Introdução: Embora os benefícios clínicos das intervenções coronarianas pareçam confirmados, seus efeitos na qualidade de vida (QV) ainda são pouco estudados. O presente estudo justifica-se pela escassez de trabalhos publicados que tenham avaliado a QV de pessoas com Doença Arterial Coronariana (DAC) submetidas a qualquer um dos três tipos de tratamento disponíveis no seguimento de 10 anos. Objetivo: Avaliar e comparar a QV nos pacientes com doença multiarterial coronariana, submetidos à revascularização cirúrgica do miocárdio (RCM), angioplastia (ATC) ou tratamento clínico (TM), de modo prospectivo e randomizado no segmento de 10 anos. Métodos: Estudo prospectivo, cujos dados foram obtidos do banco de dados do protocolo MASS II (\"The Medicine, Angioplasty or Surgery Study\") composto por 611 pacientes randomizados para um dos três tratamentos possíveis para a DAC. Para este estudo, 334 participantes foram analisados e responderam aos questionários aplicados no início do estudo, 6 meses após a inclusão e, anualmente, até completarem 10 anos de seguimento e que foram capazes de responder. A QV foi avaliada por meio do Medical Outcomes Study 36-Item Short-Form Health Survey (SF- 36). A análise estatística descritiva foi realizada pelo Qui-quadrado para variáveis categóricas; para variáveis independentes, o teste t de Student e para variáveis contínuas, a Análise de Variância (ANOVA). As médias de QV dos grupos, pela variável tempo, foram obtidas pela aplicação da ANOVA de medidas repetidas e comparações múltiplas. Resultados: 148 pacientes (47,3%) foram vitimados de IAM, 97 (25,9%) foram submetidos à RCM ou ATC; 16 (4,8%) sofreram acidente vascular cerebral e 293 (87%) referiram angina. No início do estudo, os pacientes do grupo de RCM apresentaram a pior condição no componente físico em relação ao ATC ou TM. Todas as três estratégias de tratamento alcançaram melhora significativa em todas as dimensões (P < 0,001). Tratamento médico: neste grupo, encontrou-se melhora no componente mental, em 83,7% dos pacientes, e 16,3% tiveram piora desta condição. Em relação ao componente físico, 84,7% e 15,3% alcançaram resultados de melhora ou piora em sua condição, respectivamente. Cirurgia: Em relação ao componente mental, 85,4% e 14,6% alcançaram resultados de melhora ou piora em sua condição, respectivamente. Em relação ao componente físico, 92,7% e 7,3% alcançaram resultados de melhora ou piora em sua condição, respectivamente. Angioplastia: Neste grupo, o componente mental melhorou em 77,8%; e 22,2% tiveram piora dessa condição. Em relação ao componente físico, 73,0% e 27,0% alcançaram resultados de melhora ou piora em sua condição, respectivamente. Comparando-se os grupos de tratamento em relação ao componente físico no início do estudo, houve diferença significativa entre os grupos de tratamento (P < 0,001). Todavia, quando se analisou o seguimento para 5 e 10 anos, não se encontrou diferença significativa entre as três opções terapêuticas. No componente mental, avaliado nos três momentos de investigação não foi encontrada diferença estatisticamente significante entre os grupos de tratamento. Conclusão: A melhoria da percepção da QV foi observada em todas as dimensões e nas três formas de tratamento em 5 anos e que persistiram durante os 10 anos. Estratégias de intervenção não alcançaram melhores resultados de qualidade de vida do que TM isoladamente / Background: Although clinical benefits of coronary interventions have been confirmed, their effects on quality of life (QOL) are still less studied. This study is justified by the scarcity of studies that have evaluated the QOL of patients with CAD undergoing one of three types of treatment available along 10 years of follow-up. Objective: To evaluate and compare the QOL in patients with multivessel coronary disease randomized to undergo coronary artery bypass surgery, angioplasty or medical treatment, and followed during 10 years. Methods: A prospective study whose data were obtained from the database of the protocol MASS II (\"The Medicine, Angioplasty or Surgery Study\") consisting of 611 patients randomized to one of three available treatments for Coronary Artery Disease. For this study, we analyzed 334 participants who completed the questionnaire of QOL since the beginning of the study and annually, until they reach 10 years of follow-up. The QOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). We performed descriptive statistics, chi-square test for categorical variables and the independent sample t test. Mean quality of life for the time variable groups were evaluated by analysis of variance (ANOVA) with repeated measures and multiple comparisons. Results: 148 patients (47.3%) had AMI, 97 (25.9%) underwent CABG or PCI, 16 (4.8%) suffered stroke and 293 (87%) reported angina along the 10 years of follow up. At baseline, patients in the CABG group had the worst condition in the physical component compared to PCI or MT. All three treatments strategies have achieved a significant improvement in all dimensions of QoL (P < 0.001). Medical Treatment: In this group, there was improvement in the mental component in 83.7% of patients, while 16.3% had worsening of this condition. Regarding the physical component, 84.7% and 15.3% had their condition improved and worsened, respectively. Surgery: For the mental component, 85.4% and 14.6% achieved improvement and worsening in their condition, respectively. Regarding the physical component, 92.7% and 7.3% had their condition improved and worsened, respectively. Angioplasty: In this group, the mental component improved by 77.8%, while 22.2% had worsening of this condition. Regarding the physical component, 73.0% and 27.0% had their condition improved and worsened, respectively. Comparing the treatment groups with respect to physical component at baseline, there was significant difference among the treatment groups (P < 0.001). However, no significant difference was found at 5 and 10 years of follow up among them. On the other hand, in respect to mental component, no statistically significant difference was found among the treatment groups in all time point of the study. Conclusion: Improving the perception of QoL was observed in all dimensions and in all three forms of treatment after five years and has persisted up 10 years of follow up. Intervention strategies have not achieved better results in quality of life than TM alone

INTRODUÇÃO: O sucesso a longo prazo da intervenção coronária percutânea, inicialmente realizada apenas com balão, era limitado pelo recolhimento elástico da artéria e pela hiperplasia neointimal. Com o advento dos stents convencionais (BMS) houve melhora nesse cenário e diminuição da reestenose, que é resultante de uma complexa cadeia de eventos iniciada após a injúria causada na parede vascular pela insuflação de balões e da aposição das hastes do stent. A proliferação excessiva de células musculares lisas (VSMC) tem papel fundamental na formação da neoíntima no contexto da reestenose intra-stent com a consequente redução da luz arterial. Com o advento dos stents farmacológicos (DES) houve diminuição importante da hiperplasia neointimal e um dos fármacos que se mostrou efetivo nesse papel é o sirolimo, que atua se ligando à proteína de ligação 12 e o heterodímero resultante se liga à mTOR impedindo sua ativação e causando parada do ciclo celular entre as fases G1 e S, desse modo inibindo a proliferação e migração de VSMC e das células endoteliais (HUVEC). Portanto a intervenção coronária acaba interferindo diretamente no endotélio, interferindo na produção das HUVEC não apenas no aspecto quantitativo, mas também na função das mesmas, e a qualidade funcional do endotélio é tão fundamental quanto à sua presença. Após o implante dos DES, principalmente os de primeira geração, ocorre disfunção endotelial cujo principal marcador é a perda da capacidade do relaxamento do vaso. Há correlação também entre cobertura das hastes incompleta e ocorrência de trombose dos stents. Consequentemente há espaço para o aprimoramento dos DES, para que se tornem dispositivos com eficácia já alcançada na prevenção da reestenose porém com um perfil de segurança maior. O presente trabalho tem como objetivo avaliar as alterações causadas pelos DES nas HUVEC e nas VSMC em cocultura na presença e na ausência do soro rico em plaquetas. MATERIAIS E MÉTODOS: Utilizamos células HUVEC e VSMC em modelos de monocultura e cocultura, na presença e na ausência de soro rico em plaquetas, tratadas com BMS ou DES. Realizamos a determinação da IC50 do inibidor da mTOR, avaliação da citotoxicidade pelo método colorimétrico do MTT, determinação da formação de peróxidos lipídicos, avaliação das fases do ciclo celular e da expressão de marcadores de controle de proliferação e inflamação. RESULTADOS: Na avaliação da citotoxicidade pelo método colorimétrico do MTT e determinação da IC50 as VSMC foram menos sensíveis ao sirolimo que as HUVEC (IC50 em 24/48 horas 14,85/10,47uM e 9,48/22,24 uM, respectivamente para HUVEC e VSMC). As plaquetas e fatores solúveis potencializam o estresse oxidativo gerado pela presença dos stents possivelmente por ampliar o ambiente inflamatório. Houve parada do ciclo celular na fase G0/G1 causada pelos DES somente com adição das plaquetas ao meio de cultura. Nos modelos de cultura celular sem as plaquetas a parada do ciclo celular foi em G2/M. Não houveaumento das células na fase DNA fragmentado (sub-G0) evidenciando que não houve indução de morte celular. CONCLUSÃO: As VSMC foram menos sensíveis ao sirolimo que as HUVEC. Nos modelos de cocultura com adição das plaquetas os DES eluídores de sirolimo causaram parada do ciclo celular na fase G0/G1 sem indução de morte celular, sugerindo que o sirolimo exerce seus efeitos anti-inflamatórios nessas populações celulares e consequentemente reduz a hiperplasia neointimal por um mecanismo citostático / INTRODUCTION: The long-term success of percutaneous coronary intervention, initially performed only with a balloon, was limited by the elastic recoil of the artery and by neointimal hyperplasia. There was improvement in this scenario with the advent of bare metal stents (BMS), because they decrease in restenosis, that resulting from a complex network of events initiated after the injury caused in the vascular wall by insufflation of balloons and apposition of the stent struts. Excessive proliferation of smooth muscle cells (VSMC) plays a key role in neointimal hyperplasia in the context of intrastent restenosis with consequent reduction of arterial lumen. With the advent of drug-eluting stents (DES) there was a significant decrease in neointimal hyperplasia and one of the drugs that proved effective in this role is sirolimus, which acts by binding to the binding protein 12 and the resulting heterodimer binds to mTOR preventing its activation and causing cell cycle arrest between G1 and S phases and thereby inhibiting the proliferation and migration of VSMC and also inhibiting endothelial cells (HUVEC). Therefore, coronary intervention interferes directly in the endothelium, interfering in the production of endothelial cells, not only in the quantitative aspect, but also in their function, and the functional quality of the endothelium is as fundamental as its presence. After the implantation of DES, especially those of the first generation, endothelial dysfunction occurs, whose main marker is the loss of the capacity of the vessel relaxation. There is also correlation between incomplete stem coverage and stent thrombosis. Consequently, it is possible to improve of the DES, so that they become devices with already achieved effectiveness in the prevention of restenosis but with a greater safety profile. The present study aims to evaluate the changes caused by DES in human HUVEC and VSMC in co-culture in the presence and absence of platelet-rich serum. MATERIALS AND METHODS: We used HUVEC and VSMC in monoculture and co-culture models in the presence and absence of platelet rich serum treated with BMS or DES. We performed the determination of IC50 for mTOR inhibitor, cytotoxicity evaluation by the colorimetric method of MTT, determination of lipid peroxide formation, cell cycle and expression of necrosis and inflammation markers. RESULTS: In the assessment of cytotoxicity by the MTT colorimetric method and determination of the IC50, VSMC were less sensitive to sirolimus than HUVEC (IC50 in 24/48 hours 14.85 uM/10.47uM and 9.48 uM/ 22.24 uM, respectively for HUVEC and VSMC). Platelets potentiate the oxidative stress generated by the presence of stents, possibly by increasing the inflammatory environment. Drug-eluting stents arrested VSMC and HUVEC in the G0/G1 phase of the cell cycle only with the addition of platelets to the culture medium. In cell culture models without platelets the cell cycle arrest was in G2/M. There was no increase of the cells in the fragmented DNA phase (sub-G0) evidencing that there was no induction of apoptosis. CONCLUSION: Human aorta smooth muscle cells of the were less sensitive to sirolimus than HUVEC. In coculture models with platelet addition, DES with sirolimus caused cell cycle arrest in the G0/G1 phase without induction of apoptosis, suggesting that sirolimus exerts its antiinflammatory effects in these cellular populations and consequently reduces neointimal hyperplasia via a cytostatic mechanism

A avaliação do estado de saúde percebido tem sido um tema de pesquisa imprescindível na área da saúde, visto que seus resultados contribuem para definir tratamentos, avaliar custo/benefício do cuidado, além de reduzir as taxas de morbimortalidade. Os objetivos deste estudo foram: comparar a presença de sintomas, o estado de saúde percebido e o grau de severidade da depressão, segundo o diagnóstico da Síndrome Isquêmica Miocárdica Instável (SIMI): Infarto Agudo do Miocárdio (IAM) versus Angina Instável (AI); investigar a presença de possíveis relações entre o estado de saúde percebido e o grau de severidade da depressão nos dois grupos e analisar a variância da medida do estado de saúde percebido e do grau de severidade da depressão explicada por variáveis preditoras. Estudo descritivo, correlacional e transversal, desenvolvido na Unidade Coronariana e enfermarias da cardiologia de dois hospitais públicos do interior de São Paulo. Entrevistas individuais foram realizadas pela pesquisadora com a coleta de dados para caracterização sociodemográfica e clínica, questionário de sintomas associados à SIMI, avaliação do estado de saúde percebido (SF-36) e depressão (Inventário de Depressão de Beck). Os dados foram analisados utilizando o teste de associação (Qui-quadrado), teste t de Student para amostras independentes e o teste de correlação de Pearson. Foram construídos cinco modelos de regressão linear múltipla, a fim de se verificarem as porcentagens da variância que eram explicadas por cada uma das variáveis preditoras. O nível de significância adotado foi de 0,05. Participaram da investigação 253 pacientes, sendo 142 diagnosticados com IAM, com idade média de 55,8 anos e a maioria homens (74,6%). No grupo de AI (111 pacientes), a idade média foi de 60,6 anos, e a maioria também foi do sexo masculino (62,2%). Com relação ao estado de saúde percebido, pode-se observar que as melhores avaliações foram relatadas pelos pacientes que sofreram um IAM, assim como apresentaram menor grau de severidade de depressão do que quando comparados com pacientes com AI. Foram observadas correlações negativas entre o estado de saúde percebido e a depressão nos dois grupos de pacientes, sendo de forças fracas a forte no grupo de infartados e de moderadas a forte no grupo de angina, todas são estatisticamente significantes. Utilizando como variáveis preditoras o sexo, a idade, a presença de tratamentos prévios para doenças cardiovasculares e a manifestação da SIMI, foram obtidos valores de R2 ajustados de 0,138; 0,231; 0,129 e 0,117 para os domínios Aspectos Físicos, Capacidade Funcional, Dor e Aspectos Emocionais, respectivamente. A inclusão da medida de depressão e o uso de psicofármacos elevaram os valores para 0,251; 0,349; 0,259 e 0,263, todos são aumentos estatisticamente significantes. Com relação ao modelo construído para a depressão, utilizando as mesmas variáveis preditoras dos modelos anteriores, o R2 ajustado encontrado foi de 0,149. Conclui-se que os pacientes com AI apresentaram maior comprometimento em todos os domínios avaliados pelo SF-36, quando comparados com os pacientes com IAM, assim como reportaram maior grau de severidade de depressão. Além disso, pacientes com maior grau de depressão apresentaram piores avaliações do estado de saúde percebido. / Perceived health state assessment has been a fundamental research theme in health, as its results contribute to define treatments, assess the cost/benefit of care and reduce morbidity/mortality rates. This research aimed to: compare the presence of symptoms, the perceived health state and the severity degree of depression according to the diagnosis of Acute Coronary Syndrome (ACS): Acute Myocardial Infarction (AMI) versus Unstable Angina (UA); investigate the presence of possible relations between perceived health state and the severity degree of depression in the two groups and analyze the variance in the perceived health state and the severity degree of depression measure explained by predictive variables. Study descriptive, correlational and cross-sectional, developed at the Coronary Unit and cardiology wards of two public hospitals in the interior of São Paulo, Brazil. The researcher held individual interviews, collecting sociodemographic and clinical characterization data and applying a questionnaire on ACS-associated symptoms, an instrument to assess the perceived health state (SF-36) and depression (Beck Depression Inventory). Data were analyzed using the association test (Chi-square), Students t-test for independent samples and Pearsons correlation test. Five multiple linear regression models were constructed to verify the variance percentages explained by each of the predictive variables. The significance level was set at 0.05. Research participants were 253 patients, 142 of whom were diagnosed with AMI, with an average age of 55.8 years and mostly men (74.6%). In the UA group (111 patients), the average age was 60.6 years and patients were mostly male (62.2%) too. With regard to the perceived health state, the best assessments came from patients victims of AMI, who also presented minor severity degree of depression when compared with UA patients. Negative correlations were observed between perceived health state and the severity degree of depression in both patient groups, which were weak to strong in the infarction group and moderate to strong in the angina group, all statistically significant. Using gender, age, presence of previous treatments for cardiovascular diseases and ACS manifestations as predictive variables, adjusted R2 levels amounted to 0.138; 0.231; 0.129 and 0.117 for Physical Aspects, Functional Capacity, Pain and Emotional Aspects, respectively. The inclusion of the depression measure and the use of psychotropic drugs raised levels to 0.251; 0.349; 0.259 and 0.263, all statistically significant increases. With regard to the model constructed for depression, using the same predictive variables as in earlier models, the adjusted R2 was 0.149. In conclusion, all SF-36 domains were more committed among patients with UA than among patients with AMI. UA patients also reported higher severity degree of depression more frequently. Moreover, patients with higher severity degree of depression presented worse assessments of the perceived health state.

Cheng Wai Ring Caroline. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 74-84). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / 摘要 --- p.iv / Table of contents --- p.vi / Publications --- p.x / List of figures --- p.xi / List of tables --- p.xii / Abbreviations --- p.xiii / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Coronary Heart Disease --- p.2 / Chapter 1.1.1 --- Epidemiology --- p.2 / Chapter 1.2 --- Hypercholesterolemia and CHD --- p.3 / Chapter 1.2.1 --- Atherosclerotic plaque and lipoprotein --- p.4 / Chapter 1.2.2 --- NCEP ATP III guidelines --- p.5 / Chapter 1.2.2.1 --- CHD risk assessment --- p.5 / Chapter 1.2.2.2 --- Target lipid control --- p.8 / Chapter 1.2.2.3 --- Therapeutic lifestyle changes --- p.9 / Chapter 1.2.2.4 --- Pharmacological interventions --- p.10 / Chapter 1.2.2.5 --- Adherence to lipid-lowering therapy --- p.13 / Chapter 1.3 --- Adherence to drug therapy --- p.14 / Chapter 1.3.1 --- Definition of adherence --- p.14 / Chapter 1.3.2 --- Methods to assess adherence --- p.16 / Chapter 1.3.2.1 --- Expressions of adherence measurements --- p.20 / Chapter 1.3.3 --- Time effect on adherence --- p.21 / Chapter 1.3.4 --- Predictors of adherence --- p.22 / Chapter 1.3.5 --- Impact of poor adherence to statins --- p.23 / Chapter 1.4 --- Objectives and hypotheses --- p.25 / Chapter Chapter 2 --- Materials and Methods / Chapter 2.1 --- Study site --- p.27 / Chapter 2.2 --- Patient selection criteria --- p.28 / Chapter 2.2.1 --- Inclusion criteria --- p.28 / Chapter 2.2.2 --- Exclusion criteria --- p.29 / Chapter 2.3 --- Patient recruitment --- p.30 / Chapter 2.4 --- Assessments --- p.32 / Chapter 2.4.1 --- Adherence assessment --- p.32 / Chapter 2.4.1.1 --- Electronic monitoring --- p.32 / Chapter 2.4.1.2 --- Patient report --- p.33 / Chapter 2.4.1.3 --- Pill count --- p.34 / Chapter 2.4.1.4 --- Predictors of adherence --- p.34 / Chapter 2.4.2 --- Clinical outcome assessment --- p.35 / Chapter 2.4.2.1 --- Lipid control --- p.35 / Chapter 2.4.3 --- Economic outcome assessment --- p.35 / Chapter 2.4.3.1 --- Total direct medical cost --- p.35 / Chapter 2.4.3.2 --- Healthcare cost per member per month --- p.36 / Chapter 2.5 --- Sample size --- p.36 / Chapter 2.6 --- Statistical analysis --- p.37 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Study sample --- p.40 / Chapter 3.1.1 --- Demographic characteristics --- p.41 / Chapter 3.1.2 --- Co-morbidity factors --- p.42 / Chapter 3.2 --- Adherence measurement --- p.44 / Chapter 3.2.1 --- Electronic monitoring --- p.44 / Chapter 3.2.2 --- Patient report --- p.45 / Chapter 3.2.3 --- Pill Count --- p.46 / Chapter 3.2.4 --- Correlation among methods for measuring adherence --- p.47 / Chapter 3.2.5 --- Trend of adherence and persistence over time --- p.48 / Chapter 3.2.6 --- Independent predictors of adherence --- p.49 / Chapter 3.3 --- Outcome assessment --- p.52 / Chapter 3.3.1 --- Clinical outcomes --- p.52 / Chapter 3.3.2 --- Economic outcomes --- p.52 / Chapter 3.4 --- Association between adherence and clinical outcomes --- p.53 / Chapter 3.4.1 --- Adherence and LDL-C reduction --- p.53 / Chapter 3.4.2 --- Adherence and NCEP ATP III target --- p.55 / Chapter 3.5 --- Association between adherence and economic outcomes --- p.55 / Chapter 3.5.1 --- Adherence and healthcare utilization --- p.55 / Chapter Chapter 4 --- Discussion and Conclusion / Chapter 4.1 --- Discussion --- p.59 / Chapter 4.1.1 --- Accuracy of patient report and pill count --- p.59 / Chapter 4.1.2 --- Persistence to statin therapy over time --- p.62 / Chapter 4.1.3 --- Predictors for patient adherence --- p.63 / Chapter 4.1.4 --- Clinical impacts of patient adherence --- p.66 / Chapter 4.1.5 --- Economic impacts of patient adherence --- p.68 / Chapter 4.1.6 --- Limitations --- p.70 / Chapter 4.2 --- Conclusion --- p.71 / References --- p.74 / Appendices / Appendix A-1. Framingham risk scoring system for male --- p.86 / Appendix A-2. Framingham risk scoring system for female --- p.87 / Appendix B-1. Information sheet provided to nurses of the Cardiology clinic --- p.88 / Appendix B-2. Information sheet provided to nurses of the Diabetes clinic --- p.89 / Appendix B-3. Information sheet provided to nurses of the Lipid clinic --- p.90 / Appendix C. Data collection form --- p.91 / Appendix D. Instruction sheet provided to the study patient --- p.94 / Appendix E. Unit cost of items from electronic dispensing record and Hong Kong Gazette 2003 for estimating total direct medical cost --- p.95

Na Síndrome Metabólica, ações lipotóxicas e glicotóxicas contribuem para a aceleração do processo aterogênico cuja base é a inflamação. O tecido adiposo epicárdico vem sendo reconhecido como metabolicamente ativo e foi relacionado à elevação da produção de citocinas e adipocinas inflamatórias e aumento de DAC. Pioglitazona e Sinvastatina comprovadamente atuam como drogas pleiotrópicas na redução do processo inflamatório sistêmico. O presente estudo teve como objetivo principal avaliar possíveis correlações entre a presença de citocinas inflamatórias plasmáticas versus teciduais e a resposta de ambas à terapia medicamentosa. Para tanto, foram utilizadas monoterapia com Sinvastatina ou Pioglitazona e terapia combinada Pioglitazona+Sinvastatina e acompanhadas as variáveis lipídicas, glicêmicas e inflamatórias sistêmicas, células e citocinas inflamatórias em TAE, um tipo de tecido adiposo branco visceral instalado nas adjacências de focos ateroscleróticos em artérias coronárias de pacientes portadores de DAC e SMet. O estudo envolveu 73 pacientes com DAC multiarterial, avaliada pela cinecoronariografia e SMet que foram submetidos a revascularização e 20 pacientes submetidos à cirurgia valvar para substituição de valva mitral. Os pacientes com DAC eram incluídos de forma não aleatória a um dos 4 subgrupos: controle (n = 17), Simvastatina (20 mg / dia, n = 20), Pioglitazona (15 mg ou 30 mg / dia, n = 18) e Simvastatina + Pioglitazona (20 mg / dia + 15 mg ou 30 mg / dia, respectivamente, n = 18). Amostras de tecido adiposo epicárdico foram obtidas durante a cirurgia. Infiltração de macrófagos, linfócitos e secreção adipocitocinas foram investigados por coloração imunohistoquímica e comparados aos biomarcadores inflamatórios plasmáticos. Os resultados mostraram que a infiltração de macrófagos e a presença de citocinas pró-inflamatórias tais como TNF-, IL-6, leptina and resistina foram reduzidas em TAE de pacientes DAC/SMet após monoterapia com Pioglitazona. Os pacientes tratados apenas com Sinvastatina apresentaram os menores valores plasmáticos de leptina, resistina and MCP-1. Pioglitazona+Sinvastatina foram associadas aos menores valores plasmáticos de IL-6, TNF-, resistina, ADMA, MMP-9 em comparação ao grupo de pacientes não tratados. Além disso, a terapia combinada revelou a mais alta concentração de adiponectina plasmática concomitante ao menor valor de PCRus. Esses achados refletiram não só a condição plasmática como se correlacionaram positivamente à condição tecidual mostrada pela porcentagem média de área ocupada por macrófagos no TAE e a quantidade de PCRus presente no plasma após os tratamentos. Houve correlação positiva também entre citocinas sistêmicas e teciduais após os tratamentos, exceto para o TNF- após o tratamento com sinvastatina ( r = - 0,025, p = 0,33) e leptina após o tratamento com pioglitazona (r = -0,877, p <0,0001). Nos pacientes tratados com Sinvastatina, os fragmentos de TAE apresentaram agregados de linfócitos T, B e macrófagos concentrados na borda e ao redor de vasos sanguíneos / In the Metabolic Syndrome, the concentration of free fatty acids and the elevation of glycemia result in lipotoxic and glycotoxic actions, respectively, which contribute to accelerate the atherogenic process. (MS). Inapropriate secretion of adipocytokines plays a critical role in chronic inflammatory states associated with obesity-linked diseases, such as type 2 diabetes and atherosclerosis. The pleiotropic anti-inflammatory action of Simvastatin and/or Pioglitazone may counteract such systemic effects but its influence upon human epicardial adipose tissue is unknown. To assess the anti-inflammatory action of Simvastatin, Pioglitazone or both in epicardial adipose tissue in patients with coronary artery disease (CAD) and metabolic syndrome. The study comprised 73 patients with multivessel CAD, evaluated by cinecoronariography, and MS who underwent bypass grafting and 20 valvar patients who underwent surgery for mitral valve replacement. The 73 who underwent elective bypass grafting were non-randomly allocated to one of 4 subgroups: control (n=17), Simvastatin alone (20 mg/day, n=20), Pioglitazone alone (15 mg or 30 mg/day, n=18), or Simvastatin+Pioglitazone (20 mg/day + 15 mg or 30 mg/day, respectively, n=18). Epicardial adipose tissue sample was obtained during surgery. Infiltration of macrophages, lymphocytes and adipocytokines secretion were investigated by immunohistochemical staining and compared to plasma inflammatory biomarkers. Among CAD/MS patients, treatment with Simvastatin alone, Pioglitazone alone and Simvastatin+Pioglitazone significantly reduced plasma CRP and cytokines compared with control group. Monotherapy with Simvastatin significantly reduced plasma IL-6, leptin, resistin, MCP-1 (p<0.001 for all), whereas monotherapy with Pioglitazone reduced IL-6, TNF-, resistin and MMP-9 (p<0.001 for all) compared with control group. Simvastatin+Pioglitazone treatment reduced more plasmatic variables (IL-6, TNF-, resistin, ADMA and MMP-9 vs. control group (p<0.001). All treatments increased adiponectin plasma levels (p<0.001). In the combined treatment group, higher concentration in plasma adiponectin and lower hsCRP, were found simultaneously. There was positive correlation between mean percentage macrophages area in EAT and plasma hsCRP; also between systemic and tecidual citokynes after the treatments, except for TNF- after treatment with simvastatin (r = -0.025, p = 0.33) and leptin after treatment with pioglitazone (r = -0.877, p <0.0001). In fat fragments of patients treated with Simvastatin, T- and B-lymphocytes, and macrophages clusters concentrated near the edge or around blood vessels were observed by first time. In patients with CAD and MS treatment with Pioglitazone, Sinvastatin or combination can substantially reduce both epicardial tissue and plasma inflammatory markers. Such tissue effects may contribute to the control of coronary atherosclerosis progression

Han, Jianguo. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 66-76). / Abstracts in English and Chinese. / Declaration --- p.i / Acknowledgement --- p.□ / Publication --- p.□ / Abstract (English) --- p.□xi / Abstract (Chinese) --- p.□ / Abbreviations --- p.ix / List of figures / tables --- p.x / Chapter Chapter 1. --- General Introduction / Chapter 1.1 --- Role of vascular smooth muscle cells in the control of coronary circulation --- p.1 / Chapter 1.1.1 --- Potassium channels in the coronary smooth muscle cells --- p.2 / Chapter 1.1.1.1 --- Voltage -dependent potassium (Kv) channels --- p.3 / Chapter 1.1.1.2 --- Inward rectifier K+ (Kir) channels --- p.4 / Chapter 1.1.1.3 --- ATP-sensitive potassium (Katp) channels --- p.4 / Chapter 1.1.2 --- BKCa channels in the regulation of vascular function --- p.6 / Chapter 1.1.2.1 --- The structure of BKCa channels --- p.6 / Chapter 1.1.2.2 --- Role of BKCa channels in the regulation of vascular function --- p.6 / Chapter 1.2 --- Functional alteration of the coronary SMCs during cardiac surgery --- p.7 / Chapter 1.2.1 --- Effect of ischemia on the function of SMCs in the coronary circulation --- p.8 / Chapter 1.2.2 --- Effect of cardioplegic/organ preservation solutions on the function of SMCs in the coronary circulation --- p.11 / Chapter Chapter 2. --- Materials and Methods --- p.14 / Chapter 2.1 --- Isometric force study in small coronary arteries --- p.14 / Chapter 2.1.1 --- Preparation of porcine small coronary arteries --- p.14 / Chapter 2.1.2 --- Experiment procedure --- p.15 / Chapter 2.1.2.1 --- Mounting of small coronary arteries --- p.15 / Chapter 2.1.2.2 --- Normalization procedure for small coronary arteries --- p.16 / Chapter 2.1.2.3 --- Precontraction and relaxation --- p.17 / Chapter 2.1.3 --- Data acquisition and analysis --- p.17 / Chapter 2.2 --- Patch-clamp electrophysiology --- p.18 / Chapter 2.2.1 --- Preparation of porcine coronary arteries --- p.18 / Chapter 2.2.2 --- Enzymatic dissociation of coronary arterial SMCs --- p.18 / Chapter 2.2.3 --- Primary cell culture --- p.19 / Chapter 2.2.4 --- Recording of BKca channel currents --- p.19 / Chapter 2.3 --- Statistical analysis --- p.21 / Chapter 2.4 --- Chemicals --- p.21 / Chapter Chapter 3. --- The Effect of Ischemia on BKCa channels in the Isolated SMCs of Coronary Arteries --- p.22 / Chapter 3.1 --- Abstract --- p.22 / Chapter 3.2 --- Introduction --- p.23 / Chapter 3.3 --- Experimental design and analysis --- p.25 / Chapter 3.3.1 --- Isometric force study in small coronary arteries --- p.25 / Chapter 3.3.2 --- Effect of ischemia on NS1619-induced relaxation in small coronary arteries --- p.26 / Chapter 3.3.3 --- Effect of ischemia on smooth muscle BKca channel currents --- p.27 / Chapter 3.3.3.1 --- Preparation of porcine coronary artery --- p.27 / Chapter 3.3.3.2 --- Enzymatic dissociation of coronary arterial SMCs --- p.27 / Chapter 3.3.3.3 --- Recording of BKCa channel currents --- p.27 / Chapter 3.3.4 --- Data acquisition and analysis --- p.28 / Chapter 3.4 --- Results --- p.28 / Chapter 3.4.1 --- Electrophysiological studies --- p.28 / Chapter 3.4.1.1 --- Effect of IBTX on the whole cell outward currents --- p.29 / Chapter 3.4.1.2 --- Effect of ischemia on the IBTX-sensitive BKca currents --- p.30 / Chapter 3.4.2 --- Relaxation studies --- p.30 / Chapter 3.4.2.1 --- Resting force --- p.30 / Chapter 3.4.2.2 --- U46619-induced contraction force --- p.31 / Chapter 3.4.2.3 --- Effect of IBTX on the NS1619-induced relaxation --- p.31 / Chapter 3.4.2.4 --- Effect of ischemia on the NS1619-induced relaxation --- p.31 / Chapter 3.5 --- Discussion --- p.32 / Chapter 3.5.1 --- Functional changes of the coronary smooth muscle BKca channels after ischemic exposure --- p.33 / Chapter 3.5.2 --- Role of BKca channels in SMCs during ischemia --- p.33 / Chapter 3.5.3 --- Clinical implications --- p.35 / Chapter Chapter 4. --- The Effect of Hyperkalemia on BKCa channels in the Isolated SMCs of Coronary Arteries --- p.41 / Chapter 4.1 --- Abstract --- p.41 / Chapter 4.2 --- Introduction --- p.42 / Chapter 4.3 --- Experimental design and analysis --- p.44 / Chapter 4.3.1 --- Isometric force study in small coronary arteries --- p.44 / Chapter 4.3.1.1 --- Effect of hyperkalemia on NS1619-mediated relaxation in small coronary arteries --- p.44 / Chapter 4.3.2. --- Effect of hyperkalemia on BKCa currents of SMCs --- p.45 / Chapter 4.3.2.1 --- Preparation of porcine coronary arteries --- p.45 / Chapter 4.3.2.2 --- Enzymatic dissociation of coronary arterial SMCs --- p.45 / Chapter 4.3.2.3 --- Recording of BKca channel currents --- p.46 / Chapter 4.3.3. --- Data acquisition and analysis --- p.46 / Chapter 4.4 --- Results --- p.47 / Chapter 4.4.1 --- Effect of hyperkalemia on the iberiotoxin-sensitive BKCa channel currents --- p.47 / Chapter 4.4.2 --- Relaxation studies --- p.48 / Chapter 4.4.2.1 --- Resting force --- p.48 / Chapter 4.4.2.2 --- U46619- and high K+-induced contraction force --- p.48 / Chapter 4.4.2.3 --- Effect of high K+ on the NS1619-induced relaxation --- p.48 / Chapter 4.4.2.4 --- Effect of IBTX on the NS1619-induced relaxation --- p.49 / Chapter 4.5 --- Discussion --- p.49 / Chapter 4.5.1 --- Role of BKCa channels in the isolated SMCs in hyperkalemic solution --- p.50 / Chapter 4.5.2 --- Functional changes of BKCa channels in coronary SMCs in hyperkalemia exposure --- p.51 / Chapter 4.5.3 --- Clinical implications --- p.52 / Chapter Chapter 5. --- General Discussion --- p.58 / Chapter 5.1 --- BKCa channels in porcine coronary SMCs --- p.59 / Chapter 5.2 --- Alteration of BKCa function related to ischemia in porcine coronary SMCs --- p.60 / Chapter 5.3 --- Alteration of BKCa function related to hyperkalemia in porcine coronary SMCs --- p.61 / Chapter 5.4 --- Limitation of the study --- p.62 / Chapter 5.5 --- Future investigations --- p.63 / Chapter 5.6 --- Conclusions --- p.63 / References --- p.66

A doença arterial coronária é importante e prevalente manifestação da aterosclerose. A avaliação da função diastólica pelos parâmetros mitrais obtidos com Doppler ecocardiográfico possui limitações nos coronariopatas com fração de ejeção do ventrículo esquerdo (FEVE) preservada. Nestes, a disfunção diastólica, independentemente da FEVE, associa-se a maior incidência de desfechos desfavoráveis. A elevação da pressão diastólica final (PD2) do ventrículo esquerdo (VE) é a principal consequência fisiológica da disfunção diastólica. A pesquisa por melhores formas de determinação da PD2 do VE estendeu-se às modernas técnicas ecocardiográficas de quantificação da mecânica cardíaca. O objetivo deste estudo é correlacionar as medidas de deformação miocárdica, obtidas pelo speckle-tracking ecocardiográfico bidimensional, com a medida invasiva da PD2 do VE em pacientes com insuficiência coronariana e FEVE preservada. Métodos: foram avaliados 81 coronariopatas (idade: 61 ±8 anos) com FEVE >50%, encaminhados para cineangiocoronariografia eletiva, 40 destes com PD2 elevada (>16 mm Hg). Todos os indivíduos foram submetidos à avaliação ecocardiográfica convencional imediatamente antes do cateterismo e subsequente avaliação offline, com ecocardiografia speckle tracking (EST) para obtenção de medidas sistólicas e diastólicas de strain e strain rate circunferenciais e longitudinais, e estudo rotacional do VE. Foram analisadas as variáveis diastólicas da EST, tanto de forma isolada, quanto combinada com a velocidade da onda E ao Doppler. Resultados: Comparativamente, os pacientes do grupo com PD2 do VE elevada (n=40) mostraram aumento do volume indexado do átrio esquerdo (22 ±6 mL vs 26 ±8,26 mL p=0,04), velocidade da onda E (65 ±15 cm/s vs 78 ±20 cm/s p=0,02), relação E/e\' médio (8,14 ±2,0 vs 11,54 ±2,7 p=0,03) e relação E/strain rate global circunferencial (SRGC) pico E (39 cm vs 46 cm p <0,01). Nos 81 pacientes a correlação de Spearman com a medida invasiva da PD2 do VE foi de 0,56 para a relação E/e\' (p=0,03) e de 0,43 para a relação E/ESRGC pico E (p<0,01). A área sob a curva ROC foi significativa em ambas, sendo 0,83 e 0,73 respectivamente (p<0,05). Conclusão: A relação E/SRGC pico E é capaz de identificar elevação da PD2 do VE em coronariopatas com FEVE preservada, com menor desempenho que a relação E/e\'. / Introduction: Coronary artery disease (CAD) is important and prevalent manifestation of atherosclerosis. The assessment of diastolic function by mitral Doppler echocardiographic parameters has limitations in patients with CAD and preserved left ventricular ejection fraction (LVEF). Diastolic dysfunction is associated with higher incidence of unfavorable outcomes in these patients, regardless of LVEF. The increase in left ventricle end-diastolic pressure (LVEDP) is the main physiological consequence of diastolic dysfunction. The search for better ways of determining the LVEDP extended to the quantitative evaluation of cardiac mechanics with the modern echocardiographic techniques. The aim of this study is to correlate the invasive mesures of LVEDP and myocardial deformation measurements obtained by the two-dimensional speckle-tracking echocardiography in patients with coronary artery disease and preserved LVEF. Methods: 81 CAD patients (age: 61 ± 8 years) with LVEF >50%, scheduled for elective coronary angiography were evaluated, 40 of these with high LVEDP (>16 mm Hg). All subjects underwent conventional echocardiography immediately before catheterization and subsequent offline assessment with speckletracking echocardiography (STE) to obtain systolic and diastolic values of circumferential and longitudinal strain and strain rate, and rotational LV study. Diastolic variables of EST were analyzed both isolated and combined with the speed of the transmitral Doppler E wave. Results: Patients in the group with the high LVEDP (n =40) showed increased left atrial volume index (22 ± 6 mL vs 26 ± 8.26 mL p =0.04), E wave velocity (65 ± 15 cm/s vs 78 ±20 cm/s p = 0.02), E/e\' (average) ratio ( 8.14 ± 2.0 vs 11.54 ± 2.7 p = 0.03) and E/global circumferential strain rate (GCSR) peak E (39 cm vs 46 cm p <0.01). In 81 patients, Spearman\'s correlation with the invasive measurement of LVEDP was 0,56 (p =0.03) for the E/e\' ratio and 0.43 for the E/GCSR peak E (p <0.01). The area under the ROC curve was significant for both (p < 0.05): 0.83 and 0.73 respectively. Conclusion: The E/GCSR peak E ratio is able to identify elevated LVEDP in CAD patients with preserved LVEF, with less performance than the E/e\' ratio.

A importância da doença arterial coronariana (DAC) na sociedade \"moderna\" é atestada pelo grande número de pessoas afetadas por ela. Os dados da Organização Mundial de Saúde estimam que a doença isquêmica do coração será a segunda principal causa de morte em todo o mundo até 2030. Além disso, com o advento das ferramentas de predição de riscos e estudos de associação genômica ampla (GWAS, do inglês Genome-Wide Association Studies), vários estudos tem demonstrado o uso de escores genéticos de risco para predizer DAC, porém estes escores apresentam apenas uma discreta melhora em nossa capacidade de avaliação. O presente estudo desenvolveu um escore genético de risco (GRS, do inglês Genetic risk score) para DAC, utilizando polimorfismos previamente associados a DAC e/ou a fenótipos relacionados à doença. Mil, trezentos e quarenta e nove indivíduos, provenientes do Estudo Longitudinal da Saúde do Adulto (ELSA-BRASIL), foram genotipados para nosso estudo. Usando polimorfismos de nucleotídeo único (SNP, do inglês Single Nucleotide Polymorphisms) obtidos a partir da base de dados online de GWAS avaliamos a associação de cada polimorfismo escolhido com os fatores de risco para doença cardiovascular. Os indivíduos foram submetidos à determinação do escore de cálcio (EC) coronário e um EC > 100 foi usado como desfecho. Modelos Zero-inflacionados foram utilizados para a construção do escore de risco genético (GRS). Escore de risco de Framingham para DAC em 10 anos (FRS, do inglês Framingham Risk Score) foi calculado de acordo com o descrito por Wilson e D\'Agostino. Nosso GRS foi composto de 47 variantes genéticas, ajustado por sexo e idade, associadas com DAC ou outros fenótipos da doença coronária ou fatores de risco. O GRS mostrou precisão significativamente melhor do que o Escore de Risco de Framingham para predizer o risco de CHD (AUC, 0,90; IC 95%: 0,88-0,93; P < 0,01). Também foram criados outros dois escores: o primeiro, um modelo com apenas a idade e sexo; o segundo, apenas utilizando a informação genética. Comparamos o modelo Idade+Sexo com o GRS e FRS por meio de curva ROC e avaliamos o desempenho dos modelos em comparação com FRS. Análises do NRI e IDI foram realizadas para avaliar a reclassificação do GRS e do modelo Idade+Sexo em relação ao FRS, que é o atualmente utilizado para a estratificação de indivíduos da população geral. O escore apenas com os SNPs foi utilizado para comparar sua adição a um modelo com fatores de risco. Por fim, analisamos a associação entre o GRS, fatores de risco e CAC usando modelos lineares generalizados. Em suma, criamos um GRS composto por 47 SNPs associado com doença coronariana ou fatores de risco cardiovascular que apresentou bons resultados na predição de risco para DAC. O GRS melhorou a reclassificação de risco para doença arterial coronariana, e melhorou significativamente a discriminação entre os indivíduos afetados e não afetados / Importance of coronary artery disease (CAD) in \"modern\" society is attested by the large increase of people affected by it. Data from the World Health Organization estimated that ischemic heart disease is the second leading cause of death worldwide by 2030. Futhermore, with the advent of predictive risk tools and genome-wide association studies, several studies have demonstrated the use of genetic risk scores (GRS) for predicting CAD, but these scores shows a slight improvement in the assessment. This study built a genetic risk score for CAD, using polymorphisms previously associated with CAD and phenotypes related to disease. One thousand, Three hundred forty-nine individuals, from the Brazilian Longitudinal Study of Adults Health (in Portuguese, Estudo Longitudinal da Saúde do Adulto-BRASIL), were genotyped for our study. Using single nucleotide polymorphisms (SNPs) obtained from the online database of GWAS evaluated the association of each polymorphism chosen with risk factors for cardiovascular disease. Individuals underwent determination of calcium artery coronary score (CACS) and CAC > 100 was used as the end-point. Zero inflated models were used for the construction of GRS. Framingham Risk Score (FRS) for CHD in 10 years was calculated as described by Wilson and D\'Agostino. In addition, our GRS consists of 47 genetic variants, adjusted for sex and age, associated with CHD or other phenotypes of coronary heart disease or risk factors. GRS showed significantly better accuracy than the Framingham Risk Score to predict the risk of CAD (AUC, 0.90; 95% CI: 0.88 0.93; P < 0.01). Also other two scores were created: first, a model with only age and sex; second, only the genetic information. We compare the Age+Sex model with the GRS and FRS through ROC curve and evaluate the performance of models compared with FRS. NRI and IDI analysis were performed to evaluate the reclassification of GRS and Age + Sex model in relation to the FRS model. The score only the SNPs was used to compare their addition to a model with risk factors. Finally, we analyzed the association between the GRS, risk factors and CAC using generalized linear models. In short, we create a GRS composed of 47 SNPs associated with coronary heart disease or cardiovascular risk factors that showed good results in risk prediction for CAD. GRS improved reclassification of risk for coronary artery disease, and significantly improves the discrimination between affected and unaffected individuals

No description available.

Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 186-210). Also available on the Internet.