Wei, Lihua. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 166-196). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Zhang, Yang. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 179-201). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Background and objective. Cardiovascular disease (CVD) is the most important life-threatening disease. The heart is densely innervated with sympathetic fibers, however prolonged sympathetic activation can damage the heart, resulting in chronic heart failure. Recent findings suggest that norepinephrine (NE) may contribute to cardiac fibrosis and a loss of cardiomyocytes due to apoptosis. Many studies demonstrate that NE is able to induce transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF) and vascular endothelial cell growth factor (VEGF), which are two key mediators during the cardiac remodeling process. Nowadays most of the studies in cardiac remodeling are focusing on myocytes, whereas a few studies have been paid to the role of the cardiac fibroblasts (CF). In this thesis, the role of NE in cardiac fibrosis and apoptosis was investigated in CF. The mechanisms by which NE induced TGF-beta, CTGF and VEGF expression in CF were examined. Furthermore, the therapeutic potentials in cardiac fibrosis by blocking NE with adrenergic receptor antagonists were explored. / Conclusions. NE is a pathogenic molecule involving cardiac remodeling. NE exhibited its fibrotic and apoptotic effects on CF in a concentration-dependent mariner. Up-regulation of the TGF-P/CTGF pathway could be a critical mechanism of NE-induced cardiac fibrosis, while NE was capable of activating Bax-Capase 3 to cause CF apoptosis. The presence of CTGF/VEGF complex in CF in response to NE may contribute to the inhibition of angiogenesis, which may be other mechanism of ischemic heart injury. These findings indicate that an increase in NE production associated with over activation of sympathetic system is harmful to the heart and may be a major cause of chronic heart failure. Furthermore, the ability of adrenergic receptor antagonists to block NE-induced cardiac fibrosis suggest the therapeutic approach by using NE receptor antagonists for patients with chronic heart diseases. / Methods and results. Rat CF was isolated, characterized, and stimulated with NF (0.01 to 100 muM for 6 to 72h). Procollagens (I and III), TGF-beta1, bax, bclXL, CTGF and VEGF gene expressions were measured by real-time PCR method. Collagen protein level was measured by Sirius red-based colorimetric method and Western blot. CTGF protein level, VEGF concentration, cell viability, apoptosis caspase 3 activity was measured by Western blot, ELISA, MTT assay cytometry, and flurogenic assay kit, respectively. Results showed that NE at concentrations of 0.01 to 0.1 muM was capable of up-regulating procollagens, TGF-beta1 and CTGF expression (ail p<0.05). However, NE at higher concentrations (10 to 100 muM) significantly induced CF apoptosis (p<0.01). This was demonstrated by a significant increase in bax gene expression and caspase-3 activity, while inhibiting bclXL gene expression. At this higher concentration of NE, CTGF expression was inhibited, whereas VEGF expression was promoted. However, using immunoprecipitation, the CTGF/VEGF complex was found in CF in response to NE, thereby inhibiting angiogenesis such as tube formation in cultured endothelial cells. Interestingly, addition of NE receptor antagonists produced differential effects on procollagen expression and apoptosis. For example, carvedilol and doxazosin, the alpha-receptor-associated non-selective antagonists, were able to inhibit NE-stimulated procollagens expression, but this was not inhibited by specific beta-receptor antagonists, metoprolol and propranolol, suggesting that NE signals through the alpha-receptor to mediate cardiac fibrosis. Interestingly, all four types of adrenoceptor antagonists had no effect on NE-induced CF apoptosis, which suggests that NE induces CF apoptosis via a receptor-independent mechanism. / Lai, Ka Bik. / Adviser: Yu Cheuk Man. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3419. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 160-199). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

This prospective study of acute myocarditis (AM) and endocardial fibroelastosis (EFE) was prompted by their common occurrence in infants and children in Cape Town, and by the persisting controversy regarding the possible relationship of these two conditions to each other, and to idiopathic, chronic, congestive cardiomyopathy (COCM). Patients with AM and EFE were analysed concurrently and over the long-term. The following hypotheses were investigated: A) that AM and EFE represent different phases of a common disease process, and B) that either AM or EFE evolves into COCM. From 1st June 1970 to 31st December 1976 (a study period of 6 years 7 months), 140 consecutive patients with AM or EFE were evaluated, and continually observed until 31st March 1979 (a total observation period of 8 years 10 months). Because there is no definitive, non-invasive, in-vivo diagnostic test for AM or EFE, an inclusive diagnosis of acute endomyocardial disease (EMD) was made in 123 patients who fulfilled all 4 rigid clinical criteria, i.e. a short history ( < 1 month), clinical evidence of myocardial involvement (heart failure, gallop rhythm or shock), radiological cardiomegaly (CTR > 0.55), and ST/T wave changes on electrocardiogram (ECG). Acute EMD was confirmed in all 20 patients who came to autopsy. A further 17 patients with insufficient clinical data had EMD at post-mortem.

Orientador: Humberto Santo Neto / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Médicas / Made available in DSpace on 2018-08-13T22:18:59Z (GMT). No. of bitstreams: 1 Oggiam_DaniellaSilva_M.pdf: 1790150 bytes, checksum: f55f529364fdf6fa2bae8c646e2b2d8b (MD5) Previous issue date: 2009 / Resumo: A distrofia Muscular de Duchenne (DMD) é uma miopatia progressiva causada por uma doença autossômica recessiva ligada ao sexo, que acomete crianças do sexo masculino, e evolui para incapacidade motora na puberdade até causar óbito ao redor da segunda década de vida. É causada por uma alteração no gene codificador da proteína distrofina, que mantém a integridade do sarcolema da fibra muscular. O camundongo mdx é utilizado como modelo experimental da DMD para investigações do tecido muscular esquelético e cardíaco, por apresentar muitas semelhanças com humano portador da doença. Na DMD os pacientes iam á óbito por falência respiratória, desde a evolução do tratamento com técnicas de ventilação mecânica artificial, as disfunções cardíacas tornaram-se importantes, visto que a partir disto, a maioria dos óbitos começaram a ser em função da falência cardíaca, que resulta de um processo seguido de: necrose, inflamação, fibrose evoluindo para cardiomiopatia grave. Várias estratégicas farmacológicas tem sido utilizadas para melhora da função cardíaca tanto no portador de DMD como no camundongo mdx. Um dos medicamentos utilizados é o deflazacorte, um glucocorticóide de ação anti-inflamatória, administrado por toda vida do portador de DMD. Embora os efeitos do deflazacorte sobre a função cardíaca no humano e no camundongo mdx têm sido extensivamente estudados, pouco se sabe sobre os efeitos histopatológicos no tecido cardíaco. Neste trabalho foi avaliado o efeito da administração a longo prazo de deflazacorte na progressão da fibrose miocárdica intersticial em camundongos mdx de 6 meses de idade. Os animais foram tratados diariamente com deflazacorte durante 15 meses, após foram sacrificados, o coração foi removido e congelado em nitrogênio líquido para posterior análise histológica e morfológica do tecido. O coração do grupo de camundongos mdx tratados com deflazacorte foi comparado com camundongos mdx não tratados. As áreas de fibrose miocárdica diminuíram significativamente 40% em relação ao grupo não tratado. Concluiu-se que o tratamento à longo prazo com deflazacorte é eficiente para diminuir a progressão da fibrose cardíaca. Sendo assim, como a cardiomiopatia está diretamente relacionada à disfunções celulares que acarreta a necrose dos cardiomiócitos, é de interesse investigar o acúmulo de lipofuscina, um biomarcador do envelhecimento, nos corações de camundongos mdx. Neste trabalho também foi observado o acúmulo de lipofuscina em animais controle C57BL10 e mdx de 14 dias a 23 meses de idade sem serem submetidos a qualquer tratamento. Os animais foram sacrificados, o coração removido e congelado em nitrogênio líquido para posterior análise da fluorescência dos grânulos de lipofuscina. Após contagem dos grânulos observou-se que aumentam com a idade, e dos 4 para os 6 meses ocorreu um acréscimo no acúmulo de lipofuscina. Considerando-se que o acúmulo de lipofuscina relaciona-se a disfunção celular é possível que isto contribua para lesão de cardiomiócitos em corações desprovidos de distrofina / Abstract: The Duchenne Muscle Dystrophy is a progressive myopathy caused by recessive autossomic disease connected to the gender, which attacks male kids, and involves to motor disability in the property, leading to death around the second decade of life. It is caused by an alteration in the codifier gene of the protein dystropin, which maintains the integrity of the muscle fiber sarcolemma. The mdx mouse is used as an experimental model of DMD to investigate the skeletal and cardiac muscle fiber, because it presents a lot of similarities with the human carrier of the disease. In the DMD, the patients used to die due to respiratory failure. Since there was a treatment evolution with artificial mechanical ventilation techniques, the cardiac dysfunctions became important considering that from this moment on, most of the deaths started occurring because of a cardiac failure, resulting of a process followed by necrosis, inflammation, fibrosis involving to a serious cardiomyopathy. Several pharmacological strategies have been used to improve the cardiac function both in the DMD carrier and in the mdx one of the medications utilized is the deflazacort, a glucocorticóide of anti-inflammatory action, administrated during the whole life of the DMD carrier. Although the deflazacort effects upon the cardiac function in the human being and in the mouse mdx have been extensively studied just a little is know about the histopathological effects on the cardiac tissue. In this paper, the effect of the long term administration of deflazacort daily for 15 months, after they were sacrificed, had their hearts removed and frozen in liquid nitrogen for histological and morphological tissue further analysis. The heart of the mdx mice group treated with deflazacort was compared to the heart of the untreated mdx mice group. The myocardial fibrosis areas diminished significantly in comparison to the untreated group, in 40%. It was concluded that the long term treatment with deflazacort is effective to diminish the cardiac fibrosis progression the cardiomyopathy which cause the myocites cardiac necrosis, and therefore it is interesting to investigate the lipofuscin is a pigment related to the age, it is considered an aging biomarker. In this paper, the accumulation of lipofuscin in control animals C57BL10 and mdx with ages between 14 days and 21 months without any treatment was observed that they increase with the age, and from the 4 to the 6 months there was a raise in the lipofuscin accumulation. It was so, concluded, that the myocites cardiac functioning can be harmed even before the age of 8 months, and the accumulation of lipofuscin can mean a degeneration process which is more intensive in mdx / Mestrado / Biologia Celular / Mestre em Biologia Celular e Estrutural

INTRODUÇÃO: Endomiocardiofibrose (EMF) é uma cardiomiopatia restritiva (CMR), caracterizada por uma disfunção diastólica, mas com a função sistólica e a fração de ejeção preservadas ou, em fases avançadas da doença, pouco prejudicadas. O consumo máximo de oxigênio (VO2) é um marcador de mortalidade na insuficiência cardíaca sistólica (ICS). Apesar da mortalidade ser semelhante entre a CMR e ICS, ainda não é conhecido se o treinamento físico pode melhorar o VO2 pico em pacientes com EMF. O objetivo deste estudo foi verificar se 4 meses de treinamento combinado podem melhorar a capacidade funcional e qualidade de vida em pacientes com EMF. MÉTODOS: Vinte e um pacientes com EMF (classe funcional II e III, NYHA) foram divididos em 2 grupos: treinamento físico (EMF-TF, n = 9) e sedentários (EMF-Sed, n = 12). Foram avaliados: VO2 pico, pulso de O2, relação deltaFC/deltaVO2 e relação deltaVO2/deltaW, pelo teste cardiopulmonar (TECP); volume diastólico final (VDF), volume sistólico (VS) e volume diastólico do átrio esquerdo (AE), pela ecocardiografia (Simpson); e qualidade de vida, pelo questionário Minnesota Living With Heart Failure Questionnaire (MLWHFQ). Os resultados do TECP dos pacientes com EMF foram comparados com os resultados de indivíduos controle saudáveis sedentários (CSS). Foi considerado significativo P < 0,05. RESULTADOS: Idade não foi diferente entre EMF-Sed, EMF-TF e CSS (58±9 vs. 55±8 vs. 53±6 anos, P = 0,31; respectivamente). O grupo EMF-TF apresentou um aumento do VO2 pico pós-intervenção, comparado com o momento pré e comparado com o grupo EMF-Sed, mas esse valor foi menor, comparado ao CSS (17,4 ± 3,0 para 19,7 ± 4,4 vs. 15,3 ± 3,0 para 15,0±2.0 vs. 24,5 ± 4,6 ml/kg/min, P < 0,001; respectivamente). O pulso de O2 do grupo EMF-TF no momento pós-intervenção foi maior, comparado ao momento pré e ao grupo EMF-Sed, mas foi semelhante, quando comparado ao grupo CSS (9,3 ± 2,6 para 11,1 ± 2,8 vs. 8,6 ± 2,2 para 8,6 ± 1 vs. 11,2 ± 2,9 ml/batimentos; P < 0,05; respectivamente). A relação deltaFC/deltaVO2 diminuiu no momento pós-intervenção no grupo EMF-TF, comparado ao momento pré e ao grupo EMF-Sed, igualando-se ao grupo CSS (75 ± 36 para 57 ± 14 vs. 68 ± 18 para 73 ± 14 vs. 56±17 bpm/L; P < 0,05; respectivamente). O grupo EMF-TF reduziu significativamente a relação deltaVO2/deltaW, após o período de treinemento, comparado ao momento pré e ao grupo EMF-Sed, igualando-se ao grupo CSS (12,3 ± 2.8 para 10,2 ± 1.9 vs. 12,6±1.7 para 12,4 ± 1.7 vs. 10,0 ± 0,9 ml/min/Watts; P = 0,002; respectivamente). O treinamento físico também aumentou o VDF do grupo EMF-TF, quando comparado ao grupo EMF-Sed (102,1 ± 64,6 para 136,2 ± 75,8 vs. 114,4 ± 55,0 para 100,4 ± 49,9 ml; P < 0,001; respectivamente) e o VS (57,5±31,9 para 72,2 ± 27,4 vs. 60,1 ± 25,2 para 52,1 ± 18,1 ml; P = 0,01; respectivamente), e diminuiu o volume diastólico do AE [69,0 (33,3- 92,7) para 34,9 (41,1-60,9) vs. 44,6 (35,8-73,3) para 45,6 (27,0-61,7) ml; P < 0,001; respectivamente). A qualidade de vida dos pacientes EMF-TF, quando comparados com o grupo EMF-Sed também melhorou após o período de treinamento físico (45±17 para 27±15 vs. 47±20 para 45 ± 23 pontos; P < 0,05; respectivamente). CONCLUSÃO: Esses resultados esclarecem que os pacientes com EMF se beneficiaram com o treinamento físico combinado, enfatizando a importância dessa ferramenta não farmacológica no tratamento clínico habitual desses pacientes / BACKGROUND: Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy (RCM), characterized by a diastolic dysfunction, but with preserved systolic function and preserved ejection fraction, except in severe cases, in which these two present mild reduction. Maximal oxygen consumption (VO2) is a marker of mortality in systolic heart failure (SHF). Although mortality in RCM can be similar to SHF, it is still unknown if physical training can improve peak VO2 in patients with EMF. The aim of the present study was to evaluate if 4 months of combined physical training could improve functional capacity and quality of life in patients with EMF. METHODS: Twenty one EMF patients (functional class II and III, NYHA) were divided into 2 groups: physical training (EMF-PT, n = 9) and sedentary (EMF-Sed, n = 12). Peak VO2, O2 pulse, deltaFC/deltaVO2 relation and deltaVO2/deltaW relation were evaluated by cardiopulmonary exercise test (CPX); end diastolic volume (EDV), stroke volume (SV) and left atrium diastolic volume were evaluated by echocardiography (Simpson); and quality of life was evaluated by Minnesota Living With Heart Failure Questionnaire (MLWHFQ). CPX results from EMF patients were compared to a healthy sedentary (HS) control group. Significance was considered P < 0,05. RESULTS: Age was not different between EMF-PT, EMF-Sed and HS (58 ± 9 vs. 55±8 vs. 53 ± 6 years, P = 0,31; respectively). EMF-PT group presented an increase in peak VO2 after training compared to EMF-Sed group, but was lower compared to HS (17,4 ± 3,0 to 19,7 ± 4,4 vs. 15,3 ± 3,0 to 15,0 ± 2.0 vs. 24,5 ± 4,6 ml/kg/min, P < 0,001; respectively). O2 pulse in EMF-PT group increased after training compared to EMFSed group, and was similar compared to HS (9,3 ± 2,6 to 11,1±2,8 vs. 8,6±2,2 to 8,6 ± 1 vs. 11,2±2,9 ml/betas; P < 0,05; respectively). deltaFC/deltaVO2 relation decreased after training in EMF-PT group compared to EMF-Sed group, and was similar compared to HS (75 ± 36 to 57 ± 14 vs. 68 ± 18 to 73 ± 14 vs. 56 ± 17 bpm/L; P < 0,05; respectively). deltaVO2/deltaW relation decreased after training in EMF-PT group compared to EMF-Sed group, and was similar compared to HS (12,3 ± 2.8 to 10,2 ± 1.9 vs. 12,6 ± 1.7 to 12,4 ± 1.7 vs. 10,0 ± 0,9 ml/min/Watts; P = 0,002; respectively). Physical training also increased EDV in EMF-PT compared to EMFSed (102,1±64,6 to 136,2±75,8 vs. 114,4±55,0 to 100,4±49,9 ml; P < 0,001; respectively) and SV (57,5±31,9 to 72,2±27,4 vs. 60,1±25,2 to 52,1±18,1 ml; P = 0,01; respectively), and decreased left atrium diastolic volume [69,0 (33,3-92,7) to 34,9 (41,1-60,9) vs. 44,6 (35,8- 73,3) to 45,6 (27,0-61,7) ml; P < 0,001; respectively). Quality of life in EMF-PT group improved after training when compared to EMF-Sed group (45±17 to 27±15 vs. 47 ± 20 to 45 ± 23 points; P < 0,05; respectively). CONCLUSION: These results point out that patients with EMF benefit from combined physical training emphasizing the importance of this nonpharmacological tool in the clinical treatment of these patients

A estratificação de risco para morte súbita em pacientes com cardiomiopatia hipertrófica ainda é um desafio. Sua prevenção pelo cardiodesfibrilador automático é eficaz, porém, onerosa e não isenta de riscos. Pacientes com indicação de cardiodesfibrilador automático para prevenção primária, baseada em fatores de risco clínicos, apresentam baixa taxa de terapias apropriadas. Estudos que validem novos fatores de risco são necessários, visando identificar pacientes com maior probabilidade de morte súbita e, portanto, que se beneficiam do implante do dispositivo. Estudos que correlacionam a presença de realce tardio com arritmias ventriculares e morte súbita foram realizados, entretanto, sua aplicabilidade clinica ainda não é consenso. Objetivos: Avaliar, em portadores de cardiomiopatia hipertrófica, se a presença e a extensão de realce tardio, identificado pela tomografia computadorizada, correlaciona-se com a ocorrência de taquiarritmias ventriculares registradas no monitor de eventos do cardiodesfibrilador automático, durante um seguimento clínico ambulatorial. Métodos: Foram incluídos pacientes com cardiomiopatia hipertrófica dos ambulatórios de Eletrofisiologia e Miocardiopatias do Instituto Dante Pazzanese de Cardiologia. Os pacientes foram divididos em dois grupos: grupo I composto por aqueles que receberam terapia apropriada pelo cardiodesfibrilador automático ou tiveram apenas a documentação de taquicardia ventricular não sustentada pelo cardiodesfibrilador automático; grupo II, composto por pacientes sem documentação de arritmias ventriculares no monitor de eventos. As variáveis contínuas foram comparadas utilizando-se testes t de Student pareado ou Wilcoxon; para as categóricas o teste do x2. Para análise dos dados, utilizou-se o programa SPSS. Valores de p < 0,05 foram considerados estatisticamente significativos. Resultados: Sessenta e um pacientes (idade média 39±15 anos, 51% mulheres, com seguimento médio 5,13±3,0 anos) foram avaliados. Em 91,8%, a indicação do cardiodesfibrilador automático foi por prevenção primária. Durante o seguimento clínico, cinco pacientes (8,2%) apresentaram terapias apropriadas e 15 (24,6%) tiveram taquicardia ventricular não sustentada, mas sem terapia. A densidade de fibrose (incluindo massa de ventrículo esquerdo acometida e percentual de acometimento) não foi estatisticamente diferente entre os grupos I e II (4,3±4,8% vs 7,0±7,7% nos grupos I e II, respectivamente, p = 0,13). Entretanto, 85% dos pacientes com taquicardia ventricular apresentavam fibrose à tomografia computadorizada. Maiores densidades de fibrose se correlacionaram com idades mais jovens, com menores frações de ejeção e sexo masculino. Espessura septal >= 30mm se correlacionou à maior massa de fibrose. Houve correlação entre o surgimento de fibrilação atrial e maior porcentual de fibrose do ventrículo esquerdo. Dentre os fatores que se correlacionaram com maior densidade de fibrose, nenhum deles se correlacionou com eventos arrítmicos ventriculares. A associação dos fatores clínicos ou fatores clínicos isolados que motivaram a indicação do implante do cardiodesfibrilador automático não se correlacionou com eventos arrítmicos. Os pacientes do grupo I apresentaram maior diâmetro diastólico do ventrículo esquerdo e maior diâmetro do átrio esquerdo quando comparado com os pacientes do grupo II (47,7±4,7mm vs 43.1±5,4 mm, p = 0,002 e 47,8±8mm vs 41,5±7,1mm, p = 0,003, respectivamente). Conclusões: 1. A presença de fibrose detectada pela tomografia computadorizada apresenta razoável sensibilidade para identificação de pacientes com risco para taquicardia ventricular; 2. A densidade de fibrose foi similar nos pacientes dos grupos I e II; 3. Pacientes com fibrilação atrial apresentaram maior densidade de fibrose ventricular detectada pela tomografia computadorizada em comparação aos pacientes sem fibrilação atrial; 4. O diâmetro diastólico final de ventrículo esquerdo e o diâmetro atrial esquerdo associaram-se à maior risco de taquicardia ventricular; 5. Os fatores de risco convencionais, associados ou não à fibrose, não se correlacionaram com maior probabilidade de ocorrência de eventos arrítmicos ventriculares. / Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy patients is still challenging. Primary prevention of sudden death with implantable cardioverter-defibrillator is an effective, however, costly and not risk-free method. Patients with implantable cardioverter-defibrillator indicated for primary prevention based on clinical risk factors display low rates of appropriate therapies. Studies evaluating new risk factors are needed seeking to identify who would be mostly at risk of sudden cardiac death, and therefore benefit from cardioverter-defibrillator. Studies have been conducted to establish a correlation between late enhancement and ventricular arrhythmias and sudden cardiac death; however, its clinical applicability is still controversial. Objective: To evaluate if the presence and extension of late enhancement, identified by computed tomography, correlates with the occurrence of ventricular arrhythmias in hypertrophic cardiomyopathy patients. Methods: Patients with hypertrophic cardiomyopathy followed in Electrophysiology and Cardiomyopathies divisions at Dante Pazzanese Institute of Cardiology were included in the study. Patients were divided into two groups: group I composed by those with appropriate therapies (shock or overdrive) or non-sustained ventricular tachycardia; and group II, composed by patients without documented ventricular arrhythmias. Continuous variables were compared using paired t-student test or Wilcoxon test. Categorical variables were analyzed using chi-square test. For data analysis, the SPSS program was used. P values < 0.05 were considered statistically significant. Results: Sixty one patients (mean age 39 ± 15 years, 51% female, average follow up 5.13 ± 3 years) were evaluated. In 91.8%, cardioveter-defibrillator was indicated by primary prevention. During the follow up, five patients (8.2%) had appropriate therapies and 15 (24.6%) presented non-sustained ventricular tachycardia without therapies. Fibrosis density, (including left ventricular mass compromise and percentage) was not statistically different between the groups (4.3±4.8% for group I vs. 7.0±7.7% for group II, p =0.13). However, 85% of patients with ventricular tachycardia had fibrosis on cardiac computed tomography. Larger fibrosis density correlated with younger age, reduced ejection fraction and male gender. Septum >30 mm correlated with fibrosis mass. There was a correlation between atrial fibrillation and higher left ventricular fibrosis percentage. Among the factors that correlated with higher fibrosis density, none of them had correlation with ventricular arrhythmic events. The combination of clinical factors that motivated the implantation of cardioverter-defibrillator did not correlate with arrhythmic events. Patients at group I had larger left ventricular diastolic diameter (47.7±4.7 vs. 43.1±5.4mm, respectively, p= 0.002) and left atrium diameter (47.8±8.2 vs. 41.5±7.1 mm, respectively, p=0.003). Conclusions: 1. The presence of fibrosis detected by cardiac tomography had reasonable sensitivity to identify patients at risk of ventricular tachycardia; 2. Fibrosis density was similar between groups I and II; 3. Patients with atrial fibrillation had more fibrosis density detected by cardiac tomography compared to patients without atrial fibrillation; 4. Left ventricular end diastolic diameter and left atrial diameter correlated with increased risk of ventricular tachycardia; 5. Classical risk factors, associated or not with fibrosis, did not correlate with increased probability of ventricular arrhythmic events.

Conclusion. The present results indicate that, baicalein with optimal dosage of 30 muM suppressed collagen deposition in AngII stimulated SHR CF cultures. In animal model of hypertension, high dose of baicalein feeding for 12 week showed optimal antifibrotic effect in hypertensive hearts. (Abstract shortened by UMI.) / For in-vivo study, comparing to control group, HW/BW (x1000) of SHR was significantly reduced in 12 weeks-high dose baicalein and (-0.78+/-0.23, p=0.014) 12 weeks-Valsartan group (-0.71+/-0.22, p=0.021), however, no significant change was observed in the LW/BW ratio. / In Blood pressure control, no effects on attenuation of SBP were observed after 4 weeks and 12 weeks daily administration of baicalein, only 12 weeks feeding of Valsartan significantly down-regulated the systolic blood pressure by -19.25+/-10.09 mmHg, p=0.049. / In the in-vivo study, SHR was used as a model of genetic hypertension. The objectives were: firstly, to determine the efficacy of baicalein in the prevention of myocardial fibrosis (interstitial fibrosis) in SHR, & compared with WKY rats as normal controls. Secondly, to determine if over-expression of pro-collagen I (and III, if any) gene in the ventricles could be normalized by baicalein. Thirdly, to determine if left ventricular hypertrophy in SHR is improved by baicalein. Furthermore, to determine if blood pressure and blood biochemistry parameters (plasma level of brain natriuretic peptides (BNP), and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) level could be alternated by baicalein. Besides, to determine the body weight (BW), heart weight to body ratio (HW/BW), liver weight to body weight ratio (LW/BW), serum AST and ALT level could be alternated by baicalein. Finally to evaluate by echocardiography if there are changes of ivss and ivsd in SHR after administration of baicalein. / Keywords. baicalein, wogonin, collagen, cardiac fibrosis, hypertension / Objectives. In the in-vitro study, cardiac fibroblast culture was prepared from neonatal SHR and WKY rats. The objectives were multi-fold: firstly, to determine over-expression of pro-collagen I mRNA (and III, if any) in cardiac fibroblasts cultures could be normalized by baicalein and wogonin after AngII activation. Secondly, to evaluate the efficacy of baicalein and wogonin on the suppression of total collagen protein production in cardiac fibroblasts cultures after AngII activation. Thirdly, to evaluate the mechanism (in protein level) of baicalein and wogonin on regulating collagen deposition in cardiac fibroblasts after AngII activation. Furthermore, to determine if there were any effects on cytotoxicity and membrane integrity of baicalein and wogonin towards cardiac fibroblasts cultures. Finally, to determine the optimal concentration of baicalein and wogonin for the above actions in-vitro. / Results. For in-vitro study, incubation of AngII resulted in significant up-regulation of COL-I and COL-III mRNA and total collagen protein production. Addition of either baicalein or wogonin significantly suppressed the mRNA synthesis and total collagen protein in CF with an optimal dosage of 30 muM. No effects on viability and membrane integrity were observed on baicalein and wogonin towards cardiac fibroblasts cultures. / Kong, Kam Chuen Ebenezer. / Advisers: Cheuk-Man Yu; Gabriel W. K. Yip. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0242. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 176-204). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

Orientador: Humberto Santo Neto / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-13T16:30:29Z (GMT). No. of bitstreams: 1 Barbin_IsabelCristinaChagas_M.pdf: 1008389 bytes, checksum: 5452120032625931602b36f22c3e2986 (MD5) Previous issue date: 2009 / Resumo: A Distrofia Muscular de Duchenne (DMD) é uma miopatia caracterizada pela ausência de distrofina, uma proteína estrutural da membrana plasmática. A ausência da distrofina faz com que a fibra muscular esquelética e cardíaca sofram alterações funcionais seguida de necrose. Com o avançar da idade cerca de 40% dos pacientes desenvolvem cardiomiopatia devido à progressiva fibrose miocárdica (FM) e vão a óbito por esta razão. Portanto, tratamento que impeça a progressão da FM é de importância em pacientes com DMD. O camundongo mdx, modelo animal da distrofia, também apresenta progressiva FM e por isso tem servido de modelo experimental para a cardiomiopatia na DMD. Parte da FM em camundongos mdx tem sido atribuída à deficiência em óxido nítrico. Desta forma, terapias baseadas na administração exógena de óxido nítrico têm sido aventadas e a L-arginina, substrato para óxido nítrico sintase tem se revelado uma candidata para tal. Esse trabalho tem como objetivo avaliar o efeito da administração de longo tempo da L-arginina sobre a progressão da FM em camundongos mdx. Os animais foram tratados com L-arginina durante 60 semanas. Os corações foram retirados e preparados para avaliação histomorfométrica da FM através de coloração com tricrômico de Masson. Lâminas coradas com hematoxilina e eosina (H&E) serviram para observação histológica e quantificação da densidade de células inflamatórias. Corações de camundongos mdx de mesma idade que aqueles tratados com L-arginina serviram como controle. Nossos resultados mostram que a área média de FM nos camundongos que receberam L-Arginina não foi diferente (p> 0,05) da dos camundongos do grupo controle (29.5 ± 2.5 % para controle vs 31.4 ± 2 % para L-arginina). De outro lado, a densidade de células inflamatórias foi significativamente inferior nos camundongos que receberam L-arginina comparados ao controle (169.3 ± 6.7 células/mm2 no controle vs 102 ± 6 células/mm2 em L-arginina). Baseado nisto, conclui-se que a administração por longo tempo de L-arginina não é capaz de prevenir a FM sugerindo que o uso da L-arginina pode não ser eficaz na prevenção da FM em DMD. Durante a realização do trabalho verificou-se que a administração de Larginina aumenta a já conhecida susceptibilidade dos camundongos mdx desenvolverem tumores. Cerca de 40% dos camundongos mdx que receberam L-arginina por longo tempo apresentaram tumores cuja análise histopatológica, incluindo-se a expressão de MyoD revela serem rabdomiossarcomas. Uma análise mais detalhada mostra que a maioria deles é do tipo embrionário e um do tipo alveolar. Esses resultados são importantes uma vez que esse protocolo poderá ser empregado para indução desse tipo de câncer e consequentemente servir como modelo experimental para o mesmo. / Abstract: The Duchenne Muscle Dystrophy (DMD) is a myopathy characterized by dystrophin absence, which is a structural protein of the plasma membrane. The dystrophin absence leads to functional alterations followed by necrosis in the skeletal and cardiac muscle fiber. As the patients grow older, about 40% of them develop cardiomyopathy due to progressive myocardial fibrosis (MF), and eventually die because of this. Therefore, a treatment that avoids the MF progression is very important to DMD patients. The mouse mdx, animal model of dystrophy, also presents progressive FM and thus, has been used as an experimental model for cardiomyopathy in DMD. The MF in mice mdx has been partially attributed to the deficiency of nitric oxide. This way, therapies based on the exogenous administration of nitric oxide have been quoted and the L-arginine, which is a substrate of the synthase nitric, has been revealed to be a strong candidate to these therapies. The aim of this current project is evaluating the effect of long-term administration of L-arginine on the progression of MF in mice mdx. The animals were treated with L-arginine for 60 weeks. The hearts were taken out and prepared for histomorphometric evaluation of the myocardial fibrosis through the colouring with Masson's trichrome. Slides stained with hematoxilin and eosin (H&E) were used for histological observation and quantification of the density of inflamatory cells. Hearts of mice mdx at the same age of those ones treated with L-arginine were used as control. Our results show that the average area of MF in mice which received L-arginine wasn't different (p>0,05) from the area of the control group (29,5 ± 2,5% for the control vs 31,4 ± 2% for the L-arginine). On the other hand, the density of inflamatory cells was significantly smaller in mice which received L-arginine compared to the control (169.3 ± 6.7 cells/mm² in the control vs 102 ± 6 cells/mm² in L-arginine). Based on this, we can conclude that the long-term administration of L-arginine is not enough to prevent the MF, suggesting that the use of L-arginine may not be effective to prevent the MF in DMD. During the research achievement, we could verify that the L-arginine administration increases the already known susceptibility of mice mdx of developing tumors. About 40% of the mice mdx which received L-arginine for a long time presented tumors whose histopathological analysis, including the MyoD expression, reveals them to be rhabdomyosarcomas. A further analysis reveals that most of them is the embrionic kind and one is the alveolar kind. These results are important since this protocol can be used to induce this kind of cancer and consequently serve as an experimental model for it. / Mestrado / Anatomia / Mestre em Biologia Celular e Estrutural