A doença de Chagas (DC) constitui uma causa potencial negligenciada de doença microvascular coronariana (DMC). Comparar pacientes com DMC relacionada à DC (DMC-DC) com pacientes com DMC ligada a outras etiologias (DMC-OE). De 1292 pacientes estáveis, encaminhados para angiografia coronária invasiva para elucidar o padrão hemodinâmico e a causa de angina, 247 apresentaram coronárias subepicárdicas normais, e 101 foram incluídos após aplicação dos critérios de exclusão. Desses, 15 compuseram o grupo de DMC-DC e suas características clínicas, hemodinâmicas, angiográficas, e cintilográficas foram comparadas às do grupo de 86 pacientes com DMC-OE. O nível de significância estatística para todas as comparações adotado foi de 0,05. Pacientes com suspeita de DMC-DC apresentaram características antropométricas, clínicas e angiográficas, além de alterações hemodinâmicas e de perfusão miocárdica estatisticamente comparáveis às detectadas nos 86 pacientes com DMC-OE. Disfunção ventricular diastólica, expressa por elevada pressão telediastólica do ventrículo esquerdo, foi igualmente encontrada nos dois grupos. Entretanto, em comparação a esse grupo com DMC-OE, o grupo com DMC-DC exibiu fração de ejeção ventricular esquerda mais baixa  e mais elevado escore de mobilidade da parede ventricular . A cardiomiopatia crônica da doença de Chagas esteve associada à etiologia de possível doença microvascular coronariana em 15% de amostra de 101 pacientes estáveis, cujo sintoma principal era angina requerendo elucidação por angiografia invasiva. Embora os grupos DMC-DC e DMC-OE apresentassem características clínicas, hemodinâmicas, e de perfusão miocárdica em comum, a disfunção global e segmentar do ventrículo esquerdo foi mais grave nos pacientes com DMC associada à DC em comparação à DMC por outras etiologias. :1094-1101) Por isso, tem sido interpretada como uma consequência de distúrbios isquêmicos microvasculares, constituindo um dos quatro mecanismos patogenéticos fundamentais da CCDC.6Mais de um século após sua descoberta em 1909, a doença de Chagas (DC) ainda é sério problema de saúde pública na América Latina e, devido a intensos movimentos migratórios nas últimas décadas, também em áreas não endêmicas, como nos Estados Unidos e em alguns países europeus.T. cruzifoi demonstrada por várias evidências patológicas, clínicas e experimentais.9 Estima-se que 20-40% dos pacientes com CCC queixem-se de angina, geralmente de caráter atípico, uma vez que o sintoma não tem relação direta com esforço físico ou estímulo emocional, além de duração e resposta a nitratos variáveis.10 Além disso, vários pesquisadores evidenciaram que esses pacientes apresentam anormalidades marcantes na perfusão miocárdica provocadas pelo exercício e reversíveis com o repouso, em presença de artérias coronárias sem lesões epicárdicas obstrutivas na angiografia invasiva.13 Essas anormalidades na perfusão são, portanto, atribuíveis à isquemia microvascular, e são corroboradas por estudos em modelos experimentais de infecção peloT. cruzi.15A ocorrência de isquemia microvascular em pacientes com infecção crônica pelo18Com base nessas evidências, muitos pacientes com CCC poderiam ser classificados como portadores de uma classe secundária de doença microvascular coronariana (DMC), relacionada a uma cardiomiopatia causada por doença infecciosa inflamatória crônica.Não há estudos com foco na comparação de pacientes com DMC relacionada à DC com pacientes com DMC atribuída a outras etiologias. Dessa forma, esse foi o objetivo da presente investigação.angina pectoris, referida como principal sintoma na história clínica. De total de 1292 pacientes, 601 foram excluídos devido a: tratamento prévio com angioplastia coronariana (n = 200); síndrome coronariana aguda confirmada prévia (n = 137); cardiopatia valvar (n = 113); cardiomiopatia dilatada hipertrófica ou idiopática (n = 99); cirurgia prévia de revascularização do miocárdio (n = 49) e transplante cardíaco (n = 3).Esta foi uma investigação transversal, observacional e unicêntrica, com inclusão prospectiva de pacientes estáveis, que foram encaminhados a nosso hospital universitário terciário entre 01 de janeiro e 31 de dezembro de 2018, para realização de angiografia coronariana invasiva, para elucidar o padrão hemodinâmico e a causa deNos 691 pacientes restantes, a angiografia coronariana  revelou: lesões epicárdicas obstrutivas significativas  (n = 367); artérias coronárias angiograficamente normais (n = 247); doença arterial coronariana epicárdica não significativa - estenoses <40%: (n = 77); anomalias das artérias coronárias - anomalias congênitas, ponte miocárdica, tortuosidade excessiva ou ectasia, fístula coronário-cavitária, fluxo lento (n = 81).Dos 247 pacientes clinicamente estáveis, sem doença cardíaca estrutural e cujo sintoma principal era angina (grave o suficiente para justificar a indicação de angiografia coronariana invasiva), sem anormalidades à angiografia, 101 concordaram em participar do estudo e assinaram o termo de consentimento. O protocolo de pesquisa foi aprovado pelo Comitê de Ética do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP - Processo: 8430/2011 e CAEE 07494618.3.0000.5440 Doc 3.252.539.T. cruzi.Os 101 pacientes incluídos no estudo passaram por avaliação clínica e hemodinâmica, além de angiografia coronariana invasiva no mesmo dia, para caracterização da angina, avaliação de sintomas associados tais como dispneia, fadiga, edema, palpitação, síncope, disfagia, constipação intestinal, e indícios epidemiológicos de exposição aoT. cruzi.Além disso, uma amostra de sangue periférico foi coletada de todos os pacientes para determinação dos níveis séricos de creatinina, e exclusão de danos renais e hepáticos, bem como de anemia e diabetes mellitus.Também foi aplicado um questionário sobre fatores de risco para doença arterial coronariana, tais como: hipertensão arterial sistêmica, diabetes mellitus, dislipidemia, tabagismo atual e história familiar de doença coronariana precoce. Todos os pacientes realizaram um eletrocardiograma (ECG) de 12 derivações e um subgrupo de 33 (nove e 24 pacientes em cada grupo) realizou ecocardiograma transtorácico de repouso. Todos os 101 pacientes realizaram exame sorológico para detecção de anticorpos contra o19 A pressão telediastólica do ventrículo esquerdo (PTDVE) foi registrada em repouso, seguida de duas injeções automáticas de 20-30 ml de contraste a 8-10 ml/s e gravação a 15 quadros/s, nas projeções oblíquas direita e esquerda. A ventriculografia de contraste foi então analisada de acordo com um modelo de 9 segmentos, utilizando um escore de quantificação que atribuiu 1 à mobilidade normal da parede, 2 à hipocinesia, 3 à acinesia e 4 à discinesia.20 Um escore médio de movimentação segmentar da parede ventricular foi obtido pela soma das pontuações de cada segmento, dividida pelo número de segmentos analisados21 conforme publicação recente de nossa instituição. O ventriculograma de contraste radiológico também permitiu a avaliação qualitativa de hipertrofia e dilatação do ventrículo esquerdo.Os procedimentos de cateterismo cardíaco, avaliação hemodinâmica e angiografia coronariana foram realizados sob anestesia local, preferencialmente por abordagem radial, com fios-guia e cateteres convencionais. Injeções manuais de 3-7 mL de contraste radiológico foram feitas seletivamente em cada óstio coronário, com gravação de 15 a 30 quadros/s, em várias projeções.22Um subgrupo de 19 pacientes foi submetido à cintilografia miocárdica de perfusão por tomografia computadorizada por emissão de fóton único, em repouso e durante estresse físico ou farmacológico. As imagens foram obtidas por câmera  de detector duplo, com o paciente na posição supina. A aquisição ocorreu em órbita semicircular , em 32 projeções sincronizadas com o eletrocardiograma, 8 quadros por ciclo cardíaco em 60 segundos por projeção com 50% de janela de aceitação em torno do RR médio. As imagens foram adquiridas com detectores equipados com colimadores de orifícios paralelos de baixa energia e alta resolução, utilizando uma matriz de aquisição de 64 x 64 pixels.99m foi utilizado como radiotraçador para avaliar a perfusão miocárdica regional, na dose de 12 a 15 mCi em repouso e 25 a 30 mCi em estresse. As imagens foram obtidas 1 hora após cada injeção intravenosa do radiotraçador.O exercício físico foi utilizado preferencialmente como o teste de estresse. Betabloqueadores, bloqueadores de canais de cálcio e outros medicamentos anti-isquêmicos foram interrompidos 48 horas antes dos testes nucleares. O sestamibi-TcSummed Stress Score) e repouso (SRS -Summed Rest Score) foram quantificadas para diferenciar os defeitos reversíveis – quando oSummed Difference Score(SDS) foi ≥ 1, de defeitos perfusionais irreversíveis.23Mapas polares, usando o modelo de 17 segmentos, foram gerados para avaliar a anormalidade da perfusão de acordo com uma pontuação para cada segmento definida como 0 = normal, 1 = redução leve da captação, 2 = redução moderada da captação, 3 = redução acentuada da captação, e 4 = ausência de captação. As anormalidades de perfusão no estresse  - dois testes sorológicos positivos com métodos diferentes.24 Os outros 86 pacientes, com testes sorológicos negativos, compuseram o grupo de pacientes com provável DMC por outras etiologias (DMC-OE). Os testes de Shapiro-Wilk foram utilizados para verificar se as variáveis tiveram uma distribuição normal; as variáveis não pareadas foram comparadas com teste t deStudentou o teste de Mann-Whitney não pareado. As variáveis contínuas com distribuição normal foram descritas como média ± desvio-padrão (DP), enquanto as variáveis com distribuição não normal foram descritas como mediana e intervalo interquartil (IQ). As variáveis categóricas foram descritas como valores absolutos ou relativos (percentuais ou proporções). As proporções dentro de cada grupo foram comparadas usando teste exato de Fisher. Todos os testes foram bicaudais, com p < 0,05 considerado como significante. Todas as análises foram feitas utilizando o programa Stata .Com base nos testes sorológicos específicos para detecção de anticorpos contra oT. cruzie compuseram o grupo DMC-DC . Os outros 86  compuseram o grupo DMC-OE .Dos 247 pacientes estáveis que preencheram os critérios de inclusão e eram considerados elegíveis, 101  foram recrutados. Desses, apenas 15  apresentaram dois testes sorológicos positivos com anticorpos contraNa data de início do estudo, a angina atípica foi referida por 9 (60%) pacientes do grupo DMC-DC versus 57 (66%) pacientes do grupo DMC-OE, enquanto os demais pacientes de ambos os grupos referiram presença de angina típica. No grupo DMC-DC, dispneia e palpitação também foram frequentes, com 8 (53%) e 7 (47%) pacientes, respectivamente, versus 55 (64%) com dispneia e apenas 30 (35%) com palpitações no grupo DMC-OE.diabetes mellituscom 40,0% vs 33,7%, dislipidemia com 33,3 vs 41,8% e tabagismo ativo em 13,3 vs 24,4%, respectivamente nos grupos DMC-DC e DMC-OE. Ambos os grupos estavam usando proporções estatisticamente semelhantes de medicamentos para hipertensão, diabetes mellitus, e agentes usados no tratamento de isquemia miocárdica, como estatinas, antiagregantes plaquetários e antagonistas dos canais de cálcio . Enquanto o bloqueio de ramo direito , o hemibloqueio anterior esquerdo  e a sobrecarga do VE  foram as anormalidades mais frequentes no grupo DMC-DC, a sobrecarga do VE (20%) e o bloqueio de ramo esquerdo completo  foram anormalidades predominantes no grupo DMC-OE. Ambos os grupos tiveram uma prevalência semelhante de fibrilação atrial . Nenhuma dessas diferenças entre os grupos foi estatisticamente significante.A disfunção diastólica, sugerida pelo aumento da PTDVE > 12 mmHg em repouso, foi diagnosticada em 13  e em 64  dos pacientes, nos grupos DMC-DC e DMC-OE, respectivamente; p=0,511. Os valores médios de PTDVE foram similares em ambos os grupos. Além disso, 9 (60%) e 45  pacientes apresentaram PTDVE > 20 mmHg nos grupos DCM-DC e DCM-OE, respectivamente.A ventriculografia revelou características morfológicas do VE sugestivas de hipertrofia em três pacientes (20%) do grupo DMC-DC versus 26 pacientes  do grupo DMC-OE . Em contraste, dilatação ventricular foi observada em proporção significativamente maior de pacientes do grupo DMC-DC  em comparação ao grupo DMC-OE  .vs. DMC-OE , p = 0,049 . Observou-se diferença marginalmente significativa entre os valores médios de FEVE do grupo DCM-DC = 0,049 . Adicio= 0,049 . FinalmAvaliação da Isquemia Miocárdica por Cintilografia de Perfusão MiocárdicaApós a obtenção dos resultados da avaliação hemodinâmica, 11 pacientes do grupo DCM-DC e oito pacientes do grupo DCM-OE foram submetidos à avaliação funcional com cintilografia de perfusão miocárdica SPECT .As proporções de pacientes exibindo anormalidades isquêmicas reversíveis na perfusão nos grupos DCM-DC e DCM-OE foram 45,5% e 62,3%, respectivamente . O SDS também não foi diferente entre os grupos DCM-DC  e DCM-OE  .T. cruzie compôs o grupo com provável doença microvascular coronariana causada por CCDC (DMC-DC), enquanto os outros 86 pacientes compuseram o grupo com provável doença microvascular coronariana cuja causa foi atribuída a outras etiologias (DCM-OE). Este é o primeiro relato sobre a prevalência relativa de CCDC como etiologia de disfunção microvascular entre pacientes que geralmente são considerados como portadores de uma forma primária de doença microvascular coronariana. É provável que esse número de aproximadamente 15% corresponda à estimativa real dessa etiologia, considerando que nossa instituição ainda recebe muitos pacientes de regiões endêmicas da DC. Além disso, nossa amostra de 247 pacientes com artérias coronárias angiograficamente normais foi selecionada entre 691 pacientes consecutivos, nos quais outras anormalidades foram excluídas, e corresponde a quase 36% dos indivíduos encaminhados para angiografia coronariana eletiva no período. Esse resultado é inferior aos 45% relatado recentemente por outro hospital brasileiro,25 mas é muito semelhante aos 39% de pacientes com estenoses coronárias < 20% submetidos à angiografia coronária eletiva entre os anos de 2004 e 2008, segundo o registro nacional doAmerican College of Cardiology.26Durante o ano de 2018, após aplicar os critérios de inclusão e exclusão a uma série de 247 pacientes consecutivos clinicamente estáveis, que não apresentavam doença cardíaca estrutural e queixaram-se de sintomas anginosos graves o suficiente para justificar o encaminhamento ao nosso centro terciário de coronariografia invasiva (que evidenciou artérias coronárias epicárdicas normais), uma amostra considerável de 101 pacientes  concordou em participar deste estudo prospectivo. Dos 101, cerca de um sexto (15 pacientes) apresentou resultado positivo para infecção crônica pelodiabetes mellitus,tabagismo, dislipidemia - também estavam presentes em proporções comparativamente altas de pacientes em ambos os grupos.Com exceção da média de idade discretamente mais elevada no grupo DMC-OE, vale ressaltar que os dois grupos em nosso estudo apresentavam características antropométricas e clínicas essencialmente similares, incluindo uma maior prevalência do gênero feminino, pacientes ligeiramente obesos que, além da angina atípica, também se queixaram de dispneia e palpitações. Os fatores de risco tradicionais para doença arterial coronariana - hipertensão,Outro resultado importante do nosso estudo é que, usando a ventriculografia por contraste radiológico para avaliação morfológica do ventrículo esquerdo, foram encontrados sinais de hipertrofia em vários pacientes de ambos os grupos. Em concordância com esse resultado, a disfunção diastólica do VE, expressa por conspícua elevação da pressão telediastólica ventricular, ocorreu de forma comparável nos grupos DMC-DC e DMC-OE.27 Embora a disfunção diastólica também tenha ocorrido no grupo com DMC decorrente de outras etiologias, é provável que a fibrose miocárdica, uma característica marcante da CCDC, contribua para a disfunção diastólica aqui detectada em nossos pacientes.6Nossos pacientes com DMC por DC, considerando a fase da doença em que se encontravam quando recrutados para esse estudo, exibem anormalidades que, segundo classificação recente de DMC, manifestam-se principalmente na insuficiência cardíaca com FEVE preservada.Contudo, houve ainda diferenças relevantes entre os dois grupos em relação à função sistólica do VE. A FEVE média foi menor no grupo DMC-DC, condizente com o escore mais elevado de mobilidade segmentar parietal ventricular mais deteriorada e com maior dilatação da câmara, significativamente mais prevalente no grupo DMC-DC comparado ao grupo DMC-OE.28 Embora nessa padronização seja sugerido que um quarto critério possa ser usado quando houver suspeita de angina microvascular, na presente investigação não se aplicou nenhum teste adicional para certificar a ocorrência de comprometimento da função microvascular coronariana, como o cálculo de índices de resistência ou de redução da reserva de fluxo, pois esse aspecto escapava ao contexto da pesquisa.28 No entanto, é provável que alguns de nossos pacientes do grupo DMC-DC exibam tais anormalidades, conforme relatado por outros pesquisadores.29Ambos os grupos exibiram proporções similares de pacientes com defeitos de perfusão e os escores SDS entre cintilografia miocárdica com estresse e em repouso também foram semelhantes. Importante enfatizar que a detecção de anormalidades da perfusão miocárdica, indicativas de isquemia miocárdica induzida pelo estresse, foi o terceiro critério para classificar nossos pacientes como portadores da provável síndrome da doença microvascular coronariana, segundo a mais recente classificação padronizada.T. cruzi, é provável que as peculiaridades inerentes à CCDC tenham sido responsáveis pelas manifestações relativamente mais graves da disfunção sistólica do ventrículo esquerdo, em comparação com as exibidas pelo grupo com DMC por outras etiologias.É razoável supor que os pacientes de ambos os grupos incluídos nesta pesquisa compartilham características fisiopatológicas comuns envolvidas no aparecimento de angina em indivíduos com artérias subepicárdicas angiograficamente normais, implicando a presença de distúrbios no nível microvascular coronariano. Esse conceito é sustentado pela identificação de fatores como hipertensão arterial, hipertrofia ventricular e disfunção diastólica em ambos os grupos. Entretanto, no grupo com DMC associada à infecção crônica porT. cruziem nosso estudo possuía conhecimento prévio sobre o acometimento pela doença de Chagas. Além disso, a amostra de pacientes selecionados para participar do estudo foi composta primariamente por pessoas encaminhadas para angiografia coronária invasiva, sem avaliação prévia de isquemia miocárdica com exames como o teste ergométrico com ECG, ecocardiografia sob estresse, ou cintilografia miocárdica nuclear. Assim, é provável que a maioria desses pacientes possa se beneficiar de medidas terapêuticas direcionadas tanto pelo conhecimento de sua doença de base quanto pelas consequências anatômicas e funcionais dos distúrbios microvasculares.30É importante salientar que nenhum dos pacientes que testou positivo para anticorpos contra oNão foram realizadas investigações específicas para determinar a possível etiologia da DMC nos pacientes sem CCDC, que muito provavelmente viriam a ser classificados como portadores de DMC primária. Além disso, não foram realizados testes invasivos para explorar diretamente os mecanismos responsáveis pelo comprometimento da função microvascular nos pacientes do estudo. Outra limitação reside no fato de que apenas 19 dos 101 pacientes incluídos foram avaliados com cintilografia miocárdica de perfusão SPECT. Dessa forma, embora proporções semelhantes de pacientes com distúrbios de perfusão tenham sido encontradas entre os grupos, o pequeno número de pacientes pode ter dificultado a detecção de diferenças significativas entre eles.T. cruziapresentaram características antropométricas, clínicas e angiográficas, bem como anormalidades hemodinâmicas e de perfusão miocárdica, semelhantes às detectadas nos 86 pacientes com outras etiologias para a provável disfunção microvascular. No entanto, o comprometimento da função sistólica segmentar e global do VE foi significativamente mais grave nos pacientes com sintomas de disfunção microvascular relacionada à CCDC.A CCDC foi etiologicamente associada à DMC em um sexto da amostra de 101 pacientes consecutivos estáveis, cujo sintoma principal era dor anginosa, requerendo elucidação por angiografia coronária invasiva. Esses pacientes infectados cronicamente com 2Chronic Chagas cardiomyopathy (CCC) is the most prevalent and more ominous of the clinical manifestations of CD, being essentially due to a low-grade but virtually incessant form of infectious myocarditis that is characteristically diffuse but with focal myocitolytic necrosis and intense reparative fibrosis.4Since in experimental models of ischemia/reperfusion myocitolytic necrosis is usually associated with low intensity but repetitive hypoxic or ischemic damage, this type of myocardial lesion has been interpreted as a consequence of microvascular ischemic disturbances and constitute one of the four main pathogenetic mechanisms that lead to CCC.6More than one century after its discovery in 1909 Chagas disease (CD) is still a major public health problem in Latin America and, due to migratory moves during the last decades, also in non-endemic areas, such as the United States and some European countries.T. cruzihas been demonstrated by various pathological, clinical and experimental laboratory evidence.9An estimated 20-40% of patients with CCC complain of angina, usually atypical in character since the symptom has no constant relation to physical or emotional stimulation, and variable duration and response to nitrates.10Also, several independent investigators have shown that these patients have striking myocardial perfusion abnormalities that are elicited by exercise and reversible with rest, in the presence of coronary arteries that have no epicardial obstructive lesions at invasive angiography13These perfusion abnormalities are therefore attributable to microvascular ischemia and are corroborated by studies in experimental models ofT. cruziinfection.15The occurrence of microvascular ischemia in patients chronically infected with the18On the basis of such evidence, many patients with CCC could now be classified as having a secondary class of coronary microvascular disease (CMD), related to a cardiomyopathic process caused by an inflammatory infectious disease.There have been no specific studies focusing on the comparison of patients with CMD related to CD versus patients with CMD linked to other etiologies. Thus this was the objective of the present investigation.This was a transversal, observational, unicentric investigation with prospective inclusion of stable patients who were referred to our tertiary academic hospital from January 01 to December 31 of 2018 for invasive contrast coronary angiography to elucidate the hemodynamic pattern and the cause of angina as a cardinal symptom in their medical history. Of 1292 such patients 601 were excluded because of: previous treatment with coronary angioplasty (200); previous confirmed acute coronary syndrome (137); valvular heart disease (113); hypertrophic or idiopathic dilated cardiomyopathy (99); previous coronary artery bypass surgery (49) and cardiac transplantation (3).In the remaining 691 patients coronary angiography indicated to specifically evaluate the primary possibility of coronary artery disease, revealed: significant obstructive epicardial lesions : (n = 367); angiographycally normal coronary arteries: (n = 247); non-significant epicardial coronary artery disease - stenosis < 40%: (n = 77); miscellaneous coronary artery conditions - congenital abnormalities, myocardial bridge, excessive tortuosity or ectasia, coronary-cavitary fistula, slow flow: (n = 81).Of the 247 patients who were clinically stable, with no structural cardiac disease and whose cardinal symptom was angina severe enough to warrant the indication of invasive coronary angiography but that did not show any abnormalities, 101 agreed to participate in the study and signed the informed consent. The research protocol was approved by the Ethics Committee of the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP - Processes : 8430/2011 and CAEE 07494618.3.0000.5440 Doc 3.252.539.T. cruziinfection. Also included was a questionnaire regarding the occurrence of risk factors for coronary artery disease, such as: systemic hypertension, diabetes mellitus, dyslipidemia, current smoking, and familial history of early coronary disease. All patients had a 12-lead ECG recorded, and a sub-sample of 33 (9 and 24 in each group) was examined with a transthoracic rest echocardiogram. All 101 patients had a serological examination for the detection of circulating antibodies against theT. cruzi. Also, a peripheral blood sample was collected from all patients, to allow the examination of serum levels of creatinine, and exclude the presence of renal and liver damage, as well as of severe anemia and diabetes mellitus.The 101 patients enrolled into the study had a clinical assessment performed in the same day as the hemodynamic and the invasive coronary evaluation, comprising the characterization of angina, the presence of associated symptoms such as dyspnea, fatigue, edema, palpitation, syncope, disfagia, intestinal constipation, and epidemiological hints of having been exposed to the19with recording at 15-30 frames/sec, in several projections. Left ventricular end-diastolic pressure (LVEDP) was recorded at rest, followed by two automatic injections of 20-30ml of dye at 8-10ml/sec and recording at 15 frames/sec, in the right and left oblique projections. The contrast ventriculography was then analysed according to a 9-segment model using a quantitation score that ascribed 1 to normal wall motion, 2 to hypokinesis, 3 to akinesia and 4 to dyskinesis.20An index of the global wall motion was obtained by summing the segmental scores divided by the number of segments analysed.21The ventriculogram also allowed the qualitative assessment of LV hypertrophy and dilation.These procedures were performed under local anesthesia preferably using the radial approach with conventional guide-wires and catheters. Manual injections of 3-7ml of radiological contrast were selectively done in each coronary ostium,22A subset of 19 patients were submitted to rest-exercise SPECT myocardial scintigraphy. The images were acquired in the camera range  of a double detector with the patient in the supine position during rest and stress phases. The acquisition occurred in semicircular orbit , in 32 projections synchronized with the electrocardiogram, 8 frames per cardiac cycle in 60 seconds by projection (“accepted” heartbeat) with 50% acceptance window around of average R-R. The detectors were equipped with collimators of parallel holes of low energy and high resolution, using a 64 x 64 pixel acquisition matrix.Physical exercise was used as the preferred stress test, beta-blockers, calcium channel blockers and other anti-ischemic drugs were interrupted 48 hours before the nuclear tests. Sestamibi-Tc99m was used as a radiotracer to assess regional myocardial perfusion, at a dose of 12 to 15 mCi at rest and 25 to 30 mCi at stress. Images were acquired 1 hour after each intravenous injection of the radiotracer.23Polar maps using the 17-segment model were generated to assess the perfusion abnormality according to a score defined as 0= normal, 1= slight uptake reduction, 2= moderate uptake reduction, 3= marked uptake reduction, and 4= no tracer uptake. Perfusion abnormalities in stress (SSS- Summed Stress Score) and rest (SRS- Summed Rest Score) were quantified to differentiate between reversible, when Summed Difference Score (SDS) ≥ 1 and irreversible perfusion defects.T. cruzi, 15 patients were classified as having suspected CMD due to Chagas etiology (CMD-CE) - two positive serological tests with different methods.24The other 86 patients, with negative serology tests, composed the group of patients with suspected CMD caused by other etiologies (CMD-OE). The Shapiro-Wilk tests were used to check if variables had a normal distribution, in which unpaired variables were compared with Student’s “t” tests, otherwise the Mann-Whitney unpaired tests were used. Continuous variables with normal distribution were described as mean ± standard deviation while non-normal distributed variables were described as median and IQ or range interval. Categorical variables were described as absolute or relative values (percentages or proportions). Proportions within each group were compared using Fisher exact tests. All tests were bicaudal, with p< 0.05 considered significant. All analyses were done with the Stata software.On the basis of the specific serology tests for diagnosing antibodies against theT. cruzi, and composed the group CMD-CE with 40% of males and average age of 61.3 ± 6.7 years). The other 86 (85.2%) composed the group CMD-OE with 32.5% men and higher mean age of 68.9 ± 11.0 years.Of the 247 stable patients who were initially eligible since they presented no exclusion criteria to enter the study and fulfilled the inclusion criteria of having epicardial coronary arteries that were normal at angiography, 101 (40.9%) were actually enrolled. Of those, only 15  had two serologic tests positive forOn the date of entry into the study, atypical angina was referred by 9 (60%) of the group CMD-CE versus 57 (66%) patients of the group CMD-OE, with typical angina referred by the other patients of each group. In group CMD-CE dyspnea and palpitation, were also frequent, with 8 (53%) and 7(47%) patients respectively, versus 55 (64%) with dyspnea and only 30 (35%) with palpitation in group CMD-OE.Systemic arterial hypertension was the most prevalent risk factor for coronary artery disease in both groups, with 93.3% vs 81.3%, followed by diabetes mellitus with 40.0% vs 33.7%, dyslipidemia with 33.3 vs 41.8% and active smoking in 13.3 vs 24.4% respectively in the CMD-CE and CMD-OE groups. Both groups were using statistically similar proportions of pharmacological drugs against hypertension, diabetes mellitus, statins and agents to control myocardial ischemia symptoms, such as antiplatelets and calcium antagonists. . HoweveECG abnormalities were frequent in the group CMD-CE, with only 33.3% of patients having a normal ECG on the date of the catheterization. In contrast, the group of CMD-OE had non-significantly more patients with a normal ECG (46.7%). While RBBB (26.6%), LAHB (13.3%) and LV overload (13.3%) were the most frequent abnormalities in the CMD-CE group, LV overload (20%) and complete LBBB (6.7%) were predominant abnormalities in the CMD-OE group. Both groups had a similar prevalence of atrial fibrillation (6.7%). None of those differences was statistically significant.Diastolic dysfunction as suggested by increased LVEDP > 12 mmHg at rest was diagnosed in 13 (86.6%) and 64 (74.4%) of patients respectively in the groups CMD-CE and CMD-OE, respectively; p= 0.511. The mean values of LVEDP were similar in the groups. In addition, 9 (60%) and 45 (52.3%) patients had LVEDP > 20mmHg respectively in the CMD-CE and CMD-OE groups.Using ventriculography to assess LV morphological features that suggest the presence of chamber hypertrophy this alteration was observed in 3 patients (20%) of the group CMD-CE versus 26 patients (30.2%) of the group CMD-OE (p= 0.545). In contrast ventricular dilatation by ventriculography was observed in significantly higher proportion of patients, 26% (n = 4) of the group CMD-CE versus 4.7% (n = 4) of the group CMD-OE (p= 0.04).Overall most patients had preserved global LV systolic function in both groups, with a minority of patients in both groups showing reduced LVEF values (< 50%). LVEF was marginally significant lower in the CMD-CE (54.8 ± 15.9) as compared to the CMD-OE group (61.1 ± 11.9 ), p= 0.049 . In addition, regional wall motion abnormalities were detected in a significantly higher proportion of patients in the CMD-CE group  as compared with that of patients in the CMD-OE group , p= 0.02 . LV walAfter the results of the hemodynamic evaluation were obtained, 11 patients of the CMD-CE group and 8 patients of the CMD-OE group underwent functional assessment with SPECT-myocardial perfusion scintigraphy. .The proportion of patients exhibiting ischemic reversible perfusion abnormalities for the CMD-CE and CMD-OE groups were 45.5% and 62.3% respectively (p= 0.31). The SDS was also similar for the CMD-CE (1.91 ± 3.05) and the CMD-OE (5.63 ± 7.03) groups (p= 0.134).T. cruziinfection, and composed the group of patients with suspected coronary microvascular disease due to Chagas cardiomyopathy etiology (CMD-CE), while the other 86 patients comprised the group whose suspected coronary microvascular disease must be ascribed to other etiologies (CMD-OE). This is the first report on the relative prevalence of Chagas cardiomyopathy as an etiology for suspected coronary microvascular dysfunction among patients who are otherwise generally considered as having a primary form of coronary microvascular disease. This figure of roughly 15% of is likely to correspond to the real estimate for that etiology, considering that our institution still receives many patients from regions endemic for Chagas disease. Also, our sample of 247 patients with angiographically normal coronary arteries was selected among 691 consecutive patients in whom other abnormalities had been excluded, and correspond to nearly 36% of such individuals who are referred for elective coronary angiography. This finding is inferior to 45% recently reported by another Brazilian hospital,25but is quite similar to the reported 39% of patients with coronary stenoses < 20% as the general yield by elective coronary angiography during the years 2004-2008 from an American College of Cardiology national registry.26During the whole year of 2018, following the implementation of our inclusion and exclusion criteria to a consecutive series of 247 clinically stable patients who had no structural cardiac disease and complained of anginal symptoms that were severe enough to warrant referral to our tertiary center for invasive coronary angiography but that eventually showed normal epicardial coronary arteries, a sizable sample of 101 of them (40.9%) agreed to participate in this prospective study and signed the respective informed consent. Out of the 101 about one sixth tested positive for chronicWith the exception of slightly higher mean age in the CMD-OE group, it is noteworthy that the two groups in our study had essentially similar anthropometric and clinical characteristics, including a higher prevalence of female gender, with slighthly obese patients who, in addition to atypical angina, also complained of dyspnea and palpitation. The traditional risk factors for coronary artery disease - hypertension, diabetes mellitus, smoking, dyslipidemia - were also present in comparably high proportions of patients of both groups.Another important finding from our study is that using contrast ventriculography for evaluation of left ventricle morphology, signs of chamber hypertrophy were found in several patients from both groups. In line with these findings, LV diastolic dysfunction, as expressed by striking elevation of the LV end-diastolic pressure occurred similarly in the CMD-CE and CMD-OE groups.27Although diastolic dysfunction also occurred in the group with CMD due to other etiologies, it is likely that myocardial fibrosis, a hallmark of Chagas cardiomyopathy, contributes to the diastolic dysfunction hereby detected in our patients.6In regard to this important derangement, our patients with CMD due to Chagas disease at the stage of the disease they are when enrolled in this study, show abnormalities that are described in the recent classification of coronary microvascular dysfunction as occurring mostly in the scenario of heart failure with preserved LV ejection fraction.However, there were relevant differences between the two groups regarding LV systolic function. Mean LV ejection fraction was significantly lower in the CMD-CE, in keeping with more deteriorated segmental wall motion index and more LV dilation that was significantly more prevalent in the CMD-CE as compared to the CMD-OE group.28Although in this standardization it is suggested that a fourth criterium could be used when the presence of microvascular angina is suspected, in our investigation we did not apply any additional tests to certify the occurrence of impaired coronary microvascular function, such as measurement of resistance indices or of reduced flow reserve.28However it is probable that at least some of our patients with CMD-CE could have such abnormalities, as reported by other investigators.29Both groups exhibited comparable proportions of patients with ischemic perfusion defects and their SDS between stress and rest myocardial scintigraphy were also similar. It is worthy pointing out that the objective detection of myocardial perfusion abnormalities indicative of myocardial ischemia induced by stress, represents the third criteria for classifying the patients in our study series as having the suspected syndrome of coronary microvascular disease according to a standardized recent classification.T. cruziinfection, it is likely that the inherent peculiarities of Chagas cardiomyopathy be responsible for the relatively more serious manifestations of left ventricular systolic dysfunction, in comparison with those exhibited by the group with coronary microvascular disease due to other etiologies.It is reasonable to assume that patients from both groups included in this research share common pathophysiological characteristics that are involved in the appearance of the syndrome of anginal pain with angiographically normal sub-epicardial arteries, thus implying the presence of disturbances at the coronary microvascular level. This concept is supported by the finding in both groups of factors such as hypertension, ventricular hypertrophy, and diastolic dysfunction. However, in the group whose coronary microvascular disease is associated with the chronicT. cruziin our study had previous knowledge about harboring Chagas disease. Moreover, the sample of patients eventually selected to participate in the study was composed primarily of people who were referred to invasive coronary angiography, without previous assessment of myocardial ischemia with exams such as ECG-based tests, or stress echocardiography or nuclear scintigraphy tests. Thus, it is likely that most of those patients could benefit from therapeutic measures directed by both the knowledge of their baseline disease and of the functional consequences of the microvascular disturbances.30It is relevant to emphasize that none of the patients who tested positive for antibodies against theNo specific investigations were carried out to determine the possible etiology in the patients without Chagas cardiomyopathy, although most probably they would be classified as having primary coronary microvascular dysfunction. Also, no invasive tests were done to directly explore the mechanisms responsible for the impairment of microvascular function in any patient included in this study. “Another limitation is the fact that only 19 of the 101 patients had myocardial pefusion assessed with SPECT scintigraphy. Hence, although similar proportions of the patients had perfusion defects, the small number of patients in both groups may have prevented detection of differences in regard to this important characteristic of their coronary microvascular derangements”.T. cruzishowed anthropometric, clinical, and angiographic characteristics, as well as hemodynamic and myocardial perfusion abnormalities that were similar to those detected in the remaining 86 patients with other etiologies for the suspected microvascular dysfunction. However, impairment of LV segmental and global function was signficantly more severe in the patients with symptoms of possible microvascular dysfunction related to Chagas cardiomyopathy.Chronic Chagas cardiomyopathy was found in association with the suspected syndrome of coronary microvascular disease in one sixth of a sample of 101 stable patients whose cardinal symptom was anginal pain warranting invasive coronary angiography. These patients chronically infected with the


N = 30 patients with CA, N = 20 patients with HCM and N = 15 healthy control patients without relevant cardiac disease underwent dedicated CMR studies. The CMR protocol included standard sequences for cine-imaging, native and post-contrast T1-mapping and late-gadolinium-enhancement. ECV measurements were based on pre- and post-contrast T1-mapping images. Feature-tracking analysis was used to calculate 3D left ventricular longitudinal strain (LV-LS) in basal, mid and apical short-axis cine-images and to assess the presence of relative apical sparing. Receiver-operating-characteristic analysis revealed an area-under-the-curve regarding the differentiation of CA from HCM of 0.984 for native T1-mapping (p < 0.001), of 0.985 for ECV (p < 0.001) and only 0.740 for the “apical-to-”-ratio of LV-LS (p = 0.012). A multivariable logistical regression analysis showed that ECV was the only statistically significant predictor of CA when compared to the parameter LV-LS or to the parameter “apical-to-” LV-RLS-ratio. Native T1-mapping and ECV measurement are both superior to longitudinal strain measurement  regarding the appropriate diagnosis of CA.Cardiac amyloidosis (CA) is an infiltrative disease. In the present study, we compared the diagnostic accuracy of cardiovascular magnetic resonance (CMR)-based T1-mapping and subsequent extracellular volume fraction (ECV) measurement and longitudinal strain analysis in the same patients with (a) biopsy-proven cardiac amyloidosis (CA) and (b) hypertrophic cardiomyopathy (HCM).  Amyloidoses are classified based on the misfolded protein precursor—with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis being the most commonly found forms in case of cardiac amyloidosis (CA)2. Moreover, it is well known that cardiac involvement is associated with high morbidity and poor prognosis4. Hence, early and appropriate diagnosis of cardiac involvement is highly important in order to start a targeted therapy on time.Systemic amyloidoses comprise more than 30 different disorders characterized by an infiltrative deposition of misfolded protein in various organs such as skin, eyes, lung, liver, kidneys, nervous system and heart. Depending on the variety and degree of organ involvement, the respective clinical manifestation may differ6 that are hallmarks of this restrictive cardiomyopathy, eventually leading to rapid progressive heart failure. Furthermore, deposition of amyloid fibrils in the atrial and ventricular wall may cause conduction abnormalities and contributes to the high prevalence of ventricular arrhythmias and atrial fibrillation, increasing the risk of sudden cardiac death (SCD) and thromboembolism7.The accumulation of amyloid deposits in the extracellular space of the myocardium results in both increased biventricular wall thickness and ventricular stiffness9. These mutations cause a disorganized arrangement of myocyte hypertrophy  as well as expansion of extracellular matrix, composed of interstitial and replacement fibrosis10. Such structural changes in turn result in increased wall thickness and noncompliance of the left ventricle. Clinically, most patients with HCM are asymptomatic or show just mild symptoms, but a subset will progress to suffer from symptoms of heart failure, chest pain and arrythmias with an increased risk of SCD11.In contrast to CA, hypertrophic cardiomyopathy (HCM) is most often determined by mutations of those genes encoding sarcomere proteins of the contractile apparatus13, HCM is characterized by a patchy and more focally accentuated LGE pattern predominantly occurring in the most hypertrophic septal segments of the left ventricular myocardium15.Cardiovascular magnetic resonance (CMR) has been established as an important diagnostic tool for the work-up of left ventricular hypertrophy (LVH) of unknown origin. In this context, different myocardial patterns of late gadolinium enhancement (LGE) allow to differentiate CA from HCM: While the LGE pattern in CA is rather diffuse, starts mostly from the subendocardial layer of the basal segments and eventually spreads to all myocardial layers and segments16. T1-mapping before infusion of a gadolinium-based contrast agent (native T1) and thereafter (post-contrast T1) allows to determine the extracellular volume fraction (ECV) of the myocardium17. Both native T1 and ECV are useful tools for the work-up of hypertrophic cardiac phenotypes of unknown origin. Since CA is characterized by an extensive, diffuse amyloid infiltration of the extracellular space18 while HCM mostly shows focally accentuated interstitial fibrosis in hypertrophied septal segments, the increase in global native T1 and ECV values is consistently lower in HCM as compared to CA19.More recently, T1-mapping has emerged as a new diagnostic technique, which offers tissue characterization by measurement of the intrinsic T1 relaxation time of the myocardium20. In principle, in both diseases (CA and HCM) all strain parameters are somewhat reduced in advanced cardiac phenotypes. However, whereas the physiological gradient of baso-apically diminishing strain is mostly preserved in case of HCM, a distinctive and unique pattern is mostly observed in case of CA, i.e. an inversed pattern of gradual strain increase from the basal to apical segments of the left ventricle (LV), known as “cherry on top” or “apical sparing” phenomenon22.Another popular approach in the evaluation of infiltrative cardiomyopathies such as CA is based on tissue tracking techniques that aim to measure myocardial deformation kinetics and patterns (strain). Both echocardiography- and CMR-based strain techniques have been evaluated in different cardiac diseases. Particularly, speckle tracking echocardiography (STE) and CMR feature tracking (FT) are the most validated and clinically used methods for strain analysisWith this study, we assessed the diagnostic value of T1-mapping-based approaches in comparison to strain-based techniques regarding the appropriate diagnosis and differentiation of CA and HCM.N = 30 patients with histologically proven cardiac amyloidosis (including both AL and ATTR subtypes). The second study group (HCM group) comprised N = 20 patients with “conventional” HCM showing preserved LV ejection fraction (LV-EF) ≥ 50%, LV wall thickness ≥ 15 mm  and absence of LV outflow tract obstruction. The third group (control group) comprised N = 15 patients in whom structural or functional cardiac abnormalities were ruled out and who presented with a low pre-test probability of CAD. Exclusion criteria comprised: (1) relevant valvular disease (at least grade 2 in echocardiography and/or at least moderate in CMR), (2) prosthetic valve, (3) permanent atrial fibrillation and (4) obstructive coronary artery disease. The local ethics committee  approved the study protocol and every patient gave written informed consent before enrolment.This is a comparative, monocentric, prospective study. All patients underwent a routine CMR study for work-up of suspected non-ischemic cardiomyopathy. The first study group (CA group) comprised 23. Our CMR protocol comprised a cine steady-state free precession pulse sequence for ventricular function and a two-dimensional (2D) inversion recovery fast spoiled gradient-echo sequence 10 to 15 min after administration of gadolinium-based contrast (Gadobutrol 0.15 mmol/kg) for detection of myocardial pathology. Moreover, a modified Look-Locker inversion recovery (MOLLI) T1-mapping sequence was obtained in basal, mid and apical short-axes prior to contrast agent administration and ~ 20 min thereafter to determine native T1 and ECV values. Representative CMR acquisitions from all three groups of our cohort are illustrated in Fig. All CMR studies were performed on a 1.5-T system . CMR data acquisition was performed according to the standardized protocol suggested by the Society for Cardiovascular Magnetic Resonance (SCMR)24 and the “Query Amyloid Late Enhancement” (QALE) score was reported as described in more detail elsewhere25.Image analysis and interpretation was performed using commercially available software . Analysis of ventricular volumes and function as well as LV mass was made by contouring short-axis cine images. LGE images were visually assessed26. Motion corrected native and post-contrast T1 maps were generated from the pre- and post-contrast T1 sequences. In each short-axis T1 map the endo- and epicardial contours were manually drawn. In order to further hamper contamination from blood pool and neighbouring tissues, respectively, a 10% safety margin was automatically set for both contours. Further, each short-axis map was automatically segmented (6 segments) using the RV insertion points as reference. Additionally, for ECV calculation, a region of interest was drawn in the blood pool (avoiding the papillary muscles) in all analysed T1 maps. Motion corrected and segmented ECV maps were generated from the native and post-contrast segmented T1 maps, using the patient’s haematocrit level.T1-mapping and ECV were assessed and reported based on the consensus statement of SCMR27. Landmarks for LV base  and apex were defined at end-diastole in all long-axis slices. Endocardial and epicardial borders were manually contoured in the end-diastolic frame in the three long-axis slices and in three short-axis slices, the most basal slice without through-plane distortion from the LV outflow tract, a mid-ventricular and an apical slice. Both the landmarks and the contours were automatically propagated throughout the cardiac cycle and manually corrected in case of inaccuracies. Subsequently, relative apical longitudinal strain (LS) was calculated based on the following equation: average apical LS/, as defined by Phelan et al.28.For the assessment of global LV deformation, three-dimensional (3D) LV global longitudinal strain (LV-GLS) derived from feature tracking (FT) was obtained using a validated algorithm integrated in the analysis softwarep-value < 0.05 was considered statistically significant.Statistical analysis was performed with SPSS . Continuous variables that showed a normal distribution are expressed as mean with ± standard deviation. Skewed variables are expressed as median ± interquartile range. Categorical variables are expressed as frequency with percentage. One-Way ANOVA with Bonferroni post hoc test was used for the comparison of normally distributed, homogenous data. When the assumption of homogeneity of variances was violated according to Levene’s test, Welch-ANOVA and Games-Howell multiple comparisons method were used instead. For the comparison of non-normal distributed data, we used the Kruskal–Wallis test. The Chi-square test with Bonferroni correction was used to compare categorical variables. Receiver operating characteristic curves (ROC) were analyzed to assess the diagnostic accuracy of different CMR parameters to differentiate CA from HCM patients. A univariable and subsequent multivariable logistic regression analysis was performed to identify the best predictor for the diagnosis of CA. A The study protocol complies with the Declaration of Helsinki. Written informed consent was obtained from every patient.p = 0.13). Median age differed significantly between the CA and both the HCM and control group due to the higher prevalence of CA in elderly patients. There were no other significant differences in major cardiovascular disease risk factors that could theoretically influence the results of this study.The study group characteristics are summarized in Table p < 0.001; and 61 [± 6] % in controls, p = 0.052)—but still preserved. The extent of LVH was similar in both CA and HCM patients  with a more concentric pattern of LVH in CA compared to a more asymmetric, septally pronounced pattern in HCM patients. Furthermore, the distribution of LGE was characterized by a diffuse subendocardial to transmural pattern, predominantly affecting the basal to midventricular segments, and to a much greater extent in CA patients compared to the patchier, scattered pattern of LGE in HCM patients. Accordingly, the QALE score was significantly increased in CA compared to HCM . No LGE was present in the control group.All anatomic, functional and structural CMR results are given in Table p < 0.001; and 983 ms [964–993] in controls, p < 0.001). Accordingly, global ECV was significantly higher in CA . Moreover, 3D-LV-GLS was reduced in both CA and HCM (− 6.7 [− 8.7 to − 4.9] % vs. − 10.5 [− 11.4 to − 8.1]), with a significant difference between these groups (p = 0.025). The most pronounced impairment of regional left ventricular longitudinal strain (LV-RLS) was measured in the basal segments of CA patients . The “apical-to-”-ratio of LV-RLS  was 0.96 in CA vs. 0.72 in HCM (p = 0.004) and 0.065 in controls (p = 0.001), as depicted in Table In patients with CA, global native T1 was significantly increased compared to both groups , of 0.984 for native T1-mapping (p < 0.001), of 0.848 for the QALE score (p < 0.001) and only 0.740 for the “apical-to-” LV-RLS-ratio (p = 0.012). Finally, a multivariable logistical regression analysis showed that ECV was the only statistically significant predictor of CA when compared to the parameter 3D-LV-GLS or to the parameter “apical-to-” LV-RLS-ratio (Table Receiver-operating-characteristic (ROC) analysis was performed for all novel CMR parameters, including native T1-mapping, ECV, “apical-to-” LV-RLS-ratio plus the QALE score Fig. . ROC anaThe present study focuses on a head-to-head comparison of the diagnostic performance of T1-mapping-based vs. strain-based CMR parameters in CA and HCM patients. Our study results clearly show that the novel CMR parameters native T1 and ECV show a higher diagnostic yield in the delineation of CA from HCM patients (as well as controls) compared to a strain-based approach assessing the presence of “apical sparing”.29. A major advantage of this technique compared to other strain approaches is its ease-of-use as the analysis can be performed very quickly on standard cine-CMR images after the examination. Balanced steady-state free precession (b-SSFP) sequences that are currently routinely used for standard cine imaging provide excellent blood-myocardium contrast as well as a high spatial and temporal resolution for motion tracking over the cardiac cycle. FT-CMR is most efficient in the detection of the endocardial border where the contrast between heart muscle and cavum is excellent. However, detection of the epicardial border can be challenging—in particular, when contrast between myocardium and surrounding tissue is poor. In some cases, tissue tracking may fail to find the transformation of every point within the myocardium because of the homogeneity of water content and properties of the tissue30. Moreover, it should be taken into account that a cine loop represents a reconstructed averaged cardiac cycle and thereby, in cases of high variation in heart frequency FT-CMR might give false measurements. In general, FT-CMR is a feasible and highly reproducible technique in various cardiac diseases. Noteworthy, assessment of LV-GLS by FT-CMR in case of LVH has shown good intra- und inter-observer variability with an intraclass correlation coefficient (ICC) of 0.82 (0.45–0.95) and 0.86 (0.54–0.96) respectively31. However, inter-study reproducibility seems to be poor (ICC: 0.44 [0–0.77])32.Today, FT-CMR is a popular technique for strain analysis that tracks the displacement of individual patterns representing anatomical structures over time33. It is for this reason that 3D FT-CMR measurements result in lower absolute values. Hence, in the present study, we used a 3D FT-CMR approach to obtain global as well as regional longitudinal strain and to calculate the degree of relative “apical sparing”.Recently, a 3D FT-CMR approach was introduced and permits a complete 3D interrogation of myocardial strain. Theoretically, a 3D-based strain approach is more suitable for the assessment of global myocardial deformation since 2D techniques are prone to through-plane loss of features in the third dimension. Due to LV contraction (with concomitant rotation) during systole that results in movement of some segments outside the pre-defined imaging plane, overestimation of the observed degree of muscle shortening may occur34; a finding that is confirmed by our present results. Prior to the introduction of strain analysis using FT-CMR, speckle tracking echocardiography (STE) was already widely used for years. Based on STE studies in patients with CA, the concept of relative “apical sparing”  was introduced28: As longitudinal strain impairment in CA predominantly affects the basal segments of the LV—whereas apical segments are affected to a much lower degree, the concept of relative “apical sparing” was established and initially shown to differentiate CA from other causes of LVH with a sensitivity of 93% and a specificity of 82% by Phelan et al.28. In addition to such diagnostic data, a prognostic value of STE-based assessment of “apical sparing” was described in case of CA35 and this method was therefore even considered in current amyloidosis guidelines36. Since a good agreement was shown between STE-based and FT-CMR-based strain analysis, assessment of longitudinal strain was based on FT-CMR only in the present study37.Previous studies already showed that FT-CMR-based LV-GLS is significantly decreased in patients with CA compared to HCM28. In contrast, in a more recent study, Pagourelias et al. obtained a poorer sensitivity of 63% and similar specificity of 85% for the diagnosis of CA using an optimal cut-off value of 0.8738. In our present CMR study, an optimal cut-off of 0.89 for the parameter “apical-to-” LV-RLS-ratio resulted in a 64% sensitivity and 80% specificity for the diagnosis of CA—confirming the data of Pagourelias et al.38.However, when Phelan et al. introduced the concept relative “apical sparing”, they used a cut-off value for relative “apical sparing” of 1.0 in order to differentiate CA from HCM with the aforementioned good sensitivity and specificity39. Since extracellular amyloid deposition significantly increases native T1, accurate diagnosis of CA and differentiation from other causes of LVH is possible with T1-mapping: Recently, Baggiano et al. demonstrated the high diagnostic accuracy of both native T1 and ECV  for the diagnosis of CA40. Moreover, the same group observed prognostic implications of T1-mapping-based analysis in CA patients—with ECV being independently predictive of death  in a multivariable Cox model that included (among others) N-terminal pro-B-type natriuretic peptide, LV-EF, LGE extent and LV mass41. Hence, both native T1 and ECV are highly sensitive non-invasive CMR parameters for the diagnosis of CA.In contrast to echocardiography, CMR allows not only to assess myocardial strain but also structural changes using conventional LGE techniques and novel parametric mapping approaches such as native T1-mapping and T1-mapping-derived ECV. Native T1-mapping has the advantage of detecting subtle changes in the intrinsic properties of the myocardium that may be indicative of an early stage of cardiac disease. Moreover, in pathologies with diffuse or uniform pattern, T1-mapping has a superior diagnostic accuracy than LGE-imaging that requires relative signal intensity changes and reference regions of normal myocardium in order to depict tissue abnormalitiesSurprisingly, an appropriate head-to-head comparison of the diagnostic performance of T1-mapping-based vs. FT-CMR-based parameters has not been performed in CA and HCM patients so far. To the best of our knowledge, this is the first study that provides a direct comparison of the diagnostic value between FT-CMR and T1-mapping in CA and HCM patients. In the present study, both native T1 and ECV substantially outperformed FT-CMR-based strain analysis with regard to the appropriate diagnosis of CA. Noteworthy, native T1 and ECV did not only demonstrate a substantially higher AUC based on ROC analyses compared to FT-CMR; in addition, ECV was an independent predictor of the presence of CA in multivariable regression analyses—in contrast to FT-CMR-based strain parameters. Hence, from a clinical point-of-view, strain-based assessment of relative “apical sparing” does not allow to safely rule out the presence of CA. Beyond strain measurement, novel CMR methods for myocardial tissue characterization such as T1-mapping and ECV measurement are required and should be routinely performed in patients with suspected CA and/or LVH of unknown origin. Moreover, a careful assessment of the diagnostic value of strain measurements is suggested in future recommendation and/or guideline papers addressing the diagnosis of CA.42, however sufficient for the purposes of this study. In addition, CA consists of different subtypes dependent on the precursor protein. In the present study, no distinction was made between the different types of CA (AL and ATTR) since the underlying mechanism of cardiac involvement is similar43. Furthermore, the limitations of T1-mapping and ECV measurement44 as well as of FT-CMR are well documented30. Finally, we used a non-licensed dose of Gadovist (0.15 mmol/kg) for CMR imaging purposes and future studies need to show whether the licensed dose of 0.1 mmol/kg will be sufficient for tissue mapping purposes. However, based on previous data and according society recommendations26, our approach should be appropriate.Since CA is a rare disease, the size of our study group was limitedNative T1-mapping and ECV measurement are both superior to longitudinal strain measurement  regarding the appropriate diagnosis of CA. Hence, cardiac work-up of patients with suspected amyloidosis should be based on multi-parametric CMR including T1-mapping and ECV measurement—and not limited to echocardiography- and/or CMR-based longitudinal strain analysis.Supplementary Information 1.Supplementary Information 2.


Ebstein's anomaly is characterized by the apical displacement of the septal and posterior leaflets of the tricuspid valve with atrialization of the right ventricle (RV). It is commonly associated with other heart defects including left ventricular noncompaction. We describe a case of prenatally diagnosed Ebstein's anomaly in association with left ventricular noncompaction and a septal defect between the left ventricle and the atrialized portion of the RV (Gerbode-like defect). The patient underwent a modified Blalock−Taussig shunt followed by Glenn procedure because of severe RV hypoplasia and RV outflow tract obstruction. The patient tolerated both procedures and is doing clinically well in anticipation of Fontan procedure for single ventricle palliation. Ebstein's anomaly (EA) is a rare congenital heart defect with an incidence of 0.5 in 100,000 live births . The hemβ-myosin heavy chain 7 (MYH7) mutation and α-tropomyosin 1 (TPM1) gene mutations to be associated with EA-LVNC [Left ventricular noncompaction (LVNC) is the third most diagnosed cardiomyopathy with an estimated prevalence of isolated LVNC ranging from 0.05 to 0.14 in adults , 4. It i EA-LVNC , 7. The Gerbode defect is defined as an abnormal shunting between the LV and the RA. Gerbode-like defect is shunting between the LV and the atrialized portion of the RV in case of EA. While EA has been associated with septal defects, there have only been two reports of its occurrence with a Gerbode-like defect and neither of the two cases reported left-sided cardiac defects , 9. To o2 and normal systolic function with an ejection fraction of 58%. The left ventricle was of normal size with an indexed end diastolic volume of 52 cc/m2 and normal systolic function with an ejection fraction of 73%. There was excessive trabeculation of the left ventricle with a ratio of noncompact to compact myocardium of approximately 4 : 1. Late gadolinium enhancement imaging was not performed.A 17-year-old primigravida was referred to the fetal cardiology clinic for a suspected congenital heart defect. The fetal echocardiogram (ECHO) was significant for EA, hypoplastic RV, a septal defect between the left ventricle and the atrialized portion of the RV (Gerbode-like defect) in addition to possible LVNC . These fAt 7 months of age, he underwent cardiac catheterization which showed severe EA, multilevel right ventricular outflow tract (RVOT) obstructions, Swiss cheese ventricular septum, Gerbode-like defect, and a moderate size secundum ASD. There was a minimal forward flow through the RVOT, and the Qp : Qs ratio was 0.3 : 1. A Blalock–Taussig shunt was placed at that time.Subsequent follow-up imaging studies were done at 14 months of age and included cardiac magnetic resonance imaging and cardiac computerized tomography (CT) scan which showed a severely hypoplastic RV with severe multilevel RVOT stenoses. The severely dilated right atrium with an atrialized right ventricle was also redemonstrated Figures . InteresAt 15 months of age, he underwent Glenn procedure. At his most recent cardiac evaluation, the O2 saturation was 92% on room air, and his Glenn shunt continues to exhibit a laminar flow at low velocity. The decision to proceed with a single ventricle palliation was based on the fact that the RV is severely hypoplastic and would not be able to support the pulmonary circulation in addition to the severe multilevel RVOT obstruction.LVNC has multiple known associations such as arrhythmias, congenital heart disease such as septal defects, right heart obstructive lesions, hypoplastic left heart syndrome, and EA . In a stThe first three cases of the EA-LVNC association were reported in 2004; since then, there have been several reports describing the association . Recent Patients with EA-LVNC may present with a wide range of symptoms such as right-sided heart failure, cyanosis, arrhythmia, and sudden cardiac death. Studies in younger children showed a worse outcome in patients with EA and LVNC compared to those with EA alone . A preteA left ventricle to right atrial shunt is rare and accounts for <1% of congenital cardiac defects . The dowTo our knowledge, our patient is the first reported case of an EA- LVNC- Gerbode-like defect triad. While expected genetic abnormalities associated with EA-LVNC such as TPM1 and MYH7 were negative, there may be an undiagnosed genetic association with these concurrent defects. Early diagnosis of these defects may contribute to better management and outcomes.


Arrhythmogenic right ventricular dysplasia (ARVD) is caused by mutations in genes coding for components of desmosomes in the myocardium. Mutations in these genes make desmosomes dysfunctional and account for myocyte detachment, followed by inflammation and apoptosis when it encounters undue mechanical stress. This is why ARVD is a common cause of sudden cardiac death in athletes with undiagnosed ARVD, as increased physical activity exacerbates this progression of ARVD and associated arrhythmias. We describe a case of ARVD in a 36-year-old woman who presented with an unusual sensation in her chest due to non-sustaining ventricular tachycardia, which her smartwatch failed to pick up. Many smartwatches use photoplethysmography (PPG) to monitor heart rate (HR). A typical PPG device contains two light sources (green light and infrared) and a photodetector to measure the reflected light, proportional to the beat-to-beat variation in blood volume. HR is then calculated from these variations. In ambulatory settings, smartwatches underestimate HR in most tachyarrhythmias, mainly when the HR is more than 100 beats/min. Patients using smartwatches for ambulatory heart monitoring should know that the absence of an irregular pulse notification does not exclude possible arrhythmias. Management of ARVD is mainly focused on the prevention of syncope and cardiac arrest through antiarrhythmic medications and an implantable cardioverter defibrillator. Arrhythmogenic right ventricular dysplasia (ARVD) is caused by mutations in genes coding for components of desmosomes in the myocardium. We describe a case of ARVD in a 36-year-old woman who presented with an unusual sensation in her chest due to non-sustaining ventricular tachycardia (VT), which her smartwatch failed to pick up. Wearables can passively measure pulse rate from the wrist using photoplethysmography (PPG). Longitudinal pulse data could be analyzed to assess pulse irregularity and variability to identify potential irregular heart rhythms. However, the utilization of wearables or arrhythmia detection algorithms may not be without risks. Patients using smartwatches for ambulatory heart monitoring should know that the absence of an irregular pulse notification does not exclude possible arrhythmias.A 36-year-old Cantonese-speaking female presented to our institute with a history of intermittent palpitations and dizziness for two days. Her ECG showed prolonged QTc 481 ms) with symmetric T wave inversions in the right precordial leads (V1-V3)  with an apical echogenic tissue and abnormal RV free wall motion. We scheduled her for cardiac magnetic resonance imaging (CMRI) and discharged her with an ambulatory 30-day event monitor. Two days after her discharge, she presented again to the emergency room with shortness of breath and palpitations that started while bending to lift a heavy object. She denied excess caffeine intake, syncope, chest pain, or recreational drug usage. Her ECG showed wide complex VT with a rate of more than 200 beats/min Figure . Some ar The patient was monitored with telemetry for two days after placing AICD. Telemetry revealed predominantly normal sinus rhythm with occasional premature ventricular contractions of two dominant morphologies and multiple runs of non-sustained VT. Genetic testing showed missense mutations in DSG2 and SCN5A genes associated with the autosomal-dominant version of ARVD. There has been much debate about the accuracy of ambulatory ECG monitoring with smartwatches. Many smartwatches use PPG to monitor HR. A typical PPG device contains two light sources (green light and infrared) and a photodetector to measure the reflected light, proportional to the beat-to-beat variation in blood volume. HR is then calculated from these variations. In ambulatory settings, smartwatches underestimate HR in most tachyarrhythmias, mainly when the HR is more than 100 beats/min . In one Patients using smartwatches for ambulatory heart monitoring should be aware that the absence of an irregular pulse notification does not exclude possible arrhythmias. The algorithm is designed to reduce the chances of incorrect HR readings; a common strategy is to stop recording when high levels of motion interference are detected. Unfortunately, this means that there is a high chance that a true cardiac arrhythmia will be interpreted as motion interference. It is essential to understand the limitations of these technologies to avoid inappropriate reliance on them for diagnostic purposes.


The right ventricle has long been perceived as the “low pressure bystander” of the left ventricle. Although the structure consists of, at first glance, the same cardiomyocytes as the left ventricle, it is in fact derived from a different set of precursor cells and has a complex three-dimensional anatomy and a very distinct contraction pattern. Mechanisms of right ventricular failure, its detection and follow-up, and more specific different responses to pressure versus volume overload are still incompletely understood. In order to fully comprehend right ventricular form and function, evolutionary biological entities that have led to the specifics of right ventricular physiology and morphology need to be addressed. Processes responsible for cardiac formation are based on very ancient cardiac lineages and within the first few weeks of fetal life, the human heart seems to repeat cardiac evolution. Furthermore, it appears that most cardiogenic signal pathways  act in combination with tissue-specific transcriptional cofactors to exert inductive responses reflecting an important expansion of ancestral regulatory genes throughout evolution and eventually cardiac complexity. Such molecular entities result in specific biomechanics of the RV that differs from that of the left ventricle. It is clear that sole descriptions of right ventricular contraction patterns (and LV contraction patterns for that matter) are futile and need to be addressed into a bigger multilayer three-dimensional picture. Therefore, we aim to present a complete picture from evolution, formation, and clinical presentation of right ventricular adaptation and failure on a molecular, cellular, biomechanical, and (patho)anatomical basis. The right ventricle (RV) has long been perceived as the “low-pressure bystander” of the left ventricle (LV). The lack of interest in RV pathobiology was primarily based on early studies that showed practically no increase in venous pressure when damaging the RV free wall , 2 and hOnly recently was the RV “rediscovered” due to evidence indicating that the RV can indeed be a significant contributor to functional hemodynamics and cardiac output –7, partiThe mechanisms of RV failure, its detection and follow-up, and more specifically the different responses of the RV to pressure versus volume overload are still incompletely understood. Despite many apparent similarities between the LV and RV, there are significant differences on a morphological, physiological, and molecular level, evidenced by different responses of the ventricles to current HF therapies , 16–22. In order to fully comprehend the functional anatomy of the RV and the intricate relation between form and function, we need to explore the evolutionary pathway leading to the formation of the RV. Indeed, studying common precursors could provide us with additional information on the formation and possible maladaptation of the RV dealing with altered loading conditions . When coThe emergent tree from first eukaryotic cells starts 1.5 billion years ago , 30 and 2) carrier increases the delivery of O2 by 20–40 times and this essential compound, some type of haem pigment, is present in almost all living beings [Embryogenesis of the heart shows a common step consisting of a primary cardiac tube derived from mesodermal precursor cells converging in the midline  with perg beings .All vertebrates stem from a common chordate ancestor, and cardiac tubes show sequential segments throughout the evolution of species very similar to the processes that occur during human embryogenesis  Fig. 1)1). These2 supply through diffusion. This type of myocardium functions as an adequate pump, however, generating low pressure (≤ 25 mmHg) [Another important change during evolution is the type of contractile fiber arrangement. Vertebrates have two types of arrangements: trabeculated, which is predominant in fishes and amphibians, and compact myocardium forming the entire ventricle of birds and mammals , 37, 38.25 mmHg) . TrabecuFish have a single circulatory tube with an elastic cone at the aortic root to cope with pulsatility (Windkessel effect) and a unidirectional atrioventricular and outflow valve to prevent backflow. The necessity for higher driving pressures by more active species determines the type of myocardium. More sedentary species have trabeculated myocardium, while more active species (tuna and shark) have compact myocardium with coronary arteries and pressures up to 80 mmHg .2 exchange at the site of the lungs in species with higher metabolic needs, lower pressures in the pulmonary vascular bed are necessary to prevent edema . Therefore, in birds and mammals, a complete separation of the pulmonary and systemic circulation is present [2 and nutrients and selective repartition of blood flow according to metabolic needs. Importantly, the process of complete septation evolved separately and independently in birds and mammals since the phylum of mammals took off from early terrestrial vertebrates (around 300 million years ago), whereas birds are descendants from reptiles [In order to allow for adequate O present , 41. Sepreptiles , 36.2 tension, is that it allows for thinner alveolar membranes and prevents interstitial fluid leakage. However, a major limitation of separate circulations is the fact that they are completely interdependent and necessitate, besides the reciprocal modification due to respiration of the stroke volume in each ventricle, a complex (auto)regulatory system. Another evolutionary tradeoff is the distance between the heart and the lungs; i.e., their proximity can be explained by basic physics describing that longer vessels cause a loss in pressure. It is important to note that the development of four chambers evolved out of necessity for a closed circuit and that septation occurred separating the same evolutionary ventricle into a right and left side. As such, cardiac embryological origins must have started to differ in both ventricles, however, difficult to determine when those patterns emerged through evolution  expression and contribute to left ventricular and atrial cardiomyocytes [NK homeodomain, GATA, T-box, and others have been found to exert functions of inductive signals during specification, patterning, and differentiation [ISl1, however, not being cardiac specific. In order to activate downstream targets, such as the myocyte enhancer factor 2c (Mef2c) gene, it requires co-factors such as GATA and Nkx2-5 expressed in both heart fields. A separate enhancer, Foxh1, acting downstream of Isl1, also activates Mefc2 [Fgf8, Fgf10, PITX2, and Tbx1, are also preferentially expressed in the anterior heart field where Tbx1 has recently been shown to regulate the Mef2c gene expression [Cardiac cell lineages responsible for understanding cardiogenesis are of specific importance when interpreting congenital heart malformations but also in light of cardiac adaptations and failure Fig. . Mesoderal cells , 54. Unlmyocytes . Althougmyocytes , 56. Intmyocytes , 58. Addmyocytes  acting dmyocytes . Earliesntiation . As presntiation  reflectintiation ). An expntiation , 62. Durntiation . One expes Mefc2 . Additiopression .Fig. 3InNkx2-5 [Tbx1 gene resulting in the tetralogy of Fallot due to failure of migration of neural crest cells to the heart. On the other hand, mutations in Tbx5 are responsible for Holt-Oram syndrome [It may be clear that no “master” regulatory gene is responsible for cardiogenesis and determining the evolutionary intertwinement of those core transcription factors proves to be challenging , 65. NevNkx2-5 . Deletiosyndrome . Detailesyndrome , 61, 65.2 uptake and a high resistance systemic vascular bed permitting local regulation of O2 delivery. This evolutionary design encompasses progressive septation of the heart, resulting in the building plans of the mammalian (and bird) heart. This blueprint was subsequently maintained across species, independent of lifestyle and habitat, where genetics from 3-chambered to 4-chambered hearts emerged from the same ancestor. Within the first weeks of fetal life, interspecies cardiac evolution is incorporated in embryogenesis where (1) in 20 days, a single tube (worm like) is present; (2) followed by a sequential pumping structure (fish like) with an atrium, ventricle, bulbus cordis, and truncus arteriosus at 28 days; (3) continuing into a two-chambered heart (like amphibians and reptiles at 30 days); and (4) eventually the heart gets fully septated  by days 35–50. Cardiac regulatory genes have co-evolved during cardiac evolution with upstream signaling cascades that are intertwined, however, with specific genetic profiles for the RV  and crescent (in cross section) shape with a sinus (inlet), apex and conus, or infundibulum (outlet), separated by the supraventricular crest. The shape of the RV is further determined by the interventricular septum with a concave shape towards the LV  which is unaffected by the cardiac cycle. The thin-walled RV is anchored to the LV anteriorly and posteriorly both sharing the interventricular septum. The RV contains coarse trabeculations, a trabecula septomarginalis, providing innervation from the interventricular septum to the base of the anterior papillary muscle, and crista supraventricularis. The latter has a “U-shaped” morphology and is wedged between the tricuspid and pulmonary valve at the junction of the interventricular septum and the RV anterior wall and extends to the sub-pulmonary infundibulum.Microarchitectural alignment is chamber specific, where the RV, due to different loading conditions with a resultant specific force generation pattern (as discussed below), is composed of superficial and deep muscle layers. This alignment contributes to the complex contraction pattern of the RV including torsion , translation, rotation, and thickening , 69. OneNevertheless, ventricular fiber orientation patterns of both ventricles are intertwined in a complex three-dimensional architecture defining their vectorial  anatomy Fig. , albeit This specific morphological pattern translates into a specific RV function where volume handling, in respect to the pressure driven LV, is key. In such, in order to build up pressure in the LV, it is capable of creating a “torsion movement” which is created by opposing rotational movements of the base versus the apex. In contrast, the RV anatomical properties prohibit the production of torsion, even when facing extreme afterload .2 pressure with energy production being based on carbohydrates rather than fatty acids, thus creating glucose, lactate, and pyruvate, and has been suggested to be a feature of immature cardiomyocytes [HIF-α) and vascular endothelial growth factor (VEGF) that not only promote angiogenesis but are also associated with upregulated glycogenesis leading to good tolerance to hypoxia (which is better tolerated compared with the adult) [During fetal life, pulmonary resistance is high and blood is redirected creating a parallel circulation and the RV thus functions as a (low pressure) systemic ventricle. As a consequence, the RV is the dominant chamber in fetal life and accounts for about 60% of the cardiac output; hence, its wall thickness and force generation are equal to the LV . Until tmyocytes , 6. Majoe adult) –88. Finae adult) , and phoe adult) .2 pressure and shear stress in the pulmonary circulation increase, leading to the release of vasodilators (like prostacyclin and nitric oxide) and a decrease in secreted vasoconstrictors, such as endothelin-1. As a consequence, the pulmonary vascular resistance drops (and decreases even further later on), thereby decreasing pressures leading to an increase in compliance. Both the reduction in resistance and the increase in compliance contribute to the unloading of the RV [Immediately after birth, partial Of the RV , resultif the RV . ConcomiCompared with the fetal setting, there are several shifts in physiological processes. First, the metabolic pathway is adapted from glycolysis to fatty acid oxidation resulting in more ATP , 91. Dep2 for the RV versus 87 ± 12 g/m2 for the LV [The pulmonary vascular bed has a low hydraulic impedance with high compliance. Therefore, the pressure generated by the RV is lower which, according to Laplace’s law, translates into the thickness of the RV free wall of about 3–5 mm (in adults) and a mass that is 1/3 to 1/6 of the LV  being 26r the LV . Neverthr the LV  comparedr the LV .In summary, biomechanics of the RV are complex and differ from the LV in that morphological configuration of the RV is based on a very specific physiological demand. It depends on the insertion of the fibers on the interventricular septum, intertwinement with fibers of the LV, the septum itself, the contraction of the LV, and resultant external forces from the pericardium. It may be clear that sole descriptions of RV contraction patterns (and LV contraction patterns for that matter) are futile and need to be addressed into a bigger multilayer vectorial three-dimensional picture. This being said, caution should be warranted when interpreting such results as it is difficult to match architecture with the existing morphological data  and cleaDifferences between the right and left normal ventricular morphology and physiology are summarized in Table For many years, pathobiology of the RV was extrapolated from the LV and thus specific knowledge on the response of the RV on altered loading conditions is scarce, let alone, knowledge on increased volume loading –15. PrevAnother important group is represented by patients with longstanding PAH with HFpEF where eventually RV dysfunction develops in about one-third of all patients. This cannot solely be attributed to the afterload mismatch and identifies those patients with an increased risk of death , 107. MoAdaptations to chronic pressure overload, as evidenced by experimental PAH animal models , 112–117Clearly, the design of the RV is not optimized for pressure generation, where the thinner wall and lower volume-to-surface-area ratio , 6 of th2 tension should outweigh the increase in O2 delivery mediated by the increased cardiac output.Experimental volume loading studies show that RV contractility remains preserved for a long period, although contractile reserve may be compromised , 128. AlOverall, our understanding of RV response to chronic pressure overload, but also why certain patients are able to adapt and sustain very high pulmonary artery pressures, remains incomplete. In experimental models of RV failure, RV hypertrophy is present however not related to functional adaptation , 138. AsHAND2 expression is necessary for RV formation. In such, the transcription factor Bop is known to be a transcriptional target of Mef2c and GATA4 which are mandatory for HAND2 expression. Also, GATA4 regulates gene expression of α-MHC in the cardiac muscle and the gene encoding for atrial natriuretic peptide [Nkx2-5 is upregulated which is normally only present in the fetal heart. However, up-to-date, the precise function of this factor and its pathways are incompletely understood [Genetic cardiac morphogenetic analyses already showed a different embryological origin  and resembles that of the LV [C-fos-induced growth factor (FIGF), transport protein particle (TRAPPAC), and connective tissue growth factor (CTGF) in the non-failing RV compared with the LV. But also, in the failing RV, fibrillin 2 (FBN2), CTGF, SPARC-related modular calcium binding 2 (SMOC2), and TRAPP6AC were differentially expressed with respect to the LV [FIGF protein is a member of the platelet- and vascular-derived growth factor which is active in hypoxia-induced angiogenesis, lymphangiogenesis, and endothelial cell growth. In infarcted models, FIGF acts as a profibrogenic mediator stimulating myofibroblast growth and type I collagen synthesis [FIGF expression is reduced, physiological remodeling may be impaired [CTGF  is a multicellular protein of the family of extracellular matrix-associated heparin-binding proteins and has important roles in cell adhesion, migration, proliferation, and angiogenesis [CTGF is important in normal embryological development, however, has been linked to adult pathophysiology of, for example, atherosclerosis and fibrosis [CTGF levels and RV function, the recent findings of Williams et al. suggest that the role of CTGF in fibrosis and cardiomyopathy may be increased in right heart disease and RV failure [Nevertheless, individual genetic differences play a major role as some patients, with the same degree of afterload, develop more RV hypertrophy than others. Small studies have shown that patients with a non-DD angiotensin-converting enzyme polymorphism had elevated right atrial pressures and decreased cardiac output  suggestif the LV , 16. Howo the LV . FIGF prynthesis  represenimpaired . CTGF , and FBN2 (which functions as part of the extracellular matrix in connective tissue disease) in cardiovascular disease need to be elucidated.As stated, the downregulation of FIGF and upregulation of jor part . SpecifiTGF)-β and degradation of the matrix by metalloproteinases [The extracellular matrix consists predominantly of collagen with relatively small amounts of laminectin, fibronectin, and elastin, and is able to influence the contractile function and morphological configuration of the heart –153. Matteinases , 153–156teinases , 138; hoSince fibrosis is closely coupled to end-systolic elastance, it would be interesting to try and alter the fibrotic state; nevertheless, more recently, a study by Borgdorff et al. showed no relationship between the amount of fibrosis and the degree of myocardial dysfunction . As staAn important factor correlated to cardiomyocyte hypertrophy, contractile dysfunction, and fibrosis in angiotensin II (AngII). The group of Rouleau already showed that AngII-receptors are uncoupled in a rabbit RV hypertrophic model leading to increased levels of AngII with adverse contractility which could be effectively reversed by Ramipril . Also, fIn summary, cardiomyocyte dysfunction is not the sole factor to transform the hypertrophic RV into a failing one. Chronic overload of the RV leads to extracellular matrix changes which are prominent in patients with PAH; however, fibrosis was minimal in compensated RV hypertrophy , 166 and2 demand is lower than that of the LV in normal physiology. Also, due to lower pressures in the unstressed RV, coronary blood flow occurs throughout the complete cardiac cycle [2, the RV is relatively much more resistant to irreversible ischemia than is the LV [2 demand, coronary perfusion occurs mainly in diastole [2 supply-demand imbalance [The right-sided blood supply differs from the left, as it is dependent on the dominance of the coronary system. In 80–85% of the patients, there is a right dominant coronary system supplying most of the RV, that is, the margo acuta by the marginal branches and the posterior wall and inferoseptal region by the posterior interventricular artery. The anterior wall and anteroseptal region of the RV are supplied by the anterior interventricular artery. Given the lower workload of the RV, Oac cycle , 167. Tos the LV . Howeverdiastole  leading mbalance . Also, embalance , 159, wimbalance . Nonethembalance  which ismbalance . Up-to-dmbalance  while RVmbalance . Furthermbalance . Anothermbalance  and can mbalance , 175.2 per ATP [Despite the difference in workload in the non-stressed state, energetic profiles of both ventricles are largely the same in terms of glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, cellular aerobic capacity, and volume fraction of mitochondria . However per ATP . These a per ATP , 19, 91. per ATP  and down per ATP , 6, 19.  per ATP  and in p per ATP . The dec per ATP . However per ATP .HIF-1α and p38-MAPK [HIF-1α activation is associated with mitochondrial complex II-mediated reactive oxygen (ROS) production [2 tension to show that in rats with PAH, during the transition to RV failure, there is downregulation of in vivo mitochondrial O2 consumption in the absence of hypoxia [NF-kB [Although several studies have reported either increased uptake of labeled glucose analog  or increp38-MAPK . Also, Hoduction , 185 as oduction . Furtheroduction , 186. Neoduction . Recentl hypoxia . At rest hypoxia . Interesa [NF-kB , 188. Nea [NF-kB , 190. Ina [NF-kB , predispa [NF-kB .(TNF) superfamily appears to be implemented in the pathogenesis of RV failure through the Nf-kB pathway [Nf-kB pathway in RV failure [TNF-α and pro-inflammatory cytokines were also upregulated [TNF-α was solely upregulated in the RV while IL1-a and IL-1b concentrations were increased in both ventricles indicating a progression towards biventricular failure. Whatever the experimental setting may be, it is clear that inflammatory pathways are more commonly dysregulated in RV tissue in both failing and non-failing phenotypes [This progression from eustress to distress is associated with systemic activation of pro-inflammatory cytokines which accelerates the progression of HF . Such an pathway  in progr pathway . Also, i pathway  and a pr failure . Further failure . However failure . Interesegulated ; howeverenotypes .gp91phox and GTP-binding protein Rac1 [Overall, a large amount of studies already showed that cellular changes in ventricular remodeling are stimulated by neurohormones , inflammatory cytokines, and wall stress which in part are mediated and exacerbated by the oxidative/nitrosative pathway . Based oein Rac1 , 212. Anein Rac1 , though ein Rac1 , 206.For many years, the RV was deemed to be a lesser contributor to the contractile function of the heart, mainly based on early experiments suggesting that the RV functions as a passive conduit and is subordinate to the LV. Since the Working Group Statement in 2006, progress has been made in understanding the pathophysiological and pathobiological mechanisms of RV failure due to abnormal loading conditions; however, many inconsistencies exist in the literature contributing to the present knowledge hiatus.It is important to note that the development of four chambers evolved out of necessity for closed circuits with very different mechanical properties and differences between the left and right heart components have been embedded in the genetic profile. Indeed, multiple studies showed significant differences between the RV and LV on a morphological, physiological, and molecular level, resulting in a different adaptation to altered loading conditions and providing a potential explanation for the dissimilar responses of the ventricles to current HF therapies.RV adaptation to increased afterload is characterized by dilatation, increased contractility, and hypertrophy, whereas the progression to RV failure is characterized by a progressive decline of diastolic function and, despite increased contractility, a disturbed ventricular-arterial coupling. An important part is the inefficient energy metabolism, with a metabolic switch from fatty acid to glucose utilization, which is apparent in RV adaptation; however, its role is still unclear in RV failure. Also, despite its maintained coronary blood flow throughout the cardiac cycle, the diseased RV possibly lacks the necessary increase in capillary density with a loss of coronary vasodilatory reserve. Nevertheless, the role of capillary rarefaction remains controversial and a distinct modification in cardiomyocytes exists with a decreased substrate delivery for a certain amount of workload. This hypoxic environment possibly aids the progression towards RV failure with a lack of antioxidant enzymatic response and amplifying the redox imbalance.It seems that we are only now at the beginning of our understanding of the (patho)biology of RV remodeling and it is crucial to define specific molecular pathways responsible for this downwards spiral. Better yet, defining precise molecular mechanisms that elucidate the higher susceptibility of CHD patients to progress from a compensated state to overt RV failure would provide a concrete base for the development of “chamber-specific” HF therapies. It may be clear that there is an intertwined ventricular functional continuum within the process of HF and, based on the topics presented in this review, it is our understanding that RV failure forms a separate entity within this spectrum. In such, there should be a theoretical “point of no return” within this continuum of RV maladaptation to failure where our developmental blueprint plays an important role. Future research should therefore include comparative anatomical, developmental biological, and biomechanical approaches in the search for RV specific therapies.• Specific coupling between form and function in the right ventricle• Evolutionary proxies are present in camber formation• Specific molecular entities determine right ventricular biomechanics`• Multifactorial approach necessary when describing the right ventricular failure