Realização: Departamento de Imagem Cardiovascular (DIC) da Sociedade Brasileira de Cardiologia (SBC) e Sociedad de Imágenes Cardiovasculares de Sociedad Interamericana de Cardiología Conselho de Normatizações e Diretrizes (2020-2021): Brivaldo Markman Filho, Antonio Carlos Sobral Sousa, Aurora Felice Castro Issa, Bruno Ramos Nascimento, Harry Correa Filho, Marcelo Luiz Campos VieiraCoordenador de Normatizações e Diretrizes (2020-2021): Brivaldo Markman FilhoEditora Coordenadora: Samira Saady MorhyCoeditores: Silvio Henrique Barberato, Carlos Eduardo Rochitte, Marcelo Luiz Campos VieiraDe acordo com as “Normas para Elaboração de Diretrizes, Posicionamentos e Normatizações” sancionadas pela Sociedade Brasileira de Cardiologia, este documento foi escrito para atualizar as indicações da ecocardiografia em cardiologia fetal, pediátrica e cardiopatias congênitas do adulto, e complementa o posicionamento sobre indicações da ecocardiografia em adultos, recentemente publicado.1 Tal posicionamento não pretende ser uma ampla revisão da ecocardiografia em cardiopatias congênitas, mas sim um guia básico indispensável para amparar a tomada de decisão clínica racional do médico que solicita o exame. Embora leve em consideração os significativos avanços tecnológicos recentes da ecocardiografia, sua finalidade não é descrever com detalhes os métodos ecocardiográficos, mas resumir de forma clara e concisa as principais situações em que a ecocardiografia traz benefício para o diagnóstico e/ou a orientação terapêutica nesses grupos de pacientes. Optou-se, neste manuscrito, por destacar a classe da indicação (grau de recomendação), conforme a descrição a seguir:–Classe I: condições para as quais há evidências conclusivas ou, na sua falta, consenso geral de que o exame é útil e seguro.–Classe II: condições para as quais há evidências conflitantes e/ou divergência de opinião sobre utilidade e/ou segurança do exame.–Classe IIa: evidências ou opiniões favoráveis ao exame. A maioria dos especialistas aprova.–Classe IIb: utilidade e/ou segurança menos bem estabelecidas, havendo opiniões divergentes.–Classe III: condições para as quais há evidências ou consenso de que o exame não é útil e, em alguns casos, pode ser prejudicial.Em adição, foi descrito também o nível de evidência:–A: diversos estudos clínicos randomizados concordantes ou metanálises robustas.–B: dados de metanálises menos robustas ou estudo clínico randomizado único ou estudos observacionais.–C: opinião de especialistas.Assim, convencionou-se que, em todas as tabelas com recomendação do emprego da ecocardiografia nos diferentes cenários clínicos, constam as colunas com classe de indicação e nível de evidência,,A incidência da cardiopatia congênita é estimada entre 6-12/1.000 nascidos vivos;,,–O ecocardiograma fetal pode ser realizado em idades gestacionais mais precoces, incluindo o final do primeiro e o início do segundo trimestre, geralmente em gestações de alto risco para cardiopatias congênitas, principalmente na presença de translucência nucal aumentada no ultrassom morfológico do primeiro trimestre.O período e a frequência do ecocardiograma devem ser guiados por: gravidade da lesão, sinais de insuficiência cardíaca, mecanismos de progressão e avaliação para o manejo perinatal.As recomendações para a ecocardiografia fetal estão listadas nas Os recém-nascidos deixam uma situação de circulação em paralelo com baixa resistência vascular sistêmica e alta resistência vascular pulmonar na vida fetal para uma circulação em série, em que o débito cardíaco de ambos os ventrículos deve ser igual, na presença de uma alta resistência vascular sistêmica. Essas mudanças circulatórias que ocorrem após o nascimento podem demorar de dias a semanas para se completarem, principalmente nos prematuros, por causa de uma inabilidade de as comunicações presentes na vida fetal se fecharem prontamente. Assim, a persistência do canal arterial (PCA), a persistência de altas pressões pulmonares e a incapacidade do miocárdio imaturo de bombear sangue contra uma resistência vascular sistêmica, repentinamente alta, podem levar a uma redução transitória do fluxo sanguíneo sistêmico e alterar a hemodinâmica desses pacientes.A fisiologia transicional da circulação cardiovascular no período neonatal faz com que esses pacientes precisem ser avaliados como um grupo à parte.As razões mais comuns para realização do ecocardiograma no período neonatal são para reconhecer ou excluir doenças cardíacas congênitas estruturais em pacientes com: sopro cardíaco, alteração do teste do coraçãozinho,A avaliação ecocardiográfica de pacientes internados em unidades de terapia intensiva neonatal se justifica, inclusive de forma evolutiva, como um fator de mudanças específicas no manejo clínico do neonato.As recomendações para a ecocardiografia em recém-nascidos estão listadas na Por ser um método não invasivo e prover informações anatômicas, hemodinâmicas e fisiológicas dos corações pediátricos, o ecocardiograma é o principal método diagnóstico para avaliação inicial das cardiopatias congênitas ou adquiridas em lactentes, crianças e adolescentes.,–Crianças com doenças cardíacas representam um grupo variado de pacientes, frequentemente caracterizado por malformação anatômica complexa, que necessitam de seguimento durante toda a vida. Assim, estudos seriados podem ser indicados para monitoramento de função valvar, crescimento de estruturas cardiovasculares, função ventricular e seguimento de intervenções medicamentosas ou cirúrgicas.Sinais e sintomas como cianose, déficit de crescimento, dor torácica induzida por exercício, síncope, desconforto respiratório, sopros, insuficiência cardíaca, alteração de pulsos e cardiomegalia podem sugerir doença cardíaca estrutural.Além disso, o ecocardiograma pode ser indicado mesmo sem quadro clínico específico em pacientes com história familiar de doença cardíaca hereditária, síndromes genéticas associadas à cardiopatia estrutural, exames complementares alterados .Pacientes com arritmias podem ter cardiopatia estrutural, como transposição corrigida das grandes artérias e anomalia de Ebstein, tumores cardíacos e cardiomiopatias. As arritmias sustentadas e o uso de medicações antiarrítmicas podem levar à alteração na função miocárdica, sendo importante a realização do ecocardiograma no manejo clínico desses pacientes.As recomendações para a ecocardiografia em lactentes, crianças e adolescentes estão listadas na As cardiopatias adquiridas ocorrem principalmente em doenças sistêmicas associadas a processos inflamatórios, doenças renais, uso de quimioterápicos cardiotóxicos, doença parenquimatosa pulmonar e após transplante cardíaco.–O acometimento miocárdico pode ocorrer em várias condições, tais como doenças inflamatórias sistêmicas .Nos pacientes nefropatas crônicos/hipertensos e/ou dialíticos, o ecocardiograma fornece informações preciosas ao clínico no que diz respeito à geometria ventricular, função sistólica/diastólica e volemia. Isso, muitas vezes, orienta a mudança do esquema de diálise, assim como introdução ou troca de anti-hipertensivos e de fármacos vasoativos.–Nos pacientes pneumopatas, o ecocardiograma viabiliza não apenas a estimativa de pressões pulmonares, mas também a avaliação do desempenho ventricular direito, que guarda importante correlação com o prognóstico clínico.Em crianças e adolescentes com AIDS, o ecocardiograma é utilizado para investigação de acometimento cardíaco direto pelo vírus, que podem causar miocardiopatia dilatada, hipertensão pulmonar e até hipertrofia ventricular, além dos efeitos de doenças oportunistas e/ou efeitos colaterais das medicações utilizadas.Com o número crescente de insuficiência cardíaca final em crianças, faz-se necessário avaliação pré e pós-transplante cardíaco e/ou cardiopulmonarAs recomendações para a ecocardiografia em recém-nascidos, lactentes, crianças e adolescentes com cardiopatia adquirida estão listadas na –A cardiologia pediátrica experimentou notáveis avanços nos últimos 30 anos, tanto no aspecto diagnóstico com o advento da ecocardiografia quanto no tratamento de correção das cardiopatias, inicialmente cirúrgico e posteriormente por técnica percutânea na sala de hemodinâmica. Dados recentes indicam que, em 2010, a população estimada de adultos com cardiopatia congênita nos EUA era de 1,4 milhão de pacientesstrain ou strain rate podem ser de grande utilidade, principalmente nas condições com fisiologia univentricular ou naquelas com deformação das câmaras cardíacas, principalmente do ventrículo direitoNão há dúvida de que a ecocardiografia transtorácica bidimensional tem papel importante no diagnóstico e no acompanhamento dessas malformações.A principal limitação da ecocardiografia na avaliação de adultos com cardiopatia congênita é a inadequada janela transtorácica em pacientes com cirurgia cardíaca prévia ou deformidades da parede torácica, assim como a ecocardiografia não é adequada na avaliação do arco aórtico, das artérias coronárias, das artérias pulmonares e dos vasos colaterais. Nessas situações, a ecocardiografia transesofágica, angiotomografia e a ressonância magnética (RM) são extremamente úteis.As recomendações para a ecocardiografia em adultos com cardiopatias congênitas estão listadas na O ecocardiograma transesofágico (ETE) constitui uma via de acesso alternativa, por meio do uso de transdutores especiais, que fornece maior definição das estruturas cardíacas, aumentando as possibilidades diagnósticas do método.É particularmente importante na definição de estruturas anatômicas complexas e anormalidades funcionais, nem sempre passíveis de avaliação pela ecocardiografia transtorácica isolada.Com os avanços tecnológicos e miniaturização das sondas, a adoção do ETE vem se ampliando no campo da cardiologia pediátrica, podendo oferecer importantes informações para os pacientes desde a faixa etária neonatal até adolescentes e adultos, tanto no diagnóstico, na avaliação intraoperatória, no pós-operatório imediato e tardio e na unidade de terapia intensiva quanto no laboratório de hemodinâmica, auxiliando a realização de procedimentos intervencionistas.O ETE deve ser adotado para melhor definição diagnóstica da cardiopatia, nas situações em que é necessária melhor avaliação anatômica em algumas cardiopatias congênitas específicas, na maioria das vezes em adultos, visto que a qualidade da imagem em crianças é geralmente boa ao exame transtorácico .O grande impacto da ecocardiografia transesofágica na sala cirúrgica é a detecção de defeitos residuais importantes que muitas vezes não são suspeitados. Vários autores têm demonstrado retorno à circulação extracorpórea para revisão cirúrgica após a realização do ETE intraoperatório com taxas variando de 6 a 11,4% dos casos, nas diferentes séries avaliadas.As indicações de ETE intraoperatório para cardiopatias congênitas estão listadas na A definição das imagens pelo ETT no pós-operatório imediato pode estar prejudicada pela presença de drenos, curativos, telas e ventilação mecânica, sendo necessária a adoção do ETE, que pode fornecer informações anatômicas (lesões residuais) e hemodinâmicas importantes na condução clínica e na terapêutica dos pacientes .O ETE auxilia a intervenção hemodinâmica detalhando o diagnóstico em diversas cardiopatias, monitorando o procedimento, além de fornecer informações anatômicas do resultado e de eventuais lesões residuais,––A ecocardiografia sob estresse (físico ou farmacológico) é uma técnica bem estabelecida em adultos.–Ambos os tipos de estresse, farmacológico e exercício, podem ser aplicados em crianças, com algumas peculiaridades.,A ecocardiografia tridimensional (3D) tem sido incorporada na prática clínica, adicionando informações ao ecocardiograma bidimensional (2D), principalmente para a abordagem dos defeitos congênitos nos quais a visão tridimensional oferece uma visão muito próxima dos planos anatômicos e cirúrgicos.foot print menor e com frequência mais alta (2 a 8 Mhz). Entretanto, ainda não temos a mesma qualidade de imagem quando se usa a combinação 2D-3D com o mesmo transdutor, principalmente em pacientes pequenos. Outro grande desafio ainda a ser ultrapassado é o desenvolvimento do transdutor transesofágico pediátrico, o que limita o uso do ETE 3D em pacientes acima de 30 kg de acordo com as recomendações dos fabricantes. Em crianças pequenas, recomenda-se o uso de transdutores pediátricos com frequência mais alta, e também o ecocardiograma epicárdico, nos casos realizados no intraoperatório. O ecocardiograma 3D transesofágico deve ser sempre considerado em pacientes maiores  se o 3D transtorácico não oferecer informação suficiente para o planejamento cirúrgico ou intervenção.Quando se trata de paciente pediátrico, temos uma grande vantagem pela melhor janela acústica transtorácica, e, mais recentemente, houve um avanço no desenvolvimento de transdutores com um Existe uma variedade de defeitos congênitos nos quais o ecocardiograma 3D pode adicionar informações sobre as mais diversas estruturas anatômicas, incluindo septos atrial e ventricular, as valvas semilunares e atrioventriculares, assim como as vias de saída. Como tem havido um progresso tecnológico, a aplicação está se estendendo à medida que ocorre esse progresso e adequação para população pediátrica. Atualmente, o uso baseia-se mais na necessidade clínica de informações adicionais do que em estudos randomizados sobre a vantagem do 3D sobre o 2D. Portanto, é individualizado e de acordo com o perfil do laboratório de imagem ou hospital adotar a tecnologia para lesões específicas.As lesões valvares e os defeitos septais isolados são as principais indicações; contudo, em situações em que há concomitante anomalia de conexão ventriculoarterial, como nas duplas vias de saída do ventrículo direito, a posição e o tamanho da comunicação interventricular podem ser melhor visualizados e demonstrados pelo ecocardiograma 3D.–De acordo com a área ou estrutura avaliada pelo ecocardiograma 3D transtorácico e/ou transesofágico, podemos ter informações relevantes que complementariam aquelas obtidas pelo ecocardiograma 2D.,–O ecocardiograma 3D também adiciona informação no contexto de algumas cardiopatias congênitas específicas em que existem anomalias de conexão ,Ostium Secundum, que são muito bem demonstradas por imagem em tempo real pelo ecocardiograma 3D transesofágico. O fechamento das comunicações interventriculares por dispositivos percutâneos ou transmural também pode ser guiado pelo ecocardiograma 3D, principalmente para avaliar estruturas próximas, como, por exemplo, folhetos e/ou cordas da valva tricúspide. Existem outras aplicações na sala de hemodinâmica no qual o ecocardiograma 3D pode guiar os procedimentos: fechamento das fenestrações na cirurgia de Fontan, fistulas coronárias, rupturas do seio de Valsalva, regurgitação paravalvar, perfuração de septo e localização dos eletrodos no processo de ressincronização ventricular.–A aplicação do ecocardiograma 3D na sala de hemodinâmica para fechamento de defeitos dos septos atrial e ventricular complementa as imagens 2D para delimitar as bordas dos defeitos e estruturas relacionadas,softwares disponíveis foram desenvolvidos a partir da geometria ventricular esquerda de corações normais, o que muitas vezes invalida as informações obtidas pelo 3D. Apesar de as medidas de volumes e fração de ejeção serem replicáveis, o ecocardiograma 3D tem mostrado valores menores que a RM na quantificação dos volumes, o que impede de substituir um pelo outro. Portanto, a aplicação clínica ainda tem sido dificultada por ausência de valores de normalidade na população pediátrica. Não se recomenda o uso dos softwares desenvolvidos para ventrículo esquerdo ou direito normais em ventrículos congenitamente malformados até que novos softwares ou modelos tenham sido validados.70,95-97Um dos grandes desafios em cardiopatias congênitas é a avaliação dos volumes e função ventricular, por razões intrínsecas dos defeitos congênitos . Os A recomendação geral para o uso do ecocardiograma 3D transtorácico em pediatria é que deve ser a de acordo com o tipo de paciente e com o perfil do laboratório de ecocardiograma e/ou hospital.Existe o consenso de que o 3D é uma modalidade que complementa o ecocardiograma 2D, e não uma substituição, independentemente do tipo de lesão.10. Estudo da Deformação Miocárdica em Pacientes Pediátricosstrain) vem se mostrando ferramenta útil na avaliação da função diastólica e sistólica, tanto em adultos como na população pediátrica.strain miocárdico pelo speckle-tracking é um método independente do ângulo de insonação e apresenta baixa variação intra e interobservador, o que permite quantificar a função ventricular global e regional de forma mais acurada do que os métodos tradicionais, como Doppler tecidual, fração de encurtamento ou de ejeção.strain obtido pelo speckle-tracking, reforçando sua utilidade tanto em patologias congênitas como adquiridas.A deformação miocárdica strain miocárdico como parâmetro de avaliação do impacto da reposição enzimática a longo prazo sobre a função ventricular dos portadores dessas doenças.O estudo do strain miocárdico também surge como uma possibilidade de diagnóstico precoce de inflamação miocárdica e disfunção ventricular nos casos de doença de Kawasaki.strain longitudinal de VE ao ecocardiograma inicial de pacientes com Kawasaki, que posteriormente vieram a desenvolver dilatação coronariana ou que mostraram resistência ao tratamento com imunoglobulina. Esses achados sugerem que o strain de VE pode vir a ser utilizado em breve como ferramenta de estratificação de risco em Kawasaki.A análise do strain longitudinal e circunferencial do VE parecem já estar reduzidos em fases iniciais, a despeito da fração de ejeção ainda conservada.Nos casos de disfunção miocárdica induzida por sepse pediátrica, o strain longitudinal do VE, mesmo em estágios iniciais da doença e ainda com fração de ejeção preservada. Atribui-se o comprometimento precoce da deformação miocárdica à fibrose induzida por inflamação crônica e por toxinas urêmicas. Além disso, a disfunção endotelial que acompanha a IRC pode acarretar resposta vasodilatadora inadequada, causando isquemia em um ventrículo já hipertrófico. Achados semelhantes já foram documentados também em populações pediátricas, restando estabelecer se essa redução do strain longitudinal do VE pode ser utilizada como um preditor específico de morbidade e mortalidade em crianças com IRC.Em pacientes adultos com insuficiência renal crônica (IRC), já foi comprovada a redução do strain longitudinal de VD e VE, ainda em pacientes assintomáticos e com fração de ejeção do VE normal. Diante desses resultados, Naami et al. sugeriram, em 2016, a incorporação do estudo da deformação miocárdica aos ecocardiogramas dos pacientes pediátricos com HIV, com o objetivo de identificar pacientes com disfunção subclínica e com maior risco cardiovascular.Alterações cardiovasculares são comuns em indivíduos infectados pelo HIV, mas frequentemente são subdiagnosticadas e não tratadas, o que impacta na qualidade de vida e na mortalidade a longo prazo. São atribuídas tanto ao efeito direto do vírus quanto às medicações antirretrovirais sobre o miocárdio e a vasculatura. A disfunção sistólica sintomática é normalmente encontrada apenas nos casos mais avançados da síndrome de imunodeficiência adquirida.strain longitudinal do VE. Além disso, mesmo após correção para sexo, idade, nível de ferritina sérica e índice de massa ventricular, o strain longitudinal de VE permaneceu como preditor independente de eventos adversos em pacientes talassêmicos, como insuficiência cardíaca, arritmias e óbito .Em um estudo que incluiu adolescentes e adultos jovens com talassemia submetidos a múltiplas transfusões, Chen et al.strain longitudinal do VD na população pediátrica. Um valor de strain inferior a –14% ao ecocardiograma inicial identificou pacientes que evoluíram para transplante pulmonar ou óbito com 100% de sensibilidade e 54,5% de especificidade. Concluíram que a deformação miocárdica na HPI pediátrica é ferramenta mais sensível do que os parâmetros convencionais de avaliação da função do VD  para a detecção de pacientes com pior prognóstico.strain longitudinal de VD no seguimento clínico da HPI em crianças, demonstrando que os valores de strain apresentam excelente correlação com os valores de BNP – do inglês B-type natriuretic peptide values, no decorrer do tratamento com análogos da prostaciclina.Investigando crianças e adolescentes portadores de hipertensão pulmonar idiopática (HPI), Okumura et al. comprovaram o valor prognóstico da avaliação seriada do strain longitudinal do VD em posição subpulmonar provou-se factível e reprodutível na avaliação perioperatória de diferentes cardiopatias congênitas.strain de pico sistólico longitudinal, não apresentam adequada correlação com a fração de ejeção obtida pela RM. Em situações com estenose pulmonar residual ou uma combinação de estenose e insuficiência pulmonar, a hipertrofia do VD acarreta predomínio de fibras circunferenciais, alterando o padrão de deformação dessa câmara, que habitualmente depende mais das fibras longitudinais.strain de pico sistólico circunferencial da parede livre do VD ao corte subcostal, especificamente crianças portadoras de cardiopatias congênitas com sobrecarga pressórica ao VD. Dessa forma, encontraram melhor correlação entre os valores de strain e de fração de ejeção de VD.strain de pico sistólico longitudinal biventricular. Alguns autores encontraram correlação negativa entre o strain de pico sistólico longitudinal de VD e fração de ejeção do VD e fração de regurgitação pulmonar, ambas estimadas pela RM.strain longitudinal do VE e o grau de regurgitação pulmonar, reforçando a importância da interdependência entre os ventrículos.strain que permita indicar o melhor momento para a troca valvar pulmonar.A análise do strain longitudinal nesta condição representa uma alteração na geometria ventricular direita e não disfunção sistólica real. Trata-se de um mecanismo adaptativo, que faz com que a contratilidade do VD sistêmico se torne semelhante à contratilidade do VE. Por essa razão, trabalhos recentes sugerem uma faixa de valores normais de strain de pico sistólico longitudinal do VD sistêmico que ficam abaixo do esperado para o VD subpulmonar .strain longitudinal de VD inferiores a –10% foram associados à ocorrência de eventos adversos, em PO tardio de cirurgia de Senning.O VD em posição sistêmica também demonstra mudança do padrão de deformação miocárdica, com predomínio de contração das fibras circunferenciais. A redução discreta do strain rate circunferencial pré-operatório melhora a estratificação de risco para pacientes com VU candidatos à cirurgia de Fontan, não importando se o ventrículo é de morfologia direita ou esquerda.A seleção de pacientes com ventrículo único (VU) para cirurgia de Fontan leva em consideração a resistência vascular pulmonar e a pressão diastólica final ventricular. No entanto, os critérios atuais de indicação mostram-se falhos para uma considerável parcela desses pacientes, que acabam enfrentando complicações e internações prolongadas. Quando associado à resistência vascular pulmonar e à pressão diastólica final ventricular, o strain mostra fraca correlação com a fração de ejeção obtida pela RM.No caso da anomalia de Ebstein, o estudo da deformação miocárdica acrescenta pouco à avaliação da função ventricular direita, uma vez que o strain longitudinal do ventrículo esquerdo no diagnóstico de pacientes com obstrução coronariana em PO tardio de correção de origem anômala de coronária esquerda. Um valor de strain < –14,8% ao ecocardiograma identificou segmentos miocárdicos com fibrose à RM, com sensibilidade de 92,5% e especificidade de 93,7%.Castaldi et al.strain longitudinal do VE e a presença de fibrose miocárdica, avaliando crianças e adultos jovens com estenose valvar aórtica e com fração de ejeção do VE preservada.strain longitudinal do VE têm maiores taxas de mortalidade após intervenção valvar.Dusenbery et al.speckle-tracking foi incorporado recentemente à pediatria, surgindo como ferramenta promissora para a detecção de disfunção ventricular direita. Hope et al.strain longitudinal de átrio direito em crianças com HPI. O strain atrial mostrou-se mais sensível e específico do que parâmetros convencionais de avaliação da função ventricular direita na identificação dos pacientes com HPI que vieram a apresentar desfechos desfavoráveis .O estudo da mecânica atrial direita através do strain atrial esquerdo pela técnica de speckle-tracking. O strain de átrio esquerdo, na fase de reservatório, mostrou-se mais acurado na estimativa da pressão diastólica final do VE do que parâmetros ecocardiográficos clássicos como o volume atrial esquerdo e a relação E/E', além de correlacionar-se inversamente com os níveis plasmáticos do NT-ProBNP.Diversos trabalhos têm descrito as implicações clínicas da medida do strain rate diastólico precoce e tardio, no eixo longitudinal de VD e VE, em fetos de mão diabética. Além disso, registraram redução do strain de pico sistólico longitudinal do ventrículo direito, mediante comparação com fetos normais de mesma idade gestacional. Os autores ressaltam que o comprometimento da deformação diastólica ocorreu independentemente da presença de hipertrofia septal. Concluem que o estudo da deformação miocárdica pode detectar alterações subclínicas nos fetos de mãe diabética, antes que os parâmetros ecocardiográficos clássicos sejam capazes de fazê-lo.Trabalhos recentes têm sugerido que a análise da deformação miocárdica pode contribuir para a avaliação da função sistólica e diastólica biventricular também nos fetos. Como exemplo, Miranda et al. documentaram redução de  Development: Cardiovascular Imaging Department (Departamento de Imagem Cardiovascular – DIC) of the Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia – SBC) and the Cardiovascular Imaging Society of the Interamerican Society of Cardiology Norms and Guidelines Council: Brivaldo Markman Filho, Antonio Carlos Sobral Sousa, Aurora Felice Castro Issa, Bruno Ramos Nascimento, Harry Correa Filho, Marcelo Luiz Campos VieiraNorms and Guidelines Coordinator: Brivaldo Markman FilhoCoordinating Editor: Samira Saady MorhyCo-editors: Silvio Henrique Barberato, Carlos Eduardo Rochitte, Marcelo Luiz Campos VieiraIn accordance with the “Standards for Production of Guidelines, Position Statements, and Standardizations” sanctioned by the Brazilian Society of Cardiology, this document was written to update indications for echocardiography in fetal and pediatric cardiology and congenital heart disease of the adult, and to supplement the recently-published position paper on indications for echocardiography in adults.–Class I: conditions for which there is conclusive evidence or, in the absence thereof, general agreement that the examination procedure is useful and safe.–Class II: conditions for which there is conflicting evidence and/or divergence of opinion on the utility and/or safety of the examination.–Class IIa: evidence or opinions favorable to the examination. Most experts approve.–Class IIb: utility and/or safety less well established, with divergent opinions.–Class III: conditions for which there is evidence or consensus that the examination is not useful and, in some cases, may even be harmful.Evidence levels are also presented, defined as follows:–A: agreement between multiple randomized clinical trials or robust meta-analyses;–B: less robust meta-analysis data or single randomized clinical study or observational studies;–C: expert opinion.All of the tables summarizing recommendations for use of echocardiography in different clinical scenarios will therefore include columns showing recommendation classes and evidence levels,,The incidence of congenital heart disease is estimated at 6-12/1,000 live births;,,–Fetal echocardiography can be performed at younger gestational ages, including at the end of the first and start of the second trimesters, generally in pregnancies at high risk of congenital heart disease, particularly when elevated nuchal translucency is present on morphological ultrasound in the first trimester.The timing and frequency of echocardiography should be guided by: severity of lesions, signs of heart failure, mechanisms of progression, and perinatal management assessment.Fetal echocardiography recommendations are listed in Newborn infants transition from a state in which circulation is in parallel, with low systemic vascular resistance and high pulmonary vascular resistance, during fetal life, to a state in which circulation is in series and the cardiac output of both ventricles must be equal in the presence of high systemic vascular resistance. These circulatory changes that take place with birth may take days or weeks to be completed, particularly in preterms, because the communications present during fetal life cannot close promptly. Thus, persistent ductus arteriosus (PDA), persistent high pulmonary pressures, and the incapacity of the immature myocardium to pump blood against systemic vascular resistance that has suddenly increased can cause a transitory reduction in systemic blood flow, changing these patients' hemodynamics.The transitional physiology of the cardiovascular circulation during the neonatal period means that these patients must be evaluated as a distinct group.The most common reasons for conducting an echocardiogram during the neonatal period are to detect or rule out congenital structural cardiac diseases in patients who have heart murmur, abnormal neonatal oximetry screening results,Echocardiographic assessment of patients in neonatal intensive care units is justified, including in an evolving manner, as a factor in specific changes to clinical management of the neonate.The recommendations for echocardiography in newborn infants are listed in Since echocardiography is a noninvasive method for obtaining anatomic, hemodynamic, and physiological information on the pediatric heart, it is the first-choice diagnostic method for initial assessment of congenital or acquired heart disease in infants, children, and adolescents.,–Children with cardiac diseases are a varied group of patients who often have complex anatomic malformations and require lifelong follow-up. Repeated studies may therefore be indicated to monitor heart valve function, growth of cardiovascular structures, and ventricular function and for follow-up of drug-based or surgical interventions.Signs and symptoms such as cyanosis, growth deficits, exercise-induced anginas, syncope, respiratory distress, murmurs, heart failure, pulse abnormalities, and cardiomegaly may suggest structural heart disease.Echocardiography may also be indicated even in the absence of specific clinical status in patients with family history of hereditary heart disease, genetic syndromes associated with structural heart disease, or abnormal examination findings .Patients with arrhythmia may have structural heart disease, such as corrected transposition of the great arteries and Ebstein's anomaly, cardiac tumors, or cardiomyopathies. Sustained arrhythmia and use of antiarrhythmic medications can cause changes to myocardial function and echocardiography plays an important role in clinical management of these patients.The recommendations for echocardiography in infants, children and adolescents are listed in Acquired heart diseases primarily occur in the context of systemic diseases linked to inflammatory processes, renal diseases, use of cardiotoxic chemotherapy, or parenchymatous pulmonary disease, and after heart transplantation.–Myocardial involvement can occur in several conditions, such as systemic inflammatory diseases .In patients with chronic liver disease or hypertension and/or on dialysis, echocardiography provides clinicians with valuable information on ventricular geometry, systolic/diastolic function, and blood volume. This can very often guide changes in the dialysis regimen and introduction of (or changes to) antihypertensive and vasoactive drugs.–In patients with pulmonary disease, echocardiography can be used to estimate pulmonary pressures and also to evaluate right ventricle performance, which has an important correlation with clinical prognosis.In children and adolescents with AIDS, echocardiography is used to investigate right cardiac involvement caused by the virus, which can result in dilated cardiomyopathy, pulmonary hypertension, and even ventricular hypertrophy, in addition to effects caused by opportunistic diseases and/or drug side effects.The growing number of children with end-stage heart failure must be evaluated before and after heart and/or cardiopulmonary transplantationThe recommendations for echocardiography in newborn infants, infants, children, and adolescents with acquired heart disease are listed in –Over the last 30 years, considerable advances were made in pediatric cardiology, both in the sphere of diagnosis with the advent of echocardiography and in the realm of treatment to correct heart diseases, initially surgically and more recently using percutaneous techniques in the catheterization laboratory. Recent data show that the estimated size of the population of adults with congenital heart disease in United States in 2010 was 1.4 million patients.There is no doubt that two-dimensional transthoracic echocardiography has an important role to play in diagnosis and follow-up of these malformations.The primary limitation of echocardiography for assessment of adults with congenital heart disease is a poor transthoracic acoustic window in patients with previous heart surgery or deformities of the chest wall, and echocardiography is also inappropriate for assessing the aortic arch, the coronary arteries, the pulmonary arteries, and the collateral vessels. In these situations, transesophageal echocardiography, angiotomography, and magnetic resonance (MR) are extremely useful.The recommendations for echocardiography in adults with congenital heart disease are listed in Transesophageal echocardiography (TEE) uses special transducers and a different access route, offering better definition of cardiac structures, increasing the method's diagnostic applications.It is particularly important for definition of complex anatomic structures and functional abnormalities, which cannot always be evaluated using transthoracic echocardiography alone.Technological advances and miniaturization of probes has led to increasing adoption of TEE in the field of pediatric cardiology and it can provide important information about patients from the neonatal age group up to adolescents and adults, for diagnosis, intraoperative assessment, in the immediate and late postoperative periods, and in the intensive care unit, and also in the catheterization laboratory, aiding in interventional procedures.Transesophageal echocardiography should be adopted to improve diagnostic definition of heart disease in situations in which better anatomic evaluation is needed in certain specific congenital heart diseases, in the majority of cases in adults, since in children the image quality of transthoracic echocardiography is generally good .The most important impact of transesophageal echocardiography in the operating room is detection of significant residual defects that are very often unsuspected. Several authors have reported putting patients back on extracorporeal circulation to review surgery after intraoperative TEE, with rates that vary from 6 to 11.4% of cases, in the different series analyzed.The indications for intraoperative TEE for congenital heart disease are listed in In the immediate postoperative period, the definition of TEE images may be compromised by drains, dressings, meshes, and mechanical ventilation, making it necessary to use TEE, which can provide anatomic  and hemodynamic information that is important for clinical and therapeutic management of patients .Transesophageal echocardiography is helpful during hemodynamic interventions, providing diagnostic details in a range of heart diseases and for monitoring procedures, in addition to providing anatomic information on the results and on possible residual lesions,––Echocardiography under stress  is a well-established technique in adults.–Both types of stress, pharmacological and exercise, can be administered to children, with certain peculiarities.,Three-dimensional (3D) echocardiography has been incorporated into clinical practice, providing additional information in comparison to two-dimensional (2D) echocardiography, and is primarily used for congenital defects in which the three-dimensional view offers images very close to the anatomic and surgical planes.When dealing with pediatric patients, the larger transthoracic acoustic window is a great advantage. More recently, more advanced transducers have been developed with a smaller footprint and higher frequency (2 to 8 MHz). However, the image quality is still not the same when a 2D-3D combination is used with the same transducer, particularly in small patients. Another significant challenge that remains to be overcome is development of a pediatric transesophageal transducer, which limits 3D TEE to use in patients weighing more than 30 kg, according to manufacturers' recommendations. In small children, use of a pediatric transducer with higher frequency is recommended, as well as the epicardial echocardiogram, for intraoperative scenarios. Three-dimensional transesophageal echocardiography should always by considered in larger patients  if transthoracic 3D imaging does not yield sufficient information to plan surgery or other interventions.In a variety of different congenital defects, 3D echocardiography can provide additional information on a wide range of anatomic structures, including atrial and ventricular septa, the semilunar and atrioventricular valves, and also the outflow tracts. Applications are expanding as technological progress advances and adaptations are made to suit the pediatric population. Currently, use is based more on clinical need for additional information than on randomized studies showing the advantage of 3D over 2D. Use is therefore individualized and depends on the profile of the imaging laboratory or hospital adopting the technology for specific lesions.Valve lesions and isolated septal defects are the principal indications. However, in situations in which there are concomitant anomalies of the ventriculoarterial connection, as in double-outlet right ventricle, the position and size of the intraventricular communication can be better visualized and demonstrated with 3D echocardiography.–Depending on the area or structure assessed by transthoracic and/or transesophageal 3D echocardiography, it may provide relevant information that complements the findings of 2D echocardiography.,–Three-dimensional echocardiography can provide additional information in the context of certain specific congenital heart disease in which there are connection anomalies ,–Application of 3D echocardiography in the catheterization laboratory for closure of atrial and ventricular septal defects complements 2D images for delimiting the margins of defects and related structures,,–A major challenge in congenital heart disease is evaluation of ventricular volumes and function, because of reasons that are intrinsic to the congenital defects involved . The software packages available were developed on the basis of the left ventricular geometry of normal hearts, which can often invalidate the information obtained using 3D systems. Although measurements of volumes and ejection fractions are replicable, 3D echocardiography has shown smaller volumes than MR when quantifying volumes, which prevents one from being substituted for the other. As a result, clinical application is still complicated by the absense of values for normality in the pediatric population. It is not recommended that software developed for the normal left or right ventricle be used with congenitally malformed ventricles until new software or models have been validated.The general recommendation for use of 3D transthoracic echocardiography in pediatrics is that the decision should be taken in accordance with the type of patient and the profile of the echocardiography laboratory and/or hospital.There is consensus that 3D is a modality that complements rather than substitutes 2D echocardiography, irrespective of the type of disorder.Myocardial deformation (strain) is proving to be a useful tool for evaluation of diastolic and systolic function, in both adults and the pediatric population.–Notwithstanding, myocardial strain is subject to physiological variations caused by age, sex, heart rate, preload, arterial blood pressure, and body surface area, in addition to the type of software used for the analysis.Analysis of right and left ventricular strain is particularly useful in situations in which the intention is to identify systolic and/or diastolic dysfunction while in the subclinical phase. The information obtained from strain analysis makes opportune therapeutic intervention possible in a range of systemic diseases with myocardial involvement.–Early detection of myocardial damage secondary to use of anthracyclines is one of the most important contributions of myocardial deformation imaging to date and has been incorporated into protocols for monitoring patients in oncology.A correlation has been demonstrated between the degree of inflammatory activity and the values of LV strain and systolic and diastolic LV strain rate in patients with rheumatic diseases, such as childhood-onset systemic lupus erythematosus.,Other studies have confirmed the efficacy of strain obtained using the speckle tracking technique for detection of myocarditis of both autoimmune and viral etiology.–After orthotopic heart transplantation in children, strain analysis has reasonable sensitivity and specificity for identifying which individuals will manifest vascular graft disease in later years.In young patients with Duchenne muscular dystrophy, studies have demonstrated a significant reduction in longitudinal and radial strain of the inferolateral and anterolateral walls of the LV, even before ejection fraction is compromised or symptoms of heart failure emerge.Myocardial strain imaging can also contribute to detection of myocardial compromise in storage disorders such as the mucopolysaccharidoses (MPS)Myocardial strain analysis has also emerged as a possible method for early diagnosis of myocardial inflammation and ventricular dysfunction in Kawasaki disease.In cases of myocardial dysfunction induced by pediatric sepsis, LV longitudinal and circumferential strain appear to already be reduced in the initial phases, even though ejection fraction is still unimpaired.In adult patients with chronic renal failure (CRF), reduction of LV longitudinal strain has been confirmed even in initial stages of the disease and with unimpaired ejection fraction. This early compromise of myocardial deformation has been attributed to fibrosis induced by chronic inflammation and uremic toxins. Additionally, the endothelial dysfunction that occurs in CRF may cause an inappropriate vasodilator response, leading to ischemia in an already hypertrophic ventricle. Similar findings have also been documented in pediatric populations, although it remains to be established whether this reduction in longitudinal LV strain can be used as a specific predictor of morbidity and mortality in children with CRF.Cardiovascular disorders are common among people with HIV infection, but are frequently underdiagnosed and left untreated, which impacts on patients' quality of life and on long-term mortality. They have been attributed both to the direct effects of the virus and to the effects of antiretroviral medications on the myocardium and vasculature. Symptomatic systolic dysfunction is normally only observed in more advanced cases of the acquired immunodeficiency syndrome.p = 0.033).In a study that enrolled adolescents and young adults with thalassemia who underwent multiple transfusions, Chen et al.Okumura et al. investigated children and adolescents with idiopathic pulmonary hypertension (IPH), confirming the prognostic value of serial assessment of longitudinal RV strain in the pediatric population. A strain value lower than −14% on the initial echocardiogram identified patients who progressed to lung transplant or death with 100% sensitivity and 54.5% specificity. They concluded that myocardial deformation in pediatric IPH is a more sensitive tool than conventional parameters for evaluation of RV function  to detect patients with worse prognosis.Analysis of longitudinal RV strain in a subpulmonary position proved feasible and reproducible for perioperative assessment of several congenital heart disorders.Patients with the RV in the systemic position also exhibit abnormal myocardial deformation patterns, with predominance of contraction of circumferential fibers. In this condition, the discrete reduction of longitudinal strain is indicative of changes to right ventricular geometry, and not of true systolic dysfunction. This is an adaptive mechanism, which makes contractility of the systemic RV similar to LV contractility. Recent publications therefore suggest a normal range of longitudinal systolic peak strain values in systemic RV that are below those expected for subpulmonary RV (–10% to –14.5%).Selection of patients with a single ventricle (SV) for Fontan procedure surgery takes into consideration pulmonary vascular resistance and end-diastolic ventricular pressure. However, current indication criteria have proved fallible for a considerable proportion of these patients, who are subject to complications and extended hospital stays. When associated with pulmonary vascular resistance and end-diastolic ventricular pressure, the preoperative circumferential strain rate improves risk stratification for patients with SV who are candidates for Fontan surgery, irrespective of whether the ventricle has right or left morphology.In the case of Ebstein's anomaly, myocardial deformation imaging has little to contribute to right ventricular function assessment, since strain has a weak correlation with ejection fraction measured with MR.Castaldi et al.Analysis of right atrial mechanics using speckle tracking was recently introduced in pediatrics, emerging as a promising tool for detection of right ventricular dysfunction. Hope et al.Several studies have described the clinical implications of left atrial strain measurements using the speckle tracking technique. Left atrium strain in the reservoir phase proved more accurate for estimation of end-diastolic pressure of the LV than classical echocardiographic parameters such as left atrial volume and the E/E' ratio and was also inversely correlated with plasma NT-ProBNP levels.Recent studies have suggested that analysis of myocardial deformation can also contribute to evaluation of biventricular systolic and diastolic function in fetuses. For example, Miranda et al. documented reduced early and late diastolic strain rate in the longitudinal axes of RV and LV in fetuses with diabetic mothers. Additionally, they also observed reductions in right ventricle longitudinal systolic peak strain in comparison with normal fetuses of the same gestational age. These authors pointed out that diastolic deformation compromise was irrespective of the presence of septal hypertrophy. They concluded that myocardial deformation analysis could detect subclinical changes in the fetuses of diabetic mothers before classical echocardiographic parameters are able to do so.Dusenbery et al.


The final diagnosis of cardiac sarcoidosis was established using modified JMHW guidelines. Major adverse cardiac events (MACE) were assessed as a composite of cardiovascular death, ventricular tachyarrhythmia, bradyarrhythmia, cardiac transplantation or heart failure. Statistical analysis included Cox proportional hazard models.Patients with suspected cardiac sarcoidosis were prospectively enrolled for cardiac p = 0.014. Diagnostic specificity for cardiac sarcoidosis was highest for FDG uptake (69%), elevated T2 (79%), and FDG uptake co-localizing with LGE (76%). Diagnostic sensitivity was highest for LGE, elevated T1 and ECV (100%). After median follow-up duration of 634 days, 13 patients experienced MACE. All patients who experienced MACE had LGE, elevated T1 and elevated ECV. FDG uptake , elevated T2  and native T1  were significant predictors of MACE even after adjusting for left ventricular ejection fraction and immune suppression treatment. The presence of FDG uptake co-localizing with LGE had the highest diagnostic performance overall (AUC 0.73) and was the best predictor of MACE based on model goodness of fit .Forty-two patients  were evaluated, 13 (31%) with a final diagnosis of cardiac sarcoidosis. Among patients with cardiac sarcoidosis, 100% of patients had at least one abnormality on PET/MRI: FDG uptake in 69%, LGE in 100%, elevated T1 and ECV in 100%, and elevated T2 in 46%. FDG uptake co-localized with LGE in 69% of patients with cardiac sarcoidosis compared to 24% of those without, Combined cardiac FDG-PET/MRI with T1/T2 mapping provides complementary diagnostic information and predicts MACE in patients with suspected cardiac sarcoidosis. Sarcoidosis is a multisystem disease characterized by development and accumulation of non-caseating granulomas in various organs. The most common sites of involvement are the lungs and thoracic lymph nodes  positron emission tomography (PET)   guideline as the reference standard, with exclusion of LGE as a minor criterion in order to evaluate the diagnostic accuracy of this imaging test in the study  was defined as composite of cardiovascular death, aborted sudden cardiac death (either ventricular tachyarrhythmia leading to appropriate cardioverter defibrillator discharge or successfully resuscitated cardiac arrest), symptomatic ventricular tachyarrhythmia leading to cardioverter defibrillator implantation (ICD), symptomatic bradyarrhythmia leading to pacemaker implantation, cardiac transplantation, or hospitalization for decompensated heart failure. The secondary outcome of non-sustained ventricular tachycardia (NSVT) was defined as 3 or more consecutive beats arising below the atrioventricular node with an RR interval of > 100 beats/minute lasting < 30 s. Patients who did not experience an adverse event were censored at the time of their last clinical follow-up.18F-FDG using a 3 T scanner . The interval between injection and imaging was longer than typical clinical protocols due to an intervening clinical PET/CT scan. Blood glucose immediately prior to FDG injection was 5.3 ± 1.5 mmol/L. The cardiac MRI protocol included long-axis  and a stack of short-axis balanced cine steady-state free precession (SSFP) slices; T1 mapping using a modified Look-Locker Inversion Recovery (MOLLI) technique at basal, mid and apical short-axis locations, pre- and 15 min post-contrast ; T2 mapping using a fast low-angle shot (FLASH) technique at matching short-axis locations pre-contrast; and phase-sensitive inversion recovery late gadolinium-enhanced (LGE) technique starting 12 min after contrast administration. Pixel-based T1 and T2 maps were automatically generated on the scanner with application of inline motion correction algorithms. List mode PET acquisition occurred simultaneously with the MRI examination in one bed position centered over the heart (10 min), with ECG gating and three-dimensional image reconstruction using ordered subset expectation maximization . A 2-point Dixon scan was acquired for attenuation correction, and a four-compartment model attenuation map was calculated including air, fat, water and tissue.Patients were provided with detailed preparation instructions in order to suppress physiologic myocardial glucose uptake, including a high fat, high protein, low carbohydrate diet for the entire day before PET/MRI and a complete fast other than water for the immediate 12-h period prior to imaging  using receiver operating characteristic analysis. In addition to evaluation of diagnostic test performance in the entire cohort, a sensitivity analysis was also performed, restricting the evaluation to the subgroup of patients not treated with immune suppression therapy prior to PET/MRI. Time-to-event survival analysis using Cox proportional hazard models was used to examine the association between PET/MRI findings and primary and secondary outcomes, both in univariable analysis and in multivariable analysis adjusting for left ventricular ejection fraction (LVEF) and anti-inflammatory therapy. Incremental value was assessed using nested models and the likelihood ratio test. Kaplan–Meier survival curves were calculated for visualization of cumulative event-free survival.Statistical analysis was performed using a commercially available software package, STATA v14.1 . A two-tailed n = 13). Twenty patients (48%) had biopsy-confirmed extra-cardiac sarcoidosis, and 6 (14%) were treated with immune suppression therapy at the time of PET/MRI (of whom 3 were positive on PET and 3 were negative on PET).Forty-two patients  were included in this study . The most common segments with focal FDG uptake were the basal inferolateral wall (38% for patients with and without cardiac sarcoidosis), basal anterior septum (38% in patients with cardiac sarcoidosis and 28% in those without) and mid-inferolateral wall (23% in patients with cardiac sarcoidosis and 28% in those without).FDG uptake on PET was positive in 9/13 (69%) patients with cardiac sarcoidosis compared to 9/29 (31%) without . There was no significant difference in left ventricular size, function or mass between groups. Patients with cardiac sarcoidosis had higher prevalence of LGE and higher maximum segmental T1, T2 and ECV compared to those without. Maximum segmental native T1 and ECV were elevated in all patients with LGE. The pattern of LGE in patients with cardiac sarcoidosis was most commonly mid-wall (85% vs. 41% in patients without cardiac sarcoidosis). No patient had a pattern of LGE consistent with myocardial infarction. The most common segments with LGE were the basal anterior septum (92% in patients with cardiac sarcoidosis and 34% in those without) and basal inferolateral wall (61% in patients with cardiac sarcoidosis and 34% in those without). All patients with elevated T2 had corresponding LGE and elevated T1/ECV and met updated Lake Louise criteria for myocardial inflammation . Among patients with cardiac sarcoidosis, 4 patients (31%) were negative on PET but positive on MRI and 9 patients (69%) were positive on both PET and MRI  and co-localized with elevated T2 in 46% patients with cardiac sarcoidosis   Fig. . Focal Fp = 0.045). Diagnostic sensitivity was highest for LGE presence, elevated T1 and elevated ECV . Overall diagnostic performance was highest for focal FDG uptake co-localizing with LGE or with elevated T1.In the entire cohort, diagnostic specificity for cardiac sarcoidosis was highest for focal FDG uptake (69%), elevated T2 (79%), co-localizing focal FDG uptake with LGE or with elevated T1 (76%), and co-localizing focal FDG uptake with elevated T2 83%)  and 12 patients experienced NSVT (incidence rate 20%/year).p = 0.003)  Table . The ris002 Fig. .Table 4Up = 0.002). A 10 ms increase in native T1 was associated with an 8% increase in the risk of MACE, a 1 ms increase in native T2 was associated with a 14% increase in the risk of MACE, and a 1% increase in ECV was associated with an 8% increase in the risk of MACE.All patients who experienced MACE had LGE, elevated native T1 and elevated ECV. Annualized MACE rates dichotomized by the presence and absence of LGE were 31% and 0%, respectively. Patients with elevated T2 had 8 times higher risk of MACE compared to those without  = 12.2, p < 0.001), indicating that LGE extent on MRI has independent and incremental value in predicting the risk of MACE beyond FDG uptake on PET. The presence of focal FDG uptake co-localizing with LGE or with elevated T1 was associated with 12 times higher risk of MACE compared to patients without and was the best predictor of MACE among the imaging findings evaluated based on model goodness of fit. Annualized MACE rates were significantly higher in patients with co-localizing FDG uptake and LGE (57%) compared to those without FDG uptake (9%), p < 0.001.In nested models with focal FDG uptake, model fit for MACE was improved by the addition of LGE extent (p = 0.002), elevated T2  and FDG uptake co-localizing with LGE .In multivariable analysis, combined PET/MRI findings remained as significant predictors of MACE even after adjusting for LVEF and anti-inflammatory therapy, including FDG uptake  are compared to a control group with no disease (such as patients with extra-cardiac sarcoidosis with no evidence of cardiac disease). We included a consecutive sample of patients with suspected cardiac sarcoidosis who had a range of disease severity in our study, which accounts for more modest diagnostic performance compared to other studies that evaluated patients with cardiac sarcoidosis compared to healthy controls (Puntmann et al. There is conflicting information on the prognostic significance of FDG uptake in cardiac sarcoidosis in the literature to date, with some studies demonstrating an association between FDG abnormalities and adverse cardiac events (Blankstein et al. The results of this study have several clinical implications. When available, combined PET/MRI with T1/T2 mapping could improve diagnostic performance and risk stratification of patients with suspected cardiac sarcoidosis compared to either modality alone. FDG uptake on PET is particularly useful to rule in active disease when positive and may also be an important noninvasive biomarker for monitoring response to anti-inflammatory therapy (Coulden et al. Our study has several limitations including lack of a biopsy reference standard for cardiac sarcoidosis, lack of perfusion imaging and a modest sample size. We used modified JMHW criteria as the reference standard in our study, which has been utilized in most diagnostic accuracy studies to date, although these criteria have not been validated against any other standard. It is possible that select patients could have been misclassified, particularly those that did not meet JMHW criteria but had evidence of focal FDG uptake on PET. Although cardiac sarcoidosis is relatively rare, the number of patients included is modest. FDG uptake on PET was not interpreted in the context of perfusion imaging, which could potentially account for the more modest diagnostic performance of PET compared to prior PET/CT studies. However, the focus of this study was on combined PET/MRI findings. The interval between FDG injection and imaging was longer than many clinical protocols which could impact PET imaging findings (Slart et al. In conclusion, combined cardiac FDG PET/MRI with T1 and T2 mapping provides complementary diagnostic and prognostic information in patients with suspected cardiac sarcoidosis. These data support the necessity for future large, longitudinal follow-up studies to evaluate the value of PET/MRI in assessing response to therapy and to evaluate the independent and incremental prognostic value of imaging findings over clinical parameters.


MW; GWI (p = 0.04), GCW (p = 0.03), GWW (p = 0.001) were all lower in ATTR-CA compared with HFnCA but only GWW predicted ATTR-CA, . Binary logistic univariate regression analysis showed RWT  and RELAPS  to be associated with ATTR-CA but not MW. GWI and GCW correlated with NT-proBNP (p < 0.05) and Troponin (p < 0.01), but not RWT or RELAPS. Conclusion: Myocardial work had lower accuracy, compared to RWT or RELAPS, in identifying ATTR-CA but was better related to biomarkers. Thus, MW assessment is unlikely to have additional value in improving the diagnosis of heart failure due to ATTR-CA.Background: Reduced LV longitudinal strain (GLS) and increased relative apical sparing (RELAPS) and increased wall thickness have been proposed as features for transthyretin cardiac amyloidosis (ATTR-CA). Myocardial work (MW) has recently been shown as useful afterload independent disease marker, hence we aimed to investigate its use in differentiating ATTR-CA from heart failure with increased septal thickness but no cardiac amyloidosis (CA) (HFnCA). Methods: This study included patients with HF and increased septal thickness ≥ 14 mm. We included 59 patients with hereditary (ATTRv) and 27 wild type transthyretin amyloidosis (ATTRwt) described as ATTR-CA based on DPD scintigraphy. We also enrolled 30 non-amyloidosis heart failure patients with negative DPD scintigraphy, as a control group. Myocardial work (MW) was used to assess the index (GWI), constructive (GCW) and wasted (GWW) work. Relative wall thickness (RWT) and relative apical sparing (RELAPS) were tested as conventional measures. Results: The RWT and RELAPS were higher in ATTR-CA ( Transthyretin (TTR) amyloidosis (ATTR) is the most common type of systemic amyloidosis and is classified into a hereditary type (ATTRv), and a wild type transthyretin (ATTRwt) amyloidosis ,2. TypicThis study has two clear objectives, firstly to investigate the use of MW in ATTR-CA and test its accuracy in differentiating patients with cardiac ATTR from those with heart failure and increased wall thickness but no cardiac amyloidosis (CA) (HFnCA) and Secondly, to test the accuracy of MW in predicting clinical prognosis in ATTR-CA.This is a retrospective study in patients with heart failure and increased LV septal thickness.Inclusion criteria for further investigations were: (1) patients with IVSd ≥ 14 mm, (2) absence of types of CA other than ATTRwt and (3) confirmed final diagnosis of ATTR-CA using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy examination (grade 2-3). Based on these criteria, 27 patients were identified and included in this study. Part of this cohort findings was recently published /Left ventricular (LV) diastolic diameter [LVDd]. LV mass was calculated using the Devereux formula . Trans-mPulsed wave tissue Doppler analysis was also performed to assess mean LV lateral and septal myocardial early diastolic velocities (e’) at the mitral annular level and E/e’ was calculated . All DopAnatomical landmarks were used, and care was taken for echocardiographic image acquisition to ensure adequate LV tracking, avoiding foreshortening of LV cavity when measuring global LV strain, all according to recent recommendations .Global Work Index (GWI): total work within the area of the LV GLS = area within the pressure-strain curve (mmHg/%)Global Constructive Work (GCW): work performed by the LV contributing to cavity ejection. Constructive MW is defined as shortening of the myocytes during systole added to lengthening of the myocytes during isovolumic relaxation.Global Wasted Work (GWW): work performed by the LV that does not contribute to cavity ejection. Wasted MW is defined as lengthening of myocytes (rather than shortening) during systole added to shortening during the isovolumic relaxation phase.Global Work Efficiency (GWE): constructive MW/(constructive MW + wasted MW) .Longitudinal myocardial deformation was assessed from the 2-dimensional echocardiographic acquisitions using speckle tracking technology and was analyzed off-line. From the apical four chamber-, two chamber and apical parasternal long axis views the endocardial border detection of the septal, apical and lateral LV walls was made automatically and manually adjusted, in order to analyze global LV strain (GLS) measurements. GLS was measured at end-systole with the reference point set at the onset of two consecutive QRS-complexes of the superimposed ECG. Relative apical sparing (RELAPS) was also calculated as average apical strain/. To assess MW, systolic and diastolic blood pressure were inserted, and pressure-strain curve obtained in time according to aortic and mitral valve closure and opening time. Blood pressure was taken using conventional cuff mercury manometer after the echocardiographic examination and a mean of three consecutive measurements was taken. From pressure-strain curves, strain analyses were measured using a dedicated workstation  and the following parameters calculated, All patients underwent DPD scintigraphy examination using an Infinia Hawkeye hybrid single-photon-emission computed-tomography gamma camera (SPECT-CT)  with a low-energy high-resolution collimator. An intravenous injection of ~750 MBq DPD was given 3 h prior to the acquisition of whole-body planar image, followed by a non-contrast, low dose CT scan and a SPECT acquisition, 60 projections and reconstructed to a 128 × 128 matrix  with scatter and CT-based attenuation correction. Reconstruction of SPECT images was performed on the Xeleris workstation . DPD scores were reported by 2 experienced clinicians using the Perugini’s grading system  with gra®, version 27 . Parametric data are presented as mean, standard deviation (SD), maximum and minimum values for continuous variables. Percentages were used to describe categorical variables. Categorical variables were compared using Chi-square and McNemar tests, and continuous variables were compared using the Student’s t-tests for normally distributed data or Mann-Whitney U tests for non-normally distributed data. Non-parametric data was presented as median and interquartile range 25–75. Normality was assessed by Shapiro-Wilk’s test. p-values were presented with a 0.05 level of statistical significance.Statistical analysis was preformed using SPSSThis study complies with the declaration of Helsinki and the study protocol was approved by the Regional Ethics Committee of Umeå . All subjects gave written informed consent to participate in the study.p = 0.007), lower systolic and diastolic blood pressure  and lower weight (p = 0.015) compared with the no ATTR-CA patients.Patient characteristics are presented in Echocardiographic data are shown in p < 0.001) and strongly predicted the diagnosis of ATTR-CA by DPD , GCW (p = 0.03), GWW (p = 0.001) were all lower than in HFnCA. The difference between groups disappeared after excluding patients with atrial fibrillation   and RELAPS  to be associated with ATTR-CA but not GCW or GWW (p > 0.05). MW quantification was feasible in 24 patients with HFnCA (86%) and in 53 of ATTR-CA patients (63%).On ROC analysis, GWW predicted ATTR-CA, AUC = 0.75, = 0.092) . The binp < 0.05), but only modestly. The same variables were more strongly correlated with Troponin (p < 0.01). RWT and RELAPS were not related to either BNP or Troponin, In ATTR-CA patients, GLS GWI and GCW correlated negatively with NT-proBNP  using tri-plane GLS was tested in 10 patients with ATTR-CA. The ICC was 0.96, Findings: Our results show that MW was lower in ATTR-CA compared to HFnCA but was less accurate, compared with RWT and RELAPS, in identifying ATTR cardiac amyloidosis, detected by DPD scintigraphy. On the other hand, MW was modestly related to biomarkers such as Troponin and NT-pro-BNP over and above RWT and RELAPS.Results interpretation: This study illustrates additional application of MW in the assessment of patients with heart failure. As MW incorporates both LV deformation and afterload, measured as blood pressures, it might reflect ventricular arterial coupling and therefore is potentially of interest in identifying different phenotypes and prognosis in HF. MW has previously been proposed mainly as a marker of LV dys-synchrony, although on a limited scale.  Few studOur study assessed the impact of myocardial ATTR on LV cavity MW compared with control patients with other underlying pathologies causing increased wall thickness and have demonstrated that the former pathology greatly suppresses MW compared to the latter. Interestingly, these findings were not independent of the overall cardiac performance. Indeed, MW was related to the pro-BNP levels and to a greater extent to the troponin levels, as has been shown by Roger-Rolle et al. . The mecIn contrast to the relationship between MW and cardiac endocrine and myocyte function, our results showed no relationship between MW and other LV structural function parameters in the form of RWT and RELAPS. This finding was not surprising based on the above discussed mechanisms. Importantly, the difference in MW between the two groups disappeared after excluding those with atrial fibrillation, which is a common arrhythmia in ATTRwt and is also known to reduce long axis function (GLS). This strengthens the finding that MW seems not useful in differentiating infiltrative from other causes of thickened LV wall. Finally, the failure of LV MW in predicting the diagnosis of ATTR-CA and clinical prognosis was not a complete surprise since MW reflects massive global dysfunction while diagnosis of ATTR-CA by DPD could depend on only mild segmental infiltration with minimal global function implication. As for mortality, it is a complex clinical end-product with too many factors implicating it, so unlikely for a single marker of ventricular performance to accurately predict it.Limitation: This study has limitations. The studied number of patients and controls was modest, justified by the rarity of the ATTR-CA among heart failure centers. Patients with HFnCA can be considered heterogeneous, so analyzing them as small subgroups was not scientifically feasible. We were unable to assess the rate of ATTR-CA progression, since patients did not have regular DPD follow up scans with, even, subjective assessment of the extent of myocardial infiltration. Calculation of MW involves multiple parameters including fluctuating blood pressure measurements; thus a small error is likely to be significantly exaggerated and impact the overall statistics and conclusion. Myocardial work calculation was not feasible in all patients which was mainly explained by lack of accurate image quality from all three projections. Finally, no cardiac biopsy was taken to confirm the final diagnosis.Clinical implications: Although proposed as a potentially useful marked of LV cavity performance in different conditions, LV MW has proved to be of little additional value in identifying ATTR-CA disease and its prognosis, compared with conventionally, well tested GLS measurements.Conclusion: Myocardial work failed to provide additional clinical value over and above RWT or RELAPS in identifying ATTR-CA and in predicting its prognosis. It is, however, related to biomarkers reflecting raised LV filling pressures and myocardial damage.


Hyperthyroidism often leads to heart failure when left untreated, specifically high output heart failure and left ventricular (LV) hypertrophy. A very minimal portion of those develop severe LV dysfunction. We report a case of a 65-year-old male who presented with signs and symptoms of heart failure and was found to have hyperthyroidism, severe systolic dysfunction, and severe dilated cardiomyopathy.The patient is a 65-year-old African American male with a history of hypertension (HTN) who presented with complaints of dyspnea on exertion and bilateral lower limb edema of one-week duration. A review of systems revealed paroxysmal nocturnal dyspnea, orthopnea, palpitations, fatigue, and weight loss. Physical exam showed tachycardia but otherwise no exophthalmos, no thyromegaly, no thyroid nodules, clear lungs, normal heart sounds, regular heart rhythm, normal reflexes, and 2+ edema of bilateral lower extremities up to the knees. Labs showed elevated B-natriuretic peptide, severely suppressed thyroid-stimulating hormone, elevated free triiodothyronine (FT3), and free thyroxine (FT4). Electrocardiogram (EKG) revealed sinus tachycardia, incomplete left bundle branch block, and non-specific T wave abnormality. Echocardiography revealed abnormal (LV) structure and function, with moderate to severe dilatation without LV hypertrophy, severe LV systolic dysfunction with ejection fraction (EF) 30-35%, and an abnormal LV diastolic function.The patient was managed with diuresis for acute onset heart failure and with beta-blocker and methimazole for symptomatic hyperthyroidism.Thyroid assessment is an important step in evaluating any patient with suspected heart failure. This case highlights the balance that should exist between treating hyperthyroidism symptoms and managing disease states such as acute heart failure. Thyrotoxicosis is defined as a clinical state that ensues due to high thyroid hormone levels exerting their effect on tissues. Hyperthyroidism is a form of thyrotoxicosis that is due to inappropriately elevated synthesis and secretion of thyroid hormones by the thyroid gland ,2. In thThe patient is a 65-year-old African American male with a history of hypertension (HTN) and normal thyroid studies (thyroid-stimulating hormone (TSH), free triiodothyronine FT3), and free thyroxine (FT4)) two years prior to this presentation who presented with complaints of exertional dyspnea and bilateral lower limb edema of one-week duration. Review of systems revealed 1-2 weeks duration of paroxysmal nocturnal dyspnea, orthopnea, palpitations, and fatigue. He also reported watery, non-bloody diarrhea, and weight loss of around 20 pounds (~10% of body weight) over the last two months. The patient had been on lisinopril, aspirin, atorvastatin, and metoprolol. Vitals showed elevated BP 143/81 mm of Hg, tachycardia with a pulse of 125 beats per minute, otherwise unremarkable with a body mass index of 23.3 kg/m². Physical exam revealed no exophthalmos, a supple neck, no thyromegaly, no thyroid nodules, no distal tremor, clear lungs, normal heart sounds, regular heart rhythm, tachycardia, normal reflexes, and 2+ edema of bilateral lower extremities up to the knees with no calf tenderness. Labs showed normocytic anemia, hemoglobin 12.4 g/dL with a mean corpuscular volume (MCV) of 92 fL, and a normal complete metabolic panel. Iron studies showed normal serum iron, total iron-binding capacity (TIBC), and ferritin. Troponin was negative x3 times, 0.03ng/mL, 0.033 ng/mL, and 0.017 ng/mL. The B-natriuretic peptide was elevated to 1238.34 pg/mL, the TSH was <0.005 uIU/mL, FT3 was 5.38 pg/mL, and FT4 was 2.25 ng/dL . He was closely monitored and on day 3 of admission, the patient had resolution of his bilateral lower limb edema with significant improvement in his dyspnea on exertion, paroxysmal nocturnal dyspnea, and orthopnea. Furosemide was switched to oral form and metoprolol was subsequently increased once the heart failure was deemed to be improving. Following that, his heart rate improved and remained below 100 beats per minute. Endocrinology and cardiology were both consulted for close outpatient follow-up. Unfortunately, the patient was lost to follow-up.Triiodothyronine (T3) acts on cardiac tissue through genomic and nongenomic pathways. Genomic pathways include binding of T3 with nuclear receptors that have a direct effect on activation or repression of gene expression, thereby regulating the expression of certain proteins. Nongenomic pathways include changes to the myocyte plasma membrane by alterations in sodium, potassium, and calcium ion channels, and changes in cytoskeleton polymerization ,4. ThereHeart failure is a known complication of hyperthyroidism and is usually the presenting sign of hyperthyroidism in around 6% of patients . HyperthAnother study recruited 2,225 patients across the United States, Canada, and New Zealand who suffered from systolic heart failure and were followed for five years. Of those, 13% had abnormal TSH levels at baseline. The study found that abnormal thyroid function in the setting of heart failure increases mortality by about 60% when compared to heart failure in euthyroid patients .Another complication of hyperthyroidism that was manifested in the patient discussed in this case is normochromic, normocytic anemia. Red blood cell mass and plasma volume are both increased in hyperthyroidism, but the latter is increased more, hence leading to normocytic, normochromic anemia. In anemic patients and upon receiving treatment, hemoglobin rises by an average of 0.5 g/dL .This case highlights the importance of thyroid assessment in patients presenting with heart failure, and the possibility of reversibility of the severe cardiac dysfunction. Hyperthyroidism left undiagnosed and untreated may lead to heart failure, and in a smaller number of patients to severely reduced ejection fraction. It also allows us to appreciate the balance between administering medications, such as beta-blockers, aimed at reducing hyperthyroid symptoms, with the management of heart failure, where beta-blockers might need to be held or administered at regular doses without escalation.


Background: Myocarditis, even in a severe and lethal form, may occur after COVID-19 mRNA (BNT162b2) vaccination. However, its pathway, morphomolecular characterization and treatment are still unknown. Methods: Routine hematochemical screening, ECG, Holter monitoring, 2D echocardiogram cardiac magnetic resonance (CMR) and invasive cardiac studies  are reported from three patients  with severe compromise of conduction tissue  or cardiac function compromise  after COVID-19 mRNA (BNT162b2). Results: Hematochemical data and coronary angiography were normal in the patients studied. Histology showed in all three patients extensive myocardial infiltration of degranulated eosinophils and elevation of serum cationic protein directly responsible for cardiomyocyte damage. These findings demonstrate myocarditis hypersensitivity to some component of the vaccine (spike protein?) acting as a hapten to some macromolecules of cardiomyocytes. Steroid administration  was followed by complete recovery of cardiac contractility in pt2 and pt3. Conclusions: Eosinophilic myocarditis is a possible adverse reaction to the mRNA COVID-19 vaccine. Its pathway is mediated by release of cationic protein and responds to short courses of steroid administration. Reports of myocarditis after COVID-19 mRNA (BNT162b2) vaccination have raised concerns about the potential cardiovascular risk of this vaccine enhancing the skepticism of the no-vax population.Indeed, although the incidence of acute inflammatory myocardial and/or pericardial disease has been documented in as low as 1–2 events in 100,000 vaccinated subjects  have beeMorphomolecular characterization of this entity and its treatment, as well as the possibility to distinguish it from other  forms of myocarditis, are not available so far.We report herein the endomyocardial biopsy study of three patients with severe post-vax myocarditis, where a mechanism of hypersensitivity to some component of the vaccine is suggested, and an increase in serum eosinophilic cationic protein is recognized as responsible for tissue damage, as well as a potential biomarker of the disease.In the last 6 months, 3 patients  were identified who, within a period of two weeks from the second dose of the BNT162b2 vaccine, manifested chest pain with troponin I elevation. A 39-year-old woman (pt1) also had two syncopal episodes because of junctional rhythm , and twoAll 3 patients underwent noninvasive clinical examinations  and invasive cardiac studies ).® 3, Biosense Webster, Irvine, CA, USA). Via the transfemoral approach, a decapolar catheter was positioned in the coronary sinus, and a multipolar catheter  was positioned in the right atrium (RA). EPS showed normal anterograde conduction parameter (HV 48 ms) with junctional rhythm without evidence of retrograde atrial activation. Pacing from high RA did not result in atrial capture, and the decapolar catheter did not record atrial electrograms from inside the coronary sinus. High-density mapping with the Pentaray catheter revealed the absence of endocavitary electrograms in almost the whole RA, with evidence of organized atrial activity in a small area in the anterolateral portion of the atrium (9.5 cmq), accounting for 4.9% of the total RA surface. Due to the absence of atrial activity, activation mapping was not performed. High-density substrate mapping disclosed a large low-voltage area (<0.05 mV), with a small region on the anterolateral aspect of RA with preserved voltage signals.An electrophysiological study (EPS) was performed in pt1 with an electroanatomic mapping system . In particular, the increase in T2 signal is due to the myocardial edema detector, and the positivity for areas of LGE suggests the presence of inflammatory infiltration and/or myocardial fibrosis.For histological analysis, endomyocardial biopsy was fixed in 10% buffered formalin and embedded in paraffin. The histological diagnosis of myocarditis was based on the evidence of leukocyte infiltrates (≥14 leukocytes/2 mm) associated with necrosis of the adjacent myocytes, according to the Dallas criteria . In partImmunohistochemical staining with eosinophil major basic protein (EMBP) antibody  was performed to highlight the presence of eosinophils.For histological characterization of inflammatory lesions being observed in post-COVID-19 myocarditis, endomyocardial biopsies with a diagnosis of myocarditis associated with COVID-19 infection were used for comparison.The molecular study was performed in the three patients with real-time (RT) PCR  for the Patient serum was screened for the presence of human eosinophil cationic protein (ECP), detected by the human eosinophil cationic protein ELISA assay kit ECP ELISA , according to the manufacturer’s instructions. The standards, sample and healthy control were loaded in duplicate.p < 0.05 was considered statistically significant.Statistical analysis was performed by the GraphPad Prism package, version 5.02 . Comparison between groups was performed with the Mann–Whitney test, and a value of Hematochemical screening beyond elevation of troponin I (3.5 ± 0.2 mcg/L ± n.v 0.1 ± 0.14 mcg/L) was unremarkable. In particular, normal was the leukocyte count and the peripheral amount of eosinophils.Cardiac catheterization showed elevation of LV end-diastolic pressure (>12 Hg mm), while coronary angiography was normal in all cases.EPS obtained in pt1 with junctional rhythm showed normal anterograde conduction parameter (HV 48 ms), with junctional rhythm without evidence of retrograde atrial activation. Pacing from high RA did not result in atrial capture, and the decapolar catheter did not record atrial electrograms from inside the coronary sinus. High-density mapping with the Pentaray catheter revealed the absence of endocavitary electrograms in almost the whole RA, with evidence of organized atrial activity in a small area in the anterolateral portion of the atrium (9.5 cmq), accounting for 4.9% of the total RA surface. Due to the absence of atrial activity, activation mapping was not performed. High-density substrate mapping disclosed a large low-voltage area (<0.05 mV), with a small region on the anterolateral aspect of RA with preserved voltage signals .CMR showed in our three patients a diffuse increase in both T2 and T1 myocardial value, as a result of diffuse inflammatory involvement . LGE wasEndomyocardial biopsy findings were characterized in all three cases by the presence of inflammatory infiltrates, mainly represented by degranulated eosinophils and to a very less amount of lymphocytes  focally p = 0.079.Patient serum showed an increase in serum cation protein levels in all patients (23.4 ± 17 U/mL) versus controls (6.1 ± 1 U/mL), RT-PCR for viral genomes was negative in all patients.The three patients received prednisone 1 mg/kg die for 3 days tapered to 0.33 mg/kg for 4 weeks. At the end, a new noninvasive cardiac evaluation, including ECG, Holter and cardiac magnetic resonance, was undertaken. Pt1 remained in junctional rhythm but without abnormal pauses and requiring pacemaker implantation. Pt2 and pt3 manifested a complete recovery of cardiac function, with LVEF rising to 49.5 % (from 35%) and 56% (from 28%), respectively.Myocarditis is one of the major recognized adverse reactions to the COVID-19 mRNA (BNT162b2) vaccine. Although large reports confine its incidence to 1–2 cases in 100,000 administrations, severe and even lethal cases of acute myocardial inflammation have been described . NeverthThe present report describes three cases of acute severe myocarditis occurring within 2 weeks after a second dose of the COVID-19 mRNA (BNT162b2) vaccine. Major clinical manifestations consisted of damage of conduction tissue with junctional rhythm and atrial standstill or remarkable compromise of left ventricular function (EF ≤ 35%) that made necessary an invasive cardiac study. The histological findings obtained by left ventricular endomyocardial biopsy were characterized in all instances by presence in the myocardium of prevalent eosinophilic infiltrates G, associPost-vax inflammatory lesions observed in our patients demonstrate myocarditis hypersensitivity and the formation of new antigens from macromolecules of cardiomyocytes and some component (spike protein?) of the BNT162b2 vaccine.Excellent response to moderate doses of steroids with recovery, in 4 weeks, in two cases with severely compromised cardiac function supports this interpretation. Furthermore, presence of eosinophils in myocardial infiltrates has already been described in previous reports of post-COVID19 vax myocarditis undergoing endomyocardial biopsy or post-mortem study . HoweverInterestingly, all three patients described in our report were affected by allergic disorders that would indicate some predisposition to allergic reactions to new antigens. Although the type of antigen is so far unknown, a haptenic link between spike protein and macromolecules of cardiomyocytes membrane can be hypothesized.Finally, comparison with biopsy and post-mortem myocarditis associated with COVID-19 infection indicates H a substIf our preliminary results are confirmed by larger studies, elevation of serum cationic protein could be taken as a biomarker of hypersensitivity myocarditis, suggesting the introduction of steroid treatment in patients with clinical and magnetic resonance evidence of perimyocarditis developed after COVID-19 mRNA vaccination.In conclusion, eosinophilic myocarditis is a possible adverse reaction to the mRNA COVID-19 vaccine. Its pathway is probably mediated by release of cationic protein and responds to short courses of steroid administration.


MARVEL 2 assessed the efficacy of mechanical atrial sensing by a ventricular leadless pacemaker, enabling a VDD pacing mode. The behavior of the enhanced MARVEL 2 algorithm during variable atrio‐ventricular conduction (AVC) and/or arrhythmias has not been characterized and is the focus of this study.Of the 75 patients enrolled in the MARVEL 2 study, 73 had a rhythm assessment and were included in the analysis. The enhanced MARVEL 2 algorithm included a mode‐switching algorithm that automatically switches between VDD and ventricular only antibradycardia pacing (VVI)‐40 depending upon AVC status.Forty‐two patients (58%) had persistent third degree AV block (AVB), 18 (25%) had 1:1 AVC, 5 (7%) had variable AVC status, and 8 (11%) had atrial arrhythmias. Among the 42 patients with persistent third degree AVB, the median ventricular pacing (VP) percentage was 99.9% compared to 0.2% among those with 1:1 AVC. As AVC status changed, the algorithm switched to VDD when the ventricular rate dropped less than 40 bpm. During atrial fibrillation (AF) with ventricular response greater than 40 bpm, VVI‐40 mode was maintained. No pauses longer than 1500 ms were observed. Frequent ventricular premature beats reduced the percentage of AV synchrony. During AF, the atrial signal was of low amplitude and there was infrequent sensing.The mode switching algorithm reduced VP in patients with 1:1 AVC and appropriately switched to VDD during AV block. No pacing safety issues were observed during arrhythmias. Nevertheless, despite all technological improvements over the last 6 decades, conventional pacing therapy is still associated with a complications rate ranging from 1% to 12.4% in the first 2‐month post implantation and reported up to 19.7% at 5‐year follow‐up.Leadless cardiac pacing has demonstrated an excellent safety and efficacy profile combining a high implant success rate (99.1%), a low major complication rate through 12 months (2.7%), and stable electrical parameters over time.Recently, the Micra atrial tracking using a ventricular accelerometer (MARVEL) 2 study demonstrated high AV synchronous pacing at rest (mean 89.2%) in patients previously implanted with a ventricular leadless pacemaker and presenting with third degree AV block and normal sinus rhythm between 60 and 100 beats per minute.Even if AV synchrony is maintained, a high percentage of right ventricular pacing can have deleterious effects, including increased risk of developing atrial fibrillation (AF), left ventricular dysfunction, heart failure, and death.In addition, the occurrence of paroxysmal or persistent AF is not infrequent (ranging from 3% to 39.9%) during follow‐up even if there is no history of atrial arrhythmias at the time of the implantation procedure.In this analysis of the MARVEL 2 study, we report the behavior of the MARVEL 2 algorithm in patients with AVC status other than persistent third degree AV block with normal sinus rhythm and in the presence of sinus arrhythmia, sinus bradycardia (<40 bpm), or atrial/ventricular premature beats and atrial arrhythmias.22.1The MARVEL 2 study was a prospective, non‐randomized multi‐center clinical trial.The protocol was approved by all local ethics committees and national regulatory agencies at each participating institution. All patients provided written informed consent.2.2The 75 subjects enrolled in the MARVEL 2 study who received the software download were eligible for inclusion in this analysis. These patients were older than 18 years, had a history of AV block, and were previously implanted or undergoing implant with a Micra leadless pacemaker.The MARVEL 2 study procedures have been previously described.2.3Echocardiograms were collected from each patient during VVI and VDD pacing following a standard protocol. Since patients with 1:1 AVC would have their intrinsic rhythm during both VVI and VDD mode (due to the AVC mode switch), these patients were programmed to VVI pacing with a lower rate 5–10 bpm above their intrinsic rate during VVI mode. An echocardiography core laboratory , blinded to patient and pacing mode, measured left ventricular outflow (LVOT) velocity‐time integral (VTI) during six cardiac cycles in each pacing mode.2.4The algorithm incorporates a post‐ventricular blanking period and a dual threshold detection method. The first threshold (A3 threshold) that occurs early is used for detecting the atrial contraction when A4  occurs during the A3 (passive filling) time and is less sensitive. The second threshold (A4 threshold) occurs later in the cycle after A3 has occurred and is more sensitive. Because of the importance of the A3 sensing window, a telemetry marker (VE) is displayed at the end of the A3 window Figure .2.5The AVC mode switch is designed to promote intrinsic AVC during periods of 1:1 AVC in patients with paroxysmal AV block. Periodic conduction checks are performed by switching the pacing mode from VDD to VVI with a lower rate of 40 bpm (VVI‐40) for at least two beats. If AVC is present, the device remains in VVI mode with a lower rate of 40 bpm. If at any time AVC is lost, as indicated by at least two of four beats being paced, the device switches back to VDD mode. The first check for AVC occurs after 1 min. Subsequent checks occur at progressively longer intervals  up to 8 h and then occur every 8 h thereafter.2.6The algorithm incorporates a rate smoothing feature to maintain AVS during intermittent A4 undersensing in the presence of a relatively stable sinus rate. If an atrial contraction (A4) is not detected, a ventricular pace is delivered at a programmable rate smoothed interval  longer than the recent R‐R intervals. Following a ventricular sensed beat, such as a premature ventricular contraction (PVC), the lower rate is the programmed lower rate, not the rate smoothing interval.3SD or median and interquartile range. Categorical variables are presented as counts and percentages. LVOT VTI during VVI pacing and while the MARVEL 2 algorithm features were enabled were compared using paired t tests. The Wilcoxon signed‐rank test was used to compare ventricular pacing percentage between VVI lower rate pacing and while the MARVEL 2 features were enabled. Statistical analyses were performed using SAS v9.4 (Cary) or R (www.r-project.org).Each patient's predominant heart rhythm was determined as persistent 3rd degree AV block, intact AVC, or other  based on P‐R intervals during automatic setup phase and P‐P intervals during both the automatic setup and resting phases. Continuous variables are presented as mean ± 44.1Overall, 75 patients were enrolled in the MARVEL 2 study and received the software download. The average age was 77.5 ± 11.8 years (range 21–94), 30 (40%) were female, and patients had been implanted with a Micra for a median of 9.7 months . Two of the enrolled subjects were not included in the analyses, since an assessment of the predominant rhythm was not possible due to noise on the ECG. Patient characteristics are summarized in Table 4.2Among the subjects with persistent third degree AV block the median percentage of ventricular pacing was 99.9% (IQR: 99.6%–100%) compared to 0.2% (IQR: 0.0%–2.5%) among those with 1:1 AVC , 16 had a mode switch to VVI‐40. In the other two patients, the mode remained in VDD due to sinus bradycardia less than 40 bpm. In patients with 1:1 AVC and a PR interval greater than 200 ms (n = 9), there was always correct mode switching to VVI‐40.Overall, there were 379 AVC checks in the 73 patients during an average Holter recording length of 153 ± 29 min. Among the patients with third degree AV block, there were 210 AVC checks. In all 210 AVC checks, the pacing mode appropriately returned to VDD and no pauses longer than 1500 ms were observed. In the patients with 1:1 AVC . Four patients had a median ventricular rate less than 50 bpm when the AVC mode switch was active. No patients reported symptoms related to the ventricular pacing rate during the study. Stroke volume, measured by LVOT VTI, was higher when 1:1 AVC was promoted by the AVC mode switch compared with RV pacing at slightly above the intrinsic rate .In the patients with 1:1 AVC, the median ventricular pacing with permanent pacing parameters decreased from a median of 22.8% (IQR: 7.0%–75.4%) during VVI pacing to a median of 0.2% (IQR: 0%–2.5%) during the AVC mode switch (4.3n = 7), the accelerometer signal was of low amplitude and there was infrequent sensing, resulting in either ventricular pacing at the lower rate .4.4PVCs disrupt AVS, since atrial contraction typically occurs in ventricular systole Table . Of noteThe atrial sensing behavior during PACs depends upon the coupling interval of the PACs. If the coupling interval is long, then the PAC may be tracked . When the VVI+ mode is activated, the atrial sensing is turned off, meaning that patients can present an intrinsic ventricular rhythm greater than 40 bpm without AV synchrony. If ≥2 of 4 consecutive ventricular beats are paced, it reverts to VDD pacing mode. We showed that the algorithm significantly reduced the ventricular pacing percentage in patients with intrinsic ventricular rhythm greater than 40 bpm. This represents three potential advantages for patients. First, it could reduce ventricular pacing induced left ventricular dysfunction. Second, it could reduce atrial fibrillation.The safety of the AVC mode switch was confirmed in patients with persistent third‐degree AV block as it did not induce ventricular pauses greater than 1500 ms, arrhythmias, or symptoms. Future studies will have to confirm the safety of the mode switch in clinical practice.Based on these different considerations, we recommend evaluating the activation of the AVC mode switch on a patient‐by‐patient basis. For example, physicians should consider deactivating the mode switch in different clinical situations, such as: (1) patients without ventricular escape rhythm, (2) patients with second degree AV block (2:1 AV conduction) and sinus rhythm greater than 80 bpm, or (3) patients with complete AV block and a ventricular escape rhythm greater than 40 bpm. Also, the mode switch operates independently of the AV interval: patients with long first‐degree AV block greater than 300 ms will not be paced. Finally, patients having a sinus rate less than 40 bpm with intrinsic conduction will also not benefit from this mode switch. In these patients, a dual chamber pacing system with atrial pacing is required if AVS is preferred.6.2Our study also confirmed that the MARVEL 2 algorithm behaved in a safe manner in the presence of different types of arrhythmias. The MARVEL 2 algorithm does not contain a mode switching as contained in the traditional pacemaker with electrical sensing of the atrium but its utility seems low as observed in our population including eight patients presenting with atrial arrhythmias . During atrial arrhythmias, the accelerometer signals were of low amplitude. The automatic features of the device will adjust the A4 threshold to increase sensitivity, possibly leading to intermittent oversensing of atrial activity or noise. Nevertheless, no episodes of oversensing induced tachycardia greater than 100 bpm were observed. It is worth noting that intermittent atrial oversensing could also be related to the presence of a reduced intermittent atrial mechanical activity during atrial fibrillation. Previously, Fujii et al.Second, the occurrence of atrial or ventricular premature beats is not infrequent during patient follow‐up. In the presence of frequent PACs, the behavior of the MARVEL 2 algorithm depends on the timing of the atrial event. If the PAC occurs early in the cardiac cycle after a ventricular event in post‐ventricular atrial blanking, it will not be sensed, preventing any pacemaker induced tachycardia. Conversely, in the presence of a late‐coupled PAC, an A4 signal can be recognized and be followed by a ventricular pace. The presence of frequent PVCs caused a reduction in AVS similar to that observed in conventional dual chamber pacing systems.Induction of ventricular arrhythmias by pacing facilitated short‐long‐short sequences is a known behavior of pacemaker timing.7The MARVEL 2 algorithm permits a reduction in the percentage of ventricular pacing in the presence of 1:1 AV conduction and sinus rhythm greater than 40 bpm, while it appropriately switches to VDD during episodes of high degree AV block. The algorithm behaved safely during arrhythmias, with no pacing‐related adverse events reported during the study period. These encouraging data should be confirmed by further studies in the real‐world setting.Christophe Garweg contributed to research funding, speaker/consultancy fees Medtronic. Surinder Kaur Khelae Speakers Bureau: Bayer/Schering Pharma, Boston Scientific, Medtronic, Pfizer; Joseph Yat Sun Chan: Honoraria: Medtronic; Larry Chinitz contributed to fees for services: Abbott, Biosense Webster, Pfizer, Biotronik, Medtronic. Fellowship support: Biotronik, Boston Scientific, Medtronic. Philippe Ritter contributed to fees for service: Medtronic. Jens Brock Johansen: Speakers Bureau: Medtronic, Merit Medical. Honoraria/Scientific Board: Medtronic, Biotronik. Venkata Sagi h.Supporting information.Click here for additional data file.