Submitted by Mariana Moraes Contti (mmcontti@gmail.com) on 2019-01-31T12:54:19Z No. of bitstreams: 1 TESE HOMOLOG.pdf: 3705229 bytes, checksum: 788c829d039c6d6dc4dd78578b4db8ae (MD5) / Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2019-01-31T18:08:57Z (GMT) No. of bitstreams: 1 contti_mm_dr_bot.pdf: 3705229 bytes, checksum: 788c829d039c6d6dc4dd78578b4db8ae (MD5) / Made available in DSpace on 2019-01-31T18:08:57Z (GMT). No. of bitstreams: 1 contti_mm_dr_bot.pdf: 3705229 bytes, checksum: 788c829d039c6d6dc4dd78578b4db8ae (MD5) Previous issue date: 2018-12-03 / RESUMO: A ressonância magnética cardíaca (RMC), usando o T1 nativo, é considerado método não invasivo para avaliar fibrose miocárdica sem necessidade de usar contraste paramagnético. Até o momento não há dados a respeito do T1 nativo após o transplante renal. O objetivo primário deste estudo foi avaliar mudanças no T1 nativo do miocárdio, seis meses após o transplante renal. Foram analisados prospectivamente, 44 pacientes transplantados renais, os quais foram submetidos a 2 exames de RMC (3T): o 1º nos 10 dias inicias do transplante, e o 2º realizado seis meses após. O tempo do T1 nativo foi medido na região médio- septal e diminuiu significativamente de 1.331 ±52 ms (inicial) para 1.298±42 ms, seis meses após o transplante (p = 0,001). Os pacientes foram divididos em 2 grupos segundo o algoritmo de cluster: no cluster-1 (n=30), a massa do ventrículo esquerdo indexada (MVEi) foi menor, e não foi encontrado nenhum paciente portador de diabetes. No cluster-2 (n=14), a MVEi foi maior, e 100% dos pacientes eram diabéticos. A diminuição do T1 nativo foi significativa apenas nos pacientes do cluster-1 (p = 0,001). Concluindo, o tempo de T1 nativo do miocárdio diminuiu significativamente seis meses após o transplante renal, fato que pode estar associado com regressão da fibrose reativa. O grupo de pacientes que apresentou maior prevalência de diabetes e maior MVEi não alcançou diminuição do T1. ABSTRACT: The measurement of native T1 through cardiac magnetic resonance (CMR) is a noninvasive method of assessing myocardial fibrosis without gadolinium contrast. No studies so far have evaluated native T1 after renal transplantation. The primary aim of the current study is to assess changes in the myocardium native T1 six months after renal transplantation. We prospectively evaluated 44 renal transplant patients who were undergoing two 3-Tesla CMR exams: baseline at the beginning of transplantation and the second after six months. The native T1 time was measured in the midseptal region and decreased significantly from 1,331±52 ms at the baseline to 1,298±42 ms 6 months after transplantation (p = 0.001). The patients were split into two groups through a two-step cluster algorithm: in cluster-1 (n = 30) the left ventricular mass index (LVMi) was lower, and no patient with diabetes was found. In cluster-2 (n = 14) the LVMi and diabetes prevalence were higher. Decrease in native T1 values was significant only in the patients in cluster-1 (p = 0.001). In conclusion, the native myocardial T1 time decreased significantly six months after renal transplant, which may be associated with the regression of the reactive fibrosis. The patients with greater baseline LVMi and the diabetic group did not reach a significant decrease in T1.

Orientador: Luis Gustavo Modelli de Andrade / Resumo: RESUMO: A ressonância magnética cardíaca (RMC), usando o T1 nativo, é considerado método não invasivo para avaliar fibrose miocárdica sem necessidade de usar contraste paramagnético. Até o momento não há dados a respeito do T1 nativo após o transplante renal. O objetivo primário deste estudo foi avaliar mudanças no T1 nativo do miocárdio, seis meses após o transplante renal. Foram analisados prospectivamente, 44 pacientes transplantados renais, os quais foram submetidos a 2 exames de RMC (3T): o 1º nos 10 dias inicias do transplante, e o 2º realizado seis meses após. O tempo do T1 nativo foi medido na região médio- septal e diminuiu significativamente de 1.331 ±52 ms (inicial) para 1.298±42 ms, seis meses após o transplante (p = 0,001). Os pacientes foram divididos em 2 grupos segundo o algoritmo de cluster: no cluster-1 (n=30), a massa do ventrículo esquerdo indexada (MVEi) foi menor, e não foi encontrado nenhum paciente portador de diabetes. No cluster-2 (n=14), a MVEi foi maior, e 100% dos pacientes eram diabéticos. A diminuição do T1 nativo foi significativa apenas nos pacientes do cluster-1 (p = 0,001). Concluindo, o tempo de T1 nativo do miocárdio diminuiu significativamente seis meses após o transplante renal, fato que pode estar associado com regressão da fibrose reativa. O grupo de pacientes que apresentou maior prevalência de diabetes e maior MVEi não alcançou diminuição do T1. ABSTRACT: The measurement of native T1 through cardiac magnetic resonance (CMR) is a noni... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Introdução: A miocardiopatia chagásica (MC) apresenta pior prognóstico que as etiologias isquêmica e não isquêmica de miocardiopatia, e acarreta alto custo. A fibrose miocárdica (FM) detectada pela Ressonância Magnética Cardíaca (RMC) mostrou-se um fator preditor independente de risco aumentado em diversas etiologias de insuficiência cardíaca. Na MC, a FM foi associada com marcadores conhecidos de pior prognóstico, como a disfunção ventricular esquerda e arritmia ventricular. Nossa hipótese é que a FM é um fator preditor independente de pior prognóstico na MC. Objetivos: Buscamos estabelecer o valor prognóstico da FM detectada pela RMC na predição de uma combinação de desfechos duros ou do desfecho secundário mortalidade por todas as causas. Adicionalmente, avaliamos se o valor prognóstico da FM é independente do Escore de Rassi. Métodos: Pacientes com MC foram incluídos retrospectivamente após a realização da RMC, que avaliou volumes e função cardíacos, além de quantificar a FM. Dados clínicos, de imagem e seguimento foram registrados, e o desfecho primário foi a combinação de mortalidade por todas as causas, transplante cardíaco, terapia antitaquicardia ou choque apropriado pelo cardiodesfibrilador implantável e morte súbita cardíaca abortada; o desfecho secundário foi mortalidade por todas as causas. Resultados: Foram incluídos no estudo130 pacientes, a maioria de mulher (53,9%), com idade média de 53,6±11,5 anos. A maioria dos pacientes (68,4%) não tinha sintomas de insuficiência cardíaca, apesar da dilatação ventricular esquerda (54%) e alterações da contratilidade (65,9%) serem comuns. A RMC mostrou dilatação do ventrículo esquerdo (volume diastólico final indexado médio de 118,6±50,5ml/m²) e disfunção sistólica (fração de ejeção média de 43,2±16,3%) e a FM foi identificada em 76,1%, massa média de 15,2±16,5g. Ao longo do seguimento médio de 6,8 anos, 58 (44,6%) pacientes atingiram o desfecho combinado e 45 (34,6%) faleceram. A MF associou-se ao desfecho primário como variável contínua (Razão de risco (RR) ajustada 1,031 (Intervalo de Confiança (IC) 95% 1,013-1,049; p=0.001) e nos pacientes com FM extensa ( >= 12,3g) (RR ajustado 2,107 (IC 95% 1,111-3,994I; p=0,022)) de forma independente ao Escore de Rassi. A FM expressa como variável contínua também se associou à morte por todas as causas (RRajustado1,028 (IC 95% 1,005-1,051; p=0,017)) de forma independente do Escore de Rassi, exceto quando analisada como variável categórica. Conclusões: A fibrose miocárdica é um preditor independente de pior prognóstico na miocardiopatia chagásica. Nossos dados apoiam o uso da RMC para estratificar melhor o risco nessa população e, possivelmente, guiar o tratamento / Background: Chagas cardiomyopathy (CC) portends worse prognosis than ischemic and other non-ischemic cardiomyopathies and carries a high economic burden. Myocardial fibrosis (MF) detected by cardiac magnetic resonance (CMR) has been demonstrated as an independent predictor of increased risk in several etiologies of heart failure. In CC, MF has been associated with know risk factors of poor outcome, such as left ventricular dysfunction and ventricular arrhythmia. We hypothesized that MF is an independent predictor of worse prognosis in CC. Objectives: we sought to determine the prognostic value of MF detected by CMR in predicting a combined endpoint of hard events or the secondary outcome of all-cause mortality. In addition, we evaluated if the prognostic value of MF is independent of the Rassi risk score. Methods: patients with CC were retrospectively followed after CMR evaluation of cardiac volumes, function and MF quantification. Clinical, imaging and follow-up data were recorded and the primary outcome was a combination of all-cause mortality, heart transplantation, anti-tachycardia pacing or appropriate shock from an implantable cardiac defibrillator and aborted sudden cardiac death; the secondary outcome was all-cause death. Results: 130 patients were included in the study, with a majority of females (53.9%) and a mean age of 53.6±11.5 years. Most patients (68.4%) had no symptoms of heart failure, even though left ventricular dilatation (54%) and wall-motion abnormalities (65.9%) were common. On CMR, left ventricular dilatation (mean end-diastolic volume index 118.6±50.5ml/m²) and dysfunction (mean ejection fraction 43.2±16.3%) were observed and MF was found in 76.1%, with a mean mass of 15.2±16.5g. Over a mean follow-up of > 6.2 years, 58 (44.6%) patients reached the combined endpoint and 45 (34.6%) patients died. Myocardial fibrosis mass was associated with the primary outcome both as continuous variable (adjusted HR 1.031 (1.013-1.049 95% CI; p=0.001) and in patients with extensive MF ( >= 12.3g) (adjusted HR 2.107 (1.111-3.994 95% CI; p=0.022), independently from the Rassi Score. Myocardial fibrosis mass expressed as a continuous variable was also associated with all-cause death (adjusted HR 1.028 (1.005-1.051 95% CI; p=0.017) independently from the Rassi Score, but not when analyzed as a categorical variable. Conclusions: Myocardial fibrosis is an independent predictor of adverse outcome in Chagas cardiomyopathy. Our data support the use of CMR in better stratifying risk in this population and possibly guiding therapy

Introdução: A história natural da insuficiência mitral associa-se a décadas de remodelação ventricular esquerda com fibrose intersticial. A fronteira entre o processo adaptativo e a miocardiopatia dilatada demanda avaliação clínico-histológica. Atualmente, sabe-se que o melhor método empregado para quantificar as alterações decorrentes do remodelamento que acomete o ventrículo esquerdo é a biópsia miocárdica, que analisa a doença, somente após a cirurgia ou no post mortem. O presente estudo visa avaliar a fibrose miocárdica associada à insuficiência mitral crônica, através de estudo pela Ressonância Magnética, de maneira não invasiva, precoce e rápida. Objetivos: Avaliar a capacidade e a aplicabilidade da ressonância magnética cardíaca de detectar a fibrose miocárdica na insuficiência mitral crônica importante, tendo como referência a biópsia miocárdica. Métodos: Foram selecionados 52 pacientes portadores de IM crônica pura ou associada a estenose mitral leve, com PVM e DR, e com indicação cirúrgica. Todos os pacientes foram reavaliados pelo EcoDopplercardiograma e realizaram ressonância magnética cardíaca para avaliação da função ventricular, volumes e índice de massa ventricular esquerda, através da cine-ressonância e pela técnica do realce tardio miocárdico, com injeção de 0,2 mmol/kg de contraste gadolínio para a detecção de FM, sendo submetidos a cirurgia de plástica ou troca de válvula mitral com bióspsias miocárdicas, retiradas de locais padrão, na parede lateral do ventrículo esquerdo. Todas foram coradas pela técnica do hematoxilinaeosina, e as positivas para FM, confirmadas pelo corante picrossirius, que cora colágeno, e quantificadas pelo aparelho do quantimet. Resultados: Os pacientes foram divididos em quatro grupos, conforme a RM e a biópsia. A RM diagnosticou FM em 18 pacientes, concordantes com a BM (RMC/BM +). A RM foi negativa para FM em 33 pacientes, sendo 28 concordantes com a BM (RMC/BM -). Observou-se discordância de RM com a BM, em 7 casos falsos negativos (RMC-/BM +). A sensibilidade da RMC à fibrose foi de 72%, especificidade de 100%, e acurácia de 86,3%. Nos grupos distintos estudados, a sensibilidade, especificidade e acurácia foram de 64,7%, 100% e 82,4%, respectivamente, na PVM, e de 97,5%, 100% e 92,9%, respectivamente, na DR. O índice Kappa foi de 0,724 (p<0,001) para o grupo total; 0,665 (p<0,001) para PVM e 0,857(p<0,001) na DR. VDF, VSF e IMVE tiveram correlação positiva e significativa com a porcentagem de fibrose, sendo que, quanto maiores esses valores, maior a porcentagem de fibrose. Conclusão: RMC teve boa concordância com a BM, em relação aos achados de FM / Introduction: The natural history of mitral insufficiency (MI) is associated to decades of left ventricular remodelation with intersticial fibrosis. The frontier between adaptative process and dilatade miocardiopaty needs clinic and histologic evaluation. Now a days , we know that the best method to quantify the alterations of remodelation in left ventricule is myocardial biopsies which analyses the illness only after surgery or post morten. This actual study aims to evaluate myocardial fibrosis associated with cronic MI, through the study with magnetic resonance (MR), in a not invasive, early and quickly way. Objectives: Evaluate capacity and applicability of the magnetic resonance in detection of myocardial fibrosis in chronic important mitral insufficiency in reference with myocardial biopsis. Methods: It was selected 52 patients with pure chronic MI or associated with mild mitral stenosis, with cirurgical indication. All of the patients were reevaluated by EcoDopplercardiogram and it was done cardiac MR to evaluate ventricular function, volumes and left ventricular mass rate through MR cine and myocardial late realce techinique with 0,2 mmol/Kg with gadoline contrast and myocardial fibrosis (MF) detection and being undergone plastic or mitral valvular changes surgery with myocardial biopsis (MB) were taken from the left ventricular lateral wall. All of them were colored with hematoxilin eosine and the positives were confirmated with picrossirius and quantified with quantimet device. Results: Patients were divided in four groups according to MR and biopsies. MR diagnosticated MF in 18 patients agreed with MB (MR / MB +). MR was negative for MF in 33 patients where 28 agreed with MB (MR / MB -). We observated discordance with MR and MB in 7 cases false negatives (MR- /MB+). The sensibility of MR to fibrosis was 72%, specificity was 100% and acurace was 86,3%. In the distinct groups studied, we see sensibility, specifity and acure were 64,7%, 100 % and 82,4% respectivity in PVM and 97,5%, 100% and 92,9% respectivity in reumathic disease. The Kappa indice is 0,714 (p<0,001) for the total group; 0,665 (p<0,001) for PMV and 0,857 (p<0,001) in RD. There is a positive correlation and significative between fibroses percentage with VDF, VSF, IMVE of the MR. So the higher the values, higher the fibrosis percentage. Conclusion: MR had a good concordance with MB in relation to found the MF in IMC

A cardiomiopatia hipertrófica (CMH) é uma doença cardíaca genética e se caracteriza como a principal causadora de morte súbita em jovens, com apresentação clínica variável, desde assintomáticos a morte súbita, o que dificulta sua estratificação de risco. Tanto a ressonância magnética cardiovascular (RMC) como a tomografia computadorizada com múltiplos detectores (TCMD) mostraram-se capazes de avaliar a fibrose miocárdica, que é frequentemente encontrada nos casos de CMH. Os objetivos desta tese são: avaliar a distribuição e a correlação entre as áreas de hipertrofia e fibrose miocárdica pela RMC em pacientes com CMH; comparar a avaliação da fibrose miocárdica pela TCMD com a avaliação da fibrose miocárdica pela RMC; avaliar a fibrose miocárdica pela TCMD em pacientes com CMH portadores de cardiodesfibriladores e correlacionar a fibrose miocárdica pela TCMD com as arritmias ventriculares com terapia apropriada pelo CDI. Foram selecionados 145 pacientes com CMH, dos quais 13 apresentaram critérios de exclusão, sendo, portanto, incluídos 132 pacientes em seguimento ambulatorial, que assinaram termo de consentimento livre e esclarecido. Destes, 91 pacientes foram submetidos à RMC para avaliação das características morfofuncionais do coração, incluindo a caracterização da fibrose miocárdica. Outros 15 pacientes foram submetidos tanto à TCMD quanto à RMC para avaliação e comparação da fibrose miocárdica por ambos os métodos. Finalmente, 26 pacientes hipertróficos portadores de CDI foram submetidos somente à TCMD para a avaliação da fibrose miocárdica e seguimento. Entre os 91 pacientes submetidos à RMC, a idade média foi de 37,9±17 anos, dos quais 58% eram homens. A média da espessura máxima da maior parede hipertrofiada do VE foi de 24,2±6,3mm e a média da FEVE, de 73,3±13,3%. A fibrose miocárdica foi observada em 76,9% dos 91 pacientes com uma média da massa de fibrose indexada pela superfície corpórea de 8,1±11,0g/m2. Dos 1547 segmentos miocárdicos pertencentes aos 91 pacientes, 18,9% (293) apresentaram fibrose miocárdica. Destes, 35,2% dos segmentos com fibrose apresentavam espessura miocárdica normal. Por outro lado, 58,6% dos segmentos hipertrofiados não apresentavam fibrose miocárdica. Além disso, não foi observada correlação significativa entre os segmentos hipertrofiados e os segmentos com fibrose miocárdica pela regressão linear. (r = 0,13 p = 0,21). Adicionalmente, a análise por paciente demonstrou que 65,8% dos indivíduos não apresentavam concordância significativa (Kappa < 0,40, p NS) entre a hipertrofia e a fibrose miocárdica, enquanto 34,2% apresentavam concordância moderada, boa ou excelente entre a hipertrofia e a fibrose miocárdica (Kappa > 0,40, p<0,001). A comparação da análise do porcentual da fibrose miocárdica no grupo de 15 pacientes submetidos tanto a TCMD quanto a RMC, demonstrou boa correlação com r = 0,77 e p =0,0001 e média das diferenças de 0,99 gramas. A análise da fibrose miocárdica pela TCMD dos 26 pacientes com CMH e portadores de desfibriladores implantáveis há mais de um ano demonstrou que a fibrose miocárdica estava presente em 96,1% desta população de alto risco, com média de 20,5 ±15,8 gramas de fibrose. Em um segmento médio de 38,5±25,5 meses, 50% destes pacientes apresentaram choques apropriados secundários - na maioria à fibrilação ventricular (12/13 eventos). Naqueles que receberam choques apropriados, a massa de fibrose era significativamente maior do que naqueles que não se observaram o registro das arritmias (29,10±19,13g vs 13,57±8,31g, p=0,01). Utilizando 18 gramas de fibrose como ponto de corte, a chance de registro de FV/TV com terapia apropriada pelo CDI foi de 75%. O seguimento dos pacientes demonstrou que massa de fibrose miocárdica acima de 18 gramas apresentava taxa de arritmias ventriculares com terapia apropriada pelos desfibriladores significativamente maior (p=0,02). Na análise multivariada, a massa de fibrose miocárdica foi a única a se correlacionar independentemente com as arritmias ventriculares adequadamente tratadas pelos CDIs. Concluímos que a apresentação das áreas de hipertrofia e fibrose miocárdica é heterogênea e que a correlação entre elas nas imagens de RMC é variável, não sendo significativa na maioria dos pacientes. Nossos dados de validação da TCMD permitem concluir que quando a RMC não pode ser utilizada, a tomografia pode ser uma alternativa adequada. A análise da fibrose miocárdica em pacientes com CMH e CDI demonstrou associação significativa e independente entre a magnitude da fibrose miocárdica e terapia apropriada pelos desfibriladores / Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder leading cause of sudden death in young people with extremely variable presentation, from asymptomatic to sudden death as first symptom, leads to challenging risk stratification. Recently, both cardiovascular magnetic resonance (CMR) and multidetector computed tomography (MDCT) were able to assess myocardial fibrosis (MF) often found in cases of HCM. Our objectives were to evaluate the distribution and correlation of myocardial hypertrophy (MH) and myocardial fibrosis by CMR in patients with HCM; to compare and validate the assessment of myocardial fibrosis by MDCT and CMR and to evaluate the correlation between myocardial fibrosis by MDCT and ventricular arrhythmias appropriately treated by defibrillators, due to contraindications to CMR in this group. 145 HCM patients were selected with 13 having exclusion criteria. Then 132 outpatients were included and signed informed consent for this study. First, 91 patients were submitted to CMR to evaluate the morphofunctional characteristics of the heart including myocardial fibrosis; Second, 15 patients were submitted to both MDCT and CMR in order to evaluate myocardial fibrosis by both methods, and finally 26 HCM patients with implantable cardiac defibrillator (ICD) were submitted to MDCT, for assessment MF. Among 91 patients submitted to CMR the mean age was 37.9 ± 17 years old, and 58% were men. The LV maximum end diastolic wall thickness was 24.2 ± 6.3mm and LVEF mean was 73.3% ± 13.3. MF was evident in 76.9% of patients with a mean fibrosis mass index of 8.1±11.0g/m2. Of all the 1547 myocardial segments from 91 HCM patient, 35.2% of segments with MF occurred in segments without MH, 58.6% of MH segments had no signs of MF. Linear regression showed no significant correlation between number of segments with MH and MF (r = 0.13, p = 0.21). A per patient Kappa analysis showed no significant agreement (Kappa0.40, p ns) between MH and MF in 65.8% of the population and the remaining 34.2% of this population showed a significant agreement between MH and MF (kappa > 0.40, p < 0.001). The analysis of MF% in the group of 15 HCM patients submitted by both MDCT and MR showed a good correlation by linear regression between the two methods with r = 0.77 and p = 0.0001 with mean difference of 0.99g. The MF analysis by TCMD in 26 HCM patients with ICD, clinically indicated, for at least one year demonstrated that MF was present in 96.1% of patients with a mean fibrosis mass of 20.5±15.8g. During the mean follow-up of 38.5±25.5 months, 50% of these patients present appropriated shocks due to ventricular fibrillation in most of cases (12/13 registered events). Patients with appropriate ICD shocks had significantly greater MF mass than those without (29.10±19.13g vs 13.57±8.31g, p=0.01). The best MF mass cut off was 18g, with an accuracy of 0.75 for predicting ICD firing. Patients with MF mass 18g had a significantly higher event rate in the follow up (p=0.02). MF mass was independently associated with ventricular tachycardia/fibrillation on ICD-stored electrograms by multivariate analysis. We conclude that the presentation of myocardial hypertrophy and fibrosis areas is heterogeneous and the correlation between MH and MF is variable and non significant in the most of the patients in CMR images. The validation data of MF techniques showed that in cases where CMR can not be used, MDCT may be a good alternative to assessment of fibrosis. The MF analysis in HCM patients with ICD showed a significant and independent association between MF extent and VF / VT appropriated therapy by ICDs

The general purpose of this thesis is to establish the ability of Speckle Tracking Echocardiography (STE) in assessing left atrial (LA) response to pressure and volume overload respectively in aortic stenosis (AS) and mitral regurgitation (MR), and to evaluate its accuracy in predicting LA and right ventricular (RV) fibrosis in patients with end-stage heart failure (HF) undergoing heart transplantation (HTx). I demonstrated that assessment of left ventricular (LV) long axis systolic velocity and amplitude of excursion is more sensitive than simple determination of ejection fraction (EF) for revealing the beneficial impact of MR surgery on overall LV systolic performance. Severe symptomatic AS is associated with LA enlargement and compromised mechanical function with a high incidence of peri-operative atrial fibrillation (AF). Valve replacement reverses these abnormalities and regains normal atrial function, a behaviour which is directly related to the severity of pre-operative LV outflow tract obstruction. Early identification of LA size and function disturbances, as shown by myocardial strain measurements might contribute to better patient’s recruitment for a safe valve replacement. In late stage HF patients, the right ventricle is enlarged, with reduced systolic function due to significant myocardial fibrosis. RV free wall myocardial deformation is the most accurate function measure that correlates with the extent of RV myocardial fibrosis and functional capacity. In patients with preserved EF, severe MR masks LV and LA myocardial dysfunction and correlates with symptoms and post-operative cavity function instability. Three months after MVR, the underlying myocardial disturbances are unmasked suggesting that most pre-operative measurements are subject to loading conditions. Finally LA volume and PALS remain the main predictors of post-operative AF, thus should be used for stratifying surgical risk. STE has been shown to accurately determine the severity of impairment of LA myocardial function shown by suppressed PALS which was the strongest predictor of the presence and extent of fibrosis, over and above other structure and function parameters. These findings may assist in better stratifying patients with end stage HF and identifying particularly those requiring HTx.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-04T11:32:50Z No. of bitstreams: 1 Carolina Thé Macedo Avaliação da acuracia...2015.pdf: 2036804 bytes, checksum: 926f70b1e7ec1709b317e04842607c6a (MD5) / Approved for entry into archive by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-04T11:33:56Z (GMT) No. of bitstreams: 1 Carolina Thé Macedo Avaliação da acuracia...2015.pdf: 2036804 bytes, checksum: 926f70b1e7ec1709b317e04842607c6a (MD5) / Made available in DSpace on 2016-02-04T11:33:56Z (GMT). No. of bitstreams: 1 Carolina Thé Macedo Avaliação da acuracia...2015.pdf: 2036804 bytes, checksum: 926f70b1e7ec1709b317e04842607c6a (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / Um dos principais desafios na miocardiopatia chagásica é a detecção de alterações precoces na função ventricular esquerda. A avaliação do strain pelo speckle tracking na ecocardiografia bidimensional (2-D ST) é um novo método com aplicações em diversas doenças cardíacas, tendo sido validado para pacientes com infarto do miocárdio em comparação à ressonância magnética cardíaca (RMC). Neste estudo, avaliamos a hipótese de que o strain global longitudinal (SGL) possui um valor incremental à fração de ejeção (FE) pelo método de Simpson para predição de fibrose miocárdica na RMC, em pacientes portadores de doença de Chagas (DC). Métodos: Estudo observacional, com um total de 58 pacientes portadores de DC. Todos os pacientes foram submetidos à realização de ecocardiograma convencional e com strain pelo speckle tracking, além de RMC. Resultados: A análise da curva ROC mostrou que tanto a SGL (área sob a curva: 0,78, p = 0,001) quanto a fração de ejeção (área sob a curva: 0,82, p < 0,001) tiveram significância estatística na detecção de fibrose. Em relação á porcentagem de fibrose, uma alta correlação foi observada tanto com a FE pela ecocardiografia (r = - 0,70, p < 0,001) quanto com o SGL (r = 0,64, p < 0,001). Contudo, quando ajustado pela regressão linear múltipla, o SGL perdeu a significância estatística como preditor independente de fibrose miocárdica (p = 0.111). Conclusões: SGL não possui valor incremental em relação à FE na predição de fibrose miocárdica em pacientes portadores de DC. / One of the most challenging issues of chronic Chagas disease is to provide earlier detection of heart involvement. Two-dimensional speckle tracking (2-D ST) echocardiography, a new imaging modality with useful applications in several cardiac diseases, has been validated for subjects with myocardial infarction against cardiac magnetic resonance (CMR). Here we hypothesize that the longitudinal global strain (LGS) has an incremental value to ejection fraction for predicting myocardial fibrosis in subjects with Chagas disease. Methods: This observational study comprised 58 subjects with Chagas disease, confirmed by two positive serologic tests. All subjects underwent conventional Doppler echocardiogram plus speckle tracking strain, and cardiac magnetic resonance. Results: The ROC curve analysis revealed that both LGS (Area under the curve: 0.78, p = 0.001) and ejection fraction (Area under the curve: 0.82, p < 0.001) were significant predictors of myocardial fibrosis. Regarding the percentage of fibrosis, a high correlation was observed with both ejection fraction assessed by echocardiography (r = - 0.70, p < 0.001) and LGS (r = 0.64, p < 0.001). However, when adjusted through multiple linear regression, the LGS lost statistical significance as a predictor of myocardial fibrosis (p = 0.111). Conclusions: LGS has no incremental value to conventional ejection fraction measurement in the prediction of myocardial fibrosis in subjects with Chagas disease.

Abstract A non-ischemic etiology of sudden cardiac death (SCD), mostly due to various cardiomyopathies (CMP), accounts for about 20% of all SCDs. Most of the major studies of risk factors for SCD have focused on coronary artery disease (CAD). The aim of the present study was to clarify the characteristics of non-ischemic SCD in Northern Finland. In this study, consecutive victims of SCD (n=2661) were prospectively collected, and among whom post-mortem examinations were performed between 1998 and 2007. Information about the SCD victims was obtained from a combination of available medical records, postmortem examination reports, medication used at the time of SCD, and standardized questionnaire filled out by the closest family members of the victims of SCD. We also screened the candidate genes from a Finnish family in which fatal arrhythmias was first manifestation of a cardiac disease. The collagen content of the myocardium from histological samples in victims of SCD due to idiopathic myocardial fibrosis (IMF) was also evaluated. CAD was the most common cause of death (2082 victims, 78.2%). The prevalence of non-ischemic SCDs was 21.8% of all the SCDs. After sub-grouping the non-ischemic SCDs into various categories, the most common cause of death was CMP related to obesity (23.7%), followed by alcoholic CMP (19.0%), hypertensive CMP (15.5%) and IMF (13.6%). The association of SCD with IMF is notably frequent among victims &#60;40 years old (28.3%). The prevalence of family history of SCD was significantly higher in the victims of ischemic (34.2%) than non-ischemic SCD (13.4%, P&#60;0.001) or controls (17.6%, P&#60;0.001). Lamin A/C gene mutation R541C was found from Finnish SCD family, in which the IMF was predominant pathologic-anatomic finding. Myocardial type I collagen synthesis was increased in victims of SCD due to IMF. In conclusion, the characteristics of non-ischemic SCD in Finland differ from those reported previously. Higher prevalences of CMP-associated SCDs related to obesity, IMF and alcoholic CMP were observed as clinical and/or pathologic bases for non-ischemic SCD. The family history of SCD is not significantly increased in victims of non-ischemic SCD, suggesting a larger role of sporadic occurrence than inherited traits as the cause of non-ischemic SCD. Replacement of cardiac myocytes by fibrosis can be responsible for fatal cardiac arrhythmias in subjects with the lamin A/C gene mutation. The victims of SCD due to IMF have increased myocardial type I collagen synthesis. / Tiivistelmä Ei-iskeeminen sydänperäinen äkkikuolema aiheuttaa noin 20&#160;% kaikista sydänperäisistä äkkikuolemista. Suurin osa ei-iskeemisistä sydänperäisistä äkkikuolemista johtuu erilaisista sydänlihassairauksista, kardiomyopatioista. Useimmat sydänperäisen äkkikuoleman riskitekijöitä kartoittavista tutkimuksista ovat keskittyneet sepelvaltimotautiin. Tämän tutkimuksen tarkoituksena oli selvittää ei-iskeemisen sydänperäisen äkkikuoleman tunnuspiirteitä pohjoissuomalaisessa väestössä. Tutkimuksessa käytettiin potilasaineistona sydänperäiseen äkkikuolemaan menehtyneitä vainajia (n=2661), joille on tehty oikeuslääketieteellinen ruumiinavaus. Tiedot vainajista saatiin saatavilla olevista potilaskertomuksista, ruumiinavauspöytäkirjoista, äkkikuoleman aikaisesta lääkityksestä ja lähiomaisille lähetetystä standardisoidusta kyselylomakkeesta. Kandidaattigeenit tutkittiin pohjoissuomalaisesta perheestä, jossa ensimmäinen oire sydänsairaudesta oli hengenvaarallinen rytmihäiriö. Lisäksi sydänlihaksen kollageenikoostumus analysoitiin histologisista näytteistä potilailta, joiden sydänperäinen äkillinen kuolema johtui idiopaattisesta sydänlihaksen sidekudoskasvusta. Sepelvaltimotauti oli yleisin sydänperäisen äkkikuoleman aiheuttaja (n=2082, 78,2&#160;%). Ei-iskeemisten sydänperäisten äkkikuolemien osuus oli 21,8&#160;% (n=579) kaikista sydänperäisistä äkkikuolemista. Ei-iskeemiset sydänperäiset äkkikuolemat jaettiin alaryhmiin, joista yleisimmät olivat lihavuuteen assosioituva kardiomyopatia (23,7&#160;%), alkoholikardiomyopatia (19,0&#160;%), korkeaan verenpaineeseen assosioituva kardiomyopatia (15,5&#160;%) sekä idiopaattinen sydänlihaksen sidekudoskasvu (13,6 %), joka myös oli yleisin ei-iskeemiseen sydänperäiseen äkkikuolemaan johtava syy alle 40-vuotiailla (28,3&#160;%). Positiivinen sydänperäisen äkkikuoleman sukuhistoria oli tilastollisesti merkitsevästi yleisempää iskeemisillä (34,2&#160;%) kuin ei-iskeemisillä (13,4&#160;%) sydänperäisen äkkikuoleman uhreilla. Lamin A/C – geenin mutaatio löydettiin pohjoissuomalaisesta äkkikuolemaperheestä, jossa idiopaattinen sydänlihaksen sidekudoskasvu todettiin pääasialliseksi patologiseksi löydökseksi. Tyypin I kollageenin synteesi todettiin kohonneeksi idiopaattiseen sydänlihaksen sidekudoskasvuun menehtyneillä vainajilla. Yhteenvetona voidaan todeta, pohjoissuomalaisen väestön ei-iskeemisen sydänperäisen äkkikuoleman tunnuspiirteet eroavat aiemmin raportoiduista; lihavuuteen assosioituva kardiomyopatia, alkoholikardiomyopatia, sekä idiopaattinen sydänlihaksen sidekudoskasvu olivat aiempaa yleisempiä ei-iskeemisen äkkikuoleman aiheuttajia. Positiivinen sydänperäisen äkkikuoleman sukuhistoria ei ollut tilastollisesti merkitsevästi kohonnut ei-iskeemisen sydänperäiseen äkkikuolemaan menehtyneillä. Tämä tarkoittaa, että perinnöllinen syy ei-iskeemisen sydänperäisen äkkikuoleman aiheuttajana on luultua harvinaisempi. Lamin A/C – geenimutaation kantajilla sydänlihassolujen korvautuminen sidekudoksella todettiin hengenvaarallisen rytmihäiriön aiheuttajaksi. Lisäksi, tyypin I kollageenin synteesi todettiin kohonneeksi idiopaattiseen sydänlihaksen sidekudoskasvuun menehtyneillä vainajilla.

In adult heart, pressure overload leads to cardiac hypertrophy. Higher propensity of hypertrophied myocardium to life-threatening arrhythmia is attributed to structural, mechanical and electrical remodeling. Pro-arrhythmogenic remodeling comprise several factors depending on an experimental model and a stage of heart failure. This thesis aims to characterize the impact of these factors in our unique model of pressure overloaded neonatal rat heart. The constriction of abdominal aorta was performed at postnatal day 2 in male Wistar rats. Decreased body weight, significant since week 6, was observed during development of cardiomegaly. At 12 weeks, the heart to body weight ratio was increased by 45 % and by 109 % in group with compensated (AC I) and decompensated (AC II) heart failure, respectively. At this age, the ECG was recorded and histological and immunohistochemical measurements were performed to analyze the pro-arrhythmogenic remodeling of working myocardium and cardiac conduction system. The markers of pro-arrhytmogenic remodeling such as significant prolongation of QT and QTc intervals were observed in the ECG recordings of AC II animals. However, spontaneously occurring arrhythmias was not detected. Further analysis of working myocardium showed decrease in Cx43 expression and its...

Introdução: A doença valvar aórtica grave é caracterizada por um processo de acúmulo progressivo de fibrose intersticial no tecido miocárdico. No contexto da sobrecarga mecânica crônica do VE característica dessa condição, a quantidade de fibrose intersticial pode exercer um papel importante na indesejável transição entre hipertrofia ventricular esquerda compensada e insuficiência cardíaca congestiva clinicamente manifesta. Entretanto, a avaliação quantitativa da fibrose intersticial só tem sido possível através da análise histopatológica de fragmentos miocárdicos obtidos por biopsia endomiocárdica. Objetivos: Avaliar se a ressonância magnética (RM) cardíaca com técnica do realce tardio permite a quantificação não-invasiva da fibrose miocárdica quando comparada à análise histopatológica em pacientes portadores de doença valvar aórtica grave. Adicionalmente, avaliou-se a relação entre a quantidade de fibrose miocárdica e parâmetros prognósticos importantes, tais como mortalidade e recuperação funcional do VE após cirurgia de troca valvar aórtica. Métodos: Entre Maio de 2001 e Dezembro de 2003 foram incluídos 54 pacientes com indicação de cirurgia de troca valvar aórtica. Antes da cirurgia, todos os pacientes foram submetidos a RM cardíaca com técnicas de cine-RM e realce tardio miocárdico. A quantificação da fibrose miocárdica pela RM baseou-se na análise das imagens de realce tardio utilizando um novo algoritmo semi-automático. As regiões de fibrose miocárdica foram definidas como o somatório de todos os pixels do tecido miocárdico com intensidade de sinal acima de um limiar definido como: intensidade de sinal média do miocárdio + 2 desvios padrão da intensidade de sinal média da área remota + 2 desvios padrão da intensidade de sinal média do ar. Amostras de tecido miocárdico obtidas por miectomia durante o ato cirúrgico foram submetidas a coloração pelo picrosírius para quantificação da fibrose intersticial. Os pacientes foram submetidos a um segundo exame de RM cardíaca 6 meses após a cirurgia para se avaliar as alterações evolutivas dos parâmetros funcionais do VE e todos foram acompanhados por pelo menos 24 meses quanto à sobrevida após a cirurgia de troca valvar aórtica. Resultados: O percentual de fibrose miocárdica pela RM apresentou boa correlação com os valores obtidos pela histopatologia (r=0,69; y=3,10x+13,0; p<0,0001). A quantidade de fibrose miocárdica, tanto pela histopatologia como pela RM, apresentou correlação inversa significativa com a FE ventricular esquerda basal (r=-0,63 e -0,67 respectivamente; p<0,0001). Adicionalmente, o percentual de fibrose miocárdica apresentou correlação inversa significativa com o grau de recuperação funcional do VE após a cirurgia de troca valvar (r=- 0,42, p=0,04 para a histopatologia; r=-0,47, p=0,02 para a RM). Mais importante, a análise de Kaplan-Meier revelou que o acúmulo de fibrose miocárdica associou-se a menor sobrevida 52±17 meses após a cirurgia de troca valvar (teste log-rank: 2=6,32; p=0,01 para histopatologia; 2=5,85; p=0,02 para RM). Conclusões: A RM cardíaca permite quantificar as regiões de fibrose miocárdica com boa acurácia quando comparada à análise histopatológica nos pacientes portadores de doença valvar aórtica grave. A magnitude de acúmulo de fibrose miocárdica está associada a pior recuperação funcional do VE e a menor sobrevida após a cirurgia de troca valvar aórtica. / Introduction: Severe aortic valve disease is characterized by a process of progressive accumulation of interstitial fibrosis in the myocardial tissue. It has been shown that the amount of interstitial myocardial fibrosis can play an important role in the transition from well-compensated hypertrophy to overt heart failure in the setting of chronic left ventricular mechanical overload typical of this condition. However, assessment of interstitial myocardial fibrosis has only been possible through histological analyses of myocardial fragments obtained from endomyocardial biopsies, which is a complex and invasive procedure and, therefore, with limited clinical applicability. Objectives: Determine whether delayedenhancement cardiac magnetic resonance imaging (MRI) allows for the non-invasive quantification of myocardial fibrosis when compared against histopathological analyses in patients with severe aortic valve disease. Additionally, we evaluated the relationship between the amount of myocardial fibrosis and important prognostic parameters, such as all-cause mortality and LV functional recovery after aortic valve replacement. Methods: Fifty-four patients scheduled to undergo aortic valve replacement surgery were enrolled between May 2001 and December 2003. Before surgery, all patients underwent cine and delayedenhancement MRI in a 1.5 Tesla scanner. Quantification of myocardial fibrosis by cardiac MRI was based on the assessment of the delayed-enhancement dataset using a novel semiautomatic algorithm. The regions of myocardial fibrosis were defined as the sum of pixels with signal intensity above a threshold value defined as: mean signal intensity of the myocardium + 2 standard deviations of mean signal intensity of a remote area + 2 standard deviations of mean signal intensity of air. During open-heart surgery, myectomy samples were acquired from the LV septum and later stained with picrosirius for interstitial myocardial fibrosis quantification. A second cardiac MRI study was performed 6 months after surgery to assess long-term changes in LV functional parameters, and all patients were followed for at least 24 months to evaluate survival after aortic valve replacement. Results: There was a good correlation between the values of myocardial fibrosis measured by MRI and those obtained by histopathological analyses (r=0.69; y=3.10x+13.0; p<0.0001). The amount of myocardial fibrosis, either by MRI or by histopathology, exhibited a significant inverse correlation with LV ejection fraction before surgery (r=-0.63 e -0.67 respectively; p<0.0001). Additionally, the amount of myocardial fibrosis displayed a significant inverse correlation with the degree of LV functional recovery after aortic valve replacement (r=-0.42, p=0.04 for histopathology; r=-0.47, p=0.02 for MRI). Most importantly, Kaplan-Meier and Cox regression analyses revealed that higher degrees of myocardial fibrosis accumulation were associated with worse survival 52±17 months after aortic valve replacement surgery (log-rank test: 2=6.32; p=0.01 for histopathology; 2=5.85; p=0.02 for MRI). Conclusions: Cardiac MRI allows for the non-invasive quantification of myocardial fibrosis with good accuracy when compared with histopathological analyses in patients with severe aortic valve disease. The degree of myocardial fibrosis accumulation is associated with impaired LV functional recovery and worse survival after aortic valve replacement surgery.