A ressonância magnética cardíaca (RMC) é o método de escolha para avaliar as dimensões e a função do ventrículo direito (VD), e a insuficiência pulmonar (IP). Avaliar a acurácia da ecocardiografia bidimensional (ECO 2D) em estimar a função e as dimensões do VD e o grau de IP, e comparar os resultados obtidos pela ECO 2D com os da RMC. Comparamos os relatórios de ECO e RMC de pacientes cuja indicação para RMC havia sido para avaliar VD e IP. Um valor de p < 0,05 foi considerado estatisticamente significativo. Incluímos 51 pacientes com cardiopatia congênita com idade mediana de 9,3 anos . Observou-se uma baixa concordância entre ECO 2D e RMC quanto à classificação da dimensão  e da função do VD . O tamanho do VD foi subestimado pela ECO 2D em 43% dos casos, e a função do VD foi superestimada pela ECO 2D em 29% dos casos. O grau de concordância entre os métodos quanto à classificação da IP não foi significativo . Houve uma tendência de a ECO 2D superestimar o grau da IP. A ECO 2D mostrou baixa concordância com a RMC quanto às dimensões e função do VD, e grau de IP. Em geral, a ECO subestimou as dimensões do VD e superestimou a função do VD e o grau de IP quando comparada à RMC. Assim, é fundamental otimizar as indicações da RMC e os encaminhamentos ao exame.O exame de ressonância magnética cardíaca (RMC) é considerado o método de escolha para avaliar as dimensões e a função do ventrículo direito (VD), bem como para quantificar insuficiência pulmonar (IP). Pacientes com cardiopatia congênita (CC) com envolvimento da via de saída do ventrículo direito (VD) ou da valva pulmonar estão sujeitos a desenvolverem dilatação e disfunção do VD e IP em algum estágio de suas vidas, resultante da história natural ou de procedimentos cirúrgicos ou hemodinâmicos. Nesses pacientes, a indicação da RMC é parte de uma abordagem “multi-imagem” (multi-imaging) recomendada atualmente.10 Apesar de tais limitações, na prática diária, a indicação da RMC é feita com base na avaliação de características clínicas e ecocardiográficas.O ECO 2D, por sua vez, é um método amplamente disponível e, relativamente, de baixo custo, mas limitado quanto à avaliação do VD e do grau de IP.No presente estudo, nosso objetivo foi avaliar, retrospectivamente, a acurácia do ecocardiograma transtorácico bidimensional em estimar a função e as dimensões do VD e o grau de IP, e comparar seus resultados com os da RMC.11 O estudo foi aprovado pelo comitê de ética da instituição.Este estudo foi conduzido em um centro de referência em tratamento de CC. A partir do um banco de dados de RMC, pediátrica/cardiopatias congênitas, selecionamos pacientes cuja indicação para o exame tinha sido avaliar o VD e a IP. Foram incluídos pacientes submetidos à RMC entre abril de 2015 e agosto de 2018. Comparamos laudos de ECO 2D e RMC mais próximos, quanto à data do exame, excluindo os pacientes que tivessem sido submetidos a algum tipo de tratamento invasivo entre os dois exames.Os exames foram realizados por cinco ecocardiografistas diferentes, treinados em cardiologia pediátrica e CC, com no mínimo de cinco anos de experiência, utilizando aparelho de ultrassom cardiovascular HD11 ou iE33 . Todas as informações foram coletadas de laudos de ecocardiogramas, sem revisão das imagens ou análise dos métodos utilizados para conclusão do laudo. Em nosso serviço, o laudo é emitido apenas pelo médico que realiza o exame, sem a necessidade de sua revisão por outros médicos.13 Em nosso serviço, os principais métodos para avaliar a função do VD são: análise qualitativa , TAPSE (excursão sistólica do plano do anel tricúspide do laudo), fração de variação da área do VD , e pico de velocidade da onda S´ por Doppler tecidual pulsado (DTP). Tanto o TAPSE como o DTP são também apresentados em escore-Z.15 O conjunto desses parâmetros determina a impressão final do examinador. Para a avaliação da IP, os seguintes parâmetros são geralmente utilizados: diâmetro do jato regurgitante/diâmetro da via de saída do VD, local no tronco da artéria pulmonar onde o refluxo é detectado, meio-tempo de pressão da curva de fluxo e integral da velocidade-tempo (IVT). Após essa análise, o examinador utiliza a estratificação em quatro níveis para classificação da função do VD , tamanho do VD , e grau de IP . A função do ventrículo esquerdo foi analisada pela fração de ejeção (FE) obtida pelo método de Teichholz e/ou Simpson.A análise subjetiva ou o escore-Z das medidas do VD obtidas no modo bidimensional (janela quatro câmaras) ou modo M  de acordo com as diretrizes da Sociedade Americana de Ecocardiografia são geralmente usadas para avaliar as dimensões do VD.steady state free precession ) no eixo curto do coração ou corte axial do tórax, desde o anel atrioventricular até o ápice do coração. Os volumes ventriculares e a FE foram determinados após o traçado manual em modo offline utilizando o sistema de análise MASS R MR Analytical Software System, versão 5.1 . As imagens foram obtidas a partir dos pacientes em respiração livre, com número de excitações (NEX) de três, ou em apneia (NEX de 1), dependendo da situação clínica do paciente e qualidade das imagens. Foram avaliados o volume diastólico final do VD indexado (VDFVDi), a FE do VD, o volume sistólico final do VD indexado (VSFVDi) e a FE do VE.Os exames de RMC foram realizados em um aparelho 1.5 Tesla . Os volumes ventriculares foram determinados após a aquisição de imagens bidimensionais pela técnica de precessão livre em estado de equilíbrio (SSFP 16 utilizando-se a seguinte fórmula: escore-Z = [medida do paciente – média esperada)/desvio padrão (DP)]. Para os pacientes com idade inferior a oito anos, os cálculos foram realizados com base no estudo de Valsangiacomo-Buechel ( 17 utilizando a fórmula: Z = log10 (medida/esperada)/DP . Um escore-Z entre -2 e +2 foi considerado normal; um escore-Z entre +2,01 e +3 uma dilatação leve; um escore-Z entre +3,01 e +4 dilatação moderada, e um escore-Z > +4 considerado como dilatação grave.Os volumes ventriculares indexados foram transformados em escore-Z, com base nos valores normais publicados pela Sociedade de Ressonância Magnética Cardiovascular   ,16 utilBuechel   ,17 utilA classificação da FE foi realizada da seguinte maneira:Ventrículo direito: FE> 45% = normal; FE de 36 a 45% = disfunção leve; FE de 25 a 35% = disfunção moderada; FE < 25% = disfunção acentuada.Ventrículo esquerdo: FE > 50% = normal; FE de 40 a 50% = disfunção leve; FE de 30 a 39% = disfunção moderada; FE < 30% = disfunção acentuada.A IP foi avaliada por imagens de contraste de fases, adquiridas perpendicularmente ao tronco e aos ramos pulmonares, em respiração livre (NEX de 2 ou 3), ajustando-se o número de visualizações por segmento de acordo com a frequência cardíaca do paciente, permitindo a reconstrução de 30 fases por intervalo RR. O volume e a fração de regurgitação pulmonar foram analisados pelo programa FLOW R MR Flow Quantification software, versão 3.1 . Como existem dois métodos possíveis para classificar o grau de IP por RMC (volume regurgitante e fração de regurgitação), divergências entre as classificações foram resolvidas pela análise do examinador. Os seguintes valores foram considerados para classificação:2 ou fração de regurgitação = 5-20%.IP leve: volume regurgitante = 0,3-1,0 L/min/m2 ou fração de regurgitação = 21-40%.IP moderada: volume regurgitante =1,01-2,50 L/min/m2 ou fração de regurgitação > 40%.IP acentuada: volume regurgitante > 2,5 L/min/mAs variáveis contínuas foram expressas em média ± desvio padrão ou mediana e intervalo interquartil (25-75), dependendo da distribuição dos dados. A distribuição dos dados pode ser considerada normal quando aproximadamente 95% dos dados encontram-se dentro de 1,96 desvios padrões da média . As variáveis categóricas foram apresentadas em números absolutos e porcentagens. A análise de concordância foi realizada usando o coeficiente Kappa, com auxílio do programa StatsDirect, versão 2.7.2, 2008 . A significância estatística foi considerada como p < 0,05 .Do total de 178 crianças e adultos com CC submetidos à RMC durante o período do estudo, 51 (29%) foram incluídos na análise. As características principais da população estudada estão descritas na eyeball ), haveria erros de classificação em mais nove casos e uma classificação correta em mais cinco casos. As medidas ecocardiográficas são apresentadas na As dimensões do VD foram classificadas como anormais em 96% dos casos, com dilatação leve em 16% dos casos, dilatação moderada em 43%, e dilatação acentuada em 37%. Caso os ecocardiografistas tivessem considerado apenas o escore-Z do diâmetro diastólico final do VD o (DDFVD), haveria uma piora na classificação em 42 pacientes (82%), nenhuma alteração em cinco pacientes (10%), e uma classificação melhor ou mais apropriada em quatro pacientes (8%) em comparação à RMC. A disfunção ventricular direita foi encontrada em 20% dos casos, sendo leve em 10%, moderada em 8% e acentuada em 2%. Dos 51 pacientes, 29 (57%) possuíam dados disponíveis de TAPSE, FAC, e DTP em seus lados e, desses 29 pacientes, 18 (62%) apresentavam valores abaixo do intervalo normal. Apesar desse resultado, nove desses 18 pacientes foram classificados como tendo função sistólica do VD normal. A concordância entre esses índices ecocardiográficos da função sistólica do VD e da FE do VD na RMC foi de 38%. Se o ecocardiografista tivesse considerado apenas esses índices anormais, sem considerar o exame visual  apresentaram escore-Z do VDFVDi dentro dos limites normais , três (6%) apresentaram dilatação leve , seis (12%) apresentaram dilatação moderada  e 39 (76%) dilatação grave . O VDFVEi variou entre 66,4 e 155,2 mL/m2 . O VDFVDi variou entre 84,7 e 275,6mL/m2 mL/m2   . Observ2 mL/m2   . Dos 16Observou-se uma concordância significativa entre os métodos quanto à classificação das dimensões do ventrículo direito , apesar do baixo grau de concordância. A diferença na classificação foi de um grau em 74% dos casos discordantes, com subestimação das dimensões do VD pelo ECO em 22 casos (43%), e superestimação em cinco casos (10%)   . Dos 39Observou-se uma fraca concordância entre os métodos para a classificação da função do VD . A diferença na classificação foi de um grau em 86% dos casos discordantes, com superestimação da função do VD pela ecocardiografia em 15 casos (29%), e subestimação em seis casos (12%)   . Os doiO grau de concordância entre os métodos quanto à classificação de IP não foi estatisticamente significativo . Houve discordância em 80% dos casos, com uma tendência de superestimação do grau de IP pelo ECO. Houve discordância superior a um grau em 20% dos casos   .O ECO não identificou nenhum dos 16 casos (31%) de disfunção do VE e nenhum dos 13 casos (25%) de dilatação do VE, o que não permitiu a avaliação da concordância entre os métodos. Dos 16 casos de disfunção do VE, 10 (62%) também apresentaram disfunção do VD e somente um apresentou VD com dimensões normais.A IP residual e remodelação do VD ao longo do tempo são elementos importantes na evolução tardia de pacientes que se submeteram à correção cirúrgica da via de saída do VD na infância. A tomada de decisão quanto ao tempo de se realizar uma nova intervenção cirúrgica nesses casos é desafiadora. Os critérios clínicos, eletrocardiográficos, além de achados de exames de imagens, tais como ECO e RMC, são utilizados para ajudar nessa decisão, buscando determinar o melhor momento para o tratamento cirúrgico.eyeball ) das dimensões e da função do VD é ainda muito utilizada. No entanto, a acurácia dessa avaliação é questionável e ainda fomenta mais estudos. Nosso estudo objetivou avaliar a acurácia do ECO 2D, realizado na rotina ambulatorial, em quantificar as dimensões e a função do VD e o grau de IP. Escolhemos pacientes com CC com risco de desenvolverem dilatação e disfunção do VD, bem como IP.O ECO 2D é o método de imagem mais utilizado para monitorar a evolução desses pacientes e orientar, na maioria das vezes, a tomada de decisão. Dadas as dificuldades em se realizar a avaliação do VD por ECO 2D com parâmetros objetivos, a avaliação qualitativa  para avaliar o VD e, mesmo assim, geralmente observa-se subestimação das medidas das dimensões do VD,24 é explicada por sua incompleta visualização, especialmente em casos de dilatação acentuada do VD, quando o ápice cardíaco está deslocado e tem difícil acesso no exame ecocardiográfico. Em nosso estudo, apesar de termos analisado uma população jovem, 86% dos pacientes apresentaram dilatação moderada ou grave do VD. Tal fato pode explicar a falta de acurácia, se considerarmos que quanto maior o VD, maiores são as dificuldades em avaliá-lo. Contudo, em nosso estudo, o ECO 2D foi capaz de detectar 96% dos casos de dilatação moderada e/ou grave, o que justificaria o rastreamento de pacientes que necessitaria ser submetido a um exame de RMC. Em relação à função sistólica do VD, nossos resultados estão de acordo com aqueles apresentados por Puchalski,18 que demonstrou um baixo grau de concordância entre ECO 2D e RMC. No entanto, o grau de discordância entre as classes de estratificação foi de apenas um grau em 86% dos casos, e essa diferença ocorreu principalmente na zona entre disfunção leve e função normal. Vários métodos ecocardiográficos têm sido usados para avaliar a função do VD, incluindo TAPSE, FAC, DTP, entre outros. Apesar de alguns serem reprodutíveis, nenhum mostrou uma forte correlação com a FE do VE na população pediátrica, especialmente em pacientes com DCC.27 Métodos que utilizam medidas unidimensionais, tais como TAPSE, ou medidas bidimensionais tais como a fração de variação da área do VD, não levam em consideração a complexa geometria do VD. Esses dois métodos não consideram, por exemplo, a via de saída do VD, comumente comprometida em pacientes submetidos à cirurgia de correção da tetralogia de Fallot21 Ainda, outros fatores influenciam essas medidas, tais como pericardiectomia, pré-carga, ângulo do feixe de ultrassom, qualidade da janela acústica, função do VE, entre outros. No estudo de Mercer-Rosa et al.16 TAPSE não se correlacionou com a FE do VD por RMC ou com o pico de VO2. Os mesmos autores, em 2012, observaram uma fraca correlação entre Doppler tecidual da parede livre do VD e a FE do VD por RMC, e a ausência de correlação entre o índice de Tei e a FE do VD por RMC em pacientes submetidos ao tratamento cirúrgico para tetralogia de Fallot.5 Em um estudo de Leong et al.28 com uma população adulta com insuficiência cardíaca, a avaliação da função do VD pelo ECO com speckle tracking apresentou a correlação mais forte (r = 0.77) com a FE do VD na RMC, em comparação a outras técnicas como TAPSE, FAC e DTP. No entanto, deve-se considerar que essa população geralmente não se apresente com dilatação grave do VD. A ECO 3D talvez seja o método que melhor se correlacione com a RMC,29 embora esteja longe de se tornar tão disponível como a ECO 2D, principalmente na população jovem.30 Na prática, muitos serviços optam pela avaliação qualitativa  da função do VD, combinada com alguns outros índices mencionados anteriormente para corroborarem a impressão final. Assim, a avaliação da função do VD por ECO 2D torna-se um método dependente do examinador e sujeito a diferentes interpretações.Observamos certa concordância, embora fraca, entre ECO e RMC, para a classificação das dimensões do VD. Esse resultado é similar ao encontrado por Lai et al.,5 Em seu estudo,5 muitos pacientes com IP leve pela RMC foram classificados como IP moderada ou acentuada pela ECO, utilizando a razão IVTdiastólica/IVT sistólica no tronco pulmonar. Renella et al.,31 observaram que o ECO apresentou elevada sensibilidade em identificar casos de IP grave em diferentes métodos utilizados, e recomendaram a avaliação de curvas Doppler nos ramos pulmonares, em vez do tronco pulmonar, a fim de aumentar a especificidade do método. Na prática, a literatura tem mostrado que o ECO é capaz de discriminar casos de IP leve dos casos moderados a grave, o que é corroborado por nossos resultados.Em relação ao grau de IP, não encontramos concordância entre ECO e RMC. Em 38 pacientes (75% da amostra), a IP foi classificada como acentuada pelo ECO, mas como moderada ou leve pela RMC. Em outras palavras, ECO superestimou o grau de IP na maioria dos casos, resultado similar ao observado por Mercer-Rosa et al.37 Assim, a avaliação do VE não pode ser negligenciada. Em nossa amostra, a ECO 2D mostrou função normal do VE em todos os pacientes, enquanto a RMC identificou disfunção em 31% dos casos, o que mostra limitações do 2D ECO em avaliar a função ventricular esquerda nessa situação. Dos pacientes com disfunção ventricular esquerda. Os pacientes com disfunção do VE, 62% também apresentaram algum grau de disfunção do VD, o que pode estar relacionado com interdependência ventricular.39 A nosso ver, a avaliação da função do VE em casos de dilatação ou disfunção do VD é mais difícil para o ECO devido ao movimento paradoxal do septo interventricular e deslocamento do VE por um VD dilatado ou disfuncional, o que torna sua visibilidade mais difícil.A disfunção do VE tem sido descrita em pacientes submetidos a reparo de doenças do VD e associada a eventos adversos maiores.Esse foi um estudo retrospectivo, unicêntrico, com um número limitado de pacientes. A possibilidade de viés de inclusão deve ser considerada, uma vez que a decisão de submeter o paciente à RMC é geralmente feita após análise dos achados ecocardiográficos. A análise dos resultados do ECO foi feita com base nos laudos somente, sem revisão das imagens. Considerando que os exames de ECO foram realizados por cinco ecocardiografistas diferentes, existe a possibilidade de discordâncias entre observadores e intraobservador. Ainda, o intervalo de tempo entre o ECO e a RMC foi relativamente grande. Apesar de nenhum procedimento cirúrgico ou percutâneo tenha sido realizado entre o ECO e a RMC, o ideal seria que os exames tivessem sido realizados dentro de 24 horas entre eles. O uso do escore-Z das medidas ventriculares obtidas por RMC não é uma abordagem comum na literatura, e o intervalo de classificação, bem como o impacto clínico dessas medidas, precisam ser mais bem avaliados em estudos futurosEm nossa prática e, considerando as limitações do estudo, o 2D ECO mostrou uma baixa concordância com a RMC quanto às dimensões e função sistólica do VD, bem como ao grau da IP. Em geral, o ECO subestimou as dimensões do VD e superestimou a função do VD e o grau de IP. Acreditamos que a incorporação de parâmetros ecocardiográficos mais objetivos seja necessária para uma melhor concordância com a RMC. No entanto, o impacto real dessa análise em relação à tomada de decisão clínica ainda é incerto. 2 However, CMR is less available than two-dimensional echocardiogram (2D ECHO), especially for young children, when sedation is frequent. Thus, it is crucial to optimize CMR indications and referrals for CMR.Cardiac magnetic resonance imaging (CMR) is considered the method of choice to assess dimensions and function of the right ventricle (RV), as well as to quantify pulmonary insufficiency (PI). Patients with congenital heart disease (CHD) and involvement of the right ventricular outflow tract or pulmonary valve are subject to develop dilation and dysfunction of the RV and PI at some stage in their lives, as a result of either the natural history or surgical or hemodynamic procedures. In this type of patient, indication for CMR is part of the multi-imaging approach recommended today.10 Despite this, in daily practice, indication for CMR is made based on the evaluation of clinical and echocardiographic features.In turn, 2D ECHO is a widely available and relatively low-cost method but limited in assessing the RV and the degree of PI.In our study, we sought to retrospectively assess the accuracy of transthoracic 2D ECHO in estimating the function and dimensions of the RV and the degree of PI, comparing its findings with those of CMR.11 This study was approved by the institutional review board.This study was carried out in a reference center for the treatment of CHD. We selected, from the pediatric/congenital CMR database, patients whose indication for CMR had been to assess the RV and PI. Patients who underwent CMR between April 2015 and August 2018 were included. We compared the closest (in terms of the date of the tests) 2D ECHO and CMR reports, excluding patients who underwent some type of invasive treatment between the two tests.The examinations were performed by five different echocardiographers, trained in pediatric cardiology and CHD, with at least five years of experience, using either HD 11 or iE33 cardiac ultrasound systems . All information was collected from ECHO reports, with no review of the images or analysis of the methods to conclude the report. In our service, the report is issued only by the performing physician, and there is no mandatory review of the reports by other physicians.13 In our service, the main methods to assess the function of the RV are: qualitative analysis , TAPSE (tricuspid annular plane systolic excursion), fractional area change (FAC) and the S’ wave peak systolic velocity by pulsed-wave tissue Doppler imaging (TDI). TAPSE and RV TDI s´ are also plotted in Z-scores.15 The set of these parameters determines the examiner's final impression. To assess PI, the following parameters are generally used: diameter of the regurgitant jet / diameter of the RV outflow tract, location of the pulmonary artery tree where reflux is detected, pressure half-time of the flow curve and integral velocity-time (IVT). After this analysis, the examiner uses a four-level stratification to classify right ventricular function , size of the RV  and the degree of PI . For analysis of the left ventricular (LV) function, the ejection fraction (LVEF), obtained by the Teichholz and/or Simpson method, was used.Subjective analysis or Z-score of measurements of the RV obtained in two-dimensional mode (four-chamber window) or M-mode  according to the American Society of Echocardiography guidelines are generally used to assess right ventricular dimensions.TM). Ventricular volumes were determined after acquisition of two-dimensional images in cine-SSFP (steady state free precession) in the short axis of the heart or axial section of the chest, from the atrioventricular ring to the cardiac apex. Ventricular volumes and EF were determined after manual tracing in offline analysis using the MASS R MR Analytical Software System, version 5.1 . The images were obtained in free breathing with number of excitations (NEX) of three, or in apnea (NEX of 1), depending on patient's clinical situation and quality of the images. The indexed end diastolic volume of the RV (RVEDVi), the right ventricular EF, the indexed end diastolic volume of the left ventricle (LVEDVi) and the LVEF were evaluated.The CMR examinations were carried using a 1.5 Tesla scanner /standard deviation [SD]). For patients younger than eight years old, calculations were made based on the study by Valsangiacomo-Buechel ( 17 using the formula: Z = log10 (measured/expected)/SD (SD = 0.05). A Z-score between -2 and +2 was considered normal; a Z-score between +2.01 and +3 a mild dilation; a Z-score between +3.01 and +4 moderate dilation, and a Z-score > +4 was considered severe dilation.Indexed ventricular volumes were transformed into a Z-score, based on the normal values published by the Society for Cardiovascular Magnetic Resonance   ,16 usinBuechel   ,17 usinRegarding EF classification, it was performed as follows:Right ventricle: EF > 45% = normal; EF from 36 to 45% = mild dysfunction; EF from 25 to 35% = moderate dysfunction; EF < 25% = severe dysfunction.Left ventricle: EF > 50% = normal; EF from 40 to 50% = mild dysfunction; EF from 30 to 39% = moderate dysfunction; EF < 30% = severe dysfunction.PI was evaluated by phase contrast imaging performed perpendicular to the pulmonary trunk and perpendicular to the pulmonary branches, in free breathing (NEX of 2 or 3), adjusting the number of views per segment according to patient's heart rate, allowing the reconstruction of 30 phases per RR interval. Pulmonary regurgitation volume and fraction were analyzed using the FLOW R MR Flow Quantification software, version 3.1 . As there are two possible methods to classify the degree of PI by CMR (regurgitant volume and fraction of regurgitation), discrepancies were resolved by analysis of the data by the observer. The following values were considered for classification:2 or regurgitation fraction = 5-20%.Mild PI: regurgitant volume = 0.3-1.0 L/min/m2 or regurgitation fraction = 21-40%.Moderate PI: regurgitant volume = 1.01-2.50 L/min/m2 or regurgitation fraction > 40%.Severe PI: regurgitant volume > 2.5 L/min/mContinuous variables were expressed as mean ± standard deviation or median with interquartile range (25-75), depending on data distribution. Data distribution can be considered normal when around 95% of the data fall within 1.96 standard deviations from the mean . Categorical variables were presented in absolute numbers and percentages. Agreement was analyzed using the Kappa coefficient, with the aid of the StatsDirect program, version 2.7.2, 2008 . Statistical significance was considered as p < 0.05 .Out of 178 children or adults with CHD undergoing CMR during the study period, 51 (29%) were included in the analysis. The main characteristics of the study population are shown in The dimensions of the RV were classified as abnormal in 96% of the cases, with mild dilation in 16%, moderate dilatation in 43% and severe dilatation in 37%. Had the echocardiographers considered only the right ventricular end-diastolic diameter RVEDD Z-score, there would be worsening in classification in 42 patients (82%), no changes in five patients (10%) and a better or more appropriate classification in four patients (8%) compared to CMR. Right ventricular dysfunction was reported in 20% of cases, being mild in 10%, moderate in 8% and severe in 2%. Out of the 51 patients, 29 (57%) had values of TAPSE, FAC or TDI in their reports, and among these 29 patients, 18 (62%) had measurements below the normal range. Despite this finding, nine of these 18 patients were classified as having normal systolic RV function. The agreement between these echocardiographic indices of RV systolic function and CMR right ventricular EF was 38%. Had the echocardiographer considered only these abnormal indices, disregarding the eyeball method, there would be misclassifications in nine more cases and a correct classification in five more cases. Echocardiographic measurements are presented in 2 , which corresponded to an average Z-score of +5.6 ± 2. Three patients (6%) had a RVEDVi Z-score within normal limits (91.4 ± 7.9 mL/m2 ), another three (6%) presented mild dilation (110.6 ± 4.8 mL/m2 ), six (12%) moderate dilation (120 ± 10.9 mL/m2 ) and 39 (76%) severe dilation (151.8 ± 31.5 mL/m2 ). The LVEDVi varied between 66.4 and 155.2 ml/m2 ( The examination was performed under anesthesia in 16 patients (31%). The RVEDVi varied between 84.7 and 275.6 mL/m2 ml/m2   . Dilati2 ml/m2   . Of theA significant agreement was observed between the methods for the classification of right ventricular dimensions , although the degree of this agreement was low. The difference in classification was of one degree in 74% of the discordant cases, with an underestimation of the dimensions of the RV by ECHO in 22 cases (43%) and overestimation in five cases (10%)   . Of theThere was a weak agreement between the methods for classification of the RV function . The difference in classification was of one degree in 86% of the discordant cases, with the RV function overestimated by ECHO in 15 cases (29%) and underestimated in six cases (12%)   . The twThe degree of agreement between the methods for classification of PI was not statistically significant . There was disagreement in 80% of the cases, with ECHO tending to overestimate the degree of PI. There was disagreement above one degree in 20% of the cases   .ECHO did not identify any of the 16 cases (31%) of LV dysfunction and none of the 13 cases (25%) of LV dilation, preventing the assessment of agreement between the methods. Of the 16 cases of LV dysfunction, 10 (62%) also had RV dysfunction and only one had normal-sized RV.Residual PI and remodeling of the RV over time are important elements in the long-term course of patients who have undergone RV outflow tract repair in childhood. Decision making regarding the time to perform a new surgical intervention in these cases is still challenging. Clinical and electrocardiographic criteria, in addition to findings of image examinations, such as ECHO and CMR, are used to assist in this decision, seeking to determine the optimal time to perform surgical treatment.The 2D ECHO is the most used imaging method to monitor the course of these patients, guiding, in most cases, the decision-making. Given the difficulties in performing a 2D echocardiographic assessment of the RV with objective parameters, qualitative assessment  of the dimensions and function of the RV is still widely used. However, the accuracy of this assessment is questionable and still motivates further studies. Our study sought to assess the accuracy of 2D ECHO, performed during the outpatient routine, in quantifying the dimensions and function of the RV and the degree of PI. We selected patients with CHD at risk to develop RV dilation and dysfunction and PI.4 when they applied the guidelines for the assessment of the RV using 2D ECHO in normal patients, in patients with atrial septal defects and in patients who had underwent tetralogy of Fallot repair. In their article, the authors postulate that 2D ECHO inaccuracies are inherent to the application of linear or area measurements in a complex geometry chamber. Puchalski et al.,18 in a study with a design similar to ours, obtained similar results and emphasized the great interobserver variability as a potential source of disagreement between ECHO and CMR. It is suggested that the adding of objective to subjective measures would increase the agreement between the methods.19 In this sense, Greutmann et al.20 observed, in an adult population, that the linear measurement with the best correlation with the RV diastolic volume was the RV area in the four-chamber apical view. By measuring this area, Alghandi et al.21 were able to discriminate patients with RVEDVi > 170 ml/m2 . More recent studies have investigated the use of 3D ECHO to assess the RV and, even so, it is generally observed underdimensioning of the RV24 is explained by its incomplete visualization, especially in cases of severe RV dilation, when the cardiac apex is dislocated and difficult to access by ECHO inspection. In our study, although we analyzed a young population, 86% of the patients had moderate or severe dilation of the RV. This could explain the lack of accuracy, if we consider that the bigger the RV, the greater the difficulties in evaluating it. However, in our study, 2D ECHO was able to detect 96% of cases of moderate and / or severe dilation, which may serve the purpose of screening patients who would need to undergo CMR.We observed that there was a certain, albeit weak, agreement between ECHO and CMR for the classification of right ventricular dimensions. This finding is similar to that found by Lai et al.,18 who reported a poor agreement between 2D ECHO and CMR. However, the degree of disagreement between the stratification classes was only of one grade in 86% of the cases, and this difference occurred mainly in the zone between mild dysfunction and normal function. Several echocardiographic methods have been used to assess right ventricular function, including TAPSE, FAC, TDI, Tei index, among others. Although some of them are reproducible, none of them has shown a strong correlation with the right ventricular EF in the pediatric population, especially in patients with CHD.27 Methods with unidimensional measurements, such as TAPSE, or bidimensional measurements such as FAC, do not take into account the complex geometry of the RV. These two methods do not consider the RV outflow tract, for example, commonly compromised in patients undergoing tetralogy of Fallot correction.21 In addition, there are other factors influencing these measurements, such as previous pericardiectomy, preload, ultrasound beam angulation, echocardiographic window quality, LV function, etc. In the study by Mercer-Rosa et al.16 TAPSE was not correlated to right ventricular EF by CMR, nor to the peak VO2. The same author, in 2012, observed a weak correlation between the tissue Doppler of the right ventricular free wall and the right ventricular EF by CMR, and the lack of correlation between the Tei index and the right ventricular EF by CMR in patients post-tetralogy of Fallot repair.5 In the study by Leong et al.28 in an adult population with heart failure, right ventricular speckle tracking strain showed the strongest correlation (r = 0.77) with CMR right ventricular EF, compared with other techniques including TAPSE, FAC and TDI. However, one has to consider that this population usually does not present with severe RV dilatation. 3D ECHO is perhaps the method that best correlates with CMR,29 but it is still far from becoming a method as available as the 2D ECHO, especially in the young population.30 In practice, many services end up using qualitative evaluation  of the right ventricular function, combined with some of the aforementioned indices to corroborate the final impression. The assessment of the function of the RV by 2D ECHO, therefore, becomes an examiner-dependent method and subject to different interpretations.Regarding RV systolic function, our results are in line with those of the study by Puchalski,5 In that study,5 many patients with mild PI by CMR were classified as having moderate or severe PI by ECHO, when using the diastolic VTI / systolic VTI ratio obtained in the pulmonary trunk. In turn, Renella et al.31 observed that ECHO had great sensitivity in identifying cases of severe PI in different methods used and recommend the evaluation of Doppler curves in the pulmonary branches, instead of in the pulmonary trunk, to increase the specificity of the method. In practice, the literature has shown that ECHO is able to discriminate cases of mild PI from cases of moderate or severe PI, which is corroborated by our findings.With regard to the degree of PI, we did not find any agreement between ECHO and CMR in our study. In 38 patients (75% of the sample), PI was classified as severe by ECHO, but as moderate or mild by CMR. In other words, ECHO overestimated the degree of PI in most cases, a data similar to that observed by Mercer-Rosa et al.37 Therefore, LV assessment cannot be neglected. In our sample, although the 2D ECHO showed normal LV function in all patients, CMR identified LV dysfunction in 31% of cases, which indicates the limitations of 2D ECHO in assessing LV function in this situation. Of the patients with LV dysfunction, 62% also had some degree of RV dysfunction, which may be related to ventricular interdependence.39 In our view, the evaluation of LV function in cases of RV dilation or dysfunction is more difficult to the ECHO due to the paradoxical movement of the interventricular septum and the LV dislodgement by a dilated or dysfunctional RV, making its visibility more difficult.LV dysfunction has been described in patients with RV disease repair and linked to major adverse events.This was a retrospective, single-center study with a limited number of patients. The possibility of inclusion bias should be considered, since the decision to submit the patient to CMR is often made after analysis of ECHO findings. Analysis of ECHO results was based on the reports only, without image review. Considering that five echocardiographers performed the exams, there is the possibility of intraobserver and interobserver disagreements. Also, time interval between ECHO and CMR was relatively large. Although there was no surgical or percutaneous interventional procedure between ECHO and CMR, ideally the exams should have been performed within 24 hours of each other. The use of Z-score of ventricular measurements obtained by CMR is not a common approach in the literature, and the classification range, as well as the clinical impact of these measurements, need to be better evaluated in future studies.In our practice, and considering the study limitations, 2D ECHO showed a low agreement with CMR regarding right ventricular dimensions and systolic function, and degree of PI. In general, ECHO underestimated the dimensions of the RV and overestimated the function of the RV and the degree of PI. We understand that the incorporation of more objective echocardiographic parameters is necessary for a better agreement with the CMR. However, the real impact of this analysis in relation to clinical decision-making is still uncertain.


Background: Inherent to its geometry, echocardiographic imaging of the systemic right ventricle (RV) is challenging. Therefore, echocardiographic assessment of systemic RV function may not always be feasible and/or reproducible in daily practice. Here, we aim to validate the usefulness of a comprehensive range of 32 echocardiographic measurements of systemic RV function in a longitudinal cohort by serial assessment of their correlations with cardiac magnetic resonance (CMR)-derived systemic RV ejection fraction (RVEF).Methods: A single-center, retrospective cohort study was performed. Adult patients with a systemic RV who underwent a combination of both CMR and echocardiography at two different points in time were included. Off-line analysis of echocardiographic images was blinded to off-line CMR analysis and vice versa. In half of the echocardiograms, measurements were repeated by a second observer blinded to the results of the first. Correlations between echocardiographic and CMR measures were assessed with Pearson's correlation coefficient and interobserver agreement was quantified with intraclass correlation coefficients (ICC).Results: Fourteen patients were included, of which 4 had congenitally corrected transposition of the great arteries (ccTGA) and 10 patients had TGA late after an atrial switch operation. Eight patients (57%) were female. There was a mean of 8 years between the first and second imaging assessment. Only global systemic RV function, fractional area change (FAC), and global longitudinal strain (GLS) were consistently, i.e., at both time points, correlated with CMR-RVEF . The ICC of GLS  was higher than the ICC of FAC  at both time points.Conclusion: GLS appears to be the most robust echocardiographic measurement of systemic RV function with good correlation with CMR-RVEF and reproducibility. In congenital heart disease with a systemic right ventricle (RV), the RV supports systemic circulation. This includes transposition of the great arteries (TGA) after atrial switch operation and congenitally corrected TGA (ccTGA) . The sysThere is a gap between the research setting and daily clinical practice: systemic RV geometry in combination with previous thoracotomies makes specific echocardiographic views difficult to obtain. Reported correlations between echocardiographic variables and CMR-derived RVEF differ , and intThis study aims to distill echocardiographic variables that are feasible to obtain in daily clinical practice, are consistently correlated with CMR-derived RVEF, and can be measured reliably.We aimed to validate the usefulness of a comprehensive range of echocardiographic variables of systemic RV function in a single-center cohort. Echocardiographic variables were compared with CMR-RVEF at two different points in time. All reported echocardiographic variables of systemic RV function were included. When applicable, different methods of evaluating a single variable were compared. Interobserver agreement and feasibility of the variables were assessed.A retrospective cohort study was conducted. Adult patients with a systemic RV in a biventricular circulation (TGA after Mustard or Senning procedure or ccTGA) from the outpatient congenital cardiology clinic of the Leiden University Medical Center were screened for availability of a combination of both CMR and TTE images at two different points in time at least 5 years apart. The CMR and TTE images at the same points in time should be no more than 1 year apart. All consecutive patients meeting these criteria were included. Complex (cc)TGA was defined as (cc)TGA with important additional malformations present at birth, including ventricular septal defects, left ventricular outflow tract (LVOT) obstruction, and aortic arch malformations. The Leiden University Medical Center's medical research ethics committee waived the need for informed consent. The protocol is in accordance with the 2013 Declaration of Helsinki.To identify a comprehensive range of echocardiographic variables of systemic RV function, a PubMed search was conducted with the following key terms: “systemic right ventricle,” “ transposition of the great arteries,” “echocardiography,” “atrial switch,” “Mustard,” “Senning.” From the articles found, studies in which echocardiography was conducted in cohorts of patients with a systemic RV  were screened for echocardiographic variables reflecting systemic RV function. Both studies in which echocardiographic variables were compared with CMR-RVEF and studies assessing associations between echocardiographic variables and clinical variables (such as exercise capacity) or clinical events/outcomes were screened. From these studies, all variables that could be reasonably measured in our cohort were added to the protocol.Clinically indicated echocardiograms performed with commercially available ultrasound systems were analyzed off-line in EchoPac, GE Medical Systems. Length, weight, and heart rate at the time of imaging were noted. Measurements were performed off-line by one researcher (TZ) who received training from three experienced congenital imaging cardiologists: PK (European Association of Cardiovascular Imaging [EACVI] certified for >10 years), DH (EACVI member), and EH . To assess interobserver agreement, measurements were repeated by PK in half of the echocardiograms, blinded to the measurements of TZ. Both observers were blinded to the MRI measurements. . Early and late diastolic velocities were measured from the pulsed wave doppler image of the tricuspid valve inflow. The rate of pressure build-up in the systemic RV (dP/dt) was calculated from the continuous wave image of tricuspid regurgitation in the interval for the regurgitation velocity to increase from 1 to 3 m/s. Tricuspid valve regurgitation itself was assessed semiquantitatively based on integration of several variables in accordance with the ESC recommendations as described elsewhere  were determined in the apical four-chamber view by the software package in EchoPac after manual determination of the endocardial border . The plalsewhere . The MPIlsewhere . MPI waslsewhere : first, lsewhere .The isovolumic acceleration was calculated as the slope of velocity increase of the lateral aspect of the tricuspid valve during isovolumic contraction . It was Systolic and early and late diastolic velocities of the lateral aspect of the tricuspid valve and systolic velocity of the septal aspect of the tricuspid valve were measured in the pulsed wave tissue doppler and the tissue doppler apical four-chamber images.Intraventricular dyssynchrony was calculated as the difference between the time to peak strain in speckle tracking analysis between the systemic RV mid-lateral and mid-septal wall , 19, 29.MRI studies were performed with a 1.5-T whole-body MRI scanner . The routine clinical protocol included electrocardiographically gated breath-hold, steady-state, free precession imaging in transverse orientation. Length, weight, and heart rate at the time of imaging were noted. To assess cardiac dimensions and systolic function, end-diastolic and end-systolic endocardial contours were manually drawn with software  by an experienced cardiothoracic radiologist (RW) who was blinded to the echocardiographic measurements. Trabeculations were included in the cavity. Systemic RV dimensions and free wall thickness were measured in end-diastole in the four-chamber view. Stroke volume was calculated by subtracting the end-systolic from the end-diastolic volume. Systemic right ventricular ejection fraction (RVEF) was calculated as the percentage of volume change between the end-diastolic and end-systolic volumes. Cardiac output was calculated by multiplying the stroke volume by heart rate.T-test. Correlations between echocardiographic and CMR imaging variables were tested with Pearson's or Spearman's correlation analysis as appropriate. Interobserver agreement was visually assessed by calculation of the mean difference between observed values and constructing the limits of agreement  according to Bland and Altman  (or median and interquartile range [IQR] as appropriate) or frequencies and percentages. Changes between variables over time were tested with Student's d Altman . InterobT = 1 and 2 at T = 2). The overall New York Heart Association (NYHA) class worsened between the first and second time points , FAC , and GLS   . The lat= 0.011) . All oth= 0.011) –8. As th= 0.011)  were lesT = 1 and just under the level of significance at T = 2. The correlation between GLS and RVEF was not altered by correction for heart rate  might be heart rate–dependent, analysis was repeated with correction for heart rate . After this correction, the correlations between SR A and RV CO and between septal SR A and LV SV were no longer significant. The correlation between FAC and RVEF was still apparent at art rate .p = 0.002 at T = 1; ICC = 0.62 and p = 0.009 at T = 2). The other dimensions  did not show consistent significant agreement between echocardiographic and CMR measurements  on the assessment of systemic RV function, correlations were calculated between the degree of TR, global RV function, FAC, and GLS, and CMR-RVEF . No signT = 1  and moderate at T = 2 . For GLS, the ICC is good at both time points . The measurements of both observers are visualized in Bland–Altman plots (The ICC for FAC is poor at an plots . This vip = 0.001) and 0.91 (p = 0.001), respectively. The other methods were considerably less reliable. None of the methods consistently correlated with CMR-RVEF, CO, or SV , GLS (96%), and  SR A (both 93%) were successfully obtained. For RV dP/dt and LV end-diastolic diameter from the parasternal long axis image, the image quality was often insufficient. The older echocardiograms did not contain pulsed-wave TDI images, but measurements were possible in 10 out of the 14 echocardiograms at T = 1 and in one other patient at T = 2 because the raw images were no longer available.In addition, CMR-RVEF could not be determined in one patient at We aimed to identify reproducible echocardiographic variables that consistently correlated, i.e., at two points in time, with the gold standard of CMR-RVEF in a cohort of patients with systemic RV from daily clinical practice. The key findings are  that, in2max, heart failure, higher NYHA class, ventricular arrhythmias, and mortality . Previous studies show conflicting results , 16, 37.We also found no consistent significant correlations between CMR-RVEF and TAPSE, neither lateral nor septal. Previous studies show conflicting results , 19. TAPMyocardial dyssynchrony is an important problem in patients with systemic RV, especially in patients receiving univentricular pacing . ResynchThe current data show no consistent correlation between dP/dt and CMR-RVEF. DP/dt reflects contractility: it assesses the time the systemic RV takes for the build-up of a certain level of pressure during isovolumic contraction and is, therefore, afterload independent. However, its measurement is highly subject to variation, especially with higher values.Surprisingly, we found that SR A (late diastolic SR) was consistently positively correlated with CMR-cardiac output, and septal SR A was consistently negatively correlated with CMR-LV stroke volume. However, both of these correlations disappeared after correction for heart rate, possibly because a higher heart rate shortens diastolic filling time and generally increases diastolic strain rate. This may imply that strain rate measurements need to be corrected for heart rate.In patients with a systemic RV, TR is a common consequence of systemic RV annulus dilation  and may T = 2. Also, the CMR and echocardiographic apex-base measurements show good agreement. This might indicate that RV lengthening may be a sensitive parameter of deterioration, which may be visible before the functional variables significantly deteriorate. This needs to be confirmed in larger studies.Of note, although in this study no functional echocardiographic variables changed significantly over time, the RV apex-base diameter was significantly larger at A considerable part of our cohort of patients with systemic RV did not meet the inclusion criteria regarding the availability of CMR and echocardiographic images, reflecting routine clinical practice but also limiting the sample size and introducing a possible selection bias causing patients with intracardiac devices to potentially be underrepresented. Furthermore, some correlation coefficients are based on a small sample size as their measurement was not feasible in a considerable number of cases. However, this reflects the practical applicability in routine clinical practice. Also, the interpretation of the RV wall thickness in the context of RV hypertrophy is limited as this requires short axis cine images unavailable in all but one patient. The measurements given were performed in four-chamber views, which is an inferior alternative. Last, the applicability of GLS is limited by variability introduced by spatial and temporal smoothing algorithms  and by intervendor agreement . In thisIn conclusion, from all echocardiographic variables available from literature, GLS appears to be the most robust variable to quantify systemic RV function over time. FAC can also be used well-provided that the endocardial border is traced in a consistent manner over time. In case no quantification of the systemic RV function can be made, visual assessment is an adequate substitute .The raw data supporting the conclusions of this article will be made available by the authors, upon reasonable request.The studies involving human participants were reviewed and approved by Medical Research Ethics Committee Leiden University Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.TZ aided in the design of the study, performed echocardiographic measurements, analyzed the data, and drafted and adjusted the manuscript. MJ aided in the design of the study, the interpretation of the data, guided the drafting of the manuscript, and critically revised and approved the final manuscript. RW provided input for the design of the study, performed MRI measurements, aided in the interpretation of the data, and critically revised and approved the final manuscript. AH provided input for the design of the study, trained TZ to perform echocardiographic measurements, and critically revised and approved the final manuscript. EH provided input for the design of the study, trained TZ to perform echocardiographic measurements, and critically revised and approved the final manuscript. BM guided the drafting of the statistical analysis plan, critically revised its execution and interpretation, and critically revised and approved the final manuscript. HV aided in the design of the study, the interpretation of the data, and critically revised and approved the final manuscript. AE aided in the design of the study, the interpretation of the data, guided the drafting of the manuscript, and critically revised and approved the final manuscript. MS critically revised and approved the final manuscript. PK conceived the study, trained TZ to perform echocardiographic measurements, performed echocardiographic measurements, aided in interpretation of the data, guided the drafting of the manuscript, and critically revised and approved the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We examined the dynamic response of the myocardium to infarction in a longitudinal porcine study using relaxometry, functional as well as diffusion cardiovascular magnetic resonance (CMR). We sought to compare non contrast CMR methods like relaxometry and in-vivo diffusion to contrast enhanced imaging and investigate the link of microstructural and functional changes in the acute and chronically infarcted heart.CMR was performed on five myocardial infarction pigs and four healthy controls. In the infarction group, measurements were obtained 2 weeks before 90 min occlusion of the left circumflex artery, 6 days after ischemia and at 5 as well as 9 weeks as chronic follow-up. The timing of measurements was replicated in the control cohort. Imaging consisted of functional cine imaging, 3D tagging, T2 mapping, native as well as gadolinium enhanced T1 mapping, cardiac diffusion tensor imaging, and late gadolinium enhancement imaging.Native T1, extracellular volume (ECV) and mean diffusivity (MD) were significantly elevated in the infarcted region while fractional anisotropy (FA) was significantly reduced. During the transition from acute to chronic stages, native T1 presented minor changes (< 3%). ECV as well as MD increased from acute to the chronic stages compared to baseline: ECV: 125 ± 24% (day 6) 157 ± 24% (week 5) 146 ± 60% (week 9), MD: 17 ± 7% (day 6) 33 ± 14% (week 5) 29 ± 15% (week 9) and FA was further reduced: − 31 ± 10% (day 6) − 38 ± 8% (week 5) − 36 ± 14% (week 9). T2 as marker for myocardial edema was significantly increased in the ischemic area only during the acute stage (83 ± 3 ms infarction vs. 58 ± 2 ms control p < 0.001 and 61 ± 2 ms in the remote area p < 0.001). The analysis of functional imaging revealed reduced left ventricular ejection fraction, global longitudinal strain and torsion in the infarct group. At the same time the transmural helix angle (HA) gradient was steeper in the chronic follow-up and a correlation between longitudinal strain and transmural HA gradient was detected (r = 0.59 with p < 0.05). Comparing non-gadolinium enhanced data T2 mapping showed the largest relative change between infarct and remote during the acute stage  while FA exhibited the largest relative change between infarct and remote during the chronic follow-up . Overall, diffusion parameters provided a higher contrast (> 23% for MD and > 27% for FA) during follow-up compared to relaxometry (T1 17–18%/T2 10–20%).During chronic follow-up after myocardial infarction, cardiac diffusion tensor imaging provides a higher sensitivity for mapping microstructural alterations when compared to non-contrast enhanced relaxometry with the added benefit of providing directional tensor information to assess remodelling of myocyte aggregate orientations, which cannot be otherwise assessed.The online version contains supplementary material available at 10.1186/s12968-021-00794-5. The loss of functional cardiac tissue due to myocardial infarction (MI) can lead to ventricular remodeling including myofiber disarray, myocardial wall thinning and dilatation compromising left ventricular (LV) function , 2. WithThe response to an ischemic event has been characterized as a dynamic process . During Non-viable infarcted tissue leads to an increase in the cardiac workload of the remaining viable myocardium and subsequently to compensatory hypertrophy . In addiWith changes in LV shape, alterations in function have been reported: Global longitudinal strain (GLS), global radial strain (GRS) and global circumferential strain (GCS) were found to be significantly decreased in magnitude in patients with MI when compared with controls . While aThe changes in shape and function coincide with changes in tissue composition that can be assessed by cardiovascular magnetic resonance (CMR) relaxometry. Edema present during the acute stage after myocardial ischemia/reperfusion injury  is assocComplementary to measuring changes in relaxation times, cardiac diffusion tensor imaging (cDTI) has become an important tool to non-destructively probe changes of microstructure in the anisotropic myocardium. cDTI provides parameters such as mean diffusivity (MD) and fractional anisotropy (FA), thereby granting insights into the structural integrity of tissue, as well as spatially directional parameters such as the inclination angle of cardiomyocyte aggregates, also known as helix angle. In the realm of MI, an elevated MD and a reduced FA was found within the affected region due to loss of tissue integrity resulting in fewer restrictions to water molecules and providing a prolonged mean free pathway –23. In tRelaxometry as well as cDTI both assess tissue alterations that occur at the microscopic level. While T2 and T1 mapping reflect changes in spin–spin and spin–lattice relaxation that are influenced by water content and macromolecular environment, while cDTI is sensitive to changes of water self-diffusion that is governed by the presence and architecture of restrictions such as cell membranes.In the present work, we present a longitudinal swine study to compare relaxometry and cDTI during the dynamic response of the myocardium to MI from the healthy to the acute and chronic MI stages. Using the longitudinal multi-parametric study design, we furthermore exploit the capability of cDTI to derive information on myocyte aggregate orientation to potentially link microstructural changes due to microstructural remodelling with functional alterations in the infarcted heart over time.Nine healthy female swine  were imaged on a clinical 1.5T CMR system  equipped with a gradient system delivering 80 mT/m per physical axis at a slew rate of 100 T/m/s.The study was approved by the veterinary office of the canton of Zurich under licence: ZH072/16.®-100, Graeub AG, Bern Switzerland), azaperone  and atropine . An intravenous catheter was placed and anaesthesia was deepened with propofol  followed by orotracheal intubation. Percutaneous sheaths (5F) were introduced into the femoral arteries and veins. 100 IU/kg body weight (BW) heparin was administered intravenously and was repeated every hour. General anaesthesia was maintained with isoflurane (2–3%) by positive pressure ventilation with 100% oxygen. Heart rate and rhythm and variability (ECG), inspiratory and expiratory gases , pulse oximetry, temperature, direct arterial blood pressure and urine output were monitored continuously throughout the procedure. Arterial blood gas analysis was performed hourly to assess gases , electrolyte balance , haematocrit as well as glucose, lactate and creatinine. Additionally, high-sensitive Troponin T (hsTnT) levels were measured according to study time points. Analgesia was provided by administration of buprenorphine (0.01 mg/kg) every 4–6 h throughout the procedure and by meloxicam (0.4 mg/kg) orally for 2 days.All experimental procedures were performed under general anaesthesia. The pigs were pre-medicated with an intramuscular injection of ketamine  dissolved in 100 ml 5% glucose solution]. For cardiac synchronization of the imaging sequences, ECG electrodes  were placed onto the chest between the front limbs.Before MI induction, animals received antiarrhythmic medication  week 5).The transmural HA gradient remained constant from day 6 until the end in the control group, but continued to become steeper in the MI group until week 5 (9% increase from day 6 to week 5). From week 5 to 9 there was no change found in the MI group.The corresponding correlation plots are shown in Fig. Correlation with relative scar mass showed a fair correlation with longitudinal strain (R = 0.48 p < 0.032) and good correlation with transmural HA variation (R = 0.71 p < 0.001).In this study, we observed functional and structural changes after experimental MI. Edema during the acute MI stage was captured by elevated T2 values, while elevated native T1, ECV, MD and reduced FA values were found in the infarcted region during chronic MI follow-up. A reduction of ventricular torsion as well as longitudinal strain was present during the chronic stage together with a trend towards a steeper transmural HA distribution in the remote area.Upon ischemia, a bimodal occurrence of edema has been reported in swine and humans , 41. TheThe chronic MI stage was reached by week 5 with absence of edema as T2 values normalized close to baseline values. ECV, MD and FA significantly increased in week 5 with a reduction of MD and ECV in week 9, as well as a significant decrease in FA corresponding to scar formation. Increased values of MD and decreased values of FA within scarred regions have previously been reported in in-vivo , 44 and Interestingly, diffusional parameters showed a larger relative change during chronic follow-up compared to both non-contrast methods: native T1 and T2 mapping. The underlying change in tissue properties due to scar formation was identical for both parametric mapping and cDTI. However, imaging physics differ. While native T1 and T2 imaging probe changes in spin–lattice and spin–spin interaction, MD reflects changes in viscosity of the imaged liquid as well as the mean free pathway water molecules can diffuse without restriction as imposed by semipermeable and non-permeable membranes. Correspondingly, FA is predominantly probing changes in diffusion measurements as a function of spatial orientation and hence the overall anisotropy of tissue architecture. Our results suggest a significantly higher sensitivity to changes in myocardial microstructure by cDTI. However, if contrast agents were used, ECV presented the most prominent changes in contrast favouring contrast agent-based imaging over native-contrast diffusion imaging and relaxometry mapping.In this study, the the LCX was occluded leading to an infarction area within the lateral wall of the LV. The septum was consequently chosen as remote zone.Up to week 5, an increase of LVEF, torsion as well as radial strain was found in the control cohort that may be attributed to animal growth. In the control group, the transmural HA gradient only increased within the first 21 days (baseline to day 6), remained unchanged for the remainder of the experiment. In the MI group, this trend was not seen, as LVEF decreased immediately after induction of MI reflecting acute loss of function. The acute changes in function were followed by structural remodelling in the remote zone during chronic follow-up up to week 5. With structural remodelling, torsion, radial as well as longitudinal strain reduced in magnitude. The correlation analysis suggests a link between the structural changes in the remote zone and the loss of longitudinal strain. A reduction in LGS has been shown to correlate with poor outcome , 47 and Biomechanical modelling that was performed as part of a study on patients suffering from dilated cardiomyopathy revealed an increase in GLS associated with a steeper HA . To thisIn a previous study on the comparison of LAD and LCX occlusion in swine with 1 and 3 months follow-up, a reduction in LVEF, GRS, GCS, GLS as well as torsion has been reported, when compared to a control group . In lineWhile trends in changes of functional as well as structural parameters have been found, the study cohort is too small to conclude on statistical significance on some of the trends.Control animals did not undergo a sham procedure.Occlusion of the LCX was chosen as it was deemed to be tolerated better by the animals and lead to fewer dropouts. However, the affected area was located in the lateral wall between the papillary muscles. Both papillary muscles tend to stabilize the wall during contraction, potentially reducing the overall burden to the heart, when compared to large anterior wall infarctions. This may also be a reason why no significant changes in LV shape were observed.A dependency of LV rotation , ventricWhile histology has been the standard method for validation of cDTI, more recently high resolution synchrotron imaging of entire rat hearts has been used to confirm the microstructural findings . NeitherFurthermore, CMR imaging had to be performed in different heart phases due to sequence requirements (e.g. DTI in systole and T2 mapping in diastole). The use of different imaging readouts (e.g. single shot EPI vs. multi shot gradient/spin echo) resulted in different off-resonance related image artefacts, causing geometrical and intensity distortions predominantly in the vicinity of the posterior vein . This reWe longitudinally assessed the dynamics of MI from the acute to the chronic stage by functional and microstructural CMR imaging. Considering non-contrast enhanced methods, differentiation of infarcted and remote tissue based on diffusion parameters was superior when compared to native T1 and T2 mapping in the chronic stage, indicating a higher sensitivity of cDTI compared to relaxometry in response to microstructural alterations. Moreover, the correlation between microstructural changes and reduced global contraction and rotation illustrates the multi-scale response of the heart to myofiber injury and scar formation. Therefore, the combination of functional and microstructural diffusion-based CMR imaging is considered a valuable tool to characterize MI across spatial scales.Additional file 1: Table S1. Native T1, T2, extra cellular volume (ECV), mean diffusivity (MD) and fractional anisotropy (FA) for healthy controls and for the remote as well as infarcted zone of the infarct cohort. The asterisk indicates statistically significant differences between infarcted and remote regions (p < 0.05). Fig. S1. Pearson correlation of all time points and all regions (control/remote/infarction). The asterisk indicates a p-value < 0.001. ECV, extracellular volume fraction; MD, mean diffusivity, FA, fractional anisotropy. Fig. S2. Scatter plots plotting mean diffusivity (MD) against extra cellular volume (ECV), T1 native and T2 for each region (control/remote/infarct) and each time point individually. Fig. S3. Scatter plots of fractional anisotropy (FA) against extra cellular volume (ECV), native T1 and T2 for each region (control/remote/infarct) and for each time point individually.


To assess the value of N-terminal probrain natriuretic peptide (NT-proBNP) in short-term and long-term follow-up after a modified Fontan procedure.  We retrospectively enrolled children who had undergone a modified Fontan procedure in the Heart Center of Guangzhou Women and Children's Medical Center from January 2014 to September 2020 and collected data on NT-proBNP values before bidirectional Glenn procedure, before Fontan procedure, and on 1, 3, 7, 30, 90, and 180 days and 1, 2, 3, 4, 5, and 6 year after Fontan procedure. The relationship between changes in NT-proBNP levels and the outcomes in children was analyzed.  A total of 108 children  were included in the analysis. According to one-way analysis of variance, the left ventricular type and biventricular type of single ventricle physiology showed shorter duration on cardiopulmonary bypass during the operation and lower levels of NT-proBNP after the operation than the right ventricular type and univentricular type physiology.  NT-proBNP is a good indicator for mid and long-term follow-up after a modified Fontan procedure. The left ventricular type and biventricular type of single ventricle physiology show better mid and long-term benefits from the modified Fontan procedure than the right ventricular type and univentricular type physiology. The modified Fontan procedure is a final palliative procedure for treating complex congenital heart diseases such as anatomical or functional single ventricle  that are not suitable for biventricular correction . The FonN-terminal probrain natriuretic peptide (NT-proBNP) is a marker for cardiac volume load. It is synthesized and secreted in the ventricle and released in response to the volume and pressure overload of the heart. NT-proBNP has been demonstrated to be useful in the diagnosis and treatment of heart failure , 3. HoweThis retrospective study was approved by the Ethics Committee of Guangzhou Women and Children's Medical Center. All hospitalized patients who had undergone a modified Fontan procedure (intracardiac or extracardiac conduit) with cardiopulmonary bypass in our hospital from January 2014 to September 2020 were eligible. Patients lost to follow-up were excluded. Patients were included when they had regular clinic and telephone follow-ups and had regular NT-proBNP tests and echocardiographic examinations. NT-proBNP detection principle is the electrochemiluminescence method, and we used the Roche E 601 analyzer to complete the detection. A total of 108 cases were included in the analysis. The collected clinical data included demographic features, staged anatomical features of the major blood vessels of the heart, surgical and cardiopulmonary bypass records, and follow-up data. The detailed patient data are given in All cases were classified into left ventricular type, right ventricular type, biventricular type, and univentricular type according to the functional ventricular morphology of congenital heart anomalies . The claDuring our follow-up, 1 case with right ventricular type developed progressive cardiac failure, 7 cases developed cardiac arrhythmias after surgery, including 4 patients with paroxysmal upper cardiac tachycardia, 1 patient with atrioventricular block requiring pacemaker placement, and 2 patients with ventricular arrhythmias. Significant proteinolytic enteropathy was found in 3 patients, and superior vena cava thrombosis was found in 1 patient. No pulmonary arteriovenous fistula, renal failure, and Fontan postoperative-associated liver disease were found; one patient died shortly after Fontan's operation, and no death or reoperation was found during the follow-up.The hemodynamics after a modified Fontan procedure is considerably different from that of normal biventricular physiology, leading to markedly increased long-term mortality and dysfunction in patients who have undergone Fontan operation. It has been demonstrated that the increased mortality rate after operation is mainly caused by heart failure, arrhythmia, protein-losing enteropathy, pulmonary arteriovenous fistula, thrombosis, renal failure, and Fontan-related nephropathy; thus, many indicators have been suggested to monitor Fontan circulation during follow-up .NT-proBNP, an inactive prohormone of brain natriuretic peptide, is secreted by cardiac muscle tissue in response to abnormal volume load or pressure load of the ventricle wall , 6. BNP A study of 77 cases by Lowenthal et al. reported the normal upper limit values of NT-proBNP in different palliation stages of single ventricle physiology: 300 pg/mL after a Blalock–Taussig shunt or pulmonary banding, 1100 pg/mL after bidirectional Glenn operation, and 1900 pg/mL after Fontan operation. The researchers noted that NT-proBNP is a sensitive and effective tool to evaluate cardiac function changes after Fontan operation.With a larger number of cases, our study showed a good correlation between NT-proBNP and mid and long-term cardiac functions after a modified Fontan procedure. The changes in NT-proBNP levels showed high sensitivity in reflecting the changes in cardiac function of children, especially in those with postoperative valve reflux, arrhythmia, and residual pulmonary venous obstruction, whose NT-proBNP levels were significantly increased. Our results were consistent with Chen's findings that severe valve reflux and pulmonary arterial pressure of >15 mmHg are risk factors for heart failure and show poor outcome after a modified Fontan procedure , 11.Comparison of the mid and long-term post-Fontan outcomes between different types of single ventricle physiology in our study showed that cases of left ventricular type had a relatively good long-term prognosis, and surprisingly, cases of biventricular type showed relatively good mid and long-term outcomes after Fontan operation, who would, in theory, be expected to benefit more from biventricular correction. However, prior to our study, there has been little research about the mid and long-term outcomes after modified Fontan operation in complex congenital heart disease such as double outlet right ventricle with noncommitted ventricular septal defect. The significant differences in cardiopulmonary bypass time during operation, blood oxygen saturation after operation, and NT-proBNP levels at 7 days, 30 days, and 180 days after operation indicated that left ventricular type and biventricular type physiology were associated with shorter operation time, more rapid recovery of cardiac function, and more normal blood oxygen saturation after a modified Fontan procedure than univentricular type and right ventricular type physiology. The possible reason for the poor prognosis in the right ventricular group was that the right ventricular structure and tricuspid valve could not tolerate the high afterload of systemic circulation for a long time, leading to the symptoms of gradually worsening heart failure.There were no significant differences between left ventricular type and biventricular type with respect to echocardiographic results and NT-proBNP values after Fontan operation, suggesting no significant difference in mid and long-term outcomes between the two types of single ventricle physiology. The possible reason for the difference of blood flow velocity in upper and lower lumens after modified Fontan is that the abnormal increase of pulmonary circulation resistance causes the obstruction of blood flow in upper and lower lumens, and the decline of ventricular diastolic function and valve regurgitation are the main reasons for the increase of pulmonary circulation resistance. However, this finding is limited by the small number of patients in this study, and hence, more cases should be enrolled and analyzed in future studies to validate and improve this research.This mid and long-term follow-up study found that NT-proBNP is a sensitive and reliable indicator to evaluate cardiac function after a modified Fontan procedure. The left ventricular type and biventricular type of single ventricle physiology show better outcomes after operation in terms of valve reflux, blood oxygen saturation, and blood flow velocity of the superior and inferior vena cava than the right ventricular type and univentricular type.


The evolution of cancer therapies has led to marked improvement in survival of those affected by childhood malignancies, while also increasing the recognition of early and late toxicities associated with cancer therapies. Cardiotoxicity can include cardiomyopathy/heart failure, coronary artery disease, stroke, pericardial disease, arrhythmias, and valvular and vascular dysfunction as a result of exposure to chemotherapy and/or radiation. Anthracyclines remain the most common cause of chemotherapy-induced cardiomyopathy (CCM) with varying clinical presentations including: acute, early onset, and late-onset. Many individuals develop cardiac dysfunction over the long-term, ranging from subclinical cardiac dysfunction to end-stage symptomatic heart failure. The focus of this review is on characterization of symptomatic heart failure in children with cancer therapy-related cardiac dysfunction (CTRCD) primarily due to CCM and utilization of advanced heart failure therapies, including ventricular assist device (VAD) support and heart transplantation, with consideration of unique patient-related factors. The evolution of cancer therapies has led to marked improvement in survival of those affected by childhood malignancies. The five-year survival in children and adolescents with cancer ranged from 58–68% in the 1970s to 84–85% during the 2010–2016 time frame ,4,5. TheAn understanding of risk factors for development of CTRCD is important in identifying individuals who are at increased risk for development of heart failure. Chemotherapeutic agents including anthracyclines, tyrosine kinase inhibitors, monoclonal antibodies, and immune checkpoint inhibitors can all have variable cardiotoxic side effects. Radiation therapy can also result in cardiotoxicity including pericarditis, cardiomyopathy (more commonly with a restrictive phenotype than dilated), coronary artery disease , valvular disease, and conduction system abnormalities ,5,8.Among chemotherapeutic agents, anthracyclines are commonly utilized in the treatment of hematological and solid tumors in children and adults and are most frequently linked to cardiac dysfunction ,9. The fThere are two major classifications of cardiotoxicity, which can elucidate whether there may be potential for reversible cardiac changes ,19. AnthThe onset of cardiotoxicity related to anthracyclines can be acute, defined as within a week of anthracycline therapy; subacute, occurring within a year of anthracycline therapy; or late, defined as >one year after anthracycline therapy. Acute cardiotoxicity may present as arrhythmias or ECG abnormalities, transient depression in myocardial contractility, or can mimic heart failure related to myocarditis or pericarditis in the setting of high doses. It generally resolves after removal of the offending agent. However, subacute (>one week and <one year from exposure) and late onset (>one year from exposure) cardiotoxicity are more common clinical presentations. These types of cardiotoxicities are progressive in nature and can be associated with echocardiogram features of dilated or restrictive cardiomyopathy as well as arrhythmias ,16,17,18Early detection and treatment of subclinical cardiac dysfunction is essential to prevent or delay irreversible cardiac injury and advanced heart failure. The American Heart Association and American College of Cardiology provide a framework for characterizing the spectrum of heart failure which can further guide management. This includes four stages of heart failure: Stage A—patients at risk for cardiac dysfunction; Stage B—patients with cardiac dysfunction without symptoms; Stage C—patients with cardiac dysfunction with past or current symptoms; Stage D—patients with heart failure symptoms refractory to medical therapy . This frPreventative strategies to mitigate cardiotoxicity can be employed, in some circumstances, even prior to the development of cardiac dysfunction. When using anthracyclines, this may include dose adjustment, modifying administration as a continuous infusion to avoid high serum concentrations, utilizing anthracycline analogues, and use of an iron-chelating agent such as dexrazoxane to prevent reactive oxygen species related cardiotoxicity caused by anthracyclines ,21,22.Guideline-directed medical therapies for heart failure with reduced ejection fraction are commonly utilized for patients with Stage B or Stage C heart failure. The rationale for use of standard heart failure medications such as angiotensin-converting enzyme (ACE) inhibitors and beta-blockers is largely extrapolated from the adult experience with limited pediatric data, especially specific to pediatric patients with CCM. ACE inhibitors have been shown to reduce LV wall thickness and LV afterload while improving cardiac function in many cardiac pathologies including CCM ,24,25. BAdditional studies have demonstrated that there is limited efficacy of ACE inhibitors in limiting the progression of ventricular dysfunction in childhood cancer survivors ,28. LipsThe number of patients with advanced heart failure among cancer survivors is not clearly established in the adult or pediatric population. In a review of two adult registries including United Network of Organ Sharing (UNOS) and Interagency Registry for Mechanically-Assisted Circulatory Support (INTERMACS), it was estimated that CCM was the attributable cause for advanced heart failure in 0.5–2.5% of patients ,34,35. WThe complexity of cancer therapies, comorbid conditions of patients with CTRCD, as well as the potential for relapse, require special consideration when considering timing and implementation of more advanced heart failure therapies such as VAD and cardiac transplant. Usually, VAD and transplant are reserved for those who are in complete remission and considered to be at low risk for recurrence, typically three to five years after the end of cancer therapies depending on the cancer. Ventricular assist device therapy may also need to be considered in the setting of ongoing chemotherapy as a bridge to recovery of function or as a bridge to eventual cardiac transplant when deemed cancer free for a sufficient period of time. This requires a very complex multi-team approach when considering the potential side effects of chemotherapy in regards to the possible development of pancytopenias which complicate infection issues and bleeding and clotting risks in a patient on an LVAD. Families also have to be aware that, when facing end of life issues in these complex patients, the LVAD may have to be turned off to allow the patient to die. Therefore, it is extremely important for the heart failure/transplant team to partner with the patient’s oncologist when considering these advanced therapies ,37. We will review the current literature evaluating epidemiology and outcomes of CRT, VAD and transplant therapy in treatment of advanced heart failure due to CCM and two previously reported cases from our center in children with advanced heart failure due to cancer therapies highlighting the application of VAD support and heart transplant.According to the European Society of Cardiology as well as American College of Cardiology/American Heart Association Guidelines, an implantable cardioverter-defibrillator (ICD) can prevent mortality due to sudden arrhythmic death and is recommended for individuals with symptomatic HF and left ventricular ejection fraction (LVEF) < 35% despite >three months of treatment with optimal pharmacological therapy. Cardiac resynchronization therapy (CRT) can reduce mortality while also improving cardiac function and symptoms in select adult patients with symptomatic heart failure. CRT is recommended for adult patients with symptomatic heart failure despite medical therapy in sinus rhythm with LVEF < 35%, QRS duration >150 msec, and left bundle branch block (LBBB) QRS morphology. CRT can also be considered for symptomatic patients with LVEF < 35% with intermediate QRS duration and/or non-LBBB QRS morphology ,39,40,41The application and outcome of these therapies in the pediatric population has been variable, likely due in part to the heterogeneity of causes of pediatric heart failure . Accordip = 0.03 vs. ischemic cardiomyopathy 77%; p = 0.03). It is postulated that this could be in part related to the acuity of heart failure and comorbidities at the time of clinical presentation ) [An analysis of the Pediatric Heart Transplant Society (PHTS) database from 1993–2014 compared patients with chemotherapy-induced cardiomyopathy with a propensity matched DCM cohort. Eighty children with CCM were listed for heart transplant and 78% (lignancy . Multiva< 0.01]) . Other s< 0.01]) ,62. Overall, patients with CCM can have similar heart transplant graft survival to other cohorts. A comprehensive evaluation of all factors that can impact the immune system including oncologic diagnosis, timing and intensity of previous chemotherapy exposure, radiation exposure, and infection history may be particularly helpful in post-transplant management to minimize risk of infection and malignancy .Case 1:2 of daunorubicin . She developed heart failure around the third month of cancer treatment and therapy with oral reverse remodeling agents was initiated. Three months after completion of chemotherapy, she was admitted to the hospital with decompensated heart failure. Her LV ejection fraction (EF) was 10%, her right ventricular systolic function was moderately depressed, and her brain natriuretic peptide level was 1900 pg/mL. She could not be weaned from inotropic agents. She underwent LVAD placement with a HeartWare® as a bridge to decision, as she had been in remission for only 3 months. She was followed as an outpatient on VAD support while also monitoring for cancer recurrence. She was noted to have early evidence of recovery of LV systolic function on echocardiogram three months after VAD support. Echocardiograms continued to show favorable signs of recovery with normalization of LV function and LV dimensions. She was continued on reverse remodeling agents and tolerated two pump-weaning tests well. She underwent LVAD explant 12 months after implantation (18 months after AML diagnosis). She is alive and doing well six years after completion of cancer treatment. She continues on treatment with oral reverse remodeling agents. Her echocardiograms have persistently shown mildly reduced left ventricular global longitudinal strain and normal ejection fraction [A 14-year old female was diagnosed with AML. She received chemotherapy for approximately five months, including a total cumulative dose of 300 mg/mfraction .Case 2:2 of daunorubicin  and 48 mg/m2 of mitoxantrone . The total cumulative equivalent dose of doxorubicin was 630 mg/m2. She developed worsening cardiac function 12 months after completion of chemotherapy. She was started on oral reverse remodeling agents and remained in cancer remission for 36 months. She developed symptomatic heart failure due to a mixed phenotype cardiomyopathy, with dilated and restrictive features and progressive pulmonary hypertension (PH) due to pre and post-capillary disease, indexed pulmonary vascular resistance (PVRi) 6.3 WUm2 reactive to 3.9 WUm2. She was evaluated and listed for heart transplant. She was subsequently admitted to the hospital for optimization of heart failure and pulmonary hypertension therapies. She was started on milrinone, but developed worsening heart failure and underwent HeartWare® LVAD implantation  in an effort to decompress the LV, improve pulmonary vascular resistance and allow escalation of PH therapies to improve her transplant candidacy. Her VAD course was complicated by two thromboembolic strokes requiring mechanical thrombectomy, which were likely multi-factorial in etiology, including a small LV cavity size and sinus node dysfunction/bradycardia secondary to right heart failure leading to lower VAD flows. However, she recovered well from the strokes without residual deficits and underwent heart transplantation six months after VAD implantation (~60 months after cancer diagnosis). She is alive one-year post heart transplant without evidence of rejection or malignancy recurrence [A newborn female was diagnosed with congenital AML. She received multi-drug chemotherapy with a total cumulative dose of 300 mg/mcurrence .There is an increasing awareness and understanding of the short- and long-term impacts of cancer therapies on the cardiovascular system. Advanced heart failure therapies including MCS and cardiac transplant can be successfully implemented in individuals with CTRCD. Patients with CCM undergoing MCS have similar survival to other groups but have increased risk of needing RVAD and bleeding in adult studies. Heart transplant survival is similar in patients with CCM compared to other forms of cardiomyopathy but there may be an increased risk of post-transplant infectious complications. Patient selection, optimal timing, and anticipation of the unique challenges that these patients pose are key elements to success with these interventions. Further multi-center studies are needed to better characterize the breadth of this population and their outcomes to increase timely utilization of advanced heart failure treatments, but more importantly to evaluate strategies that may mitigate the need for advanced heart failure therapies.


Disturbed autonomic function is implicated in high mortality rates in heart failure patients. High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown.n = 21) enrolled in the ANTHEM-HF clinical trial  with 24 h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on ~ 2000 spontaneous daily activity-induced heart rate acceleration/deceleration events per patient, was analyzed at screening and after 12, 24, and 36 months of chronic vagus nerve stimulation therapy .All patients (p < 0.0001), heart rate turbulence slope, an indicator of baroreceptor reflex gain , and left ventricular ejection fraction  were improved over screening at 12, 24, and 36 months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening  and 36 months .In response to chronic high-intensity vagus nerve stimulation (≥ 2.0 mA), intrinsic heart rate recovery (all time points, This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of ≥ 3 years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism. Heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) constitutes a chronically deteriorating condition resulting in increased morbidity and mortality. HFrEF is responsible for an estimated 352,000 deaths annually in the United States alone . AlthougIn their pioneering work, Schwartz, De Ferrari, and their coworkers  reportedRecently, using a novel approach, Carlson et al.  found inThe putative mechanistic basis for the capacity of intrinsic HRR to predict cardiac events is that this parameter reflects the gain of the baroreceptor reflex , 16. BarThe main goal of the present study was to determine whether VNS therapy is associated with improvements in intrinsic HRR and LVEF at 24 and 36 months. The secondary aim was to determine whether the enhancement in intrinsic HRR is linked to baroreceptor sensitivity. To evaluate this hypothesis, we examined the correlation between intrinsic HRR and HRT slope at screening and after 36 months of chronic VNS.The study design and patient selection criteria of the ANTHEM-HF interventional clinical trial  were previously described . The invBriefly, 60 patients with NYHA class II/III heart failure and age ≥ 18 years were enrolled at 10 sites. Inclusion criteria were LVEF ≤ 40%, left ventricular end-diastolic dimension ≥ 50 and < 80 mm, QRS complex width ≤ 150 ms, and receiving optimal medical management. Specifically, this included stable beta-blocker therapy for heart failure as indicated for at least 3 months and all other oral pharmacologic therapy for heart failure, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, loop diuretics, and spironolactone, for at least 1 month. No changes in heart failure medications were made during the study. Patients needed to be able and willing to perform a 6-minute walk test with a distance of 150–425 meters at screening, limited by heart failure symptoms.All ANTHEM-HF patients received a VNS system  on either the left or the right cervical vagus nerve. VNS was titrated to the maximum tolerable intensity over the course of 10–12 weeks. Chronic cyclic stimulation was delivered at a frequency of 10 Hz for 12 months and at a frequency of 5 Hz after 24 months, a pulse width of 250 μs, and a duty cycle of 14 s on/66 s off. Continuous cyclic stimulation was sustained as tolerated for the entire titration period and the 36-month follow-up period; for 8 patients, the maximum tolerable stimulation current amplitude was < 2 mA (low-intensity), and for 13 patients, amplitude was ≥ 2 mA (high-intensity).In 25 ANTHEM-HF patients, AECGs  were recorded at screening and after 12, 24, and 36 months of chronic therapy. Four patients had excess premature ventricular beats that precluded intrinsic HRR analysis; the remaining 21 patients provided the data set for the present analysis during the 3-year follow-up.De-identified 24 h AECG recordings from 54 normal subjects during normal daily activities  were acquired from the publicly available PhysioNet Normal Sinus Rhythm database . These sAs previously described , intrinsThe exponential time constant (tau) for each exponential fit was put into separate bins according to the magnitude of the heart rate surge within a window of ±8 beats. The tau values for each bin were averaged and combined into a mean banded relaxation parameter. A lower mean banded relaxation parameter indicates a steeper recovery, and a shorter time constant of recovery indicates a more rapid intrinsic HRR.Specifically, for quantification of intrinsic HRR, heart rate deceleration was modeled as a mono-exponential decay at multiple time points, where the time constant (tau) indicates heart rate decay. The equation of the trend line for this decay is:a0 is the asymptotic value of the heart rate, b is the decremented value from the peak heart rate, and tau is the time constant, which reflects intrinsic HRR such that a lower value of the time constant reflects a more rapid intrinsic HRR response.In this equation, HRT was evaluated according to the method developed and standardized by Schmidt, Bauer, and coworkers, who reviewed supporting literature in a consensus report . HRT onsEchocardiograms were recorded with standard transthoracic echocardiographic equipment and LVEF was calculated using the biplane method. The recordings were coded and de-identified of patient and sample information and sent to designated core laboratory facilities for analysis. LVEF ≤ 35% is considered indicative of stable chronic heart failure .t tests for continuous variables and with Fisher exact test for discrete variables. Effects of VNS on intrinsic HRR and other parameters presented in Table t tests with Bonferroni correction for multiple comparisons. The SAS mixed linear model was used to evaluate the covariance of LVEF, HRT slope, heart rate, and the mean banded relaxation parameter. Data are reported as means ± SEM. p < 0.05 was considered statistically significant.Results were analyzed using SAS 9.4 , which allowed verification of the normality of the data. Analyses of patient parameters in Table The characteristics at screening of the ANTHEM-HF patients whose data were included in the analyses are summarized in Table p = 0.66) . In patients with high-intensity VNS (≥ 2 mA), intrinsic HRR was improved at the 12-, 24-, and 36-month determinations by 8.9%, 11.4%, and 16.3%, respectively  (Table p = 0.63), but the intrinsic HRR response at 24 months was increased by 4.6% and at 36 months by 6.9% (both p < 0.05) compared to screening. This effect was one half of that observed in patients with high-intensity VNS (Table Intrinsic HRR increased consistently as the VNS therapy progressed across the 3-year period studied. The effect was stronger in heart failure patients with high-intensity stimulation ≥ 2 mA) but also occurred in patients with low-intensity stimulation. This effect was reflected as a decrease in the mean banded relaxation parameters for different levels of heart rate change. Mixed-model analysis showed that this effect was independent of the reduction in average heart rate observed in these patients (Table  mA but ap = 0.70)  Fig. .Fig. 3Bop < 0.02) in patients with high-intensity VNS therapy .Importantly, there was a statistically significant inverse correlation between HRT slope and mean banded relaxation parameter, a measure of intrinsic HRR, at both screening and 36 months following high-intensity VNS Fig. . Thus, tLVEF was improved by high-intensity VNS by 18.7%, 19.3%, and 34.4% at 12, 24, and 36 months, respectively, consistent with a salutary effect on parasympathetic nerve activity . Patients enrolled in ANTHEM-HF also experienced improvements in 6-minute walk test and New York Heart Association class at 6, 12, 24, and 36 months [The main finding of this study is that high-intensity chronic VNS was associated with a persistent improvement in intrinsic HRR. A sizable body of evidence indicates that an increase in HRR is associated with favorable cardiovascular outcomes , 36–38. 6 months . Left ve6 months .VNS was associated with a sustained, robust improvement in LVEF across 3 years. Notably, the increase in LVEF exceeded the ≥ 5% level regarded as a criterion for response status to CRT . The potA limited number of paired AECG recordings from the ANTHEM-HF cohort were available for analysis. However, the present study is strengthened by the inclusion of ~ 2000 heart rate acceleration/deceleration events per 24 h AECG recording for analysis, for a total of ~ 144,000 determinations in the subjects studied across the 3-year period of study. Also, exclusion of patients due to excess ventricular premature beats that precluded analysis of intrinsic HRR or unwillingness to consent to follow-up may have introduced an element of bias in the current results. Thus, there is a need to examine the utility of intrinsic HRR in larger populations of patients in a multinational, randomized, controlled clinical setting to clarify more precisely the role of this parameter in the evaluation and management of HFrEF. In future studies, it may be necessary to modify the intrinsic HRR thresholds somewhat to optimize outcomes. The ANTHEM-HF pilot study was not powered to evaluate the effects of VNS therapy on rehospitalization. The large ANTHEM-HFrEF pivotal study (NCT03425422) will address this question.This non-randomized study provides evidence that high-intensity VNS, and to a lesser extent low-intensity VNS,  are associated with a persistent improvement in intrinsic HRR and LVEF that lasts for at least 3 years. Based on the finding that there were corresponding favorable effects on HRT slope, enhanced baroreceptor function in response to VNS may be an underlying physiologic mechanism. These observations carry important scientific and practical clinical implications. Our study emphasizes the need for appropriate VNS parameters and suggests a noninvasive approach for tracking autonomic engagement, which can be evaluated using standard AECG recordings.