Orientador: Vera Therezinha Medeiros Borges / Resumo: Objetivo: Determinar o valor da concentração do BNP que se associa à presença de hipertrofia do ventrículo esquerdo (VE) em mulheres com pré-eclâmpsia (PE). Métodos: Realizou-se estudo observacional, descritivo e transversal em gestantes com diagnóstico de pré-eclâmpsia, que receberam assistência obstétrica no Hospital das Clínicas da Faculdade de Medicina de Botucatu - Unesp. Foram excluídas do estudo gestantes portadoras de patologia clínica ou gestacional associada a alterações cardiovasculares (diabetes, hipertensão arterial crônica, cardiopatias, colagenoses, nefropatias). Considerando a prevalência de hipertrofia concêntrica do VE nessa população de 27% e assumindo a margem de erro de 10% e confiabilidade de 95%, o tamanho amostral calculado foi de 76 gestantes. No momento do diagnóstico de PE as gestantes selecionadas foram submetidas à coleta de sangue venoso para determinação da concentração sérica de BNP e ao exame de ecocardiograma para identificação de hipertrofia concêntrica do VE. As correlações entre o índice de massa do VE (iMVE) e entre a espessura relativa da parede (ER) e o BNP foram realizadas pelo teste de Spearman. O ponto de corte da concentração do BNP, que identifica hipertrofia concêntrica do VE, foi estabelecido pela curva ROC, utilizando-se o programa estatístico SPSS for Windows. Resultados: A hipertrofia concêntrica do ventrículo esquerdo foi diagnosticada em 48,7% das gestantes. O ponto de corte do valor da concentração do BNP, que identifica a ... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

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Agradecemos a compreensão. on 2017-07-26T19:10:07Z (GMT) / Submitted by JULIANE ROSA POIATI null (jpoiati@yahoo.com.br) on 2017-07-27T00:19:47Z No. of bitstreams: 1 Tese Pronta recente.pdf: 1203025 bytes, checksum: 3f33e46e228494eaa8c4c9ba0d1246d1 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-07-31T14:34:20Z (GMT) No. of bitstreams: 1 poiati_jr_dr_bot.pdf: 1203025 bytes, checksum: 3f33e46e228494eaa8c4c9ba0d1246d1 (MD5) / Made available in DSpace on 2017-07-31T14:34:20Z (GMT). No. of bitstreams: 1 poiati_jr_dr_bot.pdf: 1203025 bytes, checksum: 3f33e46e228494eaa8c4c9ba0d1246d1 (MD5) Previous issue date: 2017-05-26 / Objetivo: Determinar o valor da concentração do BNP que se associa à presença de hipertrofia do ventrículo esquerdo (VE) em mulheres com pré-eclâmpsia (PE). Métodos: Realizou-se estudo observacional, descritivo e transversal em gestantes com diagnóstico de pré-eclâmpsia, que receberam assistência obstétrica no Hospital das Clínicas da Faculdade de Medicina de Botucatu - Unesp. Foram excluídas do estudo gestantes portadoras de patologia clínica ou gestacional associada a alterações cardiovasculares (diabetes, hipertensão arterial crônica, cardiopatias, colagenoses, nefropatias). Considerando a prevalência de hipertrofia concêntrica do VE nessa população de 27% e assumindo a margem de erro de 10% e confiabilidade de 95%, o tamanho amostral calculado foi de 76 gestantes. No momento do diagnóstico de PE as gestantes selecionadas foram submetidas à coleta de sangue venoso para determinação da concentração sérica de BNP e ao exame de ecocardiograma para identificação de hipertrofia concêntrica do VE. As correlações entre o índice de massa do VE (iMVE) e entre a espessura relativa da parede (ER) e o BNP foram realizadas pelo teste de Spearman. O ponto de corte da concentração do BNP, que identifica hipertrofia concêntrica do VE, foi estabelecido pela curva ROC, utilizando-se o programa estatístico SPSS for Windows. Resultados: A hipertrofia concêntrica do ventrículo esquerdo foi diagnosticada em 48,7% das gestantes. O ponto de corte do valor da concentração do BNP, que identifica a hipertrofia concêntrica do VE, foi 203pg/mL (sensibilidade de 88%, especificidade de 80%, valor preditivo positivo de 69%, valor preditivo negativo de 93% e acurácia de 83%). A área sob a curva foi 0,87 (IC 95%= 0,79 – 0,95). A correlação entre o iMVE e a ER com a concentração do BNP foi significativa (iMVE: r=0,49; p<0,0001; ER: r=0,50; p<0,0001). Conclusões: O presente estudo encontrou correlação positiva entre os valores de BNP e hipertrofia do VE, além de determinar o ponto de corte (203 pg/ml) para o diagnóstico dessa condição. Utilizar o BNP como rastreamento de hipertrofia do VE pode ajudar na racionalização da indicação do ecocardiograma para confirmação diagnóstica. / Objective: To determine BNP concentration value associated with the presence of left ventricular hypertrophy (LV) in women with pre-eclampsia (PE). Methods: An observational, descriptive and cross-sectional study was performed in pregnant women diagnosed with preeclampsia, who have received obstetric care at Botucatu Medical School Clinical Hospital - Unesp. Pregnant women with clinical or gestational pathology associated with cardiovascular alterations such as diabetes, chronic hypertension, heart diseases, collagenosis, nephropathies were excluded from the study. Considering the prevalence of LV concentric hypertrophy in this population of 27% and assuming the margin of error of 10%, as well as reliability of 95%, the calculated sample size was of 76 pregnant women. At the moment of PE diagnosis the selected pregnant women were submitted to both venous blood collection (in order to determine BNP serum concentration) and to echocardiogram examination (to identify LV concentric hypertrophy). Correlations between LV mass index (iMVL), relative wall thickness (WT) and BNP were performed with Spearman test. The cut off of BNP concentration, which identifies LV concentric hypertrophy, was established with ROC curve, using the statistical program SPSS for Windows. Results: Left ventricular concentric hypertrophy was diagnosed in 48.7% of the pregnant women. The cut off value of BNP concentration, which identifies LV concentric hypertrophy, was 203pg / mL (sensitivity 88%, specificity 80%, positive predictive value 69%, negative predictive value 93%, and accuracy 83%). The area under the curve was 0.87 (95% CI = 0.79-0.95). The correlation between iMVL and WT with BNP concentration was significant (iMVE: r=0,49; p<0,0001; ER: r=0,50; p<0,0001). Conclusions: The present study found a positive correlation between BNP values and LV hypertrophy. Moreover, it determined the cut off (203 pg / ml) for the diagnosis of this condition. Therefore, using BNP as a screening method for LV hypertrophy may help to rationalize echocardiographic indication for diagnosis confirmation.

abstract: Background Hemodialysis (HD) patients elicit an oxidant-antioxidant imbalance in addition to a selenium deficiency, possibly contributing to cardiovascular disease (CVD) mortality. Objective To evaluate the effect of selenium supplementation on CVD outcomes and antioxidant status in HD patients. Design A randomized controlled intervention trial conducted from October 2012 to January 2013. Participants/setting The study included 27 maintenance HD patients (61.1+17.5y, 14M, 13F) receiving HD in the greater Phoenix, AZ area. Intervention Patients received one of three treatments daily: 2 Brazil nuts, (5g, 181µg/day of selenium as selenomethionine [predicted]), 1 tablet of selenium (200µg/day of selenium as selenomethionine), or control (3 gummy bears). Main outcome measures Antioxidant status outcome measures included total antioxidant capacity, vitamin C, and RBC and plasma glutathione peroxidase (GSH-Px). CVD outcomes measures included brain natriuretic peptide; plasma cholesterol, high density lipoprotein, low density lipoprotein, triglycerides; blood pressure, and thoracic cavity fluid accumulation. Statistical analyses performed Repeated measures ANOVA analyzed changes over time and between groups at months 0 and 2 and months 0 and 3. Results Independent analysis showed the Brazil nuts provided 11µg of selenium/day and the pill provided 266µg of selenium/day. Consequently, the Brazil nut group was combined with the placebo group. 21 patients completed 2 months of the study and 17 patients completed the study in its entirety. Data was analyzed for months 0, 1 and 2. No significant differences were noted for antioxidant status outcome measures with the exception of plasma GSH-Px. Patients receiving the selenium pill had a significant increase in plasma GSH-Px compared to the placebo group (6.0+11 and -4.0+7.6, respectively, p=0.023 for change between month 0 and month 2). No significant differences were seen in total antioxidant capacity or for CVD outcome measures over time or between groups. Conclusions These data indicate that selenium supplementation increased plasma GSH-Px concentration in HD patients; however, oxidative stress was not altered by selenium supplementation. The low vitamin C status of HD patients warrants further research, specifically in conjunction with selenium supplementation. / Dissertation/Thesis / Ph.D. Nutrition 2013

A proteína S100B é considerada um marcador bioquímico para lesão cerebral. Entretanto, foi demonstrado que há liberação de S100B em coração isolado de rato. Neste estudo, investigou-se os níveis séricos de S100B em pacientes portadores de cardiomiopatia dilatada (CMD). Métodos e Resultados: Foram selecionados 21 pacientes com CMD, excluindo qualquer condição que pudesse influenciar os níveis séricos de S100B. O grupo controle foi composto por 21 indivíduos pareados por sexo e idade. Ambos os grupos foram submetidos à avaliação clínica, ecocardiográfica, mensuração da proteína S100B e de NT-proBNP (expressos como mediana [variação interquartil]). Os níveis de NT-proBNP no grupo de pacientes (1462 pg/ml [426 - 3591]) foram maiores do que no grupo controle (35 pg/ml [29 - 55]); P<0.001. Os níveis de S100B foram maiores no grupo de pacientes (0.051µg/L [0.022 - 0.144]) do que no grupo controle (0.017µg/L [0.003 - 0.036]); P=0.009. Houve correlação positiva entre os níveis séricos de S100B e NT-proBNP somente no grupo de pacientes (Coeficiente de Spearman r=0.534; P=0.013). Conclusão: A proteína S100B está aumentada na CMD. Embora não possamos excluir a influência de dano cerebral, houve uma correlação positiva entre os níveis séricos de S100B e NT-proBNP em pacientes com CMD / The S100B protein is considered a biochemical marker for brain injuries. However, the isolated rat heart releases S100B. In this study, the serum levels of S100B was investigated in dilated cardiomyopathy (DCM) patients in order to evaluate its levels in heart disease. Methods and Results: It was selected DCM patients, excluding any condition that could influence S100B serum levels. Control individuals were sex and age matched. Both groups were submitted to clinical evaluation and echocardiography. The S100B and NT-proBNP serum levels (expressed as median [interquartile range]) were measured. NT-proBNP levels in patients group (1462 pg/ml [426 - 3591]) were higher than in controls (35 pg/ml [29 - 55]); P<0.001. S100B serum levels were higher in patients group (0.051µg/L [0.022 - 0.144]) than in controls (35 pg/ml [29 - 55]); P<0.001. S100B serum levels were higher in patients group (0.051µg/L [0.022 - 0.144]) than in controls (0.017µg/L [0.003 - 0.036]); P=0.009. Additionally, a positive correlation between S100B and NT-proBNP serum levels only in patients group (Spearman\'s coefficient r=0.534; P=0.013) was found . Conclusions: Although the influence of S100B from brain cannot rule out, the positive correlation between S100B and NT-proBNP levels in DCM patients points to the myocardium as the main source for the rise in S100B serum levels

Abstract Abnormal placentation is associated with preeclampsia and placental insufficiency, both of which increase the risk for fetal growth restriction. So far the early recognition of the risk population for preeclampsia has been problematic. The first hypothesis of this study was that in preeclampsia, the maternal serum proteomic profile is different from that in uncomplicated pregnancies, and this difference is detectable already in early pregnancy. The findings of this study demonstrate that in clinical preeclampsia the maternal serum proteomic profile is different from that in uncomplicated pregnancies with increased levels of placental proteins and antiangiogenic factors in pregnancies with clinical preeclampsia. Furthermore, the early pregnancy maternal serum proteomic profile in women who later develop preeclampsia revealed a distinct and different pattern compared with the profile in clinical preeclampsia. In early pregnancy, the differentially expressed proteins belong to placental proteins, vascular and/or transport proteins and matrix and/or acute phase proteins, while angiogenic and antiangiogenic proteins were not significantly expressed in early pregnancy. Preeclampsia, placental insufficiency, fetal growth restriction and type-1 diabetes may have an impact on fetal cardiovascular hemodynamics. The second hypothesis in this thesis was that in placental insufficiency, abnormalities in fetal cardiovascular status correlate with biochemical markers of cardiac dysfunction and chronic hypoxia. In placental insufficiency, increases in fetal N-terminal pro-atrial (NT-proANP) and pro-B-type natriuretic peptide (NT-proBNP) and in fetal erythropoietin concentrations were related to increased pulsatility in the fetal umbilical artery and descending aorta. In addition, these fetuses demonstrated increased pulsatility in their systemic venous blood velocity waveforms. Thus, in placental insufficiency, biochemical markers of cardiac dysfunction and chronic hypoxia are associated with signs of increased fetal cardiac afterload and systemic venous pressure. Increased NT-proANP and NT-proBNP levels were also detected in fetuses of type-1 diabetic mothers with normal umbilical artery velocimetry. In these pregnancies, NT-proANP and NT-proBNP levels were related to poor maternal glycemic control during early pregnancy.

Abstract During cardiac hypertrophy individual cardiac myocytes increase in size, which is accompanied by augmented protein synthesis and selective induction of a subset of genes. These phenotypic changes of myocytes are a result from altered intracellular signaling mechanisms and molecules. B-type natriuretic peptide (BNP) gene was selected as a target gene for the study of cardiac signaling mechanisms, since it is activated by mechanical, neural and humoral stimuli during myocyte hypertrophy. To generate hypertrophy of cardiac myocytes, neonatal rat cardiac myocytes were subjected to exogenous hypertrophic agonists such as endothelin-1 (ET-1) or to cyclic mechanical stretch. The role and regulation of transcription factors were studied by utilizing promoter analysis together with site-specific mutations and measurement of DNA binding activity and phosphorylation. GATA-4 mediated signaling was inhibited by blocking DNA binding with decoy oligonucleotides or by decreasing GATA-4 synthesis via adenoviral antisense delivery. ET-1 activated GATA-4 via serine residue phosphorylation, and this effect was mediated via p38 kinase. Similarly, GATA-4 binding activity was increased by ET-1 and mechanical stretch, but it was essential for activation of BNP gene only in the latter stimulation. Importantly, downregulation of GATA-4 protein levels prevented mechanical stretch induced hypertrophy of cardiac myocytes. In contrast, separate mechanism for an ET-1 specific signaling was composed of p38 kinase regulated ETS-like transcription factor-1 (Elk-1). Finally, the effect of mechanical stretch on endogenous endothelin-1 (ET-1) synthesis in cardiac cells was studied. Intrinsic ET-1 synthesis was activated in stretched cardiac myocytes, yet the levels of ET-1 were relatively low. This work suggests that GATA-4 transcription factor is required for mechanical stretch mediated hypertrophic program, and Elk-1 may act as a downstream effector of ET-1 in cardiac myocytes. Taken together, induction of ET-1 and BNP genes as well as activation of GATA-4 and Elk-1 transcription factors are regulated via a network of mitogen activated protein kinase pathways.

Abstract There is a need to identify patients with an increased risk of dying after acute myocardial infarction (AMI), because sudden cardiac death (SCD) and potentially fatal ventricular tachyarrhythmias can be prevented by an implantable cardioverter-defibrillator, or in some cases, with aggressively optimized drug or revascularization therapy. The present study was designed to study the predictive power of non-invasive risk markers and all-cause, cardiac and arrhythmic mortality in 700 consecutive post-AMI patients discharged alive with optimal medication according to contemporary guidelines. Detrended fluctuation analysis of heart rate variability (HRV) predicted all-cause mortality beyond clinical variables as well as left ventricular function in post-AMI patients. The predictive power of the short-term scaling exponent α1 was higher than that of the traditional indexes of HRV (for α1 &lt; 0.65, the risk ratio (RR) in multivariate analysis was 5.1, with 95% confidence intervals (CI) 2.9-8.9; p &lt; 0.001). HRV results from a conventional 24-hour electrocardiographic (ECG) recording system differed significantly when compared to a system with a higher sampling frequency. The difference was generally more pronounced in post-AMI patients than in healthy subjects. The presence of sustained T-wave alternans during a predischarge exercise test after AMI was not a marker of mortality. However, the inability to perform an exercise test or to reach the heart rate of 105 beats/min predicted independently all-cause (RR 9.3, 95% CI 2.0-43.3, p &lt; 0.01) and cardiac mortality (RR 11.1, 95% CI 2.4-50.8, p &lt; 0.01). High levels of natriuretic peptides were associated with both sudden and non-sudden cardiac mortality. B-type natriuretic peptide provided more specific independent information on the risk for subsequent SCD (RR 3.9, 95% CI 1.2-12.3, p &lt; 0.05) than non-SCD. SCDs occurred mainly more than 18 months after AMI, and the proportion of SCD was less than 40% of all cardiac deaths. Common arrhythmia markers such as the presence of ventricular premature beats or episodes of nonsustained ventricular tachycardia during ambulatory recordings, the time domain parameters of HRV, baroreflex sensitivity, QT dispersion and QRS complex duration provided only limited predictive power on the risk of SCD or arrhythmic events in patients with optimized beta-blocking therapy. Many risk variables previously considered to predict SCD were better predictors of non-SCD than SCD. Conclusions: 1. The epidemiological pattern of SCD was different from that reported previously. 2. Many arrhythmia risk markers provided only limited information on the risk of SCD. 3. Short-term fractal scaling exponent α1 provided potentially useful information on the risk for all-cause mortality, and BNP was useful in predicting the risk of SCD in a post-AMI population with optimized therapy.

Abstract The first aim of this study was to investigate the relationship between Doppler ultrasonographic parameters and biochemical markers of human fetal cardiac dysfunction and myocardial cell damage in pregnancies complicated by placental insufficiency and/or fetal growth restriction. Our second aim was to examine fetal central and peripheral hemodynamic characteristics associated with retrograde aortic isthmus net blood flow. Fetuses with significant myocardial cell damage (cTnT > 0.10 ng/ml) had increased pulsatility in the blood velocity waveforms of ductus venosus, left hepatic vein and inferior vena cava, and had more often atrial pulsations in the umbilical vein. Their umbilical artery NT-proANP concentrations were higher than in fetuses without myocardial cell damage. The proportion of left ventricular cardiac output of the combined cardiac output was greater and the corresponding proportion of the right ventricle was less than in fetuses with only increased NT-proANP levels ( > 1145 pmol/l). Tricuspid regurgitation was present more often and the right ventricular fractional shortening was less in fetuses with myocardial cell damage than in fetuses with normal umbilical artery cTnT levels. In fetuses with placental insufficiency and/or growth restriction (n = 48), umbilical artery NT-proANP concentrations showed a significant positive correlation with ductus venosus, left hepatic vein and inferior vena cava pulsatility index values for veins. Fetuses with placental insufficiency and antegrade aortic isthmus net blood flow demonstrated a shift in their right ventricular cardiac output from the pulmonary to the systemic circulation, and foramen ovale volume blood flow made up the majority of the left ventricular cardiac output. Fetuses with retrograde aortic isthmus net blood flow failed to demonstrate these changes, and they had signs of increased left atrial pressure. In addition, right ventricular fractional shortening was decreased and the pulsatility in the ductus venosus blood velocity waveforms was increased. In conclusion, human fetal myocardial cell damage was associated with a rise in systemic venous pressure, a change in the distribution of cardiac output towards the left ventricle and a rise in right ventricular afterload. Fetuses with retrograde aortic isthmus net blood flow failed to rearrange the distribution of the cardiac output and they had signs of increased left atrial pressure. In addition, right ventricular afterload and pulsatility in the ductus venosus blood velocity waveforms were increased.

Abstract Estrogen replacement therapy (ERT) has been associated with favorable effects on risk factors for atherosclerosis. In observational studies ERT was also suggested to reduce the risk of cardiovascular disease in postmenopausal women, but the cardioprotective role of estrogen has been challenged after negative results in randomized trials. However, the mechanisms of estrogen action in atherosclerosis development are only partially known. In order to investigate the regulation of plasma low-density lipoprotein (LDL) cholesterol in postmenopausal women and the effects of ERT on cholesterol and glucose metabolism and blood pressure, 79 hysterectomized, non-diabetic postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate (2 mg/day) or transdermal 17β-estradiol gel (1 mg estradiol/day) for six months. At baseline the level of LDL cholesterol was related to body mass index, the fractional catabolic rate (FCR) and the production of LDL apolipoprotein B (apo B), but not to cholesterol absorption efficiency. Both peroral and transdermal ERT decreased plasma total and LDL cholesterol, while high-density lipoprotein cholesterol and triglycerides increased only in the peroral group. The LDL-lowering response was related to changes in estrogen levels, which presumably enhance LDL receptor activity shown as an increase in FCR for LDL apo B. In contrast, the determined genetic factors, apo E phenotype, EcoRI and XbaI polymorphisms of the apo B gene and polymorphism of 7α-hydroxylase gene, were not significant in regulation of LDL cholesterol, neither did they modify the response of ERT in these postmenopausal women. Similar outcomes were observed with both peroral and transdermal ERT as regards glucose metabolism and blood pressure. The overall effect of ERT on glucose tolerance was found to be neutral. Blood pressure decreased among non-hypertensive subjects on both estrogens, which could be related, at least in part, to the alterations in vasoactive peptides. The data of the present study suggest an overall favorable effect of both peroral and transdermal estrogen on common cardiovascular risk factors. However, the clinical significance of these findings in the prevention of cardiovascular diseases needs to be proven in long-term, randomized trials.

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.