Orientador: Wilson Nadruz Júnior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-15T23:44:37Z (GMT). No. of bitstreams: 1 Sales_MariaLilian_D.pdf: 3937457 bytes, checksum: 1aca22e05bdd5e09c3f3e53c2841451e (MD5) Previous issue date: 2010 / Resumo: Estudos experimentais revelaram que a inibição de componentes da via de sinalização celular regulada pelos Toll-Like Receptors (TLRs) pode atenuar a hipertrofia cardíaca em animais submetidos à sobrecarga pressora. O objetivo deste estudo foi investigar a influência dos polimorfismos Asp299Gly do TLR4 e Pro249Ser do TLR6 sobre a estrutura do ventrículo esquerdo (VE) em indivíduos hipertensos. Foram estudados 443 pacientes por meio de avaliação clínica, laboratorial e ecocardiográfica, enquanto que os polimorfismos foram detectados por reação de polimerase em cadeia/enzima de restrição. Ademais, monócitos obtidos de sangue periférico de pacientes hipertensos foram estimulados in vitro com LPS (agonista de TLR4) e zimosan (agonista de TLR6) e a produção de interleucina-6 e fator de necrose tumoral-alfa (TNF-alfa) foi avaliada de acordo com a presença da variante Asp299Gly do TLR4 e Pro249Ser do TLR6. Mulheres que carregavam o alelo TLR4 299Gly apresentaram menor espessura de parede posterior do VE, menor espessura de septo, menor índice de massa do VE e reduzida prevalência de hipertrofia cardíaca. Mulheres homozigotas para TLR6 249Ser apresentaram menor espessura da parede do VE e menor espessura relativa da parede do VE em relação às mulheres com os genótipos Pro/Ser e Pro/Pro. Estes achados foram confirmados por análise de regressão linear múltipla, que incluiu idade, pressão arterial sistólica e diastólica, índice de massa corpórea, menopausa, diabetes mellitus e uso de antihipertensivos como fatores confundidores. Por fim, estudos funcionais in vitro revelaram que monócitos de homens e mulheres que apresentaram o alelo TLR4 299Gly tiveram menor produção de interleucina-6 após estímulo com LPS e a presença do alelo TLR6 249Ser em homozigose esteve associada a uma menor produção de interleucina-6 e TNF-alfa após estímulo com zimosan apenas nos monócitos extraídos de mulheres hipertensas. De maneira geral, esses dados sugerem que pode haver uma interação entre gêneros, polimorfismos dos receptores Toll-like e fenótipo do VE em indivíduos hipertensos. Sob esta perspectiva, estudos longitudinais são necessários para avaliar o impacto destes polimorfismos sobre o risco cardiovascular em mulheres hipertensas / Abstract: Experimental studies have shown that inhibition of components of cell signaling pathway regulated by Toll-Like Receptors (TLRs) can reduce cardiac hypertrophy in animals subjected to pressure overload. The aim of this study was to investigate the influence of the polymorphisms TLR4 Asp299Gly and TLR6 Pro249Ser on the structure of the left ventricle in hypertensive subjects. We studied 443 patients by clinical, laboratory and echocardiographic, while polymorphisms were detected by the polymerase chain / restriction enzyme. Moreover, monocytes obtained from peripheral blood of hypertensive patients were stimulated in vitro with LPS (TLR4 agonist) and zymosan (TLR6 agonist) and the production of interleukin-6 and tumor necrosis factor-alpha (TNF-alpha) was assessed according to the presence of the Asp299Gly variant of TLR4 and Pro249Ser of TLR6. Women who carried the TLR4 299Gly allele had lower posterior wall thickness, thinner septum, a lower rate of left ventricular mass and reduced prevalence of cardiac hypertrophy. Women homozygous for TLR6 249Ser had lower posterior wall thickness and relative wall thickness, compared to women with the genotype Pro/Ser and Pro/Pro. These findings were confirmed by analysis of multiple linear regression that included age, systolic and diastolic blood pressure, body mass index, menopause, diabetes mellitus and use of antihypertensive drugs as confounding factors. Finally, in vitro functional studies revealed that monocytes from men and women who harbored the TLR4 299Gly allele had lower production of interleukin-6 after stimulation with LPS and the presence of homozygous 249Ser allele was associated with a lower production of Interleukin-6 and TNF-alpha after stimulation with zymosan only in monocytes hypertensive women. These data suggest that there may be an interaction between gender, polymorphisms of Toll-like receptors and ventricular phenotype in hypertensive subjects. In this regard, longitudinal studies are needed to assess the impact of these polymorphisms on the cardiovascular risk of hypertensive women / Doutorado / Clinica Medica / Doutor em Clínica Médica

Cardiac remodeling after acute myocardial infarction (MI) is an important process that leads to progressive ventricular enlargement and heart failure. Several variables have been identified to predict an increase in left ventricular (LV) volume and a decrease of LV ejection fraction (LVEF) after an acute MI including infarct size, anterior location, cardiac enzyme level, transmurality of the infarct, patency of the infarct-related artery, end systolic volume (ESV) and mitral deceleration time, etc. / Regional disturbances of LV wall motion have long been recognized to occur in patients with cardiac diseases, such as hypertrophic cardiomyopathy, unstable angina, acute ischemia, and MI. Tissue Doppler imaging (TDI) is recently established for detecting regional contractile abnormalities and asynchrony, and can predict reverse remodeling and improved synchronicity after biventricular pacing therapy in heart failure patients. However, it is unclear whether LV asynchrony plays an important role in the evolutionary changes of LV remodeling after an acute infarction and whether it can predict the changes independently. / The identification of transmural extent of myocardial necrosis and degree of non-viability after acute MI is clinically important. TDI-derived strain rate imaging (SRI) quantifies local rate of myocardial deformation and has the potential to differentiate viable from infarcted myocardium. / Therefore, in this study we aimed to investigate: (1) Whether SRI may differentiate transmural from non-transmural MI as assessed by ce-MRI in routine patients post acute infarction, and establish practical cutoff values for identifying transmural scar tissue from non-transmural or subendocardial infarction with viable myocardium. (2) Whether LV systolic and diastolic asynchrony measured by TDI occurs early after acute MI even in the absence of widening of QRS complexes, and determine if this is explained by the site and extent of the infarction measured by ce-MRI. (3) The relationships between serial measurements of infarct size on ce-MRI and LV remodeling process after an acute infarction, and determine whether early assessment of infarct size predicts progressive ventricular enlargement and cardiac dysfunction, and whether it differs with infarct location. (4) The relationships between LV asynchrony, infarct size and LV remodeling, and determine whether early assessment of LV asynchrony by TDI compared with standard clinical correlates of LV remodeling and infarct size predicts progressive ventricular enlargement and cardiac dysfunction. (Abstract shortened by UMI.) / Zhang Yan. / "April 2005." / Adviser: John E. Sanderson. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0175. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 161-192). / 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. / Abstract in English and Chinese. / School code: 1307.