IHospital Pró-Cardíaco
IIUniversidade Federal Fluminense
IIIInstituto do Coração - FMUSP
IVHospital do Coração - HCOR
VLabs D'Or - Grupo Fleury / Instituto D'Or de Pesquisa e Ensino
VIHospital Santa Izabel da Santa Casa de Misericórdia da Bahia
VIIHospital TotalCor
VIIIClínica São Vicente
IXHospital de Messejana Dr. Carlos Alberto Studart Gomes
XSanta Casa de Curitiba
XIPontificia Universidade Católica do Paraná
XIIUniversidade do Estado do Rio de Janeiro - UERJ
XIIIHospital Unimed-Rio
XIVEcocenter - Hospital SOCOR (MG)
XVFaculdade de Medicina da Universidade Federal de Minas Gerais
XVIHospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
XVIIHospital Israelita Albert Einstein
XVIIIPronto-Socorro Cardiológico de Pernambuco, Universidade de Pernambuco
XIXInstituto de Cardiologia, Fundação Universitária de Cardiologia (RS)
XXHospital Nossa Senhora da Conceição
XXIInstituto Nacional de Cardiologia
XXIIHospital Federal dos Servidores do Estado (RJ)
A verdadeira incidência de miocardite é difícil de ser estimada, devido a fatores como: apresentação clínica diversificada, pouca realização biópsia endomiocárdica e falta de critérios histológicos sensíveis e uniformizados.
Os relatos de estudos de autópsias estimam uma incidência entre 0,2 e 12% dependendo da população estudada1,2. O ensaio clínico
Manifesta maior prevalência no sexo masculino, principalmente adulto jovem, sendo uma das principais causas de morte súbita em pessoas com menos de 40 anos de idade e em crianças5. Em crianças que sobrevivem à miocardite nota-se evolutivamente ao fim de 12 anos, uma maior mortalidade e necessidade de transplante cardíaco.
A miocardite pode estar presente em outras formas de cardiomiopatias, como amiloidose e cardiomiopatia hipertrófica, assim como em pacientes com infarto agudo do miocárdio, o que confere um pior prognóstico a esses pacientes6,7.
A miocardite pode decorrer de diversas causas infecciosas e não infecciosas sendo a miocardite secundária por infecção viral a forma mais prevalente (
Entre a variedade de doenças infecciosas que podem causar miocardite, as infecções virais são as mais comuns. Os vírus cardiotróficos mais prevalentes são adenovírus, enterovirus, parvovirus-B19, herpes simples, vírus da hepatite C (HCV), citomegalovírus (CMV), e Epstein-Barr (EBV). A prevalência do perfil viral varia conforme o meio estudado. Em nosso meio observa-se prevalência de adenovírus, parvovírus e herpes, à semelhaça do que se encontra na população europeia4,9. Já população americana observa-se o predomínio de enterovírus10. Em cerca de 30% das miocardites virais observamos infecção por mais de um tipo de vírus.
Na infecção por vírus da imunodeficiência humana (HIV/SIDA) foi observada em estudo de autopsia, a presença de miocardite em mais de 50% dos pacientes. Em outras formas de infecção não viral, podemos ter o desenvolvimento de miocardite por
Na América do Sul e especialmente em algumas regiões do Brasil a miocardite chagásica causada pelo protozoário
Vários fármacos podem causar miocardite de hipersensibilidade hipereosinofílica, ou a agressão tóxica direta do miocárdio, como a ciclofosfamida, a fenitoína, a zidovudina e as anfetaminas. O diagnóstico deve ser suspeitado na presença de eosinofilia no sangue periférico ou infiltrado eosinofílico miocárdico. Também podemos ter o desenvolvimento de miocardite eosinofílica linfocítica secundária a vacinação13-15.
Doenças sistêmicas autoimunes como a síndrome de Churg-Strauss16, e a síndrome hipereosinofílica estão associadas à miocardite eosinofílica17. A miocardite de células gigantes e a sarcoidose, embora raras, quando diagnosticadas precocemente podem ter o prognóstico alterado através de tratamento adequado18,19.
Dentre as colagenoses temos a artrite reumatoide, a dermatomiosite e o lúpus eritematoso sistêmico como as de maior prevalência na agressão inflamatória miocárdica.
A cardiomiopatia periparto apresenta como possíveis fatores etiológicos: agressão viral, autoimunidade, distúrbio nutricional e origem familiar. A prevalência de miocardite é variável observada em até 62% dos pacientes submetidos a biópsia endomiocárdica. A provável infecção viral e autoimune se deve à maior suscetibilidade às infecções virais na fase gestacional e pela possibilidade de ativação imunológica pelas células fetais na fase pós-parto20,21.
A miocardite viral pode ser dividida em fase aguda, subaguda e crônica. O conhecimento dessa evolução temporal e fisiopatológica se faz importante na definição diagnóstica e nas possibilidades terapêuticas22.
A fase aguda caracteriza-se pela presença de viremia. Ocorre perda de miócitos por necrose graças a ação direta do vírus, efeitos citotóxicos de mediadores inflamatórios e produtos do estresse oxidativo associado a disfunção endotelial e isquemia23. A ação direta ocorre pela entrada do vírus na célula, por meio de receptores de membrana como o CAR (
A fase subaguda inicia-se a partir do 4º dia da inoculação e estende-se até o 14º dia. O infiltrado de linfócitos T segue na invasão do miocárdio, atingindo o seu pico em 7 a 14 dias após a inoculação viral. Nessa fase ocorre maior dano celular miocárdico. Existe também infiltração de linfócitos B, sendo que a proporção aumenta gradativamente no decorrer do 1º ao 3º mês26. A resposta imune humoral tem importante papel na lesão e disfunção miocárdica. A lesão direta ou indireta dos miócitos libera a miosina na circulação, e a presença dessa proteína promove a liberação de anticorpos contra a cadeia pesada da miosina e estimula os linfócitos CD4, os quais podem perpetuar e amplificar a lesão das células cardíacas. Essa amplificação estimulada pelos linfócitos T CD4 se dá por estímulo aos linfócitos B na produção de anticorpos antimiosina e por estimular a presença citotóxica de linfócitos T CD8. A reação cruzada de anticorpos entre antígenos virais e células miocárdicas também proporciona a lesão dos miócitos. O soro de pacientes com miocardite apresenta padrões imunohistoquímicos, que podem reagir com diferentes proteínas da membrana ou do citoplasma do miócito cardíaco27.
A terceira fase inicia-se no 15º dia e segue até o 90º dia após a inoculação viral, e caracteriza-se pela deposição intensa de colágeno no interstício miocárdico com fibrose miocárdica evoluindo para dilatação, disfunção e insuficiência cardíaca28,29.
No caso da miocardite bacteriana, além da agressão bacteriana direta aos miócitos, a produção importante de toxinas (com níveis de toxicidade variáveis dependendo do agente etiológico) e a resposta inflamatória intensa com a produção de níveis elevados de citocinas são responsáveis pelo dano celular, com predomínio de infiltrado de macrófagos e células
Na miocardite induzida por drogas, a resposta de sensibilidade pode variar de horas a meses. Parte da justificativa da hipersensibilidade se dá em resposta a componentes quimicamente reativos que se ligam a proteínas promovendo modificações estruturais. Essas partículas são fagocitadas pelas células de defesa, por vezes macrófagos, os quais as apresentam na superfície dessas células aos linfócitos T. Como uma resposta de hipersensibilidade retardada, são liberadas citocinas como interleucina 5, estimulante de eosinófilos. Esse acúmulo de interleucina 5 promove um grande infiltrado eosinofílico com aumento da resposta de hipersensibilidade e maior lesão miocárdica. A predisposição genética parece favorecer esse padrão de resposta.
A síndrome hipereosinofílica pode ocorrer em associação a diversas doenças com manifestação sistêmica, como síndrome de Churg-Strauss, câncer, infecções parasitárias e helmínticas, ou estar relacionada a vacinações. Estas podem promover uma resposta inflamatória intensa no miocárdio, levando a lesão celular com disfunção e IC30-32.
Do ponto de vista fisiopatológico, assim como em outros órgãos, ocorre um intenso infiltrado eosinofílico (principalmente CD69) no miocárdio, infiltrado este que promove a liberação de mediadores altamente agressivos ao miócito, levando a necrose e perda da estrutura miocárdica. Entre os fatores agressores estão a neurotoxina, derivada dos eosinófilos, a proteína catiônica do eosinófilo e a protease eosinofílica. Além desses fatores, a produção de citocinas inflamatórias como IL 1, TNF-alfa, IL 6, IL 8, IL3, IL5 e proteínas inflamatórias do macrófago promove a lesão e perda de miócitos, com evolução para disfunção miocárdica33.
A miocardite de células gigantes é uma forma autoimune de agressão miocárdica e caracteriza-se histologicamente por um infiltrado de células gigantes multinucleadas, além de infiltrado inflamatório de células T, eosinófilos e histiócitos. Entretanto, por vezes, um granuloma bem definido não é observado. A presença marcante de células CD8 (citotóxicas) promove intensa lesão miocítica. Essa patologia encontra-se, em até 20% dos casos, associada a doenças autoimunes como tireoidite de Hashimoto, artrite reumatoide, miastenia
A sarcoidose é uma doença multissistêmica de etiologia desconhecida, caracterizada pelo acúmulo de linfócitos T, fagócitos mononucleares e granulomas não caseosos nos tecidos envolvidos35,36. Os pulmões são afetados em aproximadamente 90% dos pacientes, e a presença de doença pulmonar contribui de forma independente para a morbimortalidade associada a essa doença.
A avaliação diagnóstica da miocardite se faz inicialmente através da suspeita clínica, juntamente com métodos diagnósticos não invasivos. A confirmação diagnóstica só é possível através da análise histológica obtida pela biópsia endomiocárdica do ventrículo direito. Na prática clínica a maioria dos diagnósticos de miocardite são de suspeição diagnóstica, pois somente a minoria dos pacientes com suspeita de miocardite são submetidos a investigação por biópsia endomiocárdica para confirmação da agressão inflamatória (
As manifestações clínicas da doença são bastante variáveis, podendo abranger formas sub-clínicas, como dilatação e disfunção ventricular assintomática, ou mesmo manifestações clínicas agudas de insuficiência cardíaca descompensada, fulminante com quadro de choque cardiogênico, dor precordial, mimetizando doença coronariana, palpitações, síncope, ou lipotimia, e morte súbita22,37,38.
A despeito do fato de que a maioria das formas de miocardite tem sua gênese em um quadro viral, a presença de infecção respiratória, gastrointestinal ou sistêmica de infecção viral é observada em somente cerca de 30% dos pacientes nas formas agudas de manifestação39.
Nas formas agudas com dor torácica, pode se manifestar de modo similar à dor anginosa, com achados semelhantes aos de uma síndrome coronariana aguda, incluindo alterações no eletrocardiograma (ECG) e elevação dos marcadores de necrose miocárdica, ou com características da pericardite, no caso do envolvimento epimiocárdico. Outras formas de apresentação clínica seriam como um quadro de insuficiência cardíaca aguda, arritmias ventriculares e atriais frequentes, choque cardiogênico e morte13,40.
Em crianças e neonatos, a miocardite usualmente apresenta-se como insuficiência cardíaca aguda, por vezes fulminante41 e com menor frequência como cardiomiopatia dilatada oligossintomática.
Nas formas subaguda e crônica, frequentemente a miocardite se manifesta primeiro como CMD de início recente ou de tempo indeterminado, em paciente assintomático ou com sintomas de insuficiência cardíaca.
Mais raramente, a miocardite pode se manifestar com alterações eletrocardiográficas apontando distúrbios de condução atrioventricular de grau variável, associados ou não a bloqueio de ramo. Em formas avançadas, os pacientes apresentam quadro de baixo débito em decorrência de bloqueio atrioventricular total com ritmo de escape42.
Outros sintomas apontam para formas mais específicas de miocardite, por exemplo: (1)
Marcadores séricos inespecíficos de inflamação, como velocidade de hemossedimentação, proteína C reativa e leucometria, podem estar elevados ou inalterados. Eles podem espelhar a inflamação miocárdica ou pericárdica, ou representarem a manifestação de doença sistêmica autoimune ou de hipersensibilidade. A detecção da elevação dos biomarcadores de necrose miocárdica na miocardite aguda depende da fase evolutiva e da extensão da agressão inflamatória no momento da investigação diagnóstica. De modo diferente do que ocorre nas síndromes coronarianas em que existe uma curva de elevação e redução habitual, os marcadores de necrose miocárdica na miocardite se mantêm em um platô por maior tempo. A elevação de troponinas (I ou T) é mais comum que da CK-MB, e níveis elevados conferem pior prognóstico (
A pesquisa do fator causal da miocardite através de exames complementares estará na dependência da suspeição clínica. Usualmente todos os pacientes devem ser investigados para doenças sistêmicas inflamatórias autoimunes, como lúpus, artrite reumatoide, sarcoidose, Churg-Strauss, doença celíaca10. A pesquisa de sorologias virais possui baixa sensibilidade e especificidade, apresentando uma correlação de somente 4% da sorologia com a infecção viral miocárdica44. Esse dado demonstra que a sorologia viral não deve ser utilizada de forma rotineira para a investigação diagnóstica da miocardite (
As alterações de eletrocardiograma na miocardite vão depender da fase de evolutiva em que se encontra a agressão inflamatória miocárdica. Usualmente esse exame possui uma sensibilidade diagnóstica de 47%45.
Na fase aguda, as alterações mais comuns são os distúrbios de repolarização e bloqueios atrioventriculares, assim como padrão sugestivo de isquemia coronariana com infra ou supradesnível do segmento ST de região cardíaca específica ou difusa, sendo que a presença de onda Q indica pior prognóstico. A presença de arritmias supraventriculares ou ventriculares é frequente27,33. Nas fases subaguda ou "crônica", predominam os sinais eletrocardiográficos de remodelamento de câmaras, como sobrecarga ventricular e presença de bloqueio de ramo esquerdo, ambos relacionados a pior prognóstico46.
Nos quadros de acometimento do pericárdio em associação ao miocárdio (perimiocardite), é comum o padrão clássico eletrocardiográfico de pericardite com supradesnível do segmento ST difuso e infra do segmento PR é comum47.
A recomendação para a realização de eletrocardiograma na miocardite encontra-se na
Os achados ecocardiográficos na miocardite são inespecíficos. As alterações ecocardiográficas espelham a agressão inflamatória miocárdica e as consequências desta sobre a função e remodelagem ventricular, podendo ser encontrados trombos intraventriculares ou atriais48,49. As alterações na contração ventricular podem ser difusas ou segmentares, indistinguíveis das alterações isquêmicas9,50.
A presença de disfunção ventricular direita é incomum, e quando ocorre indica pior prognóstico51. Na miocardite fulminante, usualmente encontramos importante disfunção sistólica com diâmetros cavitários normais, por vezes associada a aumento da espessura da parede septal, indicando edema miocárdico49,52. A presença de derrame pericárdico na ausência de IC congestiva sugere envolvimento inflamatório do pericárdio com miopericardite.
O ecocardiograma tem importante papel no diagnóstico diferencial da miocardite com outras patologias que tenham a mesma forma clínica de apresentação - como doenças valvulares agudas, cardiomiopatia inflamatória de takotsubo e infarto agudo do miocárdio - além de servir como um guia durante a realização da biópsia endomiocárdica (
Na avaliação dos pacientes com miocardite, a ressonância magnética cardíaca (RMC) permite identificar tanto a injúria miocárdica inflamatória das fases aguda e subaguda quanto as lesões cicatriciais frequentemente presentes na fase crônica da doença. As três principais técnicas de RMC utilizadas na caracterização da injúria miocárdica dos pacientes com miocardite são as sequências ponderadas em T2 (
As imagens adquiridas pelas sequências ponderadas em T2 permitem avaliar o edema miocárdico secundário ao processo inflamatório nos pacientes com miocardite aguda, e podem ser tanto do tipo regional quanto global.
Na técnica do realce global precoce, as imagens adquiridas nos primeiros minutos após a administração do gadolínio representam as áreas mais acometidas pela injúria inflamatória54,55. A avaliação consiste na medida de intensidade de sinal pré e pós a injeção de contraste baseado em gadolínio e na comparação com a variação da intensidade do músculo esquelético dentro do campo de visão (exemplo: músculo peitoral). Relações maiores que quatro vezes entre miocárdio e músculo esquelético indicam hiperemia e extravasamento capilar causados pela inflamação.
A técnica do realce tardio, por sua vez, permite avaliar as regiões de injúria miocárdica irreversível, o que permite identificar as regiões de necrose, no caso das miocardites agudas ou subagudas, e as regiões de fibrose, no caso das miocardites crônicas56-58. O padrão de distribuição do realce tardio na miocardite é muito diferente daquele observado nos casos de infarto do miocárdio. É frequentemente mesoepicárdico poupando o endocárdio, mas também pode apresentar distribuição epicárdica e transmural. As regiões de realce costumam ser multifocais, heterogêneas e esparsas, não respeitando os territórios coronarianos. Mas esse padrão de distribuição não tem se mostrado obrigatório, de modo que se pode, por vezes, observar distribuição semelhante à doença coronariana.
Diversos estudos demonstraram que, embora cada uma das técnicas apresente boa acurácia diagnóstica quando utilizada isoladamente, os melhores resultados são obtidos através da combinação dos três critérios diagnósticos48 à presença de pelo menos um dos critérios descritos acima (qualquer um dos três), a RMC mostra sensibilidade de 88%, especificidade de 48%, valor preditivo positivo (VPP) de 68%, valor preditivo negativo (VPN) de 68% e acurácia de 70%. Na presença de dois dos critérios (quaisquer dois dos três), a RMC registra sensibilidade de 67%, especificidade de 91%, valor preditivo positivo (VPP) de 91%, valor preditivo negativo (VPN) de 69% e acurácia de 78%9. Os resultados de acurácia na miocardite aguda são superiores aos do que nos casos de suspeita de miocardite subaguda ou crônica.
A RMC está indicada na avaliação diagnóstica dos pacientes com suspeita de miocardite aguda e crônica e naqueles portadores de disfunção ventricular de início recente com suspeita de miocardite prévia, independentemente da forma de manifestação. Entretanto apresenta especial valor naqueles com elevação dos marcadores de necrose miocárdica e coronárias normais na avaliação angiográfica (apresentação aguda tipo infarto). A RMC deve ser realizada o mais precocemente a partir da suspeita clínica. Exames subsequentes de reavaliação devem ser feitos com quatro e doze semanas após o episódio agudo, com o objetivo de avaliar a evolução do processo inflamatório, quando positivo o exame, e a função de remodelagem. Devido a questões logísticas inerentes ao método, a RMC não está indicada na avaliação dos pacientes portadores de miocardite fulminante com instabilidade hemodinâmica (
A presença de realce tardio positivo revela correlação com pior prognóstico evolutivo a longo prazo em pacientes com miocardite viral comprovada por biópsia endomiocárdica, sendo maiores a mortalidade total e a mortalidade cardíaca, independentemente dos sintomas clínicos e da função ventricular. A ausência de realce tardio demonstrou estar relacionada a um baixo risco de morte súbita, mesmo na presença de disfunção e dilatação ventricular59.
A tomografia computadorizada cardíaca (TCC) é mais rápida e mais acessível que a RMC, no diagnóstico diferencial de dor torácica, mas tem a desvantagem de usar contraste iodado e radiação ionizante60. Pode fornecer imagens de coronárias normais (quando trigada pelo ECG)61, excluindo a isquemia e o infarto miocárdico.
Adicionalmente, a angiotomografia coronariana pode ser utilizada no diagnóstico diferencial com síndrome coronariana aguda, para excluir a presença de DAC significativa nos pacientes com quadro tipo infarto (dor precordial, elevação dos marcadores de necrose miocárdica e alterações eletrocardiográficas) (
Os exames de medicina nuclear têm sido aplicados há mais de três décadas na avaliação de pacientes com suspeita de miocardite62. Suas principais aplicações estão relacionadas à avaliação da função ventricular esquerda, avaliação da presença de inflamação cardíaca, identificação de subtipos de miocardites e monitoração da resposta terapêutica.
Na avaliação da presença de inflamação cardíaca a presença de inflamação miocárdica pode ser detectada por diversas técnicas radionuclídicas63,64. A mais estudada na literatura é a cintilografia com 67-Gálio, que apresenta sensibilidade de 50% no diagnóstico da miocardite, sendo que sua melhor utilização diagnóstica se dá nos primeiros três meses de apresentação clínica65. Em alguns determinados tipos de miocardite como na sarcoidose, proporciona maior acurácia.
Em casos de gálio positivo associado a biópsia endomiocárdica positiva para inflamação, podemos utilizar a evolução do marcador em exames subseqüentes, para o acompanhamento da atividade inflamatória e resposta terapêutica (
A biópsia endomiocárdica (BEM) é o método "padrão-ouro" para o diagnóstico da miocardite, pesquisa de persistência viral cardíaca, assim como de outras doenças cardiovasculares não inflamatórias. A BEM tem como objetivos estabelecer o diagnóstico de inflamação miocárdica com ou sem persistência viral para definir a necessidade e o tipo de terapêutica a ser adotada66.
Nas situações clínicas onde há insuficiência cardíaca de início recente (menos de 2 semanas), com instabilidade hemodinâmica, sem resposta ao tratamento usual e/ou presença de arritmias ventriculares ou bloqueios cardíacos de alto grau, a BEM desempenha importante papel na investigação do fator causal, com impacto na terapêutica. Ela altera favoravelmente o prognóstico ao determinar o tratamento imunossupressor em cenários clínicos como o da miocardite de células gigantes, eosinofílica necrotizante e da sarcoidose67-69.
A BEM na cardiomiopatia dilatada crônica de provável etiologia viral sintomática tem sido foco de estudos, uma vez que já foi demonstrado que a terapia antiviral ou imunomoduladora ocasiona melhora da fração de ejeção em pacientes com IC sintomática após seis meses de terapia otimizada70.
A miocardite também pode ser causada por certas terapias farmacológicas, e a BEM tem papel essencial naqueles casos de dúvida diagnóstica e rápida progressão da doença, com suspeita de reação alérgica e eosinofilia auxilia na busca do diagnóstico diferencial com outras condições. Dada a sua natureza invasiva, a BEM para pacientes tratados com agentes quimioterápicos é reservada aos casos de evolução desfavorável associada a dúvida quanto à causa da disfunção cardíaca71.
São poucos os estudos, na literatura, sobre a indicação de BEM nos casos de arritmia ventricular de causa indefinida. A incidência do diagnóstico histológico de miocardite nesses eventos varia muito entre os estudos. A detecção de miocardite ativa em um paciente com arritmia ventricular maligna pode, teoricamente, levar à decisão de adiar a implantação do cardiodesfibrilador implantável até a redução da atividade inflamatória, mas esse tipo de abordagem ainda permanece controverso72.
As indicações de BEM na miocardite encontram-se na
O procedimento deve ser realizado no laboratório de hemodinâmica, por hemodinamicista com experiência na realização desse procedimento. A anestesia é local com sedação consciente, se necessário, sempre sob a supervisão do anestesiologista.
A biópsia endomiocárdica pode ser realizada de forma segura, guiada por fluoroscopia direta, e deve ter auxílio do ecocardiograma na sua realização73,74 que servirá guia para o posicionamento correto do biótomo para que se evite puncionar a parede livre do ventrículo direito (VD)75.
A realização de RMC prévia à BEM pode ser de grande utilidade na identificação das lesões focais no VD ou VE, direcionando a coleta do material76. Não existem estudos comparativos para que se recomende a biópsia endocárdica do VD ou do VE, entretanto a realização da biópsia endomiocárdica do VE deve ser realizada somente nos casos em que o processo esteja definitivamente limitado a esta cavidade, o que pode ser definido, em alguns casos, pela RMC.
As amostras devem ser obtidas no ventrículo direito, especialmente a porção distal do septo interventricular e a área trabeculada apical, evitando-se a parede livre do VD. O número de amostras dependerá da pesquisa a ser realizada77. No caso de investigação de miocardite viral, devem ser 10 amostras (6 para pesquisa viral, 2 para hematoxilina-eosina e 2 para imuno-histoquímica). No caso de investigação de doenças infiltrativas ou de depósito, 6 fragmentos (2 para hematoxilina-eosina, 2 para imuno-histoquímica e 2 para microscopia eletrônica). As amostras para HE e imunohistoquímica devem ser colocadas em frasco de formalina tamponada a 10% e não devem ser refrigeradas. As amostras para pesquisa viral devem ser colocadas em microtubos tipo Eppendorf® (sem soluções de transporte), e estes em recipientes com gelo seco, e rapidamente transferidas para refrigeradores -70 graus para armazenamento. As amostras para microscopia eletrônica devem ser acondicionadas em tubos Eppendorf® com solução oct.
As complicações da biópsia endomiocárdica felizmente são raras, da ordem de 1,7% em cerca de 2.400 pacientes78 e menos de 1% em outra série de mais de 4000 pacientes79. A utilização do ecocardiograma associado à fluoroscopia reduz de forma significativa a possibilidade de punção inadvertida que possa ocasionar perfuração miocárdica ou lesão de coronária.
As complicações descritas são: reação vaso-vagal, bloqueios AV de graus variados, perfuração de parede livre de VD, pneumotórax, perfuração do septo interventricular, hematoma de sítio de punção, fístulas intracardíacas, hematoma retroperitoneal (acesso femoral), derrame pericárdico, deslocamento de trombos, tamponamento cardíaco, ruptura de cordoalhas tricúspides, arritmias ventriculares.
O clássico critério de Dallas para miocardite requer células inflamatórias e necrose de miócitos à BEM, sendo a ausência de necrose caracterizada como miocardite borderline. Esse critério é bastante criticado pela falta de correlação com a evolução clínica, a presença de vírus e a variabilidade entre patologistas80. Recentemente tem-se proposto que o diagnóstico histológico de inflamação se faça através da contagem de linfócitos, macrófagos e expressão HLA-DR pela técnica de imuno-histoquímica81.
Para a análise de imunohistoquímica do tecido miocárdico, devemos utilizar no mínimo dois fragmentos obtidos pela biópsia endomiocárdica, que devem ser conservados em formalina tamponada a 10%, na temperatura ambiente, sem serem congelados. A avaliação diagnóstica da miocardite pela imuno-histoquímica oferece maior acurácia na detecção da presença de processo inflamatório miocárdico do que se tem através dos critérios histológicos. A imuno-histoquímica, através da análise de reações antígeno-anticorpo específicos, realiza a marcação das células mononucleares (linfócitos T e B) e de leucócitos através de anticorpos específicos, o que permite melhor identificação e contagem das células inflamatórias. A imuno-histoquímica também identifica a ativação inflamatória induzida pelas citocinas, através da detecção de antígenos de histocompatibilidade (HLADR) do tipo I e II nas células endoteliais ou intersticiais dos cardiomiócitos ou perivasculares e da expressão de receptores na superfície celular para a adesão das células inflamatórias (ICAM)83-85. A imunohistoquímica, por detectar o infiltrado inflamatório e a capacidade de adesão celular induzida pelas citocinas, permite diagnosticar a agressão inflamatória miocárdica mesmo distante do foco primário de infecção o que lhe confere uma maior acurácia do que a análise histológica convencional no diagnóstico das miocardites através da biópsia do ventrículo direito86,87.
O aumento da expressão miocárdica dos antígenos de histocompatibilidade (HLADR) e das moléculas de adesão (ICAM) pode ser difuso ou localizado, e usualmente está associado à presença de células inflamatórias com contagem de linfócitos T(CD3) superior a duas células por campo de microscopia ótica (×400) que correspondem a 7•0 células/mm288-90.
Podemos estabelecer o diagnóstico de miocardite através de um escore de pontos que combina a expressão do HLADR com a presença de infiltrado inflamatório91,92.
Devemos considerar como diagnóstico positivo para miocardite a presença de um escore igual ou superior a três para HLADR positivo ou dois ou mais para ICAM-1 positivo, associado à presença de infiltrado de células inflamatórias igual ou superior a 7•0 células/mm2. O escore entre um e três reconhece-se como possível diagnóstico de inflamação.
Podemos considerar também como diagnóstico positivo a contagem de linfócitos igual ou superior a 14•0 celulas/mm2 sendo que na presença de menos de 14 células podemos utilizar a contagem de linfócitos para a confirmação de miocardite37,93.
A
As medidas gerais no tratamento da miocardite objetivam cuidados relacionados às formas sintomáticas ou não de insuficiência cardíaca (estágios B a D). A restrição dietética do sódio a 2 a 3 g/dia é indicada na ausência de hiponatremia e restrição calórica, sendo coadjuvante fundamental nas fases mais avançadas de apresentação clínica. A restrição hídrica entre 1000 e 1500 ml por dia também é recomendada na fase sintomática.
O tabagismo, bem como o consumo excessivo do álcool, é contraindicado, havendo orientação de vigilância do peso corporal para evitar-se tanto a obesidade como a caquexia. Os anti-inflamatórios não hormonais não devem ser associados na fase aguda e na presença de insuficiência cardíaca94,95. Em relação aos exercícios físicos, estudos em animais mostram que atividade aeróbica durante a fase aguda da doença leva a aumento de mortalidade96. Em vista disso e sabendo-se que miocardite é causa de morte súbita em atletas jovens97, os pacientes não devem realizar exercícios vigorosos por até seis meses após a fase aguda, e até por mais tempo na dependência dos sintomas ou se restou comprometimento da função ventricular98,99.
Em relação à prevenção, as vacinas disponíveis (caxumba, sarampo, rubéola, poliomielite e gripe) devem ser administradas para que a miocardite secundária aos agentes dessas doenças seja evitada, e não se deve não realizar a vacinação enquanto houver com atividade de doença. Estudos em modelos animais mostram que a vacina contra o vírus da gripe previne o dano miocárdico, mas não há estudos em humanos100.
A
A modulação do sistema renina-angiotensina-aldosterona atenua a progressão da disfunção ventricular, diminuindo a fibrose, necrose e inflamação miocárdica em modelos experimentais101,102. Os inibidores da enzima de conversão (IECA) e bloqueadores do receptor da angiotensina (BRA) são utilizados em todos os casos de pacientes com disfunção ventricular, mesmo naqueles sem insuficiência cardíaca manifesta, salvo contraindicações, com doses progressivas até as máximas preconizadas. Recomenda-se a manutenção dos IECA/BRA nos casos de normalização da função ventricular. Em um estudo no qual foi suspenso o IECA, cerca de um terço dos pacientes apresentaram novo episódio de insuficiência cardíaca contra 5% dos que mantiveram a medicação103. Os BRA podem ser utilizados na presença de disfunção ventricular e intolerância ao uso de IECA
O bloqueio beta-adrenérgico na miocardite baseia-se na necessidade de reduzir a atividade simpática e os níveis de noradrenalina, impedindo assim a progressão da disfunção miocárdica e um pior prognóstico. Os betabloqueadores (BB) são utilizados em todos os casos de pacientes com disfunção ventricular e insuficiência cardíaca manifesta, salvo contraindicações, com doses progressivas até as máximas preconizadas. Recomenda-se a manutenção do BB nos casos de normalização da função ventricular, pelo período mínimo de um ano.
O uso de anticoagulante oral (ACO) está indicado nos casos de miocardite associado a fibrilação atrial (FA) paroxística, ou permanente, trombos intracavitários ou fenômenos tromboembólicos prévios104.
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A terapêutica imunossupressora na miocardite tem como objetivo suprimir a resposta inflamatória e a atividade autoimune, com consequente melhora clínica e da função ventricular, além de redução da mortalidade. Para indicação da terapêutica imunossupressora, faz-se necessária a comprovação de atividade inflamatória miocárdica através da biópsia endomiocárdica associada a pesquisa viral negativa (
Fatores como a regressão espontânea da inflamação de cerca de 50% das miocardites, a falta de uniformidade dos estudos clínicos quanto aos critérios diagnósticos, o reduzido número de pacientes na maioria dos ensaios, a heterogeneidade das características clínicas das populações estudadas e a ausência de estudos clínicos com objetivo principal de avaliar a redução da mortalidade de forma isolada dificultam a análise dos benefícios clínicos da terapêutica imunossupressora. Os estudos clínicos105 que avaliaram a melhora na sobrevida não demonstraram benefício da terapêutica imunossupressora em relação à terapêutica convencional para insuficiência cardíaca. Esses estudos apresentaram diversas falhas metodológicas, como não realizar pesquisa viral, utilizar somente de critérios de análise histológica por DALLAS e não de imunohistoquímica para o diagnóstico de miocardite. Tudo isso pode ter comprometido os benefícios esperados com a terapêutica imunossupressora, por isso permanece não definido o benefício da imunossupressão na redução da mortalidade.
Em pacientes com IC crônica com miocardite ativa, sem presença de infecção viral, a terapêutica imunossupressora demonstrou benefícios na melhora clínica, redução dos diâmetros cavitários com melhora da função ventricular e regressão da atividade inflamatória (
A terapêutica imunossupressora mais comumente utilizada nos pacientes com miocardite pós-viral é a associação de prednisona com azatioprina pelo período de seis meses (
A terapêutica antiviral tem como objetivo promover a eliminação viral como também impedir a sua replicação. Dentre as possibilidades terapêuticas, temos a infusão subcutânea de interferon-β (IFN- β) e a imunoglobulina intravenosa (IG-IV).
Em modelo experimental de miocardite viral com animais geneticamente modificados para não expressão de produção de IFN-β, foi observada extensa proliferação viral e intensa atividade inflamatória associada a maior disfunção ventricular e mortalidade, sugerindo que o IFN-β tem um importante papel para o controle da infecção viral na miocardite113.
A infusão subcutânea de IFN-β em pacientes com cardiomiopatia dilatada e persistência viral (adenovírus e enterovírus) demonstrou eliminação viral com melhora clínica da capacidade funcional e função ventricular100. Em pacientes com miocardite viral por parvovírus-B19, o IFN-β esteve associado à redução da carga viral, melhora da função endotelial e da função ventricular114. Portanto, a terapêutica com IFN-β em pacientes com miocardite viral está se consolidando como opção terapêutica antiviral.
A imunoglobulina-IV (IG-IV) apresenta atuações anti-inflamatórias, redução da resposta imune e antiviral. Ela promove a redução da ativação e ação das citocinas pró-inflamatórias, possui propriedade anti-idiotípica com consequente redução da produção e neutralização dos autoanticorpos. A IG-IV apresenta ainda ação antiviral por reduzir a replicação e favorecer a eliminação viral99.
A utilização da IG-IV em cardiomiopatia dilatada de início recente não demonstrou benefício na melhora da função ventricular frente ao placebo. Porém, algumas falhas na metodologia podem ter comprometido os resultados apresentados, pois os pacientes foram admitidos no estudo com ou sem inflamação presente na biópsia, a inflamação foi somente demonstrada somente em 16% dos pacientes e neste não foi pesquisada presença viral. O critério histológico de DALLAS foi utilizado para o diagnóstico de inflamação99.
Em miocardites virais por adenovírus e citomegalovírus, a IG-IV ocasionou redução da carga viral e da inflamação com melhora clínica e da função ventricular. Na miocardite por PV-B19 temos uma persistência de carga viral em cerca de 40% dos pacientes após a utilização da IG-IV, sendo que os pacientes que tiveram eliminação do PV-B19 evoluíram com melhora da função ventricular e redução dos diâmetros cavitários115. Esses resultados sugerem que o benefício terapêutico da IG-IV deve ser reservado ao cenário de miocardites com processo inflamatório ativo, avaliado por imunohistoquímica, e identificação viral positiva (
O processo de imunomodulação tem como objetivo reduzir a agressão inflamatória e autoimune através da remoção e modulação de possíveis agentes agressores envolvidos na patogênese da miocardite.
A terapia de imunoadsorção através de plasmaférese seletiva visa a retirada de autoanticorpos específicos associada à terapia com IG-IV para imunomodulação inflamatória das citocinas e da produção dos autoanticorpos. A utilização da imunoadsorção em pacientes com cardiomiopatia inflamatória crônica com níveis séricos elevados de autoanticorpos contra β1 neurorreceptor miocárdico associado à reposição de IG-IV, demonstrou redução da atividade inflamatória miocárdica e melhora clínica da classe funcional e da função ventricular e maior sobrevida ao fim de cinco anos. Embora esses resultados sugiram um possível benefício desta terapêutica nos pacientes com miocardite autoreativa, o número de pacientes avaliados é muito reduzido para que possamos estabelecer essa estratégia terapêutica como definitiva116.
A pentoxifilina apresenta como propriedades anti-inflamatórias o bloqueio da transcriptase do TNF-α e a redução dos níveis de interleucinas 2 e 6, com consequente redução dos efeitos de cardioagressão dessas citocinas117.
Na cardiomiopatia dilatada com IC crônica e na cardiomiopatia periparto, a utilização de pentoxifilina na posologia de 1200mg a 2400mg/dia, pelo período de seis meses, ocasionou melhora clínica da classe funcional e da função ventricular (
Os pacientes que se encontram na fase aguda de miocardite podem desenvolver tanto taquiarritmias como bradiarritmias. Essas arritmias frequentemente desaparecem após a fase aguda da miocardite, sendo a terapia, habitualmente, de suporte.
Geralmente não se recomenda terapia antiarrítmica para extrassístoles atriais e ventriculares assintomáticas. As taquicardias supraventriculares (TSV), principalmente fibrilação e flutter atrial, podem induzir ou agravar a IC. A abordagem inicial recomendada para a TSV sustentada sintomática é a restauração do ritmo sinusal através de cardioversão elétrica ou química. Para TSV sustentada recorrente, as opções incluem a ablação por cateter ou o controle da frequência ventricular.
Taquicardias ventriculares não sustentadas assintomáticas não devem receber terapia específica. As arritmias ventriculares sustentadas devem ser tratadas com drogas antiarrítmicas após a reversão elétrica aguda. A opção, porém, é limitada a amiodarona. Devido aos efeitos pró-arrítmicos, drogas de classe I e III (exceto a amiodarona) são geralmente evitadas nesses pacientes.
Bloqueio átrioventricular total e bradicardia sinusal sintomática são indicações para estimulação provisória durante a fase aguda da miocardite. Essas anormalidades de condução muitas vezes são transitórias.
Não existem dados disponíveis na literatura sobre os riscos em longo prazo de pacientes que apresentam TV ou PCR na fase aguda da miocardite, de modo que a conduta nestes casos é individualizada. O implante de cardio-desfibrilador (CDI) está indicado, na presença de terapia medicamentosa otimizada, em pacientes que desenvolvem cardiomiopatia dilatada na fase crônica da miocardite, com os critérios descritos na
Classicamente a miocardite fulminante e uma forma mais grave de manifestação da miocardite aguda, caracterizada por um curso agudo de doença, rapidamente progressiva, com ICC CF IV e choque cardiogênico e de alta letalidade quando não tratada com suporte hemodinâmico adequado122.
Na miocardite fulminante viral usualmente ocorre a persistência de uma alta viremia em indivíduos susceptíveis, com persistência da ativação de linfócitos T e formação de anticorpos responsáveis pela mediação da agressão e destruição miocitária22.
Felker e colaboradores descreveram as características da miocardite fulminante, na apresentação clínica, em período longo de seguimento de pacientes123. Esses pacientes frequentemente tiveram quadro de processo infeccioso detectado nas últimas quatro semanas e também quadro febril nas últimas 12 semanas. A apresentação é aguda, progressiva e a grande maioria dos pacientes já se encontram em CF III/IV por ocasião do seu diagnóstico. Além disso, em comparados com o que ocorre na forma não fulminante, estes pacientes são mais hipotensos, taquicárdicos e com menos dilatação ventricular.
Apesar de apresentar um quadro de dramática evolução, quando se faz o reconhecimento precoce do seu diagnóstico e as medidas de suporte clínico e hemodinâmico são adotadas imediatamente, o prognóstico pode ser muito bom, inclusive com reversão da disfunção ventricular e boa sobrevida tardia124,125.
Do ponto de vista do tratamento específico da miocardite, o reconhecimento do fator causal através da investigação histológica por BEM permite o estabelecimento de estratégias terapêuticas específicas, como a utilização de imunoglobulina nas miocardites virais e imunossupressão nas autoimunes sem presença viral, ou com o uso de corticoide em pacientes com sarcoidose ou miocardite por células gigantes. Uma opção que tem sido testada é a utilização de altas doses de imunoglobulina, que se mostrou efetiva em série de casos, porém ainda sem comprovação por estudo randomizado126,127. O tratamento de suporte deve ser realizado com drogas vasoativas e eventualmente vasopressoras, e em situações nas quais seja possível a introdução de vasodilatadores. O insucesso imediato no tratamento medicamentoso e acerto volêmico deve abrir perspectiva para indicação de suporte hemodinâmico com assistência circulatória. Os dispositivos mais utilizados são o balão intra-aórtico, dispositivos percutâneos como
As indicações na miocardite fulminante encontram-se na
A cardiomiopatia neuroadrenérgica (CNA) tem sido progressivamente mais diagnosticada nos pacientes com disfunção ventricular aguda nas salas de emergência. As mulheres idosas (pós-menopausa) representam o principal grupo de risco (em torno de 80% dos casos), sendo que a cardiomiopatia é frequentemente desencadeada por intenso estresse físico ou emocional, perdas financeiras, desastres naturais e por vezes secundária a estresse provado por outras doenças. A CNA apresenta bom prognóstico: com mortalidade intra-hospitalar de 2% e, geralmente, usualmente com recuperação da função cardíaca entre 2-4 semanas130.
Os principais achados clínicos são a presença de dor torácica, dispneia e síncope. Alterações eletrocardiográficas são comuns, como supradesnivelamento do segmento ST (34 a 56%), ondas Q patológicas inversão da onda T com QT prolongado, além de alterações inespecíficas da repolarização. A elevação dos níveis de troponinas cardíacas é frequente e o pequeno aumento das troponinas é discrepante com as anormalidades contráteis e hemodinâmicas131. A ventriculografia esquerda, ou estudo ecodopplercardiográfico, demonstra abaulamento apical com acinesia ou discinesia acometendo de metade a dois terços do VE associada a hiperdinamia dos segmentos basais. A ressonância cardíaca com gadolíneo é útil para diferenciar o CNA do IAM e da miocardite, por não demonstrar presença de edema miocárdico ou realce tardio. Podemos identificar o acometimento do ventrículo direito em 25% dos casos. As principais complicações agudas são: insuficiência cardíaca, taquicardia ventricular, fenômenos trombo-embólicos, regurgitação mitral e choque cardiogênico.
A CNA apresenta bom prognóstico evolutivo em contraste, por vezes, com a avaliação clínica com importante comprometimento hemodinâmico. O tratamento tem como base manter o suporte clíinico-hemodinâmico, para permitir a recuperação espontânea do miocárdio. Na ausência de hipotensão arterial ou sinais de baixo débito cardíaco, podem ser utilizados betabloqueador, inibidor da enzima conversora e diurético. Pacientes que cursam com hipotensão arterial necessitam de suporte hemodinâmico com uso cauteloso de inotrópicos, como dobutamina, e vasopressores na presença de hipotensão refratária. E caso não ocorra melhora clínico-hemodinâmica está indicado o suporte hemodinâmico mecânico com balão intra-aórtico. Em pacientes que estejam evoluindo com choque refratário, o emprego da circulação extracorpórea (ECMO) pode ser realizado, tendo em vista o perfil transitório da síndrome.
As Indicações para o diagnóstico de Takotsubo encontram-se na
A doença de Chagas é endêmica na América Latina132. A miocardite chagásica pode se apresentar-se como miocardite aguda durante infecção "de novo" pelo
A manifestação da miocardite aguda depende do grau de acometimento do coração e da infecção sistêmica, podendo variar de uma forma florida com taquicardia sinusal, baixa voltagem do QRS, distúrbio de condução, alteração do intervalo Q-T, sinais de alterações de repolarização ventricular, arritmias, comprometimento da função biventricular e insuficiência cardíaca aguda até as formas mais frustras em que é necessária a suspeita clínica para o diagnóstico13. Deve ser sempre suspeitada em pacientes de região endêmica, com possibilidade de transmissão vetorial ou de outras formas de transmissão como transfusão sanguínea, oral, ou ainda congênita. Pode estar associada a sinais de infecção sistêmica, hepatoesplenomegalia, febre e sinais de entrada do parasita na transmissão vetorial. A manifestação da reativação da infecção pelo
A miocardite crônica pode ser encontrada na forma crônica da doença de Chagas - que pode se manifestar após longo período de latência pós-infecção aguda, de maneira isolada ou combinada -, na forma de insuficiência cardíaca crônica ou aguda, arritmias, morte súbita e embolia pulmonar ou sistêmica134,135. Os sinais e sintomas são de miocardiopatia, podendo haver maior incidência de bradicardia e distúrbio de condução, especialmente de ramo direito. Apresenta prognóstico pior do que outras etiologias136. Os mecanismos potencialmente envolvidos na sua patogenia são lesões neurogênicas, microvasculares, apoptose, processo inflamatório crônico, fibrose, persistência do parasita, e autoimunidade137. Atualmente se tem valorizado a persistência do parasita como mecanismo desencadeador da miocardite chagásica crônica138. Entretanto, outros agentes podem influenciar a manifestação da miocardite crônica139. Na fase crônica da doença de Chagas, diante de um diagnóstico clínico altamente provável, apoiado em dados de epidemiologia compatíveis, reações sorológicas positivas, manifestações típicas de insuficiência cardíaca ou de outros comprometimentos do coração, em geral não se realiza biópsia endomiocárdica. Outros métodos podem ser utilizados140. Na fisiopatologia, a insuficiência cardíaca pode determinar elevação de BNP e maior intensidade de processo pró-inflamatório141,142. O tratamento específico para as formas sem insuficiência cardíaca é controverso, e nas formas com insuficiência cardíaca é contraindicado143,144. O tratamento é o mesmo para outras formas de insuficiência cardíaca, quer na forma compensada, quer na descompensada145-148. Procedimentos cirúrgicos antes potencialmente favoráveis foram abandonados149-151 e no nos casos de evolução em estágio final está indicado o transplante cardíaco para melhora da qualidade de vida e sobrevida152-155 ou a utilização de dispositivos de assistência circulatória156. O transplante necessita de seguimento diferenciado devido ao maior número de comorbidades, incluindo neoplasia e reativação da infecção, mas tem resultado melhor do que para outras etiologias157-161.
Indicações para o diagnóstico e tratamento da miocardite chagásica estão na
A história natural das miocardites varia de acordo com a causa, sendo que dados clínicos e hemodinâmicos podem ajudar a estabelecer o prognóstico (
Existem diferentes formas clínicas e patológicas da miocardite, e a biópsia endomiocárdica pode estabelecer não somente o diagnóstico, mas também contribuir com a avaliação prognóstica. Isto pode ser feito, primeiramente, pela identificação de formas específicas de miocardite, como a miocardite fulminante, miocardite de células gigantes, miocardite ativa crônica, miocardite eosinofílica e sarcoidose. Os achados clinicopatológicos podem ajudar a diferenciar, por exemplo, miocardite linfocítica fulminante de miocardite linfocítica aguda, o que tem grande importância prognóstica (
No passado, a baixa sensibilidade aliada à utilização única e exclusiva do critério de Dallas não permitia que achados da histologia pudessem ser bem correlacionados com a evolução do paciente45. Atualmente, a constatação da presença de vírus pode auxiliar a predizer essa evolução. Em um estudo observacional envolvendo 59 biópsias realizadas em 48 crianças com diagnóstico clínico e histológico de miocardite ou cardiomiopatia dilatada, a presença de PCR (reação em cadeia da polimerase) positiva para vírus revelou pior prognóstico, resultando em transplante cardíaco ou morte164.
Outro dado importante que frequentemente é capaz de predizer morte ou necessidade de transplante cardíaco é o comprometimento da função do ventrículo direito76.
Não existem dados epidemiológicos oficiais no Brasil referentes ao comprometimento pericárdico. Mesmo os disponíveis na literatura internacional são escassos e certamente sofrem a influência das características de cada centro. Os dados referentes a serviços de emergência mostram que 5% dos pacientes com queixa de dor torácica nos quais foi afastada insuficiência coronariana aguda165 e 1% daqueles com supradesnível de segmento ST tinham pericardite aguda166.
Quanto ao derrame pericárdico, é mais frequente quando o comprometimento é por tuberculose ou neoplasia, e o mesmo acontece em relação ao tamponamento cardíaco. Já nos casos em que outras etiologias são responsáveis pelo quadro clínico, a frequência é menor.
Pericardite é um processo inflamatório do pericárdio que tem múltiplas causas e se apresenta tanto como doença primária quanto secundária. Geralmente benigna e autolimitada, a pericardite pode cursar com derrame ou constrição pericárdica, o que aumenta sua morbidez167,168. As pericardites são classificadas de acordo com a evolução e forma de apresentação clínica153,169:
• Pericardite aguda;
• Pericardite crônica;
• Derrame pericárdico e tamponamento cardíaco;
• Pericardite constritiva;
• Pericardite recorrente.
As causas de pericardite são divididas em infecciosas e não-infecciosas (
A pericardite bacteriana manifesta-se geralmente com derrame pericárdico, e sua origem pode estar em situações como pneumonia, empiema, disseminação hematogênica, pós-cirurgia cardíaca ou torácica - possui ampla gama de agentes infecciosos como causa. A pericardite tuberculosa tem diminuído com o controle efetivo da tuberculose pulmonar, mas mostra-se presente principalmente em pacientes HIV positivos171,172.
Já o envolvimento autoimune do pericárdico acontece especialmente nos casos de lúpus eritematoso sistêmico, artrite reumatoide, esclerodermia, polimiosite e dermatomiosite.
A pericardite pós-infarto pode ocorrer precocemente nos três primeiros dias do infarto agudo do miocárdio (IAM), pericardite epistenocárdica. Nesses casos está relacionada ao acometimento do epicárdio e pericárdio adjacente e, tardiamente, de três semanas a seis meses, a atividade autoimune denominada síndrome de Dressler. A insuficiência renal é causa comum de doença pericárdica, produzindo derrame em 20% dos pacientes. Pode se manifestar como pericardite urêmica ou pericardite associada a diálise. Já as pericardites neoplásicas são devidas à invasão tumoral ou linfática, ou ocorrem por disseminação hematogênica167.
A pericardite aguda classicamente se manifesta como uma síndrome febril com frequente acometimento de vias aéreas superiores, dor torácica e atrito pericárdico. A dor torácica pode variar com a respiração ou posição do tórax, variando também de intensidade e duração. O atrito pericárdico pode compreender de um a três tempos e pode ser transitório. Podemos ter acometimento pleural, associado à presença de derrame ou atrito pleural. Por vezes, a pericardite encontra-se associada a miocardite, que deve ser suspeitada na presença de exame clínico de disfunção ventricular aguda.
Os marcadores de alto risco da pericardite aguda são: elevação de enzimas de necrose miocárdica, febre acima de 38ºC e leucocitose (elevada possibilidade de pericardite purulenta), derrames pericárdicos volumosos com ou sem tamponamento cardíaco, pacientes imunocomprometidos, história prévia de anticoagulação oral, disfunção global pelo ecocardiograma, sugerindo miopericardite. Esses marcadores indicam a necessidade de admissão hospitalar, intensificação da avaliação etiológica e otimização terapêutica173,174.
Abaixo, o fluxograma de avaliação admissional na pericardite (
O saco pericárdico contém uma pequena quantidade de líquido (30 a 50 ml) que envolve o coração. Quando uma quantidade significativa de líquido se acumula e ultrapassa a capacidade de distensão do tecido fibroelástico pericárdico, ocorre progressiva compressão de todas as câmaras cardíacas decorrente do aumento da pressão intrapericárdica, redução do volume de enchimento cardíaco e maior interdependência ventricular175.
O desenvolvimento do tamponamento depende da velocidade de instalação e do fator causal: o tamponamento cardíaco agudo ocorre em minutos, devido ao trauma, ruptura do coração e aorta, ou como complicação de procedimentos diagnósticos e terapêuticos (biópsias cardíacas, estudo eletrofisiológico, oclusão de apêndice atrial, oclusores de septo interatrial etc.), resultando num quadro de choque. Já o tamponamento cardíaco subagudo ocorre entre dias e semanas e poder estar associado com dispneia e fadiga. Tamponamento de baixa pressão (oculto) ocorre em pacientes que estão hipovolêmicos, com consequente redução da pressão intracardíaca, favorecendo a compressão extrínseca do derrame pericárdico. Tamponamento cardíaco regional ocorre quando um derrame localizado ou um hematoma produz compressão regional em uma única câmara168.
O diagnóstico é clínico, baseado na história e no exame físico: taquicardia, pressão venosa elevada, hipotensão arterial e a presença de pulso arterial paradoxal.
A pericardite constritiva frequentemente está associada a um paciente sintomático com dispneia de esforço e/ou fadiga associada a disfunção diastólica e presença de ascite desproporcional ao edema de membros inferiores. No pulso venoso jugular observamos colapso "Y" proeminente e sinal de Kussmaul. No pulso arterial podemos encontrar a presença de pulso paradoxal em um terço dos casos.
Formas transitórias de pericardites efusivas constritivas (constrição sem importante espessamento do pericárdio parietal, geralmente associada a derrame) podem acontecer no contexto da pericardite aguda, frequentemente associada a tuberculose, neoplasias malignas e hemopericárdio.
Níveis elevados de marcadores miocárdicos são observados em pacientes com pericardite aguda, sendo mais frequente a elevação de troponina I (TnI) do que de CKMB, uma vez que esta pode estar elevada em decorrência da miosite periférica por infecções virais176,177. Estudo retrospectivo avaliou 55 pacientes com pericardite aguda e observou elevação de TnI em 27% dos casos178. Estudo pequeno sugere que o pico de TnI em geral ocorre no segundo dia após início dos sintomas e seus níveis permanecem elevados por tempo mais prolongado do que os de CKMB177. A elevação da TnI é marcador de comprometimento miocárdico associado (miopericardite).
Os marcadores de atividade inflamatória de fase aguda como VHS, leucocitose e Proteína C reativa (PCR), encontram-se elevados em aproximadamente 75% dos pacientes, sendo que a ausência desses marcadores na avaliação inicial de pacientes e não afasta o diagnóstico, principalmente nos que estão em uso de anti-inflamatórios não hormonais ou com comprometimento imunológico. Estes tendem a normalizar ao fim de duas semanas, sendo que valores persistentemente elevados indicam a necessidade de terapêutica anti-inflamatória prolongada e maior risco de recorrência da pericardite179. A dosagem seriada de PCR é útil para o diagnóstico e avaliação de resposta ao tratamento da pericardite aguda.
Os níveis de peptídeo natriurético atrial do tipo B (BNP) e da fração N-terminal do BNP (NT-proBNP) podem estar elevados em doenças pericárdicas180,181. No entanto, não há evidências suficientes que justifiquem seu uso rotineiro para o diagnóstico de pericardite aguda.
A avaliação sorológica em busca de um fator causal deve incluir dosagem de hormônios tireoidianos; provas reumatológicas; função renal; hemoculturas, na suspeita de infecção bacteriana. A pesquisa viral através de sorologia em sangue não deve ser realizada, pois não possui correlação com os achados no pericárdio. Na presença de derrame pericárdico volumoso, a análise histológica e imuno-histoquímica do pericárdio e do líquido pericárdico para avaliação de tuberculose (dosagem de adenosina deaminase), neoplasia, pesquisa viral e de outros fatores pode aumentar a chance de diagnóstico etiológico de forma significativa182. Na pericardite aguda idiopática recorrente, a presença de autoanticorpos antinúcleo em baixos títulos é comum e sugere uma possível patogênese autoimune183.
A
As alterações eletrocardiográficas da pericardite são bastante amplas (
Na pericardite aguda, as alterações eletrocardiográficas acontecem em quatro estágios185. São eles:
Alterações do ritmo podem ocorrer em qualquer estágio e variam de taquicardia sinusal até arritmias atriais diversas188.
Baixa amplitude do QRS acontece na presença de derrame pericárdico, que melhora após pericardiocentese189,190. A alternância na morfologia ou amplitude do QRS está associada à pericardite com derrame pericárdico volumoso e sinais de tamponamento cardíaco191.
Os principais diagnósticos diferenciais das alterações eletrocardiográficas são infarto agudo do miocárdio, tromboembolismo pulmonar, áreas discinéticas e repolarização precoce192.
A diferenciação da pericardite com repolarização precoce pode ser feita através da razão entre a amplitude do início do ST sobre a amplitude da onda T (ST/T) em V6. O diagnóstico de pericardite ocorre quando a razão ST/T é igual ou maior que 0,25 193.
Na pericardite crônica observam-se predominantemente ondas T invertidas e baixa amplitude do QRS194.
Na pericardite aguda, a radiografia de tórax é normal na maioria das vezes. A presença de cardiomegalia ocorre apenas quando há mais de 200 ml de fluido no saco pericárdico. O aumento progressivo do derrame pericárdico, que ocorre, por exemplo, no tamponamento cardíaco, resulta em formato globular da silhueta cardíaca à radiografia de tórax195.
Estudos mostram que o aumento da silhueta cardíaca à radiografia de tórax tem sensibilidade moderada (70%), porém baixa especificidade (41%) para o diagnóstico de derrame pericárdico. Não há estudos que avaliam a sensibilidade e especificidade do método para o diagnóstico de pericardite, mas considerando que a pericardite pode não ser acompanhada por derrame pericárdico em grande parte das vezes e que não há outras alterações específicas desta patologia, não é possível definir pericardite com base apenas em dados radiológicos196.
A presença de calcificação do pericárdio, que pode ser evidenciada facilmente pela radiografia de tórax, sugere fortemente pericardite constritiva em pacientes com insuficiência cardíaca. No entanto, está presente em apenas 25% dos pacientes com pericardite constritiva (
A ecocardiografia tem se mostrado uma ferramenta muito útil no diagnóstico das doenças do pericárdio, assim como no acompanhamento da resposta terapêutica e do prognóstico. Também tem sido utilizada como guia na drenagem do derrame pericárdico.
Comumente, os achados ao ecocardiograma associados a pericardite aguda envolvem aumento do espessamento pericárdico e derrame pericárdico. No entanto, podemos ter casos de pericardite aguda sem alterações ao ecocardiograma, usualmente denominados "pericardite aguda seca".
A ecocardiografia bidimensional permite a avaliação semiquantitativa do derrame pericárdico e de sua repercussão hemodinâmica. Em geral, quando o tamanho do derrame ao modo M é < 10 mm e é visualizado apenas na parte posterior ao ventrículo esquerdo, trata-se de um derrame pequeno. Quando mede entre 10 e 20 mm e circunda todo o coração, é moderado. Finalmente, espaços livres de eco > 20 mm caracterizam derrame importante198. Derrames pequenos geralmente só são vistos posteriores ao ventrículo esquerdo, enquanto os que são suficientemente grandes para causar tamponamento cardíaco geralmente são vistos circundando todo o coração. O ecocardiograma pode oferecer informações sobre a etiologia, pois permite caracterizar a natureza do líquido (se transudato ou exsudato), verificar se existe fibrina (como na tuberculose), cálcio, coágulos, massas sugestivas de tumor ou cisto, permitindo portanto inferências sobre o diagnóstico etiológico.
O pericárdio deve ser avaliado em todos os cortes possíveis. Na suspeita de pericardite constritiva, a espessura do pericárdio deve ser medida (espessura > 3 mm ao ETE 95% de sensibilidade e 86% de especificidade para pericárdio espessado).
Os achados ecocardiográficos usuais na presença de síndrome clínica de tamponamento são: dilatação das cavas com pouca variação respiratória, colapso diastólico da parede livre do ventrículo direito, do átrio direito, do átrio esquerdo e raramente do ventrículo esquerdo. O colapso do AD é um sinal mais sensível de tamponamento, ao passo que o do VD, quando dura mais de 1/3 da diástole, é mais específico. Ao Doppler podemos observar aumento do fluxo tricúspide e redução do fluxo mitral na inspiração, e na expiração, um aumento no fluxo mitral de até 25% e redução do tricúspide. Os achados ao Doppler ecocardiograma nada mais são do que a expressão ecocardiográfica do pulso paradoxal.
De uma forma geral, 80% dos casos podem registrar espessamento pericárdico. Porém, como este nem sempre pode ser detectado pela ecocardiografia, mesmo que pelo ETE, outros métodos diagnósticos, como ressonância ou tomografia computadorizada, podem ser indicados.
Os achados usuais na presença de constrição pericárdica são: movimentação anormal do septo interventricular, aumento moderado biatrial do fluxo restritivo, variação respiratória maior que 25% na velocidade do fluxo mitral. Essa variação não é patognomônica da pericardite, já que também ocorre nas doenças respiratórias (doença pulmonar obstrutiva crônica). Nestas, contudo, ocorre grande variação respiratória do fluxo da veia cava superior, que na pericardite é menor.
Outro achado útil para o diagnóstico de pericardite constritiva, especialmente no seu diagnóstico diferencial das síndromes restritivas, é a presença de velocidade normal da onda e' ao Doppler tecidual (> 8 cm/seg), o que não ocorre nas cardiopatias restritivas. É importante destacar: na presença de doenças do pericárdio, deve ser usada a onda e' septal, e não a lateral, devido à possível influência do espessamento/derrame pericárdico na parede livre do VE. Além disso, a calcificação do anel mitral pode levar à diminuição da onda e' septal199. A relação linear que existe entre o índice
As indicações da ecocardiografia transtorácica na pericardite encontram-se na
Na pericardite aguda, a TCC pode encontrar pericárdio uniformemente espessado, derrame pericárdico e algum realce precoce após contraste venoso. O derrame pericárdico pode ser loculado, com septações, e eventualmente a presença de gás é associada à presença de microrganismos. Os septos formados também captam contraste. A densidade do derrame deve ser observada, pois transudatos têm baixa densidade (0-10 UH), ao contrário de exsudatos, hemorragias e neoplasias200.
Na pericardite constritiva a TCC identifica espessamento pericárdico, calcificações pericárdicas, ou ambos201. A espessura normal do pericárdio mede menos que 2 mm, e só é identificada adequadamente quando há gordura envolvendo-o. O espessamento pode envolver todo ou quase todo o pericárdio ou ser localizado202,203. A constrição cardíaca causada pelo espessamento do pericárdio dá ao coração uma forma estreita tubular. Se a constrição predominar na fossa atrioventricular, forma-se uma cintura. Há distensão dos átrios e das veias cavas. Derrame pericárdico e ascite também podem ser achados.
Na pericardite neoplásica, além de derrame pericárdico e espessamento dos folhetos, pode ser identificável a presença de massas no pericárdio ou a infiltração de tecidos adjacentes, comprometimento das bordas ventriculares, septos espessados e captantes de contraste.
A
A RMC está indicada na avaliação diagnóstica das pericardites aguda e crônica (
Entre as principais aplicações da medicina nuclear no diagnóstico não invasivo das pericardites devemos destacar: (1) diagnóstico diferencial em pacientes atendidos com dor torácica e alterações eletrocardiográficas sem curva enzimática características, em especial na ausência de RMC disponível ou em pacientes com contraindicações à RMC; (2) diagnóstico de pericardite por BK em atividade (novas evidências têm apontado para uso de PET com FDG); (3) diagnóstico de pericardite em pacientes com doenças sistêmicas como meningite, sepse pneumocócica, artrite reumatoide, lúpus; (4) acompanhamento de pacientes com pericardite induzida por quimioterápicos ou radioterapia; e (5) suspeita clínica de pericardite em que há indefinição diagnóstica após investigação com ecocardiograma e RMC204,205.
A pericardiocentese é um procedimento invasivo utilizado com objetivo terapêutico e diagnóstico. Ela está indicada na presença de quadro clínico de tamponamento pericárdico, como medida terapêutica salvadora.168,195 A pericardiocentese também está indicada na suspeita clínica de hemopericárdio pós trauma, pericardite bacteriana ou neoplásica (
Nos derrames pericárdicos importantes assintomáticos (mais de 20 mm ao ecocardiograma na diástole), a pericardiocentese está indicada para avaliação diagnóstica e pela possibilidade de evolução para tamponamento pericárdico de forma súbita207.
A pericardiocentese pode ser feita à beira do leito do paciente sob anestesia local ou na hemodinâmica com radioscopia. A via de acesso pode ser transtorácica, mediana ou subxifoide. O acesso pela via subxifoide permite uma exposição limitada do pericárdio, resultando em baixo índice de positividade208. A agulha para punção pericárdica deve ser guiada por monitorização eletrocardiográfica ou por método de imagem. A pericardiocentese guiada pelo ecocardiograma apresenta menor risco de complicações e maior sucesso. Além disso, a injeção salina permite a localização da agulha durante o procedimento209. Após a introdução do cateter é importante a aferição da pressão da cavidade pericárdica seguida da aspiração do seu líquido. O alívio dos sintomas deve ser imediato.
Nos casos de pericardite-efusivo-constritiva, há a persistência da elevação da pressão atrial direita após redução da pressão intrapericárdica para níveis normais após drenagem do derrame pericárdico210. O líquido pericárdico deve ser encaminhado para análise citológica, cultura, pesquisa de células neoplásicas pesquisa viral por PCR, dosagem de adenosina deaminase, de acordo com a suspeita etiológica: viral, bacteriana, tuberculosa, fúngica, neoplásica. A contraindicação absoluta é a dissecção aórtica e as relativas são: coagulopatia, anticoagulação, trombocitemia menor que 50.000/mm3, derrame pequeno, posterior ou loculado.
Com a finalidade de aumentar a sensibilidade diagnóstica, novas estratégicas diagnósticas e terapêuticas surgiram, como a vídeopericardioscopia que permite ampla ressecção do pericárdio e maior exposição da cavidade pericárdica211.
A biópsia pericárdica, por sua vez, está indicada na investigação diagnóstica em pacientes com pericardite persistente refratária ao tratamento clínico, sem diagnóstico definitivo estabelecido. A biópsia pode ser coadjuvante na drenagem pericárdica terapêutica para o tamponamento pericárdico recidivante ou em derrames volumosos associados à importantes sintomas clínicos.
A biópsia pericárdica também pode ser realizada através de pericardioscopia, que pode, guiar o local para retirada dos fragmentos212,213. Essa técnica tem demonstrado ser de grande auxílio na melhora da acurácia diagnóstica da pericardite por doença neoplásica, como também na suspeita de tuberculose ou infecção bacteriana214,215.
A presença de derrame pericárdico favorece a realização da biópsia por pericardioscopia e sua capacidade diagnóstica, em comparação com as pericardites sem derrame pericárdico associado. Os tecidos obtidos pela biópsia devem ser submetidos a análise histológica (2 fragmentos) e imunohistoquímica (2 fragmentos), além de a pesquisa viral através da reação em cadeia da polimerase viral (4 a 6 fragmentos), que demonstra maior capacidade de detecção viral que a pesquisa no líquido pericárdico216-218.
Na
O quadro histológico pode ser agrupado segundo categorias etiológicas, sendo a etiologia da tuberculose a mais frequente. Acredita-se que alguns vírus causem pericardite autolimitada. Quando a inflamação é acentuada, existe proliferação exuberante de células mesoteliais reativas com atipias nucleares que impõem o diagnóstico diferencial com infiltração neoplásica. Para essa finalidade, a imunohistoquímica é útil, pois contém a diferenciação por marcadores de células epiteliais e mesoteliais212,219.
A
A hospitalização é desejável na maioria dos pacientes para determinação da etiologia - observar sinais ou sintomas de tamponamento e iniciar com anti-inflamatórios não hormonais (AINH) e tratamento sintomático. AINH são a droga principal para o início do tratamento. Ibuprofeno é preferido, com raros efeitos colaterais e efeitos favoráveis no fluxo coronariano em altas doses.
O tratamento com corticosteroides sistêmicos deve ser restrito a doenças do tecido conjuntivo, doenças autoimunes ou pericardite urêmica. A aplicação intrapericárdica de corticosteroides evita efeitos colaterais sistêmicos e é altamente efetiva para retirar prednisona, ibuprofeno ou colchicina220,221, e devem ser introduzidos precocemente. Pacientes em recuperação devem ser observados para possível recorrência ou constrição.
Se o paciente necessitar de anticoagulantes, a heparina é recomendada com observação estrita.
Os AINH são os principais medicamentos para o tratamento das pericardites idiopática e viral. O objetivo principal do tratamento é o alívio da dor e a resolução do processo inflamatório222,223.
Os AINH devem ser utilizados nas doses anti-inflamatórias: ácido acetil salicílico (AAS), 500 a 750mg a cada 6 ou 8 horas, por 7 a 10 dias, seguido de redução gradual de 500 mg por semana, por três semanas; ibuprofeno, 400 a 800mg a cada 6 ou 8 horas, por 14 dias; indometacina, 75 a 150 mg ao dia. Na pericardite pós-infarto agudo do miocárdio, deve-se evitar o uso de indometacina, por estar relacionada à redução do processo cicatricial da área infartada224,225.
O tempo de tratamento da pericardite com AINH é em torno de 14 dias, usualmente, podendo ser guiado pelos níveis séricos da PCRT como marcador de atividade inflamatória. A retirada dos AINH deve ser progressiva e lenta para reduzir a possibilidade de recorrência226. Todos os pacientes devem fazer uso de inibidores de prótons para proteção da mucosa gástrica.
A colchicina tem demonstrado ser efetiva como terapêutica coadjuvante da pericardite aguda, no alívio da dor e na prevenção da recorrência ao fim de dezoito meses220,227. A dose é de 0,5 mg de 12/12 horas ou 0,5 mg a cada 24 horas nos pacientes com menos de 70 kg, pelo período de três meses no primeiro evento e 6 meses na pericardite recorrente228,229. Nas formas mais graves e recorrentes, alguns estudos sugerem o uso da colchicina por 12 a 24 meses após o último evento de recorrência com retirada gradual230,231.
O principal efeito adverso da colchinha é a diarreia que acomete cerca de 8% dos pacientes, e, com menos frequência, hepatotoxidade, miotoxidade e supressão da medula óssea. Assim, deve ser evitada em pacientes com insuficiência renal severa, disfunção hepática, discrasia sanguínea e distúrbios da motilidade gastrointestinal232-234.
A utilização de corticoides para supressão da atividade inflamatória da pericardite usualmente ocasiona dramática melhora clínica e inflamatória. Mas devem-se levar em consideração vários aspectos clínicos e fisiopatológicos que limitam a sua eficácia clínica como: 1) A terapia com corticoides favorece o desenvolvimento de recorrência por ocasionar o fenômeno de ancoramento imunológico; 2) Deve-se tentar definir o fator etiológico da pericardite para se ter uma previsão da resposta terapêutica, assim como de sua posologia; 3) Na suspeita de pericardite viral, deve-se pesquisar a presença viral através de análise do líquido pericárdico e por biópsia endopericárdica, para se afastar a presença viral antes da utilização do corticoide235.
A indicação da terapia com corticoide na pericardite aguda idiopática é para as situações de ausência de resposta terapêutica aos anti-inflamatórios não hormonais e à colchicina, ou quando a pericardite é secundária a doença autoimune, doença do tecido conectivo ou pericardite urêmica. A posologia recomendada é de 1 mg/kg de peso com duração de 2 a 4 semanas. Para se evitar o fenômeno de recorrência imunológica com reativação da pericardite, a retirada do corticoide deve ser lenta e deve-se se associar colchicina na dose de 1 mg por dia168,228.
A utilização de corticosteroide intrapericárdico demonstrou importante melhora clínica e baixa recorrência de pericardite ao fim de um ano. A vantagem dessa forma de terapêutica é evitar os efeitos do uso do corticoide sistêmico e o desenvolvimento de recorrência. O esquema terapêutico é a infusão de triancinolona 300 mg/12-12h/dose única, associada ao uso de colchicina por 6 meses. Todos os pacientes foram submetidos a biópsia pericárdica e epimiocárdica, para comprovação do processo inflamatório e para se afastar a presença de infecção viral ou de outros agentes etiológicos. A limitação desse procedimento se deve ao seu caráter invasivo221,236.
Na pericardite recorrente o primeiro aspecto a ser analisado é a pesquisa do possível fator causal: 1) esquema terapêutico inadequado; 2) posologia inadequada; 3) uso de corticoide associado a uma retirada rápida; 4) reativação em decorrência a replicação viral por uso de corticóide; 5) reinfecção; 6) reativação de doença autoimune ou do tecido conectivo. Na ausência de um desses fatores, consideramos o uso de corticoide nos pacientes com crises frequentes e com importante comprometimento das condições clínicas; recomenda-se o uso de prednisona 1-1,5 mg/kg, por 4 semanas com retirada lenta, de cerca de três meses. Em pacientes com recorrência frequente pode-se associar azatioprina na dose de 75-100mg/dia ou ciclofosfamida. Além disso, deve-se associar colchicina para redução da recorrência206,237.
A utilização de baixas doses de prednisona (0,2 a 0,5 mg/kg/dia/4 semanas) demonstrou a mesma eficácia terapêutica quando comparada a doses de 1 mg/kg/dia, mas com menor taxa de desenvolvimento de paraefeitos238.
As pericardites virais podem ser ocasionadas por diversos agentes virais. O diagnóstico é estabelecido através de pesquisa viral no tecido epimiocárdico, pericárdico e no líquido pericárdico. A terapêutica antiviral tem como objetivo não somente a melhora dos sintomas e a remissão da doença como também evitar a sua recorrência. Nas pericardites virais vários esquemas terapêuticos antivirais estão sendo testados: 1) pericardite por citomegalovírus: hiperimunoglobulina (4 ml/kg nos dia 0, 4, e 8; 2 ml/kg nos dias 12 e 16; 2); Coxsackie B: interferon alfa (2.5 milhões IU/m2, s.c. por 3 semanas); 3) adenovírus e PVB-19: imunoglobulina intravenosa (10 g nos dias 1 e 3). Embora o uso da imunoglobulina siga o mesmo racional de utilização da miocardite viral, faltam estudos clínicos randomizados para definir a eficácia desta terapêutica239,240.
Esse tratamento é a drenagem do líquido pericárdico de forma a reduzir a pressão intrapericárdica e, dessa forma, melhorar a hemodinâmica do paciente. Na estabilização da hemodinâmica do paciente, anterior à drenagem pericárdica, pode-se fazer a infusão rápida de cristaloide com objetivo de melhorar a perfusão, e na presença de bradicardia indica-se a utilização de aminas ou atropina. A drenagem pericárdica pode ser realizada através de inserção de uma punção percutânea e colocação de um cateter de drenagem ou através drenagem cirúrgica aberta com ou sem pericardioctomia (janela pericárdica), ou ainda através de pericardioscopia assistida do vídeo241. A pericardiocentese por cateter deve ser guiada pela ecocardiografia, que permite a identificação do melhor local e ângulo de pressão, reduzindo as complicações e aumentando as taxas de sucesso242. A drenagem por cateter pode necessitar alguns dias e o cateter não deve ser removido até a drenagem ser inferior a 20-30 ml/24h.
A drenagem cirúrgica tem a vantagem de permitir a realização de biópsia pericárdica, sendo a forma recomendada em casos de recidiva do derrame após a drenagem via cateter e em casos de coágulos ou derrames localizados não acessíveis pela via percutânea197.
A síndrome de constrição pericárdica é tratada pela excisão do pericárdio. Por causa de aderências densas e calcificação que podem penetrar no miocárdio, a ressecção pericárdica pode ser um desafio técnico. Na maioria dos centros, o procedimento é feito através de esternotomia mediana, com a eventual necessidade do uso de circulação extracorpórea243. O objetivo do procedimento é liberar os ventrículos do pericárdio densamente aderido. Cuidado especial deve ser tomado ao dissecar nas regiões dos vasos coronarianos epicárdicos. O objetivo é ressecar o pericárdio de nervo frênico a nervo frênico, e também, posteriormente, em torno da entrada das veias cavas e veias pulmonares. A ressecção completa deve restaurar a curva de pressão-volume244. A ressecção completa do pericárdio, entretanto, não é viável em todos os casos, notadamente na pericardite constritiva induzida por radiação. A mortalidade operatória tem sido relatada tão alta quanto 10 a 20%245,246. A sobrevida a longo prazo é menor em pacientes com cirurgia cardíaca prévia, e particularmente em pacientes com pericardite constritiva induzida por radiação247,248.
A
A doença renal crônica (DRC) grave é causa comum de doença pericárdica, incluindo pericardite e efusões pericárdicas. Múltiplos fatores contribuem para seu aparecimento, sendo em geral descritas de duas formas: urêmica e dialítica249.
A pericardite urêmica ocorre em torno de 10% dos pacientes, antecedendo a diálise ou logo após o seu início250. Sua fisiopatologia é pouco conhecida e parece não ter relação com a causa base da DRC (exceto no LES e na esclerodermia), mas principalmente com os níveis de ureia. Costuma ter boa resolutividade com a continuidade da terapia dialítica (TD).
A pericardite associada à diálise ocorre em torno de 15% dos pacientes em hemodiálise e mais raramente na diálise peritoneal. Está associada principalmente a hipervolemia e diálise inadequada. Por isso, a correção volêmica e adequação da TD são essenciais251.
As manifestações clínicas e laboratoriais são similares às observadas em pacientes não urêmicos com afecções pericárdicas semelhantes, exceto pela dor torácica, que costuma ocorrer menos nos pacientes com DRC terminal, e pelo eletrocardiograma não apresentar as alterações típicas da pericardite aguda, por ausência de inflamação miocárdica252,253.
A maioria dos pacientes respondem prontamente à diálise, com resolução da pericardite em cerca de uma a duas semanas. No manuseio do quadro álgico e inflamatório, podem ser utilizados AINH e corticosteroides, sendo que demonstraram menor eficácia nos pacientes refratários à diálise. Nesses casos, o uso de colchicina tem demonstrado algum benefício255. Já o uso de heparina durante a TD deve ser controlado. Raramente a pericardite urêmica evolui para constrição pericárdica.
Os pacientes que evoluem com tamponamento pericárdico ou derrame pericárdico de volume persistente sintomático devem ser tratados com pericardiocentese, associada com instilação intrapericárdica de corticoide (triamcinolona 50 mg, 6-6 horas por 3 dias)256. A pericardiectomia está indicada na pericardite recorrente com dor persistente refratária ao tratamento anti-inflamatório257.
A síndrome pós-pericardiotomia (SPP) acomete em torno de 10 a 15% dos pacientes submetidos a trauma cirúrgico cardíaco, pericárdico ou ambos, ocorrendo após dias ou até meses (80% no primeiro mês)258. Acredita-se que a fisiopatologia seja mista com o trauma cirúrgico, gerando em primeiro momento inflamação e, na sequência, processo autoimune (anticorpos antissarcolemais cardíacos)259.
A grande maioria dos pacientes cursa com envolvimento pleuropericárdico, como febre após a primeira semana pós-operatória (sem evidência de infecção sistêmica ou focal), dor torácica pleurítica, efusão pleural nova ou piora de preexistente. Com menos frequência, pode apresentar atrito pericárdico (1/3 dos pacientes) e alterações eletrocardiográficas típicas260. A evolução para tamponamento pericárdico ou pericardite constritiva é menos comum, porém a SPP frequentemente prolonga o internamento ou provoca recorrências e readmissões precoces.
Sugere-se como predisponente para a SPP o uso de ácido aminocaproico durante a cirurgia - cirurgias valvares ou combinadas (coronarianas e valvares). E, em estudo recente, o sexo feminino e a incisão pleural foram registrados como fatores de risco independentes261.
A prevenção primária com colchicina262 por curto período sugere ser especialmente útil, porém não há evidências que suportem o uso de metilprednisolona ou ácido acetilsalicílico260.
O tratamento na fase aguda da SPP é semelhante ao da pericardite aguda, compreende o uso de AINH e colchicina por semanas ou meses, até o desaparecimento da efusão - e a colchicina também está indicada nas recorrências229,263. Em casos refratários, o uso de corticoides por via oral (3 a 6 meses) ou pericardiocentese e instilação intrapericárdica de triancinolona são opções relatadas.
Derrame pericárdico é uma grave complicação de tumores malignos. Essa doença metastática é bem mais frequente, sendo o câncer de pulmão sua principal causa, seguido do câncer de mama, da melanoma, do linfoma e da leucemia264.
A evolução clínica costuma ser benigna. Casos sintomáticos podem apresentar desde queixas como desconforto torácico e dispneia, até grave evolução para tamponamento cardíaco265. O diagnóstico diferencial da efusão na maioria das vezes é difícil, por isso o diagnóstico definitivo é realizado através do exame citológico do líquido pericárdico.
Para alívio imediato de sintomas a drenagem percutânea e a abordagem cirúrgica são as opções. Na prevenção de recorrências, várias abordagens têm sido propostas: esclerose local, janela pericárdica, quimioterapia sistêmica e/ou local, radioterapia266. A bleomicina para esclerose intrapericárdica, em comparação com a drenagem pericárdica isolada, revelou apenas modesto benefício267. Nos casos secundários ao adenocarcinoma de pulmão a drenagem cirúrgica parece ser a melhor opção268.
A pericardite induzida por radiação pode ocorrer agudamente durante o tratamento radioterápico ou até anos após o seu término. Os pacientes podem se apresentar oligossintomáticos ou com os sintomas mascarados pela doença neoplásica de base. O derrame pode ser hemorrágico ou seroso, podendo evoluir com aderências e constrição. A pericardite deve ser tratada de forma conservadora na ausência de sintomas, ou com pericardiocentese para avaliação na dúvida diagnóstica e nos pacientes com tamponamento. A pericardiectomia está indicada nos pacientes que evoluem com constrição pericárdica, e apresenta alta mortalidade operatória e baixa sobrevida em 5 anos269.
A pericardite tuberculosa (PTBC) ocorre em 1-4% da população com tuberculose (TBC) pulmonar270,271 e a TBC é responsável por 7% dos casos de tamponamento171.
A PTBC pode apresentar-se em quatro estágios: seco, efusivo, fase absortiva e fase constritiva272. A mortalidade da PTBC não tratada é de aproximadamente 85%. A constrição pericárdica ocorre em 30-50%273.
Sua apresentação clínica é variável: pericardite aguda com ou sem derrame; tamponamento cardíaco silencioso; febre persistente; pericardite constritiva aguda, subaguda, efusiva ou crônica; e calcificações pericárdicas274.
A PTBC é insidiosa no começo, mas pode começar súbita e dramaticamente em 20-25%271. O ecocardiograma é o melhor método para a confirmação da presença de derrame pericárdico. O diagnóstico é feito pela identificação do
Na PTBC, o líquido pericárdico apresenta alta contagem de proteína e a contagem de leucócitos é altamente variável (700 a 54000/ml). Esses achados não são específicos e somente 40 a 60% dos pacientes com PTBC submetidos à pericardiocentese tiveram bacilo no exame direto275. Também a especificidade do teste tuberculínico tem baixa predictabilidade em áreas onde há alta incidência de TBC. O teste tuberculínico realizado na pele pode ser falso negativo em 25-33% dos pacientes, e falso positivo em 30-40% em se tratando de pacientes idosos276.
A cultura do líquido pericárdico tem sensibilidade modesta e especificidade de 100%277. A alta atividade da adenosina deaminase (ADA) e a concentração de interferon-c no líquido pericárdico são também diagnósticos, com uma alta sensibilidade e especificidade278.
Outro método para detecção de
Já o uso do teste do interferon-gama (TIG) está aprovado para uso em sangue periférico e não em outros líquidos, tais como líquido pleural ou pericárdico. Não é certo que o TIG no fluido pericárdico tenha vantagens significativas comparadas com a ADA.
O envolvimento perimiocárdico da TBC é também associado com altas titulações de anticorpos antimiosina e antimiolema280.
A biópsia pericárdica permite que se faça um rápido diagnóstico, com melhor sensibilidade do que a pericardiocentese (100% vs. 33%). A mortalidade relatada em estudos com endoscópio rígido foi de 2,1%281 e 3,5%282 devido à indução anestésica em pacientes com derrame pericárdico muito volumoso.
Várias combinações de drogas antituberculose de diferentes períodos de duração de tratamento (6, 9, 12 meses) têm sido aplicadas283. Somente pacientes com PTBC comprovada ou muito provável devem ser tratados. A prevenção da constrição no derrame pericárdico crônico de etiologia indeterminada com medicação antituberculose não obteve sucesso284.
O uso de esteroides permanece controverso. Uma meta-análise de pacientes com PTBC com derrame e constritiva sugerem que o tratamento via tuberculostáticos combinado com esteroides poderia estar associado com redução da mortalidade, menor necessidade de pericardiocentese ou pericardiectomia285,286. Se, a despeito da terapia combinada, há o desenvolvimento de constrição, a pericardiectomia está indicada.
O tratamento medicamentoso para todos os pacientes com PTBC (outras formas de TBC extrapulmonar) é um regime inicial de quatro drogas (
A fase inicial do tratamento geralmente consiste em terapia diária, ilustrada em cada uma das diferentes opções (
As pericardites purulentas apresentam elevada morbidade e mortalidade, porém são raras nos adultos288. As condições predisponentes são doença de derrame pericárdico pré-existente, cirurgia cardíaca ou trauma torácico recente, DRC, imunossupressão, abuso de álcool, artrite reumatoide e neoplasias malignas. A etiologia fúngica é mais rara ainda e habitualmente ocorre em pacientes com infecções fúngicas em outros sítios289.
A apresentação mais comum é a de doença infecciosa aguda, sendo pouco frequentes a dor torácica e o atrito pericárdico. Podem-se observar anemia, leucocitose, alterações eletrocardiográficas e radiográficas, porém o ecocardiograma é um dos métodos mais utilizados para detectar e quantificar derrames pericárdicos. Outros métodos podem ser utilizadosm, como a tomografia computadorizada e a ressonância cardíaca290.
A suspeita diagnóstica se faz através do quadro clínico, quando da presença de derrame pericárdico ao ecocardiograma. A confirmação diagnóstica depende da pericardiocentese com realização de Gram, cultura, além de pesquisa para fungos e tuberculose. Os agentes Gram positivos são mais prevalentes (64,2%), seguidos pelos Gram negativos (27,7%) e fungos (1,4%)291,292.
O tratamento é através de drenagem do líquido pericárdico por pericardiocentese e uso de antimicrobianos, inicialmente para estafilococo, até se obter os resultados da cultura. Em casos de derrames septados em várias lojas, o uso de trombolíticos pode ser considerado, em especial a estreptoquinase na dose de 500.000UI a cada 12 horas (total de três doses)293,294. A realização de drenagem pericárdica com pericardiectomia é o procedimento de escolha, principalmente nas formas persistentes ou recorrentes168.
As indicações para o diagnóstico e tratamento da pericardite purulenta se encontram na
Processos autoimunes de envolvimento sistêmico podem resultar em pericardite295 como observado em artrite reumatoide, lúpus eritematoso sistêmico, esclerose sistêmica múltipla, polimiosite, doença mista do colágeno, espondilites soronegativas, síndrome de Sjogren, vasculites sistêmicas, síndrome de Behcet, granulomatose com poliangeíte, sarcoidose, entre outras.
O quadro clínico varia desde o de um achado assintomático até uma manifestação de pericardite aguda, menos comumente de tamponamento, havendo registros de pericardite constritiva transitória296. Sua evolução para pericardite constritiva crônica é rara. O manuseio das formas habituais geralmente se dirige para o tratamento habitual da causa subjacente.
Uma forma isolada de pericardite autoimune tem sido descrita, quando uma sistemática procura de evidências de autoagressão é demonstrada, por exemplo, pelo predomínio de linfócitos ou o achado de autoanticorpos contra sarcolema297 no líquido pericárdico. Exclui-se a presença de vírus ou de outros agentes infecciosos (ausência de IgM contra vírus cardiotrópicos no líquido pericárdico e pesquisa de PCR negativo para tais agentes), além de doenças sistêmicas ou neoplásicas.
O tratamento é o usual da pericardite aguda e do derrame pericárdico, associado à abordagem terapêutica da doença de base (
O uso de triancinolona intrapericárdica 300 mg/m2/24h diluída em 100 ml de soro, mostrou-se eficaz em aliviar sintomas e prevenir recorrências, evitando os efeitos colaterais de corticoide oral298.
Quilopericárdio se refere à condição de acúmulo de material de drenagem do ducto torácico no pericárdio como resultado de fístula, complicando cirurgia de mediastino, cirurgia cardiovascular, traumatismo torácico, tumores mediastínicos ou anomalias congênitas do ducto torácico250.
O líquido pericárdico é de aspecto branco leitoso, opalescente, com alto conteúdo de triglicerídeos (5-50 g/L) e proteína(22-60 g/L) e gorduras. A ressonância magnética traz grandes subsídios para firmar o diagnóstico por meio da sequência dos sinais T1 e T2299.
Eventualmente se confunde com o de outras etiologias e somente é esclarecido após exploração cirúrgica do pericárdio300. O tratamento é de acordo com a etiologia e a quantidade de líquido pericárdico. Em situações em que este é secundário a cirúrgica cardíaca ou torácica, sem sinais de tamponamento, o tratamento poderá ser conduzido com punção ocasional e dieta com triglicérides de cadeia média301. Em casos refratários ao tratamento conservador, cirurgia com derivação pericardioperitoneal ou de forma alternativa à ligadura do ducto torácico, quando se consegue identificar o seu percurso302.
Derrame pericárdico em hipotireoidismo é relativamente comum, sendo registrado em 30 a 80% dos casos mais avançados da doença e em 3 a 6% das formas mais precoces303. Embora raramente se complique por tamponamento, essa ocorrência pode ser registrada, e uma pista para seu desenvolvimento pode ser a da presença de frequência cardíaca inesperadamente elevada num quadro de hipotireoidismo, com baixa voltagem de QRS304.
O tratamento do derrame pericárdico é facilmente obtido com o tratamento do hipotireoidismo (
As duas formas de manifestação da pericardite após o IAM são a pericardite epistenocárdica, com apresentação "precoce", também chamada pericardite peri-infarto, e a pericardite "tardia" pós-infarto, ou síndrome de Dressler. A incidência de ambas está em declínio305,306. Dor pericárdica e atrito pericárdico definem a pericardite peri-infarto e geralmente ela se desenvolve no 2º ou 3º dia após um IAM transmural. As manifestações eletrocardiográficas são de difícil identificação, pois são superpostas pelas alterações do infarto. A persitência de ondas T invertidas ou a normalização destas pode sugerir a presença de pericardite. O curso clínico é benigno, e o prognóstico do paciente não é alterado pelo desenvolvimento desta complicação.
A pericardite pós-infarto ocorre em aproximadamente 5% a 6% de pacientes trombolisados e desenvolve-se normalmente durante a segunda semana, podendo vir a se manifestar meses pós o IAM. Deve ser suspeitada em qualquer paciente com dor pleuropericárdica. Atrito pericárdico pode ou não se manifestar. A diferenciação de pericardite e angina recorrente pode ser difícil, mas uma história cuidadosa e avaliação eletrocardiográfica seriada podem ajudar na distinção. A maioria dos casos tem curso benigno; no entanto, como está associada a infartos maiores, a taxa de mortalidade global em longo prazo é maior307.
Complicações raras incluem hemopericárdio, tamponamento cardíaco e pericardite constritiva. A terapia é direcionada para o alívio da dor, geralmente respondendo bem a antiinflamatórios não esteroidais. No entanto, permanece em grande parte empírica devido à relativa falta de ensaios clínicos controlados308,309. Além disso, a duração do tratamento também não está bem estabelecida: podemos, entretanto, gerar algumas recomendações. O ibuprofeno, 1600-3200 mg/dia, por até 2 semanas, tem sido o fármaco de escolha por aumentar o fluxo sanguíneo coronariano e apresentar menor incidência de efeitos adversos224,310. AAS, 2-4 g/dia, por 2 a 5 dias também pode ser utilizado com igual eficácia (4). Para pacientes com sintomas refratários e recorrentes, a colchicina, 0,6mg, duas vezes ao dia, é preferível a corticosteroides orais, que devem ser restritos a baixas doses (prednisona, 0,2-0,5 mg / kg / dia)223,311,312.
A doença pericárdica é a manifestação clínica mais frequente da doença cardiovascular em pacientes com AIDS. O derrame pericárdico (DP) ocorre em 20% (10 a 40%), sendo volumoso em 4%313-316, sendo 2/3 são causados por infecção ou neoplasia, e esta relacionada a um pior prognóstico317.
O quadro clínico da pericardite no HIV é similar ao de outras etiologias. O achado do
O tratamento da pericardite em portadores de HIV é sintomático e preventivo. Se o derrame é sintomático, recorrente ou crônico, com confirmada infecção viral, o tratamento específico deve ser instituído242.
O tamponamento cardíaco ocorre entre 33 e 40% dos casos, e a drenagem imediata é necessária. Se o derrame pericárdico for volumoso em pacientes portadores de AIDS, sem etiologia estabelecida, o tratamento empírico para
A pericardite pós-traumática é secundária a acidentes ou ferimentos iatrogênicos, sendo que, nestes casos, situações mais graves podem levar ao derrame e tamponamento pericárdico, o que gera necessidade de intervenção cirúrgica de emergência. A lesão do tórax e do coração, fechada ou penetrante com contusão miocárdica, pode provocar pericardite. Essa pericardite, no entanto, possui pouca significância clínica e pode se desenvolver dias ou meses após a lesão cardíaca ou torácica. O processo inflamatório parece ser devido à produção de anticorpos como resposta à injúria miocárdica. A pericardite pós-cirurgia cardíaca tem sido reportada em 20% dos casos de cirurgia de revascularização miocárdica, desenvolvendo-se de dias a meses após a intervenção.
A pericardite iatrogênica ocorre infrequentemente em menos de 0.2% de intervenções percutâneas. Entre as mais frequentes temos valvuloplastia mitral percutânea, punção transeptal, transecção de artéria coronária após angioplastia, biópsia endomiocárdica, implante de eletrodo de marcapasso no ventrículo direito ou implante de eletrodos epicárdicos.
Outra situação de pericardite por injúria ocorre nos casos de radiação torácica ou mediastinal, utilizada para a terapêutica de uma variedade de neoplasias, principalmente a doença de Hodgkin, os linfomas não Hodgkin e o carcinoma de mama. A probabilidade de desenvolver a pericardite está relacionada à fonte de aplicação da radiação, à dose, ao fracionamento, à duração, ao volume de exposição, ao campo de aplicação e à idade do paciente. A pericardite induzida pela radiação pode ocorrer durante a terapia ou meses e anos mais tarde167,168.
Na dissecção aórtica o derrame pericárdico ocorre em 17-45% dos pacientes e em 48% das autópsias329. A dissecção da aorta ascendente é comumente complicada com hemopericárdio que pode ser fatal. O diagnóstico é estabelecido usualmente por ecocardiograma transesofágico, tomografia do tórax ou ressonância do coração e da aorta330.
A pericardiocentese está contraindicada pelo risco de aumentar o sangramento e agravar a dissecção. Os pacientes devem ser submetidos imediatamente a cirurgia para correção da aorta e drenagem pericárdica331.
A pericardite recorrente geralmente ocorre de 18 a 20 meses após um episódio inicial de pericardite que foi resolvida. Ela pode surgir em cerca de 15 a 32% dos casos e apresenta-se sob duas formas: intermitente (períodos sem sintomas na ausência de tratamento) e incessante (a suspensão do tratamento faz com que os sintomas retornem)168,254. Os mecanismos envolvidos no desenvolvimento da recorrência são: 1) tratamento inadequado com AINH ou corticoide (dose, tempo); 2) uso inadequado de corticóide, ocasionando replicação viral; 3) reinfecção viral; 4) reativação de doença autoimune.
A utilização de colchicina é a terapêutica mais segura e eficaz para prevenção da pericardite, principalmente quando o uso de AINH ou corticoide não falharam em impedir a recorrência332.
A terapia com corticoides está indicada nos pacientes com recorrência frequente ou com importante comprometimento clínico. Na ausência de resposta adequada ao corticosteroide, pode-se associar azatioprina ou ciclosporina206. Um dos principais fatores determinantes da recorrência é a redução rápida da dose de corticoide, que não deve ser feita num período inferior a três meses.
A pericardiectomia está indicada para os casos com recorrência frequente, muito sintomática e refratária à terapêutica333-335.
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261. Imazio M, Brucato A, Markel G, Cemin R, Trinchero R, Spodick DH, et al. Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome. Am J Cardiol. 2011;108(4):575-9.
262. Ashikhmina EA, Schaff HV, Sinak LJ, Li Z, Dearani JA, Suri RM, et al. Pericardial effusion after cardiac surgery: risk factors, patient profiles, and contemporary management. Ann Thorac Surg. 2010;89(1):112-8.
263. Imazio M, Trinchero R, Brucato A, Rovere ME, Gandino A, Cemin R, et al. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur Heart J. 2010;31(22):2749-54.
264. Cocco G, Chu DC, Pandolfi S. Colchicine in clinical medicine: a guide for internists. Eur J Intern Med. 2010;21(6):503-8.
265. Maisch B, Ristic A, Pankuweit S. Evaluation and management of pericardial effusion in patients with neoplastic disease. Prog Cardiovasc Dis. 2010;53(2):157-63.
266. Balghith M, Taylor DA, Jugdutt BI. Cardiac tamponade as the first clinical manifestation of metastatic adenocarcinoma of the lung. Can J Cardiol. 2000;16(7):925-7.
267. Lestuzzi C. Neoplastic pericardial disease: old and current strategies for diagnosis and management. World J Cardiol. 2010;2(9):270-9.
268. Kunitoh H, Tamura T, Shibata T, Imai M, Nishiwaki Y, Nishio M, et al; JCOG Lung Cancer Study Group, Tokyo, Japan. A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer. 2009;100(3):464-9.
269. Kim SH, Kwak MH, Park S, Kim HJ, Lee HS, Kim MS, et al. Clinical characteristics of malignant pericardial effusion associated with recurrence and survival. Cancer Res Treat. 2010;42(4):210-6.
270. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010;7(10):564-75.
271. Fowler NO. Tuberculous pericarditis. JAMA. 1991;266(1):99-103.
272. Sagristà-Sauleda J, Permanyer-Miralda G, Soler-Soler J. Tuberculous pericarditis: ten year experience with a prospective protocol for diagnosis and treatment. J Am Coll Cardiol. 1988;11(4):724-8.
273. Ortbals DW, Avioli LV. Tuberculous pericarditis. Arch Intern Med. 1979;139(2):231-4.
274. Long R, Younes M, Patton N, Hershfield E. Tuberculous pericarditis: long-term outcome in patients who received medical therapy alone. Am Heart J. 1989;117(5):1133-9.
275. Fowler NO, Manitsas GT. Infectious pericarditis. Prog Cardiovasc Dis. 1973;16(3):323-36.
276. Porte HL, Janecki-Delebecq TJ, Finzi L, Métois DG, Millaire A, Wurtz AJ. Pericardioscopy for primary management of pericardial effusion in cancer patients. Eur J Cardiothorac Surg. 1999;16(3):287-91.
277. Ewer K, Deeks J, Alvarez L, Bryant G, Waller S, Andersen P, et al. Comparison of T-cell-based assay with tuberculin skin test for diagnosis of
278. Reuter H, Burgess L, van Vuuren W, Doubell A. Diagnosing tuberculous pericarditis. QJM. 2006;99(12):827-39.
279. Lee JH, Lee CW, Lee SG, Yang HS, Hong MK, Kim JJ, et al. Comparison of polymerase chain reaction with adenosine deaminase activity in pericardial fluid for the diagnosis of tuberculous pericarditis. Am J Med. 2002;113(6):519-21.
280. Piersimoni C, Scarparo C. Relevance of commercial amplification methods for direct detection of
281. Nugue O, Millaire A, Porte H, de Groote P, Guimier P, Wurtz A, et al. Pericardioscopy in the etiologic diagnosis of pericardial effusion in 141 consecutive patients. Circulation. 1996;94(7):1635-41.
282. Koh KK, Kim EJ, Cho CH, Choi MJ, Cho SK, Kim SS, et al. Adenosine deaminase and carcinoembryonic antigen in pericardial effusion diagnosis, especially in suspected tuberculous pericarditis. Circulation. 1994;89(6):2728-35.
283. Strang JI, Kakaza HH, Gibson DG, Allen BW, Mitchison DA, Evans DJ, et al. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet. 1988;2(8614):759-64.
284. Dwivedi SK, Rastogi P, Saran RK, Narain VS, Puri VK, Hasan M. Antitubercular treatment does not prevent constriction in chronic pericardial effusion of undetermined etiology: a randomized trial. Indian Heart J. 1997;49(4):411-4.
285. Alzeer AH, FitzGerald JM. Corticosteroids and tuberculosis: risks and use as adjunct therapy. Tuber Lung Dis. 1993;74(1):6-11.
286. Mayosi BM, Ntsekhe M, Volmink JA, Commerford PJ. Interventions for treating tuberculous pericarditis. Cochrane Database Syst Rev. 2002;(4):CD000526.
287. Strang JI. Rapid resolution of tuberculous pericardial effusions with high dose prednisone and anti-tuberculous drugs. J Infect. 1994;28(3):251-4.
288. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN, et al. American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167(4):603-62.
289. Parikh SV, Memon N, Echols M, Shah J, McGuire DK, Keeley EC. Purulent pericarditis: report of 2 cases and review of the literature. Medicine (Baltimore). 2009;88(1):52-65.
290. Skiest DJ, Steiner D, Werner M, Garner JG. Anaerobic pericarditis: case report and review. Clin Infect Dis. 1994;19(3):435-40.
291. Majid AA, Omar A. Diagnosis and management of purulent pericarditis: experience with pericardiectomy. J Thorac Cardiovasc Surg. 1991;102(3):413-7.
292. Imazio M, Mayosi BM, Brucato A, Markel G, Trinchero R, Spodick DH, et al. Triage and management of pericardial effusion. J Cardiovasc Med (Hagerstown). 2010;11(12):928-35.
293. Imazio M, Brucato A, Mayosi BM, Derosa FG, Lestuzzi C, Macor A, et al. Medical therapy of pericardial diseases: part I: idiopathic and infectious pericarditis. J Cardiovasc Med (Hagerstown). 2010;11(10):712-22.
294. Tomkowski WZ, Gralec R, Kuca P, Burakowski J, Orłowski T, Kurzyna M. Effectiveness of intrapericardial administration of streptokinase in purulent pericarditis. Herz. 2004;29(8):802-5.
295. Augustin P, Desmard M, Mordant P, Lasocki S, Maury JM, Heming N, et al. Clinical review: intrapericardial fibrinolysis in management of purulent pericarditis. Crit Care. 2011;15(2):220.
296. Rose NR. Recurrent pericarditis: an autoimmune disease? Heart. 2010;96(10):734-5.
297. Haley JH, Tajik AJ, Danielson GK, Schaff HV, Mulvagh SL, Oh JK. Transient constrictive pericarditis: causes and natural history. J Am Coll Cardiol. 2004;43(2):271-5.
298. Caforio AL, Brucato A, Doria A, Brambilla G, Angelini A, Ghirardello A, et al. Anti-heart and anti-intercalated disk autoantibodies: evidence for autoimmunity in idiopathic recurrent acute pericarditis. Heart. 2010;96(10):779-84.
299. Maisch B, Ristic AD, Seferovic PM, Spodick DH. Intrapericardial treatment of autoreactive myocarditis with triamcinolon: successful administration in patients with minimal pericardial effusion. Herz. 2000;25(8):781-6.
300. Frank H, Globits S. Magnetic resonance imaging evaluation of myocardial and pericardial disease. J Magn Reson Imaging. 1999;10(5):617-26.
301. Weyne A, Lampaert A, Clement D. Chyle: a masquerading etiology of pericardial effusion. Int J Cardiol. 1987;14(1):106-9.
302. Gabriel Martínez J, Marco E, Marín F, Ibáñez A, Quiles JA, Cabezas A, et al. [Chylopericardium after acute pericarditis]. Rev Esp Cardiol. 1996;49(3):226-8.
303. Scholten C, Staudacher M, Girsch W, Wolf G, Grimm M, Binder T, et al. A novel therapeutic strategy for the management of idiopathic chylopericardium and chylothorax. Surgery. 1998;123(3):369-70.
304. Kabadi UM, Kumar SP. Pericardial effusion in primary hypothyroidism. Am Heart J. 1990;120(6 Pt 1):1393-5.
305. Lee KO, Choo MH. Low voltage electrocardiogram with tachycardia in hypothyroidism--a warning sign of cardiac tamponade. Ann Acad Med Singapore. 1993;22(6):945-7.
306. Gregoratos G. Pericardial involvement in acute myocardial infarction. Cardiol Clin. 1990;8(4):601-8.
307. Shahar A, Hod H, Barabash GM, Kaplinsky E, Motro M. Disappearance of a syndrome: Dressler's syndrome in the era of thrombolysis. Cardiology. 1994;85(3-4):255-8.
308. Indik JH, Alpert JS. Post-myocardial infarction pericarditis. Curr Treat Options Cardiovasc Med. 2000;2(4):351-6.
309. Berman J, Haffajee CI, Alpert JS. Therapy of symptomatic pericarditis after myocardial infarction: retrospective and prospective studies of aspirin, indomethacin, prednisone, and spontaneous resolution. Am Heart J. 1981;101(6):750-3.
310. Imazio M, Brucato A, Trinchero R, Spodick D, Adler Y. Individualized therapy for pericarditis. Expert Rev Cardiovasc Ther. 2009;7(8):965-75.
311. Boden WE, Sadaniantz A. Ventricular septal rupture during ibuprofen therapy for pericarditis after acute myocardial infarction. Am J Cardiol. 1988;55(13 Pt 1):1631-2.
312. Eppert A. Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: colchicine as an adjunct to nonsteroidal anti-inflammatory drugs for the treatment of acute pericarditis. Emerg Med J. 2011;28(3):244-5.
313. Lotrionte M, Biondi-Zoccai G, Imazio M, Castagno D, Moretti C, Abbate A, et al. International collaborative systematic review of controlled clinical trials on pharmacologic treatments for acute pericarditis and its recurrences. Am Heart J. 2010;160(4):662-70.
314. Corallo S, Mutinelli MR, Moroni M, Lazzarin A, Celano V, Repossini A, et al. Echocardiography detects myocardial damage in AIDS: prospective study in 102 patients. Eur Heart J. 1988;9(8):887-92.
315. Himelman RB, Chung WS, Chernoff DN, Schiller NB, Hollander H. Cardiac manifestations of human immunodeficiency virus infection: a two-dimensional echocardiographic study. J Am Coll Cardiol. 1989;13(5):1030-6.
316. De Castro S, Migliau G, Silvestri A, D'Amati G, Giannantoni P, Cartoni D, et al. Heart involvement in AIDS: a prospective study during various stages of the disease. Eur Heart J. 1992;13(11):1452-9.
317. Heidenreich PA, Eisenberg MJ, Kee LL, Somelofski CA, Hollander H, Schiller NB, et al. Pericardial effusion in AIDS: incidence and survival. Circulation. 1995;92(11):3229-34.
318. Estok L, Wallach F. Cardiac tamponade in a patient with AIDS: a review of pericardial disease in patients with HIV infection. Mt Sinai J Med. 1998;65(1):33-9.
319. Maher D, Harries AD. Tuberculous pericardial effusion: a prospective clinical study in a low-resource setting--Blantyre, Malawi. Int J Tuberc Lung Dis. 1997;1(4):358-64.
320. Dronda F, Suzacq C. [Pericardial tuberculosis complicated with heart tamponade as presentation form of acquired immunodeficiency syndrome]. Rev Clin Esp. 1997;197(7):502-6.
321. Nogueira G, Macedo AJ, Paixão A, Nunes MA, Ferreira M, Bernardino L, et al. [Cardiovascular morbidity in children with human immunodeficiency virus infection]. Acta Med Port. 1998;11(12):1051-7.
322. Sá I, Môço R, Cabral S, Reis AH, Pereira LS, Torres S, et al. Constrictive pericarditis of tuberculous etiology in the HIV-positive patient: case report and review of the literature. Rev Port Cardiol. 2006;25(11):1029-38.
323. Sudano I, Spieker LE, Noll G, Corti R, Weber R, Lüscher TF. Cardiovascular disease in HIV infection. Am Heart J. 2006;151(6):1147-55.
324. Ntsekhe M, Mayosi BM. Cardiac manifestations of HIV infection: an African perspective. Nat Clin Pract Cardiovasc Med. 2009;6(2):120-7.
325. Campbell PT, Li JS, Wall TC, O'Connor CM, Van Trigt P, Kenney RT, et al. Cytomegalovirus pericarditis: a case series and review of the literature. Am J Med Sci. 1995;309(4):229-34.
326. Acierno LJ. Cardiac complications in acquired immunodeficiency syndrome (AIDS): a review. J Am Coll Cardiol. 1989;13(5):1144-54.
327. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med. 1991;324(5):289-94.
328. Sunderam G, McDonald RJ, Maniatis T, Oleske J, Kapila R, Reichman LB. Tuberculosis as a manifestation of the acquired immunodeficiency syndrome (AIDS). JAMA. 1986;256(3):362-6.
329. Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis. 2007;50(3):218-36.
330. Nienaber CA, von Kodolitsch Y, Nicolas V, Siglow V, Piepho A, Brockhoff C, et al. The diagnosis of thoracic aortic dissection by noninvasive imaging procedures. N Engl J Med. 1993;328(1):1-9.
331. Erbel R, Alfonso F, Boileau C, Dirsch O, Eber B, Haverich A, et al. Diagnosis and management of aortic dissection. Eur Heart J. 2001;22(18):1642-81.
332. Mellwig KP, Vogt J, Schmidt HK, Gleichmann U, Minami K, Körfer R. [Acute aortic dissection (Stanford A) with pericardial tamponade - extension of the dissection after emergency pericardial puncture]. Z Kardiol. 1998;87(6):482-6.
333. Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, et al; CORP (COlchicine for Recurrent Pericarditis) Investigators. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med. 2011;155(7):409-14.
334. Miller JI, Mansour KA, Hatcher CR Jr. Pericardiectomy: current indications, concepts, and results in a university center. Ann Thorac Surg. 1982;34(1):40-5.
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Marcelo W. Montera Rua Dona Mariana, 209 - 2º andar - Botafogo Rio de Janeiro Cep: 22280-020 E-mail:
IHospital Pró-Cardíaco
IIUniversidade Federal Fluminense
IIIInstituto do Coração - FMUSP
IVHospital do Coração - HCOR
VLabs D'Or - Grupo Fleury / Instituto D'Or de Pesquisa e Ensino
VIHospital Santa Izabel da Santa Casa de Misericórdia da Bahia
VIIHospital TotalCor
VIIIClínica São Vicente
IXHospital de Messejana Dr. Carlos Alberto Studart Gomes
XSanta Casa de Curitiba
XIPontificia Universidade Católica do Paraná
XIIUniversidade do Estado do Rio de Janeiro - UERJ
XIIIHospital Unimed-Rio
XIVEcocenter - Hospital SOCOR (MG)
XVFaculdade de Medicina da Universidade Federal de Minas Gerais
XVIHospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
XVIIHospital Israelita Albert Einstein
XVIIIPronto-Socorro Cardiológico de Pernambuco, Universidade de Pernambuco
XIXInstituto de Cardiologia, Fundação Universitária de Cardiologia (RS)
XXHospital Nossa Senhora da Conceição
XXIInstituto Nacional de Cardiologia
XXIIHospital Federal dos Servidores do Estado (RJ)
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The true incidence of myocarditis is difficult to estimate due to factors such as diversified clinical presentation, the continued infrequency of endomyocardial biopsy (EMB) performance, and the lack of sensitive and standardized histological criteria.
Based on autopsy reports, the estimated incidence of myocarditis varies from 0.2 to 12% and depends on the investigated population1,2. The
The prevalence of myocarditis is higher in males, especially in young adults, and it represents a main cause of sudden death in children and adults younger than 40 years old 5. Pediatric survivors of myocarditis exhibit increased mortality and requirements for heart transplantation over a 12-year span.
Myocarditis might also be present in other types of cardiomyopathy, such as amyloidosis and hypertrophic cardiomyopathy, as well as in patients with acute myocardial infarction, for which it is a factor of poor prognosis6,7.
Myocarditis can be triggered by several infectious and non-infectious causes, and the most prevalent form occurs secondarily to viral infections (
Viral infections are the most common of the various infectious diseases that can induce myocarditis. The most prevalent cardiotropic viruses include adenoviruses, enteroviruses, parvovirus B19, the herpes simplex virus, the hepatitis C virus (HCV), cytomegalovirus (CMV), and the Epstein-Barr virus. Variations in viral prevalence profiles depend on the investigated geographical area. Adenoviruses, parvoviruses, and herpes viruses are prevalent in Brazil and in Europe, whereas enteroviruses predominate in the United States10. Multiple viral infections occur in approximately 30% of viral myocarditis cases.
According to autopsy reports, myocarditis is found in more than 50% of human immunodeficiency virus (HIV/AIDS)-infected patients. Non-viral infectious microbial causes of myocarditis include
In South America, particularly in some areas of Brazil, Chagas myocarditis, which is caused by the protozoan
Drugs such as cyclophosphamide, phenytoin, zidovudine, and amphetamines can induce eosinophilic hypersensitivity myocarditis or exhibit direct myocardial toxicity. Eosinophilic hypersensitivity myocarditis must be suspected if peripheral blood eosinophilia or myocardial eosinophilic infiltrates are observed. Vaccination-induced eosinophilic-lymphocytic myocarditis should also be considered13-15.
Autoimmune systemic diseases such as Churg-Strauss syndrome16 and hypereosinophilic syndrome are associated with eosinophilic myocarditis17. Although rare, prognoses of giant-cell myocarditis and sarcoidosis might change as a function of early diagnosis and appropriate treatment18,19.
Of the connective tissue diseases, rheumatoid arthritis, dermatomyositis, and systemic lupus erythematosus are associated with the highest rates of myocardial inflammatory activity.
Possible etiological factors of peripartum cardiomyopathy include viral activity, autoimmunity, nutritional disorders, and family origin. The prevalence of myocarditis is variable and could occur in as many as 62% of the patients who were subjected to endomyocardial biopsy. Likely, myocarditis in response to viral infections and autoimmune diseases is due to a higher susceptibility to viral infections during pregnancy and postpartum immune responses to fetal cells20,21.
Viral myocarditis is comprised of acute, subacute, and chronic phases. These temporal and physiopathological stages indicate important diagnostic and therapeutic considerations22.
The acute stage is characterized by the presence of viremia. Myocyte loss due to necrosis occurs as a direct result of viral activity, the cytotoxic effects of inflammatory mediators, and oxidative stress products associated with endothelial dysfunction and ischemia23. Direct effects result from viral entry into the cells, which is mediated by membrane receptors such as CAR (
The subacute phase lasts from day 4 to day 14 post-inoculation. T lymphocyte infiltration of the myocardium reaches a peak level at 7 to 14 days post-inoculation, and the greatest myocardial cell damage occurs during this period. Additionally, B lymphocyte infiltration appears and gradually increases from the first to the third month26. The humoral immune response plays an important role in the processes of myocardial damage and dysfunction. Direct or indirect myocyte injury releases myosin into the circulation, promoting the release of anti-myosin heavy chain antibodies, and also stimulates CD4+ T lymphocytes, which can perpetuate and amplify cardiac cell damage. CD4+ T lymphocyte-stimulated amplification stimulates the production of anti-myosin antibodies from B-lymphocytes, as well as the cytotoxic activity of CD8+ T lymphocytes. Antibody cross-reactivity between viral antigens and myocardial cells can also contribute to myocyte damage. Sera from myocarditis patients exhibits immunohistochemical motifs that could react with various cardiac myocyte membrane or cytoplasmic proteins 27.
The chronic phase extends from day 15 to day 90 post-inoculation and is characterized by intense collagen deposition in the myocardial interstitium, myocardial fibrosis, and progression to heart dilation, dysfunction and failure28,29.
In addition to direct bacterial effects on myocytes, bacterial myocarditis-related cell damage is caused by the considerable production of toxins (variations in toxicity levels depend on the etiological agent) and intense inflammatory responses, which are characterized by high cytokine levels and infiltration of inflammatory cells such as macrophages and natural killer cells.
In drug-induced myocarditis, sensitivity responses can vary from hours to months. Hypersensitivity is partially explained as a response to chemically reactive components that bind to proteins and promote structural alterations. These particles are phagocytized by defense cells and macrophages, which subsequently present then to T lymphocytes through surface receptor. Cytokines such as interleukin-5 (IL-5), which stimulates eosinophils, are released as part of the delayed hypersensitivity response. IL-5 accumulation promotes high levels of eosinophilic infiltration, increased hypersensitivity responses, and increased myocardial injury. Genetic predisposition seems to favor this type of response.
Hypereosinophilic syndrome is associated with several systemic diseases such as Churg-Strauss syndrome, cancer, and parasitic and helminth infections, as well as vaccinations. Those can trigger an intense inflammatory response in the myocardium that results in cell injury, dysfunction, and heart failure30-32.
From a pathophysiological perspective, intense eosinophilic infiltrates (mainly CD69-positive cells) occur in the myocardium and other organs and promote the release of mediators that cause extreme damage to the myocytes, thus resulting in necrosis and loss of the myocardial structure. These aggressive factors include eosinophil-derived neurotoxin, eosinophil cationic protein, and eosinophil protease. Additionally, inflammatory cytokines such as tumor necrosis factor (TNF)-a, the interleukins IL-1, IL-6, IL-8, IL-3, and IL-5, and macrophage inflammatory protein also promote myocyte damage and loss and the progression to myocardial dysfunction33.
Giant-cell myocarditis is an autoimmune form of myocardial injury that is histologically characterized by the infiltration of multinucleated giant-cells as well as inflammatory T lymphocytes, eosinophils, and histiocytes. However, well-defined granulomas are not always observed. Cytotoxic CD8+ T cells are present in significant numbers and promote intense myocyte injury. This condition is observed in 20% of patients with autoimmune diseases, including Hashimoto's thyroiditis, rheumatoid arthritis, myasthenia gravis, and Takayasu arteritis. The release of large amounts of inflammatory cytokines and oxidative stress mediators causes considerable myocyte damage and results in myocyte loss and fibrotic deposition. The intense damage accelerates the progression of myocarditis and is accompanied by rapid losses of ventricular function and unfavorable clinical prognosis34.
Sarcoidosis is a multisystemic disease of unknown etiology that is characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and non-caseating granulomas in the affected tissues35,36. The lungs are affected in 90% of sarcoidosis patients, and the presence of lung disease is an independent factor that correlates with sarcoidosis-associated morbidity and mortality.
Initially, diagnostic assessment of myocarditis is performed by non-invasive diagnostic methods in response to clinical suspicion of disease. However, a diagnosis must be confirmed by a histological analysis of endomyocardial biopsy samples from the right ventricle. Most clinical cases remain at the level of diagnostic suspicion because only a very small fraction of the patients are subjected to EMB to confirm the presence of inflammatory activity (
Clinical manifestations of myocarditis are highly variable and range from subclinical forms such as asymptomatic ventricular dilation and dysfunction to acute clinical manifestations such as decompensated heart failure, fulminant myocarditis with cardiogenic shock, chest pain, myocarditis that mimics coronary heart disease, palpitations, syncope or presyncope, and sudden death22,37,38.
Although most cases of myocarditis occur in response to viral infection, respiratory, gastrointestinal, or systemic viral infections are found in only 30% of patients with acute clinical symptoms39.
Acute forms with chest pain can be clinically similar to angina and include characteristics similar those typically observed in acute coronary syndrome, including electrocardiogram alterations and increased levels of myocardial necrosis markers. Acute myocarditis might also present with similar characteristics to pericarditis when the epimyocardium is affected. Other clinical presentations include acute heart failure, frequent ventricular and atrial arrhythmias, cardiogenic shock, and death13,40.
In newborns and children, myocarditis usually manifests as acute heart failure, sometimes as fulminant heart failure41, and less frequently as oligosymptomatic dilated cardiomyopathy.
The subacute and chronic forms of myocarditis often manifest initially as dilated cardiomyopathy of recent or indeterminate onset in asymptomatic patients or patients with symptoms of heart failure.
Myocarditis rarely presents with electrocardiographic alterations that indicate variable degrees of atrioventricular conduction disorders that can be associated or not with bundle branch block. More advanced cases exhibit signs of reduced cardiac output due to complete atrioventricular block such as an escape rhythm42.
Other symptoms point to more specific forms of myocarditis, including rash, fever, and peripheral eosinophilia, which are suggestive of hypersensitivity myocarditis;) dilated cardiomyopathy with thymoma, autoimmune disorders, ventricular tachycardia, or advanced block, which are suggestive of giant-cell myocarditis; and ventricular arrhythmias and advanced block, which might indicate sarcoidosis43.
Nonspecific serum inflammatory markers such as the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, and white blood cell counts might be increased or unaltered. Such markers can reflect either the presence of myocardial or pericardial inflammation or the underlying systemic autoimmune or hypersensitivity disease. The detection of increased levels of myocardial necrosis markers depends on the stage of acute myocarditis progression and the extent of inflammatory activity at the time of diagnosis. Unlike coronary syndromes, which exhibit typical increasing/decreasing curves, the levels of myocardial necrosis markers remain at a plateau in myocarditis. Increased (I or T) troponin levels are more common than increased creatine kinase-MB (CK-MB) levels; high levels indicate a worse prognosis (
Tests used to investigate the cause of myocarditis depend on the clinical suspicion. As a rule, all patients should be investigated for systemic autoimmune inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, Churg-Strauss syndrome, and celiac disease10. Viral serological tests often exhibit low sensitivity and specificity and only 4% correlate with myocardial viral infection44. Thus, viral serological tests should not be routinely included in diagnostic assessments of myocarditis (
Electrocardiographic alterations depend on the myocardial inflammatory activity stage. As a rule, the ECG diagnostic sensitivity is 47%45.
In acute myocarditis, the most common findings are repolarization disorders and atrioventricular block, as well as patterns that suggest coronary ischemia with ST segment elevation or depression (specific area or diffuse); the presence of Q waves indicates a worse prognosis. Supraventricular or ventricular arrhythmias are frequent findings27,33. In the subacute or chronic phases, electrocardiographic signs of chamber remodeling such as ventricular overload and left bundle branch block are common and indicate a worse prognosis46.
When the pericardium and myocardium are simultaneously affected (perimyocarditis), the classical electrocardiographic pattern of pericarditis with diffuse ST segment elevation and PR segment depression is commonly observed 47.
Recommendations for the use of an electrocardiogram in myocarditis are described in
Echocardiographic findings are nonspecific for myocarditis. The echocardiographic alterations reflect myocardial inflammatory activity and consequences to ventricular function and remodeling; additionally, intraventricular or atrial clots might also be found48,49. Alterations in ventricular contractions might be diffuse or segmental and are indistinguishable from signs of ischemia9,50.
Right ventricular dysfunction is uncommon and its presence is a sign of worse prognosis51. Fulminant myocarditis is usually accompanied by important systolic dysfunction that is characterized by normal chamber diameters and sometimes associated with increased septal wall thickness, which denotes myocardial edema49,52. Pericardial effusion in the absence of congestive heart failure suggests pericardial inflammation such as myopericarditis.
Echocardiography plays an important role in the differential diagnosis of myocarditis over other conditions with similar clinical presentations, such as acute valvular heart disease, takotsubo inflammatory cardiomyopathy, and acute myocardial infarction. It also serves as guide for endomyocardial biopsies (
Cardiac magnetic resonance imaging (MRI) permits the identification of myocardial inflammatory injuries in the acute and subacute phases of myocarditis, as well as scars that are often present in chronic myocarditis. The three main MRI techniques used to characterize myocardial injury in patients with myocarditis are the T2-weighted sequences (
T2-weighted images permit the assessment of myocardial edema secondary to regional or systemic inflammation in patients with acute myocarditis.
In the early global enhancement technique, images acquired during the first minutes after gadolinium administration represent the areas most affected by inflammatory injury54,55. This assessment measures the signal intensity before and after the injection of gadolinium-based contrast agents and compares the values to the variation of intensity in skeletal muscle tissue within the visual field (e.g. the pectoral muscle). Signal intensity ratios of myocardium to skeletal muscle greater than 4:1 denote inflammation-induced hyperemia and capillary extravasation.
The late enhancement technique permits the assessment of areas with irreversible myocardial injury and thus the identification of necrotic and fibrotic areas in acute or subacute and chronic myocarditis cases, respectively56-58. The late enhancement pattern of distribution in myocarditis and myocardial infarction are very different. In myocarditis, the pattern is often mesocardial and the endocardium is spared; however, the distribution is occasionally epicardial and transmural. The enhanced areas are usually multifocal, heterogeneous, sparse, and not restricted to the coronary territories. However, this pattern of distribution does not occur in every case; some cases exhibit patterns similar to those of coronary disease.
Although each of the abovementioned individual techniques exhibits satisfactory diagnostic accuracy, several studies have shown that optimal results are achieved when the 3 diagnostic criteria are combined48. When at least 1 criterion is present, MRI exhibits sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy rates of 88%, 48%, 68%, 68%, and 70%, respectively; when 2 of the criteria are present, the respective rates are 67%, 91%, 91%, 69%, and 78%9. The diagnostic accuracy is greater in acute myocarditis cases than in suspected subacute or chronic cases.
MRI is indicated for the diagnostic assessment of patients with suspected acute or chronic myocarditis and also for patients with recent-onset ventricular dysfunction and suspicion of past myocarditis, regardless of manifestation. However, MRI has particular value in cases with increased levels of myocardial necrosis markers and normal coronary arteries according to angiography (acute infarction-like presentation). MRI must be performed as early as possible when myocarditis is clinically suspected. Follow-up tests must be performed 4 and 12 weeks after the acute episode to assess inflammatory progression and remodeling in positive cases. Due to logistical issues that are inherent to the method, MRI is not indicated for the assessment of patients with fulminant myocarditis and hemodynamic instability (
Positive late enhancement correlates with worse long-term prognosis in patients with endomyocardial biopsy-confirmed viral myocarditis. The global mortality and heart disease-related mortality rates are higher in such patients, regardless of clinical symptoms and ventricular function. Negative late enhancement correlates with a low risk of sudden death, regardless of ventricular dysfunction and dilation59.
Computed tomography angiography (CTA) is faster and more widely accessible than MRI, relative to differential chest pain diagnoses. However, disadvantages of CTA include the use of iodinated contrast agents and ionizing radiation60. CTA might provide normal coronary images (when triggered by ECG)61 and thus rule out ischemia and myocardial infarction.
Additionally, coronary CTA might be used in the differential diagnosis of acute coronary syndrome to exclude significant coronary heart disease in patients who exhibit infarction-like clinical manifestations (chest pain, elevated myocardial necrosis markers, and ECG alterations;
Nuclear medicine analyses have been used to assess patients with suspected myocarditis for more than three decades62. The main applications of such modalities are related to assessments of left ventricular function, the presence of cardiac inflammation, myocarditis subtype identification, and therapeutic responses.
In assessments of cardiac inflammation, myocardial inflammation can be detected by various radionuclide techniques63,64. Of these, gallium-67 scintigraphy is the most widely used and has a 50% sensitivity rate in myocarditis diagnosis. The best results are achieved when gallium-67 scintigraphy is performed within the first three months from the clinical disease onset65. The accuracy of gallium-67 scintigraphy is particularly high in some specific forms of myocarditis (e.g. sarcoidosis).
In gallium-positive cases with inflammation, as indicated by endomyocardial biopsy, changes in the marker over time can be used to monitor inflammatory activity and treatment response (
Endomyocardial biopsy (EMB) is the gold standard for myocarditis diagnosis, investigations of viral persistence in the myocardium, and other non-inflammatory cardiovascular diseases. The aim of EMB is to establish a diagnosis of myocardial inflammation with or without viral persistence and thus to define the need for and type of treatment66.
In cases of recent-onset heart failure (less than two weeks) with hemodynamic instability that is non-responsive to usual treatment and/or with ventricular arrhythmias or high-grade heart block, EMB is important in investigations of the causal factors that might affect treatment. EMB can indicate a need for immunosuppressant treatment and thus can improve the prognoses of conditions such as giant-cell and necrotizing eosinophilic myocarditis and cardiac sarcoidosis67-69.
Studies have focused on EMB for symptomatic chronic dilated cardiomyopathy with possible viral etiology because antiviral or immunomodulating therapies were found to improve the ejection fraction in patients with symptomatic heart failure after six months of optimized treatment70.
Myocarditis can also be induced by some pharmacological agents. EMB plays a crucial role in cases with unclear diagnoses and rapid disease progresses with suspicion of allergic reactions and eosinophilia, as these contribute to a differential diagnosis from other conditions. Due to the invasive nature, EMB is restricted to cases with unfavorable progression and unknown cardiac dysfunction etiology in patients subjected to chemotherapy 71.
Few studies have reported indications of EMB in ventricular arrhythmias of unknown cause. The incidence of histological myocarditis diagnoses in these studies is highly variable. The detection of active myocarditis in a patient with malignant ventricular arrhythmia could theoretically lead to a decision to defer the installation of an implantable cardioverter-defibrillator until the inflammatory activity decreases. Nevertheless, such an approach remains controversial72.
The indications of EMB in myocarditis are described in
EMB must be performed in a hemodynamics laboratory by a specialist with procedural experience. Local anesthesia is used, with conscious sedation if necessary, under the continuous supervision of an anesthesiologist.
EMB can be performed safely when guided by direct fluoroscopy, with echocardiographic support73,74 to indicate the proper positioning of the bioptome to avoid puncturing the right ventricular (RV) free wall75.
MRI prior to EMB might be helpful to identify focal right or left ventricular lesions and thus indicate sites for sample collection76. Although no comparative studies support the recommendation to perform EMB in either the right or the left ventricle (LV), EMB should be performed in the LV only if the full extent of disease is limited to the LV, which in some cases might be determined by MRI.
Samples must be taken from the distal portion of the interventricular septum and apical trabecular area of the RV while avoiding the free wall. The number of collected samples depends on the study aims 77. In cases of viral myocarditis, 10 samples are needed (six for viral investigation, two for hematoxylin-eosin (HE) staining, and two for immunohistochemical analysis). In cases of infiltrative or storage diseases, six samples are needed (two for HE staining, two for immunohistochemistry, and two for electron microscopy). The samples for HE staining and immunohistochemistry must be stored in 10% buffered formalin and should not be refrigerated. The samples for viral investigation must be collected in Eppendorf® microtubes (without transport solution), placed on dry ice, and quickly stored at -70 ºC. The samples for electron microscopy must be placed in Eppendorf® tubes with OCT solution.
EMB complications are rare; the complication frequencies were 1.7% in a case study of approximately 2,400 patients78 and less than 1% in another study of more than 4,000 patients79. The use of echocardiogram associated with fluoroscopy resulted in significant reductions in the likelihood of involuntary punctures and subsequent myocardial perforation or coronary injury.
The reported complications include vasovagal syncope, variable grades of atrioventricular (AV) block, perforation of the RV free wall, pneumothorax, perforation of the ventricular septum, puncture site hematoma, intracardiac fistula, retroperitoneal hematoma (femoral access), pericardial effusion, clot displacement, cardiac tamponade, tricuspid chord rupture, and ventricular arrhythmia.
The Dallas classic criteria for myocarditis require the presence of inflammatory cells and myocyte necrosis in the endomyocardial biopsy; the absence of necrosis characterizes the so-called borderline myocarditis. The Dallas criteria are widely criticized for a lack of correlation with clinical progression, viral presence and interexaminer variability80. More recently, a suggestion was made to base histological diagnoses of inflammation on lymphocyte and macrophage counts associated with immunohistochemical evaluations of HLA-DR expression81.
To perform immunohistochemical analyses of myocardial tissues, at least two endomyocardial biopsy samples are needed. The samples must be stored in 10% buffered formalin at room temperature and must not be frozen. The diagnostic accuracy of immunohistochemistry for the detection of inflammation in myocarditis is higher than that of the histological criteria. The immunohistochemical assessment is based on the analysis of specific antigen-antibody reactions; for this purpose, mononuclear cells (T and B lymphocytes) and other leukocytes are labeled with specific antibodies to improve both inflammatory cell identification and counts. Immunohistochemistry can also identify the cytokine-induced activation of inflammation through the detection of class I and II histocompatibility antigens (HLA-DR) in the endothelial cells or interstitium of cardiomyocytes or perivascular cells, as well as the expression of intercellular adhesion molecule (ICAM) receptors on cell surfaces83-85. Because it detects inflammatory infiltrates as well as cytokine-induced cell adhesion capabilities, immunohistochemistry can identify myocardial inflammation that is distant from the primary infection site, which renders it more accurate than conventional histological analyses for right ventricular endomyocardial biopsy-based myocarditis diagnoses86,87.
The increased myocardial expression of HLA-DR and ICAM might be diffuse or localized and is usually associated with the presence of inflammatory cells (more than two CD3+ T lymphocytes per optical microscopy field (400X), which corresponds to 7·0 cells/mm2)88-90.
A diagnosis of myocarditis can be established from a score that combines HLA-DR expression and inflammatory infiltration91,92.
To establish a diagnosis of myocarditis, the HLA-DR positive score must be at least three or the ICAM-1 positive score must be at least two; additionally, the presence of at least 7.0 inflammatory cells/mm2 should be observed. Scores from one to three indicate a possible diagnosis of inflammation.
A diagnosis of myocarditis might also be established when lymphocyte counts are at least 14·0 cells/mm2. If the count is less than 14 cells/mm2, the lymphocyte count might be used for to confirm myocarditis37,93.
The general measures indicated for myocarditis treatment target symptomatic or asymptomatic heart failure (stages B to D). The restriction of dietary sodium intake to two to three g/day is indicated in the absence of hyponatremia and calorie restriction and is a crucial adjuvant in more advanced clinical stages. Fluid restriction to 1,000 - 1,500 ml/day is also recommended during the symptomatic stage.
Smoking and excessive alcohol consumption are contraindicated, and the patients must monitor body weight to avoid both obesity and cachexia. Non-steroidal anti-inflammatory agents should not be used during the acute phase nor in the presence of heart failure94,95. Animal studies showed that aerobic activity during the acute disease phase resulted in increased mortality96. Therefore, because myocarditis is a cause of sudden death in young athletes97, patients should not perform intense physical exercise for up to six months or longer after the acute phase, depending on the symptoms or the presence of residual effects on ventricular function98,99.
Available prophylactic vaccines (mumps, measles, rubella, poliomyelitis, and influenza) should be administered to reduce rates of myocarditis from the corresponding viruses. Vaccination should not be performed during the active disease phase. Studies in animal models show that influenza vaccination prevents myocardial damage but no studies have been conducted in human beings100.
Modulation of the renin-angiotensin-aldosterone system attenuates the progression of ventricular dysfunction and reduces myocardial fibrosis, necrosis, and inflammation in experimental models101,102. Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARB) are administered to all patients with ventricular dysfunction, even in the absence of heart failure, provided there are no contraindications; ACE and ARB are administered in increasing doses up to the recommended maximum. Maintenance ACE inhibitors/ARB regimens are recommended after ventricular function is normalized. In one study of ACE inhibitor discontinuation, approximately 33% of the patients exhibited new episodes of heart failure versus 5% of patients who did not discontinue the medication103. ARB can be used in cases of ventricular dysfunction and intolerance to ACE inhibitors.
The indication for beta-adrenergic blockers in myocarditis arises from the need to reduce the levels of sympathetic activity and noradrenaline and thus to hinder the progression of myocardial dysfunction and improve the prognosis. Beta-blockers are indicated for all patients with ventricular dysfunction and heart failure in increasing doses up to the recommended maximum, provided there are no contraindications. A maintenance regimen of beta-blockers is recommended for at least 1 year after ventricular function is normalized.
The use of oral anticoagulants (OAC) is indicated in patients with myocarditis associated with paroxysmal or permanent atrial fibrillation (AF), intracavitary clots, or a previous history of thromboembolism104.
The aim of immunosuppressive treatment for myocarditis is to suppress inflammatory responses and autoimmune activity, to induce consequent improvements in clinical manifestations and ventricular function, and to reduce mortality. Indications for immunosuppressive therapies require a confirmation of myocardial inflammatory activity via endomyocardial biopsy and the exclusion of viral presence (
Factors such as the spontaneous regression of inflammation, which occurs by approximately 50%. Of cases, the lack of standardization of the diagnostic criteria used in studies, the small number of patients in most trials, the clinical heterogeneity of the investigated populations, and the lack of clinical studies that seek to assess the reduction of mortality alone have resulted in difficulties in analyses of the clinical benefits of immunosuppressant therapy. Clinical studies105 that assessed survival improvements did not find additional benefits from immunosuppressant therapy when compared to conventional treatments for heart failure. However, those studies had several methodological flaws, including a lack of viral investigation and the exclusive use of the Dallas histological criteria to diagnose myocarditis without immunohistochemical analysis. Because these flaws could compromise the results of immunosuppressive therapies, the potential effects of such therapies on mortality reduction remain unexplored.
In patients with chronic heart failure with active myocarditis and without viral infection, immunosuppressive treatment correlated with clinical improvement, reduction in chamber diameters, improvement of ventricular function, and regression of inflammatory activity (
A combination of prednisone and azathioprine, administered over six months, is the most commonly used immunosuppressant regimen in patients with post-viral myocarditis (
Antiviral therapy is used to eliminate viruses and prevent viral replication. Available regimens include subcutaneous interferon-β (IFN-β) infusion and intravenous immunoglobulin (IG-IV).
In an experimental model of viral myocarditis in animals genetically modified for IFN-β-deficiency, extensive viral proliferation and intense inflammatory activity were associated with greater ventricular dysfunction and mortality. These results suggest that IFN-β is important to the control of viral infection in myocarditis113.
Subcutaneous IFN-β infusion in patients with dilated cardiomyopathy and viral persistence (adenoviruses and enteroviruses) is associated with viral elimination and clinical improvements in functional capacity and ventricular function100. In patients with parvovirus B19-induced myocarditis, IFN-β infusion correlated with reduced viral loads and improved endothelial and ventricular function114. Therefore, IFN-β treatment is an increasingly reliable antiviral treatment option for patients with viral myocarditis.
IG-IV exhibits anti-inflammatory activities and thus reduces immune antiviral responses. It promotes the reduced pro-inflammatory cytokine activity and exhibits anti-idiotypic properties associated with the reduced production and neutralization of autoantibodies. Additionally, IG-IV exhibits an antiviral activity by reducing viral replication and favoring viral elimination99.
The use of IG-IV in recent onset dilated cardiomyopathy was not associated with improved ventricular function when compared to a placebo. However, some methodological flaws might have compromised the results because patients with or without inflammation in endomyocardial biopsies were included; in this study, inflammation was confirmed only in 16% of patients, viral presence was not investigated, and inflammation was diagnosed according to the Dallas criteria99.
In adenoviruses and cytomegalovirus (CMV)-induced myocarditis, IG-IV reduced both the viral load and inflammation and consequently improved the clinical state and ventricular function. In parvovirus B19-induced myocarditis, the viral load persisted in 40% of the patients after IG-IV; patients that eliminated the virus exhibited improvements in ventricular function and reduced chamber diameters115. These results suggest that the therapeutic benefit of IG-IV is restricted to myocarditis with active inflammation as assessed by immunohistochemistry and positive virus identification (
Immunomodulation is used to reduce inflammatory and autoimmune responses by removing and modulating the aggressive agents that might be involved in myocarditis pathogenesis.
Immunoadsorption therapy by selective plasmapheresis aims to remove specific autoantibodies and can be used with IG-IV to modulate inflammatory cytokines and autoantibody production. Immunoadsorption is associated with IG-IV-induced reductions myocardial inflammatory activity, improvements in functional class and ventricular function, and longer survival after a five-year follow-up period in patients with chronic inflammatory cardiomyopathy and high serum levels of anti-β1 myocardial adrenoceptor autoantibodies. Although those results point to the possible benefits of immunoadsorption for patients with autoimmune myocarditis, the number of investigated patients was too small to establish a definitive treatment strategy116.
The anti-inflammatory properties of pentoxifylline include blocking of TNF-α transcriptase and reduced IL-2 and IL-6 levels with consequent reductions in cytokine-induced cardiac damage117.
Pentoxifylline, administered in doses of 1,200 to 2,400 mg/day over six months, resulted in improvements in functional class and ventricular function in patients with dilated cardiomyopathy with chronic heart failure and peripartum cardiomyopathy (
During the acute phase of myocarditis, patients can develop tachy- or bradyarrhythmias. Such arrhythmias often disappear after the acute phase and thus only supportive treatment is normally provided.
As a rule, antiarrhythmic treatment is not recommended for asymptomatic atrial and ventricular extrasystoles. Supraventricular tachycardia (SVT), especially atrial fibrillation and flutter, can induce or exacerbate heart failure. The recommended initial approach to symptomatic sustained SVT is restoration of the sinus rhythm by electrical or chemical cardioversion. For cases of recurrent sustained SVT, therapeutic options include catheter ablation and ventricular frequency control.
Cases of asymptomatic nonsustained (NS) ventricular tachycardia (VT) should not be specifically treated. Sustained ventricular arrhythmias should be treated with antiarrhythmic agents after acute electrical reversion. Only amiodarone is available for such treatments because other class I and III drugs are normally avoided in these patients due to the proarrhythmic effects.
Complete atrioventricular (AV) block and symptomatic sinus bradycardia represent indications for temporary stimulation during the acute phase of myocarditis. These conduction disorders are often transient.
As no data exists in the literature about long-term risks for patients with VT or cardiac arrest during the acute phase of myocarditis, management is decided on an individual basis. The implant of a cardiac defibrillator (ICD) is indicated after optimized pharmacological therapy in patients who develop dilated cardiomyopathy during the chronic phase of myocarditis, according to the criteria described in
Traditionally, fulminant myocarditis was thought to be the most severe form of acute myocarditis. It is characterized by an acute and extremely fast disease progression with functional class IV congestive heart failure, cardiogenic shock and high lethality in the absence of appropriate hemodynamic support122.
In fulminant viral myocarditis, persistently high viral levels usually occur in susceptible individuals in combination with persistent T lymphocyte activation and the production of antibodies that mediate injury responses against myocytes22.
Felker et al. described the characteristics clinical fulminant myocarditis over a long-term follow-up period123. Frequently, in such patients infectious responses were observed during the last four weeks as well as febrile syndromes during the last 12 weeks. The presentation is acute and progressive and the vast majority of patients exhibit functional class III/IV symptoms at the time of diagnosis. Additionally, the affected patients exhibit higher levels of arterial hypotension and tachycardia and reduced ventricular dilation than those with non-fulminant myocarditis.
Despite the dramatic progression, the prognosis for fulminant myocarditis can be very good if a diagnosis is established early and clinical and hemodynamic supportive treatments are started immediately; eventually, reversion of the ventricular dysfunction and satisfactory late survival rates are observed124,125.
Concerning the specific treatment for myocarditis, identification of causal factors by EMB and histological investigation permits the establishment of specific therapeutic strategies such as immunoglobulin in viral myocarditis cases, immunosuppressants in virus-negative autoimmune myocarditis cases, and corticosteroids in sarcoidosis or giant-cell myocarditis cases. High doses of immunoglobulin were tested and were effective in a case study; however, this result has not yet been confirmed in randomized trials126,127. inotropic agents and eventually vasopressor drugs should be included in supportive treatment regimens Immediate failures of pharmacological treatment and fluid replacement indicate a need for hemodynamic support via circulatory assist devices. Frequently used devices such as intra-aortic balloon pumps, percutaneous devices (e.g. TandemHeart and Impella), extracorporeal circulation (ECMO), and paracorporeal artificial ventricles (CENTRIMAG) provide a bridge to recovery or to heart transplantation. Short-term devices are indicated for seven-to-10 days of supportive treatment128. If stabilization is not achieved in that time period, ECMO or artificial ventricles might provide additional support and thus increase the odds of ventricular dysfunction recovery129.
The indications in fulminant myocarditis are described in
Stress cardiomyopathy diagnoses in emergency care settings have increased in patients with acute ventricular dysfunction. Older postmenopausal women represent the largest risk group (approximately 80% of cases). Cardiomyopathy is frequently triggered by intense physical or emotional stress, financial losses, or natural disasters and sometimes by stress from other diseases. The prognosis of stress cardiomyopathy is good; the in-hospital mortality rate is 2% and normally, cardiac function is fully recovered in two to four weeks130.
The main clinical findings are chest pain, dyspnea, and syncope. Electrocardiographic alterations occur frequently and include segment ST depression (34 to 56%), pathologic Q waves, inverted T wave with QT interval prolongation, and nonspecific repolarization disorders. Cardiac troponin levels are often elevated and small increases in troponin conflict with the contractility and hemodynamic disorders131. Left ventriculography and Doppler echocardiography show apical ballooning with dyskinesis or akinesis, which affects 50-67% of the left ventricle and is associated with hyperdynamic basal segments. Gadolinium-contrast MRI is helpful to distinguish stress cardiomyopathy from AMI and myocarditis because myocardial edema and late enhancement are absent. The right ventricle is affected in 25% of the cases. The main acute complications are heart failure, ventricular tachycardia, thromboembolism, mitral regurgitation, and cardiogenic shock.
Stress cardiomyopathy has a good long-term prognosis, which sometimes contrasts with the significant hemodynamic impairment revealed upon clinical assessment. Treatment regimens provide clinical-hemodynamic support to permit spontaneous myocardial recovery. Beta-blockers, ACE inhibitors and diuretics can be used in the absence of arterial hypotension or signs of low cardiac output. Hemodynamic support in patients with arterial hypotension requires the cautious use of inotropic agents such as dobutamine, and vasopressor drugs must be used in cases with refractory hypotension. Mechanical hemodynamic support via an intra-aortic balloon pump is indicated when the clinical-hemodynamic state does not improve. ECMO can be used in patients who progress into refractory shock, due to the transient nature of this condition.
The indications for the diagnosis of takotsubo cardiomyopathy are described in
Chagas disease is endemic in Latin America132. Chagas myocarditis might present as acute myocarditis during
The manifestation of acute myocarditis depends on the degrees of cardiac involvement and systemic disease and thus varies from symptomatic forms (sinus tachycardia, low QRS voltage, conduction disorders, QT interval alterations, signs of altered ventricular repolarization, arrhythmias, biventricular function impairment, acute heart failure) to subclinical forms, in which a diagnosis depends on clinical suspicion13. Acute myocarditis must always be considered in patients who reside in endemic areas or in whom transmission could occur through vectors or other forms such as oral, congenital and blood transfusions. Acute myocarditis might be associated with signs of systemic infection, such as fever and hepatosplenomegaly, as well as signs of parasitic entry in cases of vector-mediated transmission. Reactivated
Chronic myocarditis can be found in chronic Chagas disease, which can manifest after a long latency period because acute infection, alone or combined with another disorder, can present as chronic or acute heart failure, arrhythmia, sudden death, and pulmonary or systemic embolism134,135. The signs and symptoms are typical of cardiomyopathy, with an eventual higher incidence of bradycardia and conduction disorders that particularly affect the right bundle branch. The prognosis for this form of cardiomyopathy is poor when compared to other forms136. The potential mechanisms involved in the pathogenesis of this form include neurogenic and microvascular injury, apoptosis, chronic inflammation, fibrosis, parasite persistence, and autoimmunity137. Currently, parasitic persistence is indicated as an important trigger of Chagas chronic myocarditis138. However, other agents might also influence the development of chronic myocarditis139. During the chronic phase of Chagas disease, when the clinical diagnosis is highly suggestive and based on compatible epidemiological data, positive serological tests, and typical manifestations of heart failure or other cardiac disorders, an endomyocardial biopsy is usually not performed and other methods may be used140. Heart failure might result in BNP elevation and a more intense pro-inflammatory process141,142. Specific treatments for the forms without heart failure are controversial and contraindicated in forms with heart failure143,144. The treatment regimens are identical to those used for other forms of both compensated and decompensated heart failure145-148. Previously, some surgical procedures were considered to be potentially favorable but were later forsaken149-151. In the terminal stage, heart transplantation or the use of circulatory assist devices156 is indicated to improve the quality of life and survival152-155. Although transplantation requires special monitoring due to the higher number of comorbidities, including neoplasia and the reactivation of infection, the outcomes are better for this form of myocarditis than for other forms57-161.
The indications for the diagnosis and treatment of Chagas myocarditis are described in
The natural progression of myocarditis varies in a cause-dependent manner, and clinical and hemodynamic data can contribute to a determination of prognosis (
There are several clinical and pathological forms of myocarditis, and endomyocardial biopsies not only serve to establish diagnoses but might also contribute to prognostic assessments. This is primarily accomplished through the identification of the specific forms of myocarditis such as fulminant, giant-cell, chronic active and eosinophilic myocarditis and sarcoidosis. Clinical and pathological findings might help to distinguish, for example, fulminant lymphocytic from acute lymphocytic myocarditis, with important prognostic implications (
Previously, the low sensitivity and exclusive use of the Dallas criteria did not permit a strong correlation between histological findings and clinical progression in patients45. Currently, indications of viral presence might contribute to predictions of clinical outcomes. In one observational study of 59 biopsy samples that were collected from 48 children with clinical and histological myocarditis or dilated cardiomyopathy diagnoses, viral presence as detected by polymerase chain reaction (PCR) correlated with a poorer prognosis that resulted in heart transplantation or death164.
The impairment of right ventricular function is also frequently predictive of death or a requirement for heart transplantation76.
There are no official reports of epidemiological data relative to pericardial disorders in Brazil. Additionally, the available data in the international literature are scarce and are influenced by the characteristics of each institution. Data from emergency departments indicate that 5% of patients with chest pain in whom acute coronary insufficiency is ruled out165 and 1% of patients with ST segment elevation have acute pericarditis166.
Pericardial effusion and cardiac tamponade appear more frequently in response to tuberculosis or neoplasms. The frequencies of these findings due to other causes are lower in pericarditis.
Pericarditis is an inflammatory process of the pericardium in response to multiple causes. It can manifest as primary or secondary disease. Although it is usually benign and self-limited, pericarditis can be associated with pericardial effusion or constriction, which result in increased morbidity167,168. Pericarditis is classified according to clinical progression and presentation as153,169:
• Acute pericarditis
• Chronic pericarditis
• Pericardial effusion and cardiac tamponade
• Constrictive pericarditis
• Recurrent pericarditis
Pericarditis has both infectious and non-infectious causes (
Generally, bacterial pericarditis presents with pericardial effusion. It can occur in response to conditions such as pneumonia or empyema, through hematogenous dissemination, or after heart or chest surgery and can be induced by a wide variety of bacterial species. Although the frequency of tuberculous pericarditis (TBP) decreased in response to the effective control of pulmonary tuberculosis (TB), it can still be found, particularly among HIV-infected individuals171,172.
Pericardial autoimmune involvement is found mainly in cases of systemic lupus erythematosus, rheumatoid arthritis, scleroderma, polymyositis and dermatomyositis.
Post-infarction pericarditis might occur early (e.g. within the first three days after acute myocardial infarction (pericarditis epistenocardica)) and in such cases, can affect the adjacent epicardium and pericardium. Alternatively, it might appear from three weeks to six months after an infarction due to autoimmune activity; such instances are known as Dressler's syndrome. Kidney failure is a common cause of pericardial disease that induces effusion in 20% of patients and can manifest as uremic or dialysis-associated pericarditis. Neoplastic pericarditis occurs in response to tumoral or lymphatic invasion or hematogenous dissemination167.
Acute pericarditis classically manifests as a febrile syndrome that frequently affects the upper airways and includes chest pain and pericardial friction rub. Chest pain might vary in response to respiration or chest position; additionally, the intensity and duration are variable. The pericardial friction rub might have one, two, or three sounds and can be transient. Pleural involvement is denoted by a pleural effusion or friction rub. Occasionally, pericarditis is associated with myocarditis, which must be suspected when clinical signs of acute ventricular dysfunction are present.
High-risk markers in acute pericarditis include elevated levels of myocardial necrosis enzymes, fevers higher than 38ºC, leukocytosis (high risk for purulent pericarditis), large pericardial effusion with or without cardiac tamponade, immunosuppression, previous use of oral anticoagulants, and global dysfunction on echocardiogram suggestive of myopericarditis. The presence of these markers indicate a need for hospital admission, more aggressive etiological investigation, and therapeutic optimization173,174.
A flowchart of assessment of pericarditis on admission is shown below (
The pericardial sac contains a small amount of fluid (30 to 50 ml) that surrounds the heart. If a large amount of fluid accumulates and surpasses the distension capability of the pericardial fibroelastic tissue, the heart chambers are progressively compressed due to the increased intrapericardial pressure, reduced cardiac volume, and greater ventricular interdependence175.
Tamponade progression depends on the speed of installation and the causal factor; acute cardiac tamponade develops within a few minutes after trauma, heart or aortic rupture, or as a complication of diagnostic and therapeutic procedures (cardiac biopsy, electrophysiological studies, atrial appendage occlusion, interatrial septum occluders, etc.) and results in shock. Subacute cardiac tamponade develops in days to weeks and might be associated with dyspnea and fatigue. Low-pressure (occult) tamponade occurs in hypovolemic patients with a consequent reduction in intracardiac pressure, which favors extrinsic compression by the pericardial effusion. Regional cardiac tamponade occurs when a localized effusion or hematoma exerts regional compression on one single chamber168.
Diagnosis of tamponade is clinical and is based on the history and physical evaluation of symptoms such as tachycardia, increased venous pressure, arterial hypotension, and paradoxical arterial pulse.
Constrictive pericarditis should be suspected in symptomatic patients with dyspnea upon exertion and/or fatigue associated with diastolic dysfunction and ascites that is disproportionate to lower limb edema. In such cases, the jugular venous pulse exhibits a prominent "y" descent and Kussmaul's sign. Additionally, 33% of the cases exhibit a paradoxical arterial pulse.
Transient forms of constrictive-effusive pericarditis (constriction without considerable pericardial wall thickening, usually associated with effusion) can occur within the context of acute pericarditis; these occur more frequently in association with tuberculosis, malignant neoplasms, and hemopericardium.
High levels of myocardial markers are found in patients with acute pericarditis. Troponin I (TnI) is more frequently elevated when compared to CK-MB because it may be due to peripheral myocarditis rather than viral infection176,177. A retrospective study assessed 55 patients with acute pericarditis and found that TnI was elevated in 27% of the cases178. A small study suggested that TnI was expressed on the second day after symptom onset and that TnI levels remained high for longer times than CK-MB levels177. Increased TnI is a marker for associated myocardial impairment (myopericarditis).
Markers of acute inflammatory activity, such as ESR, leukocytosis, and CRP, are elevated in approximately 75% of patients, and normal levels of these markers at the initial assessment do not rule out a diagnosis of pericarditis, especially in patients who use non-steroidal anti-inflammatory agents or have immune affections. The levels of acute phase markers generally return to normal after two weeks; persistent elevation indicates a need for long-term anti-inflammatory treatment and a higher risk for pericarditis recurrence179. Serial CRP measurements are helpful in diagnoses of acute pericarditis and in assessments of response to treatment.
The levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) might be elevated in pericardial disease180,181. However, there is not sufficient evidence to justify the routine use of these markers in the diagnosis of acute pericarditis.
A serological assessment to investigate causal factors must include a measurement of thyroid hormones, rheumatologic tests, kidney function tests, and blood cultures if bacterial infection is suspected. Viral analysis via blood serological testing should not be performed because, those not correlate with the pericardial findings. In the presence of significant pericardial effusion, histological and immunohistochemical assessments of the pericardial tissue and fluid must be performed for tuberculosis (adenosine deaminase), neoplasms, viruses, and other factors to significantly increase the likelihood of an etiologic diagnosis182. In idiopathic recurrent acute pericarditis, low titers of antinuclear antibodies are a common finding and indicate a possible autoimmune pathogenic mechanism183.
The range of electrocardiographic alterations is quite wide in pericarditis (
In acute pericarditis, the electrocardiographic alterations evolve over the following four stages185:
Rhythm alterations can occur at any stage and can range from sinus tachycardia to various atrial arrhythmias188.
Low QRS amplitude denotes pericardial effusion; this improves after pericardiocentesis189,190. Alternations in QRS morphology or amplitude denote pericarditis that is associated with a large pericardial effusion and signs of cardiac tamponade191.
The main differential diagnoses suggested by electrocardiographic alterations are acute myocardial infarction, pulmonary thromboembolism, presence of dyskinetic areas, and early repolarization192.
Differentiation between pericarditis and early repolarization might be established by estimating the ratio of the ST segment onset amplitude to the T wave amplitude (ST/T) in the lead V6. A pericarditis diagnosis is established when the ST/T ratio is equal to or greater than 0.25 193.
The predominant findings in chronic pericarditis are inverted T waves and low QRS amplitude194.
Usually, chest radiographs are normal in acute pericarditis cases. Cardiomegaly occurs only when the fluid volume in the pericardial sac is greater than 200 ml. Progressive increases in pericardial effusion, as in cardiac tamponade, result in a globular shaped heart on the chest radiograph195.
Some studies show that an increased heart silhouette on chest radiographs has moderate sensitivity (70%) but low specificity (41%) for diagnoses of pericardial effusion. There are no studies that assess the sensitivity and specificity of radiography in the diagnosis of pericarditis, but considering that in most cases, pericarditis is not accompanied by pericardial effusion and that this disease has no other specific changes, a diagnosis of pericarditis cannot be established solely on the basis of radiological data196.
The presence of pericardial calcification, which is easily visualized on chest radiographs, strongly suggests a diagnosis of constrictive pericarditis in patients with heart failure. However, this appears in only 25% of constrictive pericarditis cases (
Echocardiography is a very useful tool for the diagnosis of pericardial diseases as well as the prognosis and follow-up evaluations of responses to treatment. It has also been used as a guide during pericardial effusion drainage.
As a rule, the echocardiographic findings in acute pericarditis involve pericardial thickening and effusion. However, some cases of acute pericarditis might not exhibit any echocardiographic alterations (e.g. the so-called "acute dry pericarditis").
Two-dimensional echocardiography permits semi-quantitative assessments of pericardial effusions and hemodynamic repercussions. Small effusions are defined as those that are < 10 mm in size on M-mode and are only visualized behind the left ventricle. Moderate effusions are those that range in size from 10 to 20 mm and extend around the entire heart. Finally, large effusions are defined as echo-free areas > 20 mm198. Small effusions are usually only visible behind the left ventricle, whereas the effusions large enough to cause cardiac tamponade can be visualized around the entire heart. The echocardiogram might provide etiological information because it can characterize the nature of the fluid (transudate or exudate) and identify the presence of fibrin (as in tuberculosis), calcium, clots and masses that are suggestive of tumors or cysts; thus, the echocardiogram permits inferences about the etiological diagnosis.
All possible sections of the pericardium must be assessed. When constrictive pericarditis is suspected, the pericardial thickness must be measured; a thickness > three mm on a transesophageal echocardiogram (TEE) indicates a thickened pericardium with sensitivity and specificity rates of 95% and 86%, respectively.
The usual echocardiographic findings associated with the clinical signs of cardiac tamponade include the dilation of the vena cava with little respiratory variation and diastolic collapse of the free wall of the right ventricle, right atrium, left atrium, and more rarely, the left ventricle. Right atrial collapse is the most sensitive indicator of cardiac tamponade, whereas a right ventricular collapse that lasting for more than one-third of the diastole is the most specific sign. Doppler echocardiograms show increased tricuspid and reduced mitral flow on inspiration and increased mitral flow up to 25% and reduced tricuspid flow on expiration. The findings from Doppler echocardiograms merely represent the echocardiographic expression of a paradoxical pulse.
Up to 80% of the cases might exhibit pericardial thickening. However, this is not always detectable on echocardiography, including TEE, and thus other diagnostic methods such as MRI or computed tomography (CT) might be indicated.
The usual findings in pericardial constriction include abnormal motion of the ventricular septum, moderate restrictive flow increases in both atria, and respiratory variations greater than 25% of the mitral flow velocity. These variations are not pathognomonic of pericarditis but also occur in respiratory diseases (chronic obstructive pulmonary disease). However, in respiratory diseases the respiratory variation of the superior vena cava flow is much greater than in pericarditis.
Another useful finding for the diagnosis of constrictive pericarditis, and more particularly to distinguish it from restrictive syndromes, is the presence of
The indications for transthoracic echocardiography in pericarditis are described in
In acute pericarditis, cardiac CT might show uniform pericardial thickening, pericardial effusion, and some early enhancement of the intravenous contrast agent. The pericardial effusion might be loculated and exhibit septa; eventual observations of gas indicate the presence of microorganisms. The septa also exhibit contrast uptake. The effusion density must be investigated because it is low in transudates (0-10 HU) and high in exudates, hemorrhage, and neoplasms200.
In constrictive pericarditis, cardiac CT can identify pericardial thickening and/or calcification201. The normal pericardial thickness is less than two mm and is only properly identified when there is fatty tissue around the pericardium. Thickening can have diffuse or localized effects on the pericardium202,203. Cardiac constriction induced by a thickened pericardium gives the heart a narrow tubular shape. A sulcus is formed when constriction predominates in the fossa ovalis. The atria and vena cava are distended and pericardial effusion and ascites might be observed.
In neoplastic pericarditis, masses in the pericardium, infiltration of the adjacent tissues, impairment of the ventricular margins, and thickened septa that exhibit contrast uptake might be identified in addition to pericardial effusion and leaflet thickening.
MRI is indicated in the diagnostic assessment of acute and chronic pericarditis (
Among the main applications of nuclear medicine for the non-invasive diagnosis of pericarditis, the following stand out: differential diagnosis in patients with chest pain and electrocardiographic changes but without characteristic enzymatic curves, especially when MRI is not available or is contraindicated; diagnosis of pericarditis by active tuberculosis (new evidence indicates the use of [18F]fluorodeoxyglucose-positron emission tomography, FDG-PET); diagnosis of pericarditis in patients with systemic diseases such as meningitis, pneumococcal sepsis, rheumatoid arthritis, and systemic lupus erythematosus; monitoring of patients with chemotherapy or radiotherapy-induced pericarditis; and the clinical suspicion of pericarditis with diagnostic uncertainty after echocardiogram and MRI204,205.
Pericardiocentesis is an invasive procedure used for diagnostic and therapeutic purposes. It is indicated as a life-saving treatment in cardiac tamponade.168,195 Pericardiocentesis is further indicated when there is clinical suspicion of post-traumatic hemopericardium, bacterial pericarditis or neoplastic pericarditis (
In cases of significant but asymptomatic pericardial effusion (> 20 mm at diastole on echocardiogram), pericardiocentesis is indicated for diagnostic assessment and in response to the possibility of sudden progression into cardiac tamponade207.
Pericardiocentesis may be performed at the patient bedside under local anesthesia or in a cat lab via radioscopy. Although the access point may be transthoracic, median or subxyphoid, the latter provides limited exposure to the pericardium, which result in a low success rate208. The pericardial puncture needle must be guided by electrocardiographic monitoring or by imaging methods. Echocardiogram-guided pericardiocentesis carries a lower risk of complications and a higher rate of success. Additionally, saline injection permits localization of the needle during the procedure209. Once the catheter is introduced, the pericardial cavity pressure must be measured and the fluid aspirated. Relief of symptoms should ensue immediately.
In cases of constrictive-effusive pericarditis, the right atrial pressure remains high after the reduction of the intrapericardial pressure to normal levels in response to pericardial effusion drainage210. The pericardial fluid must be subjected to a cytological analysis, a microbiological culture, an investigation of neoplastic cells, a PCR-mediated viral analysis, and measurements of adenosine deaminase according to the suspected etiology (viral, bacterial, tuberculous, fungal or neoplastic). Aortic dissection is an absolute contraindication of pericardiocentesis; relative contraindications include clotting disorders, anticoagulation, platelet counts below 50,000/mm3, and small, posterior or loculated effusions.
To increase the diagnostic sensitivity of pericardiocentesis, new diagnostic and therapeutic strategies such as video pericardioscopy, which allows for large pericardial excision and wider exposure of the pericardial cavity, were developed211.
Furthermore, pericardial biopsy is indicated in the diagnostic investigation of patients with persistent pericarditis that is refractory to clinical treatment and lacks a definitive diagnosis. Biopsy might play an adjuvant role in therapeutic pericardial drainage for recurrent cardiac tamponade or large effusions that present with significant clinical symptoms.
Pericardial biopsy can also be performed by pericardioscopy, which indicates the sites for sample collection212,213. Pericardial biopsy was shown to improve diagnostic accuracy for pericarditis due to neoplastic disease, tuberculosis and bacterial infection214,215.
The presence of pericardial effusion favors biopsy via pericardioscopy and improves the likelihood of diagnosis, compared to pericarditis without associated pericardial effusion. The specimens must be subjected to histological (two fragments) and immunohistochemical (two fragments) analysis, as well as viral analysis by PCR (four to six fragments), which affords greater viral detection capability than viral analysis of the pericardial effusion fluid216-218.
The histological status can be classified according to etiologic categories. In this regard, tuberculosis is the most frequent cause of pericarditis. It is believed that some viruses induce self-limited pericarditis. In cases with considerable inflammation, there is an exuberant proliferation of reactive mesothelial cells with nuclear atypia, which require a differential diagnosis from neoplastic infiltration. Immunohistochemistry is useful because it achieves differentiation with markers for epithelial and mesothelial cells212,219.
Hospitalization is desirable in most cases of pericarditis to investigate the etiology, monitor the signs and symptoms of cardiac tamponade, and begin a non-steroidal anti-inflammatory drug (NSAID) and symptomatic treatment regimen. NSAIDs are the primary treatment drugs; ibuprofen is the most widely used because it seldom exhibits side effects and induces favorable effects on the coronary flow when used in high doses.
Treatment with systemic corticosteroids must be restricted to connective tissue disorders, autoimmune diseases and uremic pericarditis. Intrapericardial application of corticosteroids bypasses the systemic side effects, is highly effective in the withdrawal of prednisone, ibuprofen and colchicine220,221, and should be introduced early. Recovering patients should be monitored for possible recurrence or constriction.
Heparin is recommended under close supervision in cases that require anticoagulants.
NSAIDs are the pharmacological agents of choice for the treatment of idiopathic and viral pericarditis. Treatment is administered mainly to relieve pain and resolve inflammation222,223.
NSAIDs must be administered in anti-inflammatory doses; for example, acetylsalicylic acid (ASA) at 500 to 750 mg every six or eight hours over seven to 10 days, followed by a gradual reduction of 500 mg per week over three weeks; ibuprofen at 400 to 800 mg every six to eight hours over 14 days; or indomethacin at 75 to 150 mg/day. Indomethacin should be avoided in cases of post-myocardial infarction pericarditis because it impairs healing of the infarcted area224,225.
The normal length of NSAID treatment is approximately 14 days and can be monitored using serum levels of CRP as a marker of inflammatory activity. Tapering off of NSAID therapy must be gradual and slow to decrease the odds of recurrence226. All patients must use proton-pump inhibitors (PPI) to protect the gastric mucosa.
Colchicine was shown to be effective as an adjuvant treatment for pain relief and prevention of recurrence after an 18-month follow-up in acute pericarditis cases 220,227. It is used in doses of 0.5 mg, given every 12 or 24 hours to patients who weigh less than 70 kg, for three months after the first event and six months in cases of recurrent pericarditis228,229. According to some studies, in more severe and recurrent forms, colchicine should be given for 12 to 24 months after the last event, followed by a gradual withdrawal230,231.
The main adverse effect of colchicine is diarrhea, which affects approximately 8% of patients. Less frequent effects are associated with hepatotoxicity, myotoxicity and bone marrow suppression. Thus, colchicine should be avoided in patients with severe kidney failure, liver dysfunction, blood disorders and gastrointestinal motility disorders232-234.
The use of corticosteroids to suppress inflammation usually induces a dramatic improvement of the clinical state and inflammatory response in pericarditis. Nevertheless, the following clinical and physiopathological features that limit the clinical efficacy of these agents must be taken into consideration: treatment with corticosteroids favors the recurrence of pericarditis and A possible explanation is that some recurrences may be provoked by acute or chronic viral infections,and corticosteroids could promote viral replication, or through the phenomenon of autoimmune recurrence, or through the phenomenon of autoimmune recurrence; the cause of pericarditis should be identified to predict the response to treatment and determine the treatment regimen; and when viral pericarditis is suspected, viral presence should be ruled out through an analysis of the pericardial fluid and endopericardial biopsy before administering corticosteroids235.
Corticosteroids are indicated for the treatment of idiopathic acute pericarditis cases that do not respond to non-steroidal anti-inflammatory agents and colchicine. This indication also applies to cases of pericarditis due to autoimmune disease, connective tissue diseases or uremia. The recommended dose is one mg/kg body weight over a two to four week period. To avoid autoimmune recurrences and consequent reactivation of pericarditis, corticosteroids should be tapered off slowly and colchicine should be given at a dosage of one mg/day168,228.
Intrapericardial corticosteroid use was shown to induce considerable clinical improvement and low recurrence rates of pericarditis after a one-year follow-up period. The advantage of this route of administration is that bypasses the side effects of systemic corticosteroid administration and prevents the recurrence of pericarditis. The therapeutic regimen for this purpose involves the use of triamcinolone, 300 mg every 12 hours in combination with colchicine, over a six month period. All patients were subjected to pericardial and epimyocardial biopsies to investigate the state of inflammation and rule out viral infection or other etiological agents. The limitations of this procedure derive from its invasive nature221,236.
The first feature that requires attention in recurrent pericarditis cases is the investigation of the possible causal factor, which may include an inadequate therapeutic regimen, inadequate dosing, rapid withdrawal from corticosteroids, viral replication due to corticosteroid use, reinfection, and the reactivation of autoimmune or connective tissue disease. If none of those factors are identified, corticosteroids can be used in patients who present with frequent crises and severely impaired clinical conditions. Thus, prednisone at a dose of 1-1.5 mg/kg is recommended over a four week period with a slow taper off over three months. In patients with frequent recurrences, azathioprine at a dose of 75-100 mg/day or cyclophosphamide might be combined. Additionally, colchicine must be included in the therapeutic regimen to reduce the odds of recurrence206,237.
The use of low doses of prednisone (0.2 - 0.5 mg/kg/day over four weeks) exhibited the same therapeutic efficacy a dose of one mg/kg/day with lower incidences of side effects238.
Viral pericarditis can be induced by several viral species. Diagnosis is established after a positive viral assessment in the epimyocardial and pericardial tissue, as well as in the pericardial fluid. The aim of antiviral therapy is not only to induce the improvement of symptoms and remission of disease but also to avoid disease recurrence. Several antiviral regimens are currently being tested. These include the use of hyperimmunoglobulin (four ml/kg on days zero, four, and eight; two ml/kg on days 12 and 16) to treat CMV-induced pericarditis, interferon-a (2.5 millions IU/m2, per subcutaneous route, over three weeks) for Coxsackie B-induced pericarditis, and intravenous immunoglobulin (10 g on days one and three) for adenovirus and parvovirus B19-induced pericarditis. Although the rationale for the use of immunoglobulin is the same as for viral myocarditis, randomized trials are still needed to establish the efficacy of this therapeutic strategy239,240.
Cardiac tamponade is treated by pericardial drainage to reduce intrapericardial pressure and thus improve the patient hemodynamic condition. A rapid crystalloid infusion might be indicated to improve perfusion and stabilize the patient hemodynamic state prior to pericardial drainage, whereas amines or atropine are used when bradycardia is present. Pericardial drainage might be performed by percutaneous puncture and catheter placement, open surgical drainage with or without pericardiectomy (pericardial window), or video-assisted pericardioscopy241. Pericardiocentesis with a catheter must be guided by echocardiography, which permits identification of the best site and pressure angle, thus reducing the risk of complications and increasing the rate of success242. Catheter drainage might occur over a few days, and the catheter should not be removed until the drainage rate is below 20 - 30 ml/24 hours.
The advantage of surgical drainage is that it permits the performance of a pericardial biopsy. It is recommended in cases of effusion relapse following catheter drainage as well as for clots or effusion that are located in sites not accessible by the percutaneous route197.
Pericardial constriction syndrome is treated by pericardial excision. Pericardial resection can be a technical challenge due to the presence of dense adherences and calcifications that might penetrate into the myocardium. In most centers, the procedure is performed through a median sternotomy and might eventually require extracorporeal circulation243. The aim of this procedure is to rid the ventricles of the densely adhered pericardium. Special attention must be given in cases with epicardial coronary vessel dissection. The goal is to resect the pericardium from phrenic nerve to phrenic nerve and posteriorly around the entry of the vena cava and pulmonary veins. Although a complete resection will restore the pressure-volume curve244, it is not possible in all cases, particularly in cases of constrictive radiation-induced pericarditis. The surgical mortality may be as high as 10 to 20%245,246. Long-term survival is lower in patients with a history of previous heart surgery, especially those with constrictive radiation-induced pericarditis247,248.
Severe chronic kidney disease (CKD) is a common cause of pericardial disease, including pericarditis and pericardial effusion. Several factors contribute to the development of pericardial diseases under this condition, which are generally described as two forms, uremic and dialysis-associated pericarditis249.
Uremic pericarditis occurs in approximately 10% of patients before or immediately after the onset of dialysis250. The pathophysiology is poorly understood and seemingly does not bear any relationship to the underlying cause of CKD (except for systemic lupus erythematosus and scleroderma), although it is related to urea concentrations. Generally, it is easily resolved with continued dialysis therapy.
Dialysis-associated pericarditis occurs in approximately 15% of the patients who undergo hemodialysis and less often among patients who undergo peritoneal dialysis. It is mainly associated with hypervolemia and inappropriate dialysis; therefore, fluid correction and adequate dialysis are of paramount importance251.
The clinical and laboratory manifestations are similar to those of non-uremic patients with similar pericardial diseases, except for chest pain, which occurs less often in individuals with terminal CKD, and the lack of electrocardiographic alterations that are typical of acute pericarditis due to the absence of myocardial inflammation252,253.
Most patients respond promptly to dialysis and the pericarditis is resolved in approximately one to two weeks1. Pain and inflammation can be managed with NSAIDs or corticosteroids, both of which are less effective in patients who are refractory to dialysis. In such cases, colchicine has shown some benefit255. The use of heparin during dialysis treatment should be controlled. Uremic pericarditis seldom progresses into pericardial constriction.
Patients who progress into pericardial tamponade or develop symptomatic volume-persistent pericardial effusion should be treated by pericardiocentesis combined with intrapericardial corticosteroid instillation (triamcinolone 50 mg every six hours over three days)256. Pericardiectomy is indicated for cases of recurrent pericarditis with persistent pain that is refractory to anti-inflammatory treatments257.
Postpericardiotomy syndrome (PPS) occurs in approximately 10 to 15% of the patients who are subjected to surgical heart and/or pericardial trauma and can occur days or even months after the trauma (80% within the first month)258. PPS is thought to have a mixed pathophysiology, in which surgical trauma causes primary inflammation, followed by the development of an autoimmune response (heart anti-sarcolemma antibodies)259.
The vast majority of patients exhibit pleuro-pericardial involvement, such as a fever that appears after the first postoperative week (without evidence of systemic or focal infection), pleuritic chest pain, and a new pleural effusion or aggravation of a pre-existing effusion. Less frequent findings include pericardial friction rub (one-third of patients) and typical electrocardiographic alterations260. Progression into pericardial tamponade or constrictive pericarditis is less common, but hospitalization is usually of longer duration in PPS cases, and PPS is associated with early recurrence and hospital readmission.
The use of aminocaproic acid (valvular or combined coronary and valvular surgery) during surgery has been reported as a predisposing factor for PPS. A recent study found that female gender and pleural incision behave as independent risk factors261.
Primary prevention with short courses of colchicine treatment seems to be particularly useful262, whereas there is no evidence to support the use of methylprednisolone or acetylsalicylic acid260.
Treatment of acute PPS is similar to that of acute pericarditis and includes the use of non-steroidal anti-inflammatory agents and colchicine over weeks or months until the effusion is resolved; colchicine is also indicated for recurrences229,263. The alternatives described for refractory cases include oral corticosteroids (three to six months) or pericardiocentesis with an intrapericardial instillation of triamcinolone.
Pericardial effusion is a severe complication of malignant tumors. Metastatic disease is much more common than primary tumors, and the most common cause is lung cancer, followed by breast cancer, melanoma, lymphoma, and leukemia264.
The clinical course is usually benign. Symptomatic cases can exhibit complaints that range from chest pain and dyspnea to a severe progression into cardiac tamponade265. Very often, the differential diagnosis of effusion is difficult; therefore, a definitive diagnosis is based on a cytological analysis of the pericardial fluid.
Therapeutic options for the immediate relief of symptoms are percutaneous or surgical drainage. Several strategies have been suggested to prevent recurrence, including local sclerosis, pericardial window, systemic and/or local chemotherapy, and radiotherapy266. Intrapericardial sclerosis with bleomycin was shown to have modest benefits when compared to pericardial drainage alone267. Surgical drainage seems to be the best option for lung adenocarcinoma metastases268.
Radiation-induced pericarditis can occur acutely during radiotherapy treatment or several years after the end of therapy. Patients may exhibit few symptoms, or clinical manifestations might be masked by the underlying neoplastic disease. Effusions might be hemorrhagic or serous, and can progress with formations of adherences and constriction. Pericarditis must be treated in a conservative manner in asymptomatic cases. Pericardiocentesis is indicated to facilitate a diagnosis and for patients with cardiac tamponade. Pericardiectomy is indicated for patients who progress into pericardial constriction; the surgical mortality rate is high, whereas the five-year survival is low269.
Tuberculous pericarditis (TBP) occurs in 1-4% of the individuals affected by pulmonary tuberculosis (TB)270,271; TB accounts for 7% of cardiac tamponade cases171.
TBP exhibits four stages of progression: dry, effusive, absorptive and constrictive272. The mortality rate of untreated TBP is approximately 85%. Pericardial constriction occurs in approximately 30 - 50% of cases273.
The clinical presentation of TBP is quite variable and may include acute pericarditis with or without effusion, silent cardiac tamponade, persistent fever, acute, subacute, effusive, or chronic constrictive pericarditis, and pericardial calcification274.
Although the onset of TBP is insidious, it can also begin suddenly and dramatically in 20 - 25% of cases271. Echocardiogram is the best method to confirm the presence of a pericardial effusion. Diagnosis is established upon the identification of
In TBP, the pericardial fluid has a high protein concentration and highly variable leukocyte counts (from 700 to 54,000 cells/ml). The findings are unspecific and the bacillus is found on direct examination in only 40 to 60% of the patients subjected to pericardiocentesis275. The specificity of the tuberculin test also exhibits poor predictability in areas of high TB incidence. The skin tuberculin test yields false-negative results in 25-33% of patients and false-positive results in 30-40% of elderly patients276.
Pericardial fluid culture has a modest sensitivity rate and a specificity rate of 100% 277. Increased adenosine deaminase (ADA) activity levels and interferon-c concentrations in the pericardial fluid have high diagnostic sensitivities and specificities 278.
Polymerase chain reaction (PCR) is another method that can detect
The interferon-g test (IGT) is approved for use in peripheral blood but not in other fluids such as the pleural and pericardial fluids. It is not known whether IGT of the pericardial fluid has significant advantages over ADA.
Perimyocardial TB involvement is also associated with high anti-myosin and anti-myolemmal antibody titers280.
Pericardial biopsy permits fast diagnosis and exhibits higher sensitivity than pericardiocentesis (100% vs. 33%). The mortality associated with this type of biopsy, as reported in studies with a rigid endoscope, was 2.1%281 and 3.5%282; mortality was due to anesthetic induction in patients with very large pericardial effusion volumes.
Several combinations of anti-TB drugs with different treatment durations (6, 9 and 12 months) have been used283. Only patients with confirmed or highly probable TBP must be treated. Attempts to prevent constriction in chronic pericardial effusions of indefinite etiology with anti-TB agents were unsuccessful284.
Steroid use remains controversial. A meta-analysis of patients with constrictive-effusive TBP suggests that a combined treatment of anti-TB drugs and steroids might correlate with reduced mortality and a reduced need for pericardiocentesis or pericardiectomy285,286. Pericardiectomy is indicated when constriction develops in spite of the combination therapy.
The pharmacological treatment for all patients with TBP (and other forms of extrapulmonary TB) is comprised of an initial four-drug regimen (
The initial treatment phase usually involves a daily regimen; the various options are described in
Although purulent pericarditis has high morbidity and mortality rates, it occurs rarely in adults288. Predisposing conditions include previously existing pericardial effusive disease, recent heart surgery or recent chest trauma, chronic kidney disease, immunosuppression, alcohol abuse, rheumatoid arthritis, and malignant neoplasms. Fungal etiology is even more rare and usually appears in patients with fungal infections at other sites289.
The most common clinical presentation is an acute infectious illness; chest pain and pericardial friction rub are infrequent. Anemia, leukocytosis, electrocardiographic and radiological alterations might be present; however, the echocardiogram is one of the most widely used methods to detect and quantify pericardial effusions. Other diagnostic modalities that can be used are CT and MRI290.
Diagnostic suspicion is based on the clinical presentation and presence of pericardial effusion via echocardiogram. Diagnostic confirmation depends on the performance of pericardiocentesis with Gram staining and culture of the pericardial fluid, in addition to investigations of fungi and TB. Gram-positive bacteria are the most prevalent (64.2%), followed by Gram-negative microorganisms (27.7%) and fungi (1.4%)291,292.
Treatment includes pericardial drainage by pericardiocentesis and antibiotics. The initial regimen must target staphylococci and can be replaced later according to the culture results. In the case of multiloculated effusions by septa, the use of thrombolytic agents might be considered, particularly streptokinase in three doses of 500,000 IU, administered every 12 hours293,294. Pericardial drainage via pericardiectomy is the procedure of choice for persistent and recurrent forms168.
The indications for the diagnosis and treatment of purulent pericarditis are described in
Systemic autoimmune processes can induce pericarditis295, and this disorder occurs in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, polymyositis, mixed connective tissue disease, seronegative spondylitis, Sjögren's syndrome, systemic vasculitis, Behçet's syndrome, granulomatosis with polyangiitis, and sarcoidosis, among others.
The clinical presentation varies from an asymptomatic finding to acute pericarditis; cardiac tamponade is less frequent. Cases of transient constrictive pericarditis have also been reported296. Progression to chronic constrictive pericarditis is rare. Management of the usual forms is directed at the underlying cause.
An isolated form of autoimmune pericarditis was described after a systematic search for evidence of auto-aggression and was confirmed by lymphocytic predominance or the presence of anti-sarcolemma autoantibodies297 in the pericardial fluid. The presence of viruses or other infectious agents is excluded (no IgM against cardiotropic viruses in the pericardial fluid, and negative PCR for those same agents) in addition to systemic or neoplastic diseases.
Treatment is the same as for acute pericarditis and pericardial effusion associated with treatment of the underlying disease (
Intrapericardial administration of triamcinolone at a dose of 300 mg/m2/24 hours in 100 ml of normal saline solution proved to be efficacious for the relief of symptoms and prevention of recurrence while avoiding the side effects of systemic corticosteroids298.
Chylopericardium is the pericardial accumulation of the matter drained by the thoracic duct due to a fistula, complications of mediastinal surgery, cardiovascular surgery, chest trauma, mediastinal tumors or congenital anomalies of the thoracic duct250.
In such cases, the pericardial fluid has a milky white, opalescent appearance and high triglyceride (5 - 50 g/L), protein (22- 60 g/L) and fat concentrations. Magnetic resonance T1- and T2-weighted images provide data that permit a definitive diagnosis299.
However, sometimes it is difficult to distinguish chylopericardium from other causes of pericardial effusion. In such instances, surgical exploration of the pericardium is required to establish a diagnosis.300 Treatment depends on the cause of chylopericardium and the amount of pericardial fluid. When the cause is chest or heart surgery and there are no signs of cardiac tamponade, treatment might merely consist of an occasional puncture and a medium-chain triglyceride-based diet301. Cases refractory to conservative treatment might require a surgical pericardioperitoneal shunt or an alternative ligation of the thoracic duct when its location can be established302.
Pericardial effusion is a relatively common occurrence in hypothyroidism and affects 30 to 80% of advanced and 3 to 6% of early cases303. Although very rare, cardiac tamponade is a possible complication and might be indicated by an unexpectedly fast heart rate in a patient with hypothyroidism and low QRS voltage304.
Treatment of pericardial effusion is easily achieved by the overall treatment of hypothyroidism (
There are two forms of pericarditis manifestation after AMI. One occurs early and is known as pericarditis epistenocardica or peri-infarction pericarditis; the other occurs late and is known as post-infarction pericarditis or Dressler's syndrome. Currently, the incidence of both forms is decreasing305,306. Peri-infarction pericarditis is defined by pericardial pain and pericardial friction rub and usually appears two or three days after the establishment of a transmural AMI. The electrocardiographic signs are difficult to identify because they overlap those of AMI. Persistent inverted T waves or the return of T waves to baseline levels might indicate pericarditis. The clinical course is benign and patient prognosis is not affected by this complication.
Post-infarction pericarditis occurs in approximately 5 to 6% of the patients subjected to thrombolysis and usually appears during the second week but can also manifest several months after AMI. It should be suspected in any patient who presents with pleuropericardial chest pain. Pericardial friction rub is not always present. A differential diagnosis between pericarditis and recurrent angina may be difficult; however, close attention to the patient history and serial electrocardiographic assessments can help to elucidate a diagnosis. Most cases have a benign course; however, because this form of pericarditis is associated with large infarctions, the overall long-term mortality rate is higher307.
Rare complications include hemopericardium, cardiac tamponade, and constrictive pericarditis. Treatment regimens target pain, which usually responds well to non-steroidal anti-inflammatory drugs. Nevertheless, treatments remain largely empirical due to a relative lack of controlled clinical trials308,309. Furthermore, the duration of treatment is not well established. However, despite such shortcomings, we suggest the following regimens: ibuprofen, at doses of 1,600 - 3,200 mg/day for up to two weeks, is the first-line drug because it increases coronary flow and exhibits the lowest incidence of side effects224,310; ASA, at doses of 2 to 4 g/day over two to five days, exhibits the same efficacy as ibuprofen In patients with refractory and recurrent symptoms, colchicine, at a dose of 0.5 mg twice per day, is preferable to oral corticosteroids, which should be used only in low doses (prednisone 0.2 - 0.5 mg/kg/day)223,311,312.
Pericardial disease is the most frequent clinical manifestation of cardiovascular disease in patients with HIV/AIDS. Pericardial effusion occurs in approximately 20% (range: 10 to 40%) of patients, and 4% has large effusion313-316. Two-thirds of the cases are caused by infection or neoplasia; the latter correlates with poorer prognosis317.
The clinical manifestations of pericarditis in HIV/AIDS patients are similar to those of pericarditis by other causes.
The treatment of pericarditis in HIV-infected patients is both symptomatic and preventive. When the effusion is symptomatic, recurrent, or chronic and viral infection is confirmed, specific treatment must be instituted242.
Cardiac tamponade occurs in 33 to 40% of cases, and immediate drainage is needed. When the pericardial effusion is large and has no established etiology, empirical anti-TB treatment is indicated326-328.
Posttraumatic pericarditis occurs after accidental or iatrogenic wounds. The most severe cases progress to pericardial effusion and tamponade and require emergency surgical treatment. Closed or penetrating chest or heart wounds with myocardial contusions can cause pericarditis. However, this form of pericarditis has little clinical significance and might develop days or months after the heart or chest injury. Inflammation seems to be due to production of antibodies in response to the myocardial injury. Pericarditis after heart surgery is reported to occur in 20% of myocardial revascularization procedures and can appear days to several months after intervention.
Iatrogenic pericarditis is rare; it occurs in less than 0.2% of percutaneous interventions. The procedures most frequently associated with pericarditis are percutaneous mitral valvuloplasty, transseptal puncture, coronary artery transection following angioplasty, endomyocardial biopsy, implantation of pacemaker electrodes in the right ventricle, and epicardial electrode implantation.
Injury-induced pericarditis also occurs in cases of chest or mediastinal radiation for the treatment of several types of neoplasms, especially Hodgkin disease, non-Hodgkin lymphomas and breast carcinoma. The odds of developing pericarditis are associated with the radiation source, dose, fractionation, duration, volume of exposure and field of application, as well as patient age. Radiation-induced pericarditis can occur during the course of treatment or months to several years afterwards167,168.
Pericardial effusion occurs in 17-45% of patients with aortic dissection and in 48% of autopsies of aortic dissection fatalities329. Dissection of the ascending aorta is commonly complicated by a potentially fatal hemopericardium. Diagnosis is usually established by transesophageal echocardiogram, chest tomography, or cardiac and aortic resonance330.
Pericardiocentesis is contraindicated due to the risk of increased bleeding and aggravation of the dissection. Patients must be subjected immediately to aortic corrective surgery and pericardial drainage331.
Recurrent pericarditis usually occurs 18 to 20 months after the initially resolved episode. It appears in approximately 15-32% of cases and manifests in two forms, intermittent (asymptomatic intervals without treatment) and incessant pericarditis (symptoms return every time treatment is discontinued)168,254. The mechanisms involved in the development of recurrence are inadequate treatment with non-steroidal anti-inflammatory agents or corticosteroids (dose, duration), inappropriate corticosteroid use that permits viral replication, viral reinfection, and reactivation of autoimmune disease.
Colchicine is the safest and most efficacious therapy for the avoidance of recurrent of pericarditis, particularly when NSAIDs or corticosteroid treatment failed to prevent recurrence332.
Corticosteroid treatment is indicated in patients with frequent recurrence or important clinical manifestations. When responses to corticosteroids are inappropriate, azathioprine or cyclosporine may be administered concomitantly206. A main determinant of recurrence is rapid corticosteroid withdrawal; withdrawal should be done over a period of at least three months.
Pericardiectomy is indicated in cases with frequent, highly symptomatic, and treatment-refractory recurrence333-335.
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