京都大学 / 新制・課程博士 / 博士(医科学) / 甲第24843号 / 医科博第151号 / 新制||医科||10(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 齋藤, 潤, 教授 遊佐, 宏介, 教授 松田, 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--University of Stellenbosch, 2009. / Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, is considered a model for studying left ventricular hypertrophy (LVH) in the absence of increased external loading conditions. The disease manifests extreme variability in the degree and pattern of LVH, even in HCM patients with the same causal mutation. The clinical phenotype of HCM can therefore be viewed as a product of the effect of sarcomere dysfunction and of additional genetic modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) are plausible candidate modifiers because of their effect on blood pressure and their direct hypertrophic effect on cardiomyocytes. The present study investigated genes encoding components of the RAAS for association with cardiac hypertrophy traits, in 353 individuals comprised of genetically and echocardiographically affected and unaffected family members, belonging to 22 HCM families with HCM founder mutations by employing a multi-SNP approach with TaqMan allelic discrimination technology. Gene-gene interaction analysis was also performed to investigate the effect of epistasis on hypertrophy. Candidate genes for analysis included the angiotensin II type 2 receptor (AT2 receptor), renin, renin-binding protein (RnBP), the (pro)renin receptor, the mineralocorticoid receptor as well as genes encoding subunits of the epithelial sodium channels (ENaC) and Na+/K+-ATPase that showed evidence for cardiac expression. The present study demonstrates for the first time that variations in the renin and RnBP genes play a role in modulating hypertrophy in HCM, independent of blood pressure and confirms the involvement of the AT2 receptor in hypertrophy in HCM. Additionally we report an association between Na+/K+-ATPase α1- and β1-subunits as well as the ENaC α- and β-subunits and hypertrophy. Significant evidence for epistasis was found between renin and downstream RAAS effectors, suggesting a complex interplay between these RAAS variants and the hypertrophic phenotype in HCM. The identification of such modifiers for HCM may offer novel targets for hypertrophy research and ultimately antihypertrophic therapy.

Cardiac myosin binding protein-C (cMyBP-C) is a structural and regulatory component of cardiac thick filaments. It is observed in electron micrographs as seven to nine transverse stripes in the central portion of each half of the A band. Its C-terminus binds tightly to the myosin rod and contributes to thick filament structure, while the N-terminus can bind both myosin S2 and actin, influencing their structure and function. Mutations in the MYBPC3 gene (encoding cMyBP-C) are commonly associated with hypertrophic cardiomyopathy (HCM). In cardiac cells there exists a population of myosin heads in the super-relaxed (SRX) state, which are bound to the thick filament core with a highly inhibited ATPase activity. This report examines the role cMyBP-C plays in regulating the population of the SRX state of cardiac myosin by using an assay that measures single ATP turnover of myosin. We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type. A smaller, non-significant decrease is observed when thoracic aortic constriction is used to induce cardiac hypertrophy in mutation negative mice. These results support the proposal that cMyBP-C stabilises the thick filament and that the loss of cMyBP-C results in an untethering of myosin heads. This results in an increased myosin ATP turnover, further consolidating the relationship between thick filament structure and the myosin ATPase. Crown Copyright (C) 2016 Published by Elsevier Ltd. All rights reserved.

Introdução: A miocardiopatia hipertrófica é a mais frequente doença cardiovascular de origem genética e está associada a arritmias e morte cardiovascular. O aumento do átrio esquerdo e a fibrilação atrial são considerados marcadores de morte por insuficiência cardíaca em pacientes com miocardiopatia hipertrófica. A apneia obstrutiva do sono é o distúrbio respiratório do sono mais comum, caracterizando-se por episódios recorrentes de colapso parcial ou total das vias aéreas superiores durante o sono. A apneia obstrutiva do sono é muito prevalente entre as populações com doença cardiovascular, como hipertensão arterial e insuficiência cardíaca, e está associada a remodelamento cardíaco e arritmias. Objetivos: O objetivo deste estudo foi determinar a prevalência dos distúrbios respiratórios do sono em pacientes com miocardiopatia hipertrófica e avaliar a associação da apneia obstrutiva do sono com o remodelamento cardíaco (ventricular e atrial) e fibrilação atrial em pacientes com miocardiopatia hipertrófica. Métodos: Foram estudados pacientes consecutivos estáveis clinicamente, com um diagnóstico confirmado de miocardiopatia hipertrófica acompanhados no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Os pacientes foram submetidos à avaliação clínica, questionário de sonolência, bioquímica sanguínea, ecocardiograma e monitorização respiratória noturna com poligrafia portátil. Foi utilizado um valor de corte de 15 e 30 apneias e hipopneias por hora de registro para o diagnóstico de apneia obstrutiva do sono e apneia obstrutiva do sono grave, respectivamente. Resultados: Foram avaliados 80 pacientes consecutivos com miocardiopatia hipertrófica. Apneia obstrutiva do sono foi diagnosticada em 32 pacientes (40%). Apneia obstrutiva do sono grave esteve presente em 17 pacientes (21%). Pacientes com apneia obstrutiva do sono foram significativamente mais velhos (56 [41-64] vs. 39 [30-53] anos, p < 0,001), apresentaram maior índice de massa corporal (28,2 ± 3,5 vs. 25,2 ± 5,2 Kg/m2, p < 0,01), maior dimensão do átrio esquerdo (45 [42-53] vs. 41 [39-47] mm, p = 0.01) e maior diâmetro da aorta (34 [30-37] vs. 29 [28-32] mm, p < 0,001) em comparação com pacientes sem apneia obstrutiva do sono. Dois modelos de regressão linear múltipla para identificar os fatores associados ao aumento do átrio esquerdo e da aorta ascendente mostraram que o índice de apneia e hipopneia foi a única variável associada ao aumento atrial (p = 0,05) e da aorta (p = 0,01), respectivamente. A fibrilação atrial permanente esteve presente em 31% vs. 6% dos pacientes com e sem apneia obstrutiva do sono, respectivamente (p < 0,01). A apneia obstrutiva do sono (p = 0,03) e o diâmetro do átrio esquerdo (p = 0,03) foram os únicos fatores independentemente associados à fibrilação atrial em um modelo multivariado. Conclusão: A apneia obstrutiva do sono é muito prevalente em pacientes com miocardiopatia hipertrófica e está associada com aumento do átrio esquerdo e da aorta ascendente. A apneia obstrutiva do sono está independentemente associada à fibrilação atrial, um fator de risco para óbito cardiovascular nesta população / Background: Hypertrophic cardiomyopathy is the most common genetic cardiovascular disease and is associated with arrhythmias and cardiovascular death. Left atrial enlargement and atrial fibrillation are considered markers for death due to heart failure in patients with hypertrophic cardiomyopathy. Obstructive sleep apnea is the most common sleep disordered breathing and is characterized by recurrent episodes of partial or complete collapse of the upper airway during sleep. Obstructive sleep apnea is extremely prevalent among populations with cardiovascular disease, such as systemic hypertension and heart failure and is independently associated with heart remodelling and arrhythmias. Objectives: The aim of this study was to determine the prevalence of sleep disordered breathing in consecutive patients with hypertrophic cardiomyopathy and evaluate the association of obstructive sleep apnea with heart remodelling (ventricular and atrial) and with atrial fibrillation in patients with hypertrophic cardiomyopathy. Methods: We studied consecutive clinically stable patients with a confirmed diagnosis of hypertrophic cardiomyopathy followed in the Heart Institute Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, by clinical evaluation, sleep questionnaire, biochemical blood analysis, echocardiography and sleep study (overnight portable respiratory monitoring). We used a cut-off value of 15 and 30 apneas and hypopneas per hour of recording in the sleep study for the diagnosis of obstructive sleep apnea and severe obstructive sleep apnea, respectively. Results: We evaluated 80 consecutive patients with hypertrophic cardiomyopathy. Obstructive sleep apnea was present in 32 patients (40%). Severe obstructive sleep apnea was present in 17 patients (21%). Patients with obstructive sleep apnea were significantly older (56 [41-64] vs. 39 [30-53] years, p < 0.001), presented higher body mass index (28.2 ± 3.5 vs. 25.2 ± 5.2 Kg/m2, p < 0.01), increased left atrial diameter (45 [42-53] vs. 41 [39-47] mm, p = 0.01) and aorta diameter (34 [30-37] vs. 29 [28-32] mm, p < 0.001) compared with patients without obstructive sleep apnea. Two models of stepwise multiple linear regression to identify variables associated with left atrial and ascending aorta enlargement showed that apnea-hypopnea index was the only variable associated with left atrial enlargement (p = 0.05) and aorta diameter (p = 0.01), respectively. Permanent atrial fibrillation was present in 31% vs. 6% in patients with and without obstructive sleep apnea, respectively (p < 0.01). Obstructive sleep apnea (p = 0.03) and left atrial diameter (p = 0.03) were the only factors independently associated with atrial fibrillation in a multivariate model. Conclusions: Obstructive sleep apnea is highly prevalent in patients with hypertrophic cardiomyopathy and it is associated with left atrial and ascending aorta enlargement. Obstructive sleep apnea is independently associated with atrial fibrillation, a risk factor for cardiovascular death in this population

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

A cardiomiopatia hipertrófica (CMH) é a cardiopatia mais diagnosticada em felinos e responsável por morbidade e mortalidade elevadas. A desorganização do sarcômero no miocárdio de gatos afetados com a CMH tem relação com a mutação do gene miosina ligado à proteína C (MYBPC3). A concentração plasmática de biomarcadores cardíacos como o aminoterminal peptídeo natriurético atrial (NTproANP) e o aminoterminal peptídeo natriurético tipo B (NT-proBNP) liberados, respectivamente, secundária ao estresse da parede miocárdica dos átrios e ventrículos; a troponina I cardíaca (cTnI), liberada secundariamente à lesão miocárdica; e a endotelina tipo 1 (ET-1), um peptídeo vasoconstrictor potente cuja concentração plasmática aumenta em pacientes com insuficiência cardíaca, tem incrementado o diagnóstico de cardiopatias em humanos. A CMH é diagnosticada pela ecocardiografia convencional pela evidenciação de hipertrofia cardíaca (HC) segmentar ou difusa. Este estudo utilizou 57 gatos da raça Maine Coon, testados geneticamente para a mutação (M), que foram separados em quatro grupos: GIA com M e com HC (n= 4); GIB com M e sem HC (n= 10); GIIA sem M e com HC (n= 5); GIIB sem M e sem HC (n= 38) e avaliados por meio de ecocardiografia convencional e determinação dos biomarcadores cardíacos NT-proANP, NTproBNP, cTnI e ET-1. A prevalência da mutação nos gatos estudados foi de 24,56%. Diferenças estatísticas significantes foram observadas nos valores de NT-proBNP entre os grupos GIA e GIIB e GIA e GIB; de cTnI entre GIA e GIIB. Quando considerado apenas a presença ou ausência da mutação ou da hipertrofia, foram encontrados valores maiores de NT-proBNP em animais com HC e de cTnI em animais com mutação. Com base na metodologia utilizada, estabeleceu-se um ponto de corte para o NT-proBNP, considerando a presença de hipertrofia de 189,9 pmol/L, com sensibilidade de 77,8%, especificidade de 81,3%, valor preditivo positivo de 43,8% e valor preditivo negativo de 95,1 para o NT-proBNP, e o outro ponto de corte de 0,015 ng/mL, com sensibilidade de 64,3%, especificidade de 81,4%, valor preditivo positivo de 52,9% e valor preditivo negativo de 87,5% para a cTnI. A perspectiva para novos estudos concerne à cTnI e sua relação com a presença da mutação MYBPC3. / Hypertrophic cardiomyopathy (HCM) is the most common feline heart disease and is responsible for high morbidity and mortality rates. Sarcomere disorganization in the affected myocardium of cats with HCM is related to the myosin binding protein C (MYBPC3) gene mutation. The plasma concentration of cardiac biomarkers such as atrial aminoterminal natriuretic peptide (NT-proANP) and Type B aminoterminal natriuretic peptide (NT-proBNP) released, respectively, by atrial and ventricular myocardium secondary to wall stress; cardiac troponin I (cTnI), released secondary to myocardial injury; and type 1 endothelin (ET-1), a potent vasoconstrictor peptide have been increasingly used for evaluation of human heart disease which are increased in patients with heart failure (HF). HCM is diagnosed by the presence of segmental or diffuse cardiac hypertrophy (CH) through conventional echocardiography. This study enrolled 57 Maine Coon cats screened for mutation (M) that were assigned to four groups: GIA with M and with CH (n= 4); GIB with M and without CH (n= 10); GIIA without M and with CH (n= 5); GIIB without M and without CH (n= 38) and evaluated by conventional echocardiography and cardiac biomarkers NT-proANP, NT-proBNP, cTnI and ET-1 measurements. The prevalence of the mutation in this study was 24.56%. Statistically significantly differences were observed in NT-proBNP among GIA and GIIB groups and among GIA and GIB groups; and in cTnI between GIA and GIIB groups. When considering only mutation and CH presence or absence, higher values of NT-proBNP were found in CH cats, and higher values of cTnI in those with mutation. Based on proposed methodology, cut-off value to NT-proBNP considering CH presence of 189.9 pmol/L had a sensitivity of 77.8%, specificity of 81.3%, predictive positive value of 43,8% and predictive negative value of 95,1% and the cut-off value of 0.015 ng/mL for cTnI considering mutation presence had a sensitivity of 64.3%, specificity of 81.4%, predictive positive value of 52,9% and predictive negative value of 87,5%. This study opened new perspectives to studies related to cTnI and MYBPC3 mutation.