coronary arteries from inflammatory and pathogenic substances12; mechanical protection of the coronary arteries, providing space for the arterial wall expansion in the early stages of atherosclerosis; local source of fatty acids for the myocardium during of high-demand moments13, and thermogenic effects related to brown adipose tissue14.
EF increases in states of positive energy balance, when the free fatty acids in the blood are converted into triglycerides and accumulated initially in adipocytes and then in nonfat cells15. Magnetic resonance and spectroscopy have demonstrated the strong correlation (r = 0.79, p < 0.01) between EF volume and triglyceride concentration in the myocardium16. Not only the accumulation of triglycerides, but also disorders of glucose-insulin metabolism and low-grade chronic inflammation, with production of pro-and anti-inflammatory cytokines by adipocytes10 are associated with metabolic syndrome17,18 and are phenomena also identified in EF19.
Adipokines are cytokines mainly produced by adipose tissue that have a role in the regulation of other cytokines and in the metabolism of glucose-insulin and lipids. Leptin and resistin are associated with increased cardiovascular risk10,20 and show greater concentration in EF21.
Adiponectin is an anti-inflammatory cytokine that increases insulin sensitivity, decreasing circulating free fatty acids and intracellular triglyceride content in the liver and muscle. Adiponectin levels are lower in obese individuals10 and in those with increased cardiovascular risk22-24 and are inversely associated with deposits of abdominal visceral, epicardial and intrathoracic fat25.
In addition to these systemic effects shared with other fat deposits, it is possible that EF has paracrine effects. Due to the anatomical proximity with the coronary arteries and heart, cytokines and fatty acids are disseminated locally through microcirculation and vasa vasorum. The perivascular cytokine concentration is higher than that in subcutaneous fat26 and can locally accelerate the atherosclerotic process by endothelial dysfunction, local proliferation of smooth muscle cells27, increased oxidative stress (leptin) plaque instability via apoptosis (TNF-α) and neovascularization (MCP-1)28. A recent study investigating coronary arteries through optical coherence tomography found an association between the amount of pericoronary fat and markers of plaque instability29.
Echocardiographic allows adequate assessment of pericardial space in most clinical situations and it has been used to measure EF, mainly by Iacobellis et al30, since 2003. Computed tomography (CT) and magnetic resonance imaging (MRI) have been traditionally used as adjuvants to echocardiography, but their role is increasing due to high spatial resolution and the possibility of volumetric assessment.
There is no consensus regarding its use in clinical practice, but some recommendations are suggested for EF measurement by echocardiography1. Epicardial fat thickness should be measured on the right ventricular free wall in at least two locations, from both parasternal longitudinal and transverse parasternal views (
Another controversial point is which time in the cardiac cycle is the most suitable for measuring EF thickness in echocardiography. Some recommend the measurement during systole to prevent possible deformation by EF compression during diastole1 and others in diastole, to coincide with other imaging modalities (CT and MRI)6,33. The mean values described for EF thickness in systole by Iacobellis et al34 during the investigation of cardiovascular risk were 6.8 mm (1.1 to 22.6 mm) and 9.5 mm (7.0 to 20.0 mm) for men and 7.5 mm (6.0 -15.0 mm) for women in a sample of obese and overweight patients35. When measured in diastole, Jeong et al36 found a mean value of 6.4 mm (1.1 to 16.6 mm) in more than 200 individuals submitted to coronary angiography and Nelson et al37 found a mean of 4.7 ± 1.5 mm in 356 asymptomatic patients. Even though some of these studies have suggested higher cutoffs, measurements > 5 mm should represent a relevant cutoff to define increased EF, especially in low-risk populations.
MRI is considered the gold standard for the assessment of total body fat and reference modality for the analysis of ventricular volumes and mass38,39, thus making it a natural choice for the detection and quantification of EF31.
EF evaluation by MRI usually includes structural assessment with sequences that allow the characterization of the fat (black blood sequences) and functional sequences (bright blood sequences). Once characterized, EF is manually delimited to calculate the volume or measure its thickness40,41 (
Epicardial fat the total volume can be estimated using the modified Simpson method, in which the epicardial tissue is contoured in each short axis at the end of diastole. The interobserver reproducibility of EF volume measurement seems to be superior to the EF thickness measurement (coefficient of variability of 5.9% for the volumetric method and 13.6% for EF thickness at the long axis); however, it is technically more difficult. The measurement of maximum EF thickness is more feasible, without significant accuracy decrease. Flutcher et al42 evaluated EF thickness by MRI using the mean of maximum EF thickness at several points of the right ventricular free wall and found mean values comparable to those found by Schejbal et al43 in 200 autopsies (mean thickness: 4.12 ± 1.4 mm).
The MRI and EF studies published to date have evaluated small samples of patients, of which population representativeness is questionable to define reference values.
It is possible to measure the EF with CT scanners with 16 or more detectors using acquisitions used for coronary calcium score evaluation coronary angiography44. In coronary calcium score examinations, the images are prospectively collected using the electrocardiographic tracing. Radiation exposure occurs at a predetermined phase of the cardiac cycle (65-85% of RR interval). There is no need to use contrast. The acquired images are reconstructed in slices with 2-3 mm thickness45 (
CT angiography examinations allow the reconstruction of images with greater detail, with slices < 1.0 mm, but which require contrast use and greater technical care in image acquisition to minimize radiation exposure46.
Epicardial fat thickness, volume and total area can be accurately measured by CT. It has been demonstrated an independent association between pericardial fat and cardiovascular risk factors, coronary calcification and the presence of CAD. Epicardial and paracardial/intrathoracic fat deposits are individualized outlining the parietal pericardium, however, some of these studies did not differentiate between epicardial and pericardial fat, raising doubts about the relevance of paracardial fat measurement in this context. Even with different properties, the measurement of pericardial fat as a surrogate marker of EF would be operationally simpler and faster by dispensing pericardial delineation, having as rationale the strong correlation between the two measurements (Spearman correlation coefficient = 0.92, p <0.001)9.
EF thickness can be measured in the right ventricular free wall and around the main coronary arteries21,47, the latter limited by the slice thickness, usually higher in tests assessing coronary calcium score. The measurement of pericoronary fat is performed in the axial view, perpendicular to the heart surface at the level of the three main coronary arteries (right, left anterior descending and circumflex arteries). Fat thickness can also be measured in different regions of the heart surface, such as the right ventricular free wall and the inter- and atrioventricular grooves. The difficulty in standardizing measurement locations limits the determination of EF thickness reference values by CT.
Similarly to echocardiography, EF thickness assessment by CT seems to be more susceptible to interobserver variability, a fact that seems to be minimized by performing the measurement of EF volume (intraclass correlation coefficient of 0.95)4,47. Several studies have been published using the semi-automated technique for measuring the amount of EF44,47-50. This technique requires an adequate tool at the workstation to determine the volume of fat. The chest area where EF is visualized must be delimited by the operator, including slices 1 cm above the emergence of the left main coronary artery to the cardiac apex. The pericardium must be outlined manually by the operator at each cross-section, thus determining the area of interest. There may be difficulties to recognize the pericardium in lean individuals9. Studies assessing the pericardial fat (epicardial and paracardial) consider the chest wall as the anterior limit and the aorta and bronchi as the posterior limit, without pericardium delineation. At the end, the software recognizes in the delimited area, the content with density between -30 and -200 HU, characteristic of fatty tissue. The sum of the volume of all sections provides the overall EF volume. More recently, proprietary software have been used aiming the automation of the EF measurement51.
The mean volume of EF found in population-based studies ranges from 68 ± 34 mL to 124 ± 50 mL5,52. In a study including patients from the Framingham cohort, the mean EF volume was 110 ± 41 mL in women and 137 ± 53 mL in men8. In 2011, Shmilovich et al53 published a study that aimed to determine the upper limit of normal EF volume by tomography in a population at low cardiovascular risk. In this cohort of 226 patients, the 95th percentile of EF volume indexed to body surface area was 68.1 mL/m2.
In addition to methodological factors, there is a broad individual variation in the amount and distribution of EF, attributable to their clinical and demographic characteristics.
The association between obesity and EF has been described34,49; moreover, reduction in body weight (mean reduction of 40 ± 14 kg) in patients undergoing bariatric surgery decreased the EF thickness from 5.3 ± 2.4 mm to 4.0 ± 1.6 mm (p <0.001)54.
Epicardial fat seems to increase with age4,50,55, being 22% thicker in individuals older than 65 years44. During the aging process, there is a decrease in lean body mass and increase in fat mass, with fat tissue redistribution to the trunk and viscera56. These changes seem to occur at a different rate and intensity between men and women, with a greater redistribution seen in older women57.
There is no consensus in the literature on the impact of gender on the amount of epicardial fat. Based on the data from the Framingham cohort, Rosito et al8 suggest that EF is more associated with risk factors in women than in men; however, two other studies of the same cohort did not find this association5,53. Taking this into consideration, it is not possible to attribute these differences to the gender or to other concomitant characteristics.
Ethnicity may also contribute to the amount of EF. In general, individuals with black skin color have less central obesity than whites, although they are more insulin-resistant58, suggesting that in those with black skin color, the adiposity has a more diabetogenic than atherogenic nature, by mechanisms not yet clearly understood59.
There are little data on ethnicity and EF, but these are consistent with those found for visceral fat, where it is lower in individuals with black skin color60.
Associations between EF and several outcomes have been reported, particularly particularlywith metabolic syndrome and coronary artery disease. To investigate these associations, we performed a systematic review of the literature (details in Appendix). The results shown in the following text and in
Most studies8,21,31,34,61-64 described a higher amount of EF in individuals with metabolic syndrome (MS), across different clinical characteristics and prevalences of MS (
Inflammation21,22,24,28, derangements in insulin sensitivity31,65 and arterial hypertension50,63,66, which characterize MS, have been associated with EF. In general, there is a moderate association between EF and MS, but most of these effects can be explained by obesity.
Epicardial fat is also moderately associated with glycemic levels 67 and with the prevalence of DM68.
Overall, observational studies in patients undergoing coronary angiography identified a direct association between the amount of EF and the presence/severity of coronary artery disease (CAD). The magnitude of the association is quite variable, being even non-existent in some studies37,69, a which could be attributed to differences in CAD severity among individuals and to the research methods used.
Two studies found a moderate association between EF and clinical outcomes. Cheng et al70, in a case-control study of incident cases during a four-year follow-up, compared 58 patients with major adverse cardiac events with 174 controls free of events, matched by sex and a propensity risk score that included age, risk factors and coronary calcium score. The researchers found a higher risk of events (OR = 1.74, 95% confidence interval [95% CI]: 1.03-2.95) with a two-fold increase in EF volume. Ding et al9 performed a case-cohort study in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort, investigating a random sample of 998 participants and the 147 individuals who developed coronary events. EF was associated with CAD (relative risk for increase of one standard deviation in EF = 1.26, 95% CI: 1.01-1.59) even after adjustment for cardiovascular risk factors.
Coronary artery calcification (CAC) has been used as a marker of subclinical atherosclerosis in representative population samples. Associations between EF and CAC were found both in the Framingham8 and in the MESA studies52.
It is speculated that the increase in EF and fatty infiltration in the myocardium may cause other deleterious effects, such as interfering with diastolic relaxation, affecting the cardiac conduction system and predisposing to AF71,72. EF is inversely associated with ejection fraction and left ventricular mass33,73. Additionally, EF may be a manifestation of lipodystrophy associated with subclinical atherosclerosis in patients with HIV, particularly after the introduction of highly active antiretroviral therapy74.
The epicardial fat is a visceral fat deposit that partially shares its systemic metabolic and inflammatory effects. In addition, there is a rationale for the local atherosclerotic effect of EF on the coronary artery walls. EF is consistently associated with metabolic syndrome and coronary artery disease, although the magnitude of these associations is probably lower than previously expected. Inconsistencies in the nomenclature and measurement methods are limitations to its implementation. According to current knowledge, EF thicknesses > 5 mm , or a volume > 125 mL or 68 mL/m2 might be considered abnormal.
Despite the availability of different methods to assess EF, there is no rationale for the primary indication of examinations for its measurement. However, the identification of abundant amounts of EF in patients clinically referred for cardiac imaging may raise concerns about cardiometabolic conditions of the patient.
Search strategy: Two reviewers searched independently in PubMed database, additional references were identified by reviewingbibliographic references of these articles . The following key words were used (epicardial or pericardial or subepicardial) AND (fat or adipose) for the title and summary of the article, restricted to articles in Portuguese and English published between January 1990 and April 2012.
Article selection: Initially, 771 articles were found. Reviews (51) were excluded, as well as editorials and correspondence (31), meta-analyses (1) and society consensuses (1), and articles in experimental models or the ones that evaluated only laboratory variables. The outcome selection criteria were restricted to the key words: metabolic syndrome, coronary artery disease, coronary calcium score. At the end, 37 original articles were identified describing the association between epicardial fat /pericardial measurement and MS, CAD or coronary calcium score.
Data extraction and summarizing: The two reviewers extracted the following data from the articles: sample size, demographic characteristics (gender, age, body mass index, cardiovascular risk) study inclusion criteria (convenience sample or population study), exposure factor and method employed (CT, MRI, echocardiography), measurement assessed (thickness or volume), outcome of interest (MS, CAD, calcium score) and mean values and measurements of association between groups. Due to the heterogeneity of methods employed in the studies as well as the populations studied, we considered inappropriate to summarize the results in the form of meta-analysis. The results of the systematic review are described in
Conception and design of the research, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Bertaso AG, Bertol D, Duncan BB, Foppa M; Acquisition of data: Bertaso AG, Bertol D, Foppa M; Statistical analysis: Bertaso AG, Bertol D.
No potential conflict of interest relevant to this article was reported.
There were no external funding sources for this study.
This article contains parts of the theses of master submitted by Angela Gallina Bertaso and Daniela Bertol, from Universidade Federal do Rio Grande do Sul
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Murilo Foppa Hospital de Clinicas de Porto Alegre - Unidade de Metodos Nao Invasivos Rua Ramiro Barcelos, 2350 Sala 2061 CEP 90035-903, Porto Alegre, RS - Brazil E-mail:
Manuscript received September 15, 2012, revised manuscript January 05, 2013, accepted January 17, 2013..
Angela Gallina Bertaso and Daniela Bertol contributed equally to this work.