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.

Introduction: Inflammatory cardiomyopathy (DCMi) represents a non-familial form of dilated cardiomyopathy (DCM) and endomyocardial biopsy (EMB) is crucial for its diagnosis. Aims: To assess the prevalence of DCMi in patients with DCM of unclear origin, to evaluate the significance of serological tests for antibodies against infectious cardiotrophic agents and to analyze the effect of specific therapy guided by EMB results. Methods: EMB was performed in 56 subjects (mean age 52 ± 10 years) with DCM of unclear etiology and left ventricular (LV) ejection fraction (EF) < 40% with a history of heart failure less than 1 year. EMB samples were analyzed by immunohistochemistry, polymerase chain reaction (PCR) and electron microscopy. Results: Immunohistochemical examination revealed myocardial inflammation in 26 patients (46%), the PCR method detected genome of microbial agents in 32 patients (57%). Electron microscopy showed the presence of particles of microbial agents in 41 patients (73%). Serological blood tests found no IgM antibody positivity against any of the investigated microbial agents. Targeted antibiotic therapy in patients with evidence of Borrelia burgdorferi (Bb) genome in the EMB led to a reduction in LV size, improvement of LV EF and alleviate symptoms of heart failure. Conclusion: DCMi...

Introduction: Inflammatory cardiomyopathy (DCMi) represents a non-familial form of dilated cardiomyopathy (DCM) and endomyocardial biopsy (EMB) is crucial for its diagnosis. Aims: To assess the prevalence of DCMi in patients with DCM of unclear origin, to evaluate the significance of serological tests for antibodies against infectious cardiotrophic agents and to analyze the effect of specific therapy guided by EMB results. Methods: EMB was performed in 56 subjects (mean age 52 ± 10 years) with DCM of unclear etiology and left ventricular (LV) ejection fraction (EF) < 40% with a history of heart failure less than 1 year. EMB samples were analyzed by immunohistochemistry, polymerase chain reaction (PCR) and electron microscopy. Results: Immunohistochemical examination revealed myocardial inflammation in 26 patients (46%), the PCR method detected genome of microbial agents in 32 patients (57%). Electron microscopy showed the presence of particles of microbial agents in 41 patients (73%). Serological blood tests found no IgM antibody positivity against any of the investigated microbial agents. Targeted antibiotic therapy in patients with evidence of Borrelia burgdorferi (Bb) genome in the EMB led to a reduction in LV size, improvement of LV EF and alleviate symptoms of heart failure. Conclusion: DCMi...

Introduction: Inflammatory cardiomyopathy (ICM) frequently leads to myocardial fibrosis, resulting in permanent deterioration of the left ventricular function and an unfavorable outcome. Soluble suppression of tumorigenicity 2 receptor (sST2) is a novel marker of inflammation and fibrosis in cardiovascular tissues. sST2 was found to be helpful in predicting adverse outcomes in heart failure patients with reduced ejection fraction. The aim of this study was to determine the association of sST2 plasma levels with cardiac magnetic resonance (CMR) and echocardiography imaging features of left ventricular impairment in ICM patients, as well as to evaluate the applicability of sST2 as a prognosticator of the clinical status in patients suffering from ICM. Methods: We used plasma samples of 89 patients presenting to the Heart Center Leipzig with clinically suspected myocardial inflammation. According to immunohistochemical findings in endomyocardial biopsies (EMB) conducted in the context of patients’ diagnostic work-up, inflammatory cardiomyopathy was diagnosed in 60 patients (ICM group), and dilated cardiomyopathy in 29 patients (DCM group). All patients underwent cardiac catheterization for exclusion of coronary artery disease and CMR imaging on 1.5 or 3 Tesla. sST2 plasma concentration was determined using ELISA. Results: Mean plasma concentration of sST2 in the whole patient cohort was 45.8 ± 26.4 ng/mL (IQR 27.5 ng/mL). In both study groups, patients within the highest quartile of sST2 plasma concentration had a significantly lower left ventricular ejection fraction (LV-EF) compared to patients within the lowest sST2 plasma concentration quartile (26 ± 11% vs. 40 ± 13%, p = 0.05 for ICM and 24 ± 13% vs. 51 ± 10%, p = 0.004 for DCM). sST2 predicted New York Heart Association (NYHA) class III/IV at 12 months follow-up more efficiently in ICM compared to DCM patients (AUC 0.85 vs. 0.61, p = 0.02) and was in these terms superior to NT-proBNP and cardiac troponin T. ICM patients with sST2 plasma concentration higher than 44 ng/mL at baseline had a significantly higher probability of being assigned to NYHA class III/IV at 12 months follow-up (hazard ratio 2.8, 95% confidence interval 1.01–7.6, log rank p = 0.05). Conclusion: Plasma sST2 levels in ICM patients reflect the degree of LV functional impairment at hospital admission and predict functional NYHA class at mid-term follow-up. Hence, ST2 may be helpful in the evaluation of disease severity and in the prediction of the clinical status in ICM patients.

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