Cardiovascular disease remains a leading a cause of mortality and morbidity. Primary prevention is known to reduce the incidence of cardiovascular disease. The use of medication is currently targeted at those at increased predicted risk of cardiovascular disease using risk prediction tools developed from large epidemiological studies. However these have poor external validity particularly for those at low or intermediate risk: a significant number of cardiovascular events still occurs in these groups. We hypothesised that screening for asymptomatic pre-clinical cardiovascular disease using B-type natriuretic peptide (BNP) and whole body contrast enhanced magnetic resonance imaging (MRI) could identify those at low/intermediate risk or disease whowill develop clinical disease and thus facilitate improved targeting of primary prevention at those most likely to benefit. The Tayside Screening for Cardiac Events (TASCFORCE) study is a prospective normal volunteer cohort study. Men and women aged 40 years or older free from cardiovascular disease and with a predicted 10-year coronary heart disease risk less than 20% were recruited. All had comprehensive baseline cardiovascular risk information and a BNP level measured. If the BNP level was greater than the median for their gender participants were invited to attend for a whole body contrast enhancedMRI scan comprising cardiac imaging and whole body angiography. The images were analysed to measure left ventricular mass (LVM), left ventricular volumes and left ventricular function. These were indexed for body size using height, height1.7, height2.7 and body surface area. Angiogram images were analysed for the presence and degree of intraluminal stenosis. All participants are being followed up using anonymised electronic data linkage for incident cardiovascular disease and death. 4423 participants (39.3% male) were recruited between November 2007 and February 2013. Median age was 51.2 years. The median 10-year coronary heart disease (CHD) 23 risk was 2% and 13.6% had a CHD risk of 10-19.9% (intermediate risk). The medianBNP results for men and women were 7.5 and 15.3 pg/ml respectively. Age, female sex and high density lipoprotein were independently associated with BNP level. Heart rate, total cholesterol and ex-smoking status were independently inversely associated with BNP level. 1528 (74.8% of those invited) underwent an MRI scan. Mean left ventricular mass was 129.2g and 87.0g for men and women respectively. LVM and left ventricular mass index (LVMI) were significantly higher in men than women. The vast majority (94.6%) of arterial segments analysed were normal and 50.6% of individuals had no evidence of luminal stenosis. From follow up data obtained 2 years after the end of recruitment 18,364 person years at risk were analysed. 17 cardiovascularevents and no deaths occurred in those not invited for an MRI scan based on their BNP result and 16 events and 1 death occurred in those invited for an MRI scan. There was no significant difference in event rates between those with above and below median BNP levels, between those with higher or lower LVM or LVMI or between those with and without the presence of stenosis on angiography. As expected we have not demonstrated the ability of LVM, LVMI or stenosis burden determined using magnetic resonance imaging to predict cardiovascular disease in a population at low or intermediate risk of CHD. We have also not demonstrated the ability of BNP to identify those at low orintermediate risk of CHD who will develop clinical CV disease. However it is the pre-planned longer-term follow up where difference might be expected. The low number of events at this early stage in follow up mean that it is difficult to draw firm conclusions. As follow up continues and further events accumulate we hope to determine if these measures will be shown to predict cardiovascular events in future analyses. We have characterised the normal values and distribution of a range of left ventricular structural and functional parameters derived using a steady state free precision sequence MRI in a population at low or intermediate risk of CHD which will provide a useful reference for normal values that are different to other imaging modalities including chocardiography and other protocols of MRI scanning.

Aquaporin proteins significantly increase water permeability across tissues and cell membranes. Ocular tissues, including the trabecular meshwork (TM) and retinal pigment epithelium (RPE), are especially reliant on aquaporin mediated water movement for ocular homeostasis. Even though bulk fluid movement is paracellular through the TM and transcellular through the RPE, both express aquaporin-1 (AQP1). The role and regulation of AQP1 as it relates to homeostasis in different ocular tissues is not well understood. I hypothesized that ocular tissues respond to external mechanical and molecular cues by altering AQP1 expression and function in order to regulate ocular fluid movement and maintain homeostasis.To test how AQP1 function is altered in response to external cues in order to maintain tissue-specific homeostasis, I addressed the following two aims. The first aim was directed at determining how mechanical strain, an external stimulus that routinely affects TM function, influences AQP1 expression and TM homeostasis. Primary cultures of human TM were subjected to static and cyclic stretch and then analyzed for changes in AQP1 expression by western blot and cell damage by activity of lactate dehydrogense (LDH) in conditioned media. The results show AQP1 expression and LDH release significantly increased with static stretch. Analysis of LDH release with respect to AQP1 expression revealed an inverse linear relationship (r² = 0.7780).The second aim was directed at characterizing signaling mechanisms responsible for regulating fluid transport in RPE, previously shown to be dependent upon AQP1. I treated primary cultures of human RPE with either atrial natriuretic peptide (ANP) or 8-bromo-cyclic guanosine monophosphate (8-Br-cGMP) in the presence or absence of Anantin (ANP-receptor inhibitor) or H-8 (Protein Kinase G inhibitor). The results show that ANP and 8-Br-cGMP significantly increased apical to basal net fluid movement (p < 0.05, n = 3). Inhibition of these effects was successful with Anantin treatment but not with application of H-8.The data presented demonstrate a novel role of protection for AQP1 in TM, and also expand upon cGMP dependent regulation of RPE fluid transport. The combined studies indicate tissue specific AQP1 regulation may offer new avenues to target water movement in treatment of ocular pathologies.

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

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.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22726号 / 医博第4644号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 柳田 素子, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

The response of the atrial natriuretic peptide (ANP) secreting cells from both rat atria and the apex of the ventricles to dexamethasone (DEX) was analyzed by the plaque assay. In right atrial cardiocytes, 25% of the cells secreted ANP basally; DEX treatment did not alter this percentage. However, in the left atrial secretory population, a discordance between the basal (15%) and DEX stimulated (25%) percent plaque formation was found. ANP secreting cells from the ventricular apex responded similarly to DEX exposure (26%), with 8% of the cells basally releasing the hormone. These data suggest that in both the left atria and apex of the rat ventricles, exposure to DEX recruits ANP secretory cells from a non-secreting population. Consequently, the release of ANP from these tissues would increase after glucocorticoid stimulation.

Die kardialen Hormone Atriales (ANP) und B-Typ (BNP) Natriuretisches Peptid üben bekannte renale und kardiovaskuläre Effekte aus, welche durch ihren gemeinsamen, cGMP-bildenden Guanylatzyklase-Rezeptor A (GC-A) vermittelt werden. Diese Effekte sind entscheidend an der physiologischen Aufrechterhaltung des arteriellen Blutdrucks sowie des intravaskulären Blutvolumens beteiligt. Darüber hinaus zeigen aktuelle Studien, dass NPs die Mobilisierung von Fettsäuren aus dem Fettgewebe und deren Oxidation durch die Skelettmuskulatur steigern sowie die Thermogenese in braunem und weißem Fettgewebe aktivieren können. Dadurch können NPs den Energieverbrauch erhöhen und die Insulinsensitivität verbessern. Desweiteren ist Übergewicht mit einer gestörten NP/GC-A/cGMP-Signalübertragung verbunden, die möglicherweise zur Entwicklung von Diabetes Typ 2 und dessen kardio-metabolischen Folgeerkrankungen beiträgt. In vitro stimuliert synthetisches ANP über GC-A die Glukose-stimulierte Insulinsekretion aus kultivierten pankreatischen Inseln und die β-Zellproliferation. Die Bedeutung für die systemische Insulin/Glukosehomöostase in vivo ist jedoch unklar. Um zu untersuchen, ob die endogenen Herzhormone die sekretorische Funktion und/oder die Proliferation von β-Zellen unter (patho)physiologischen Bedingungen in vivo modulieren, haben wir ein neues genetisches Mausmodell mit selektiver Deletion des GC-A-Rezeptors in β-Zellen (ß GC-A KO) generiert. In kultivierten Inseln von β GC-A KO-Mäusen waren die insulinotropen und proliferativen Effekte von ANP aufgehoben. Übereinstimmend damit führte die Infusion von BNP bei Kontroll-Tieren in vivo zu leicht erhöhten basalen Plasma-Insulinspiegeln und verbesserter Glukose-induzierter Insulinsekretion. Dieser Effekt von exogenem BNP konnte bei β GC-A KO-Mäusen nicht beobachtet werden, was die effiziente Deletion des GC-A-Rezeptors in β-Zellen bestätigt. Interessanterweise hatte die Ablation des GC-A-Rezeptors auf ß-Zellen unter basalen Bedingungen keinen Einfluss auf physiologische und metabolische Parameter in vivo. Sowohl männliche als auch weibliche ß GC-A KO-Tiere zeigten keine Unterschiede in der basalen Insulin- und Glukosehomöostase, da sie ähnliche Nüchtern-Blutzucker- und Insulinspiegel (nach Fasten über Nacht) aufwiesen wie die Kontroll-Mäuse. Allerdings zeigten die mit HFD gefütterten β GC-A KO-Tiere frühzeitiger Glukose-Intoleranz sowie eine verminderte adaptive β-Zellproliferation. Abgesehen davon war das konsistenteste Ergebnis der in vivo-Studien der geschlechtsabhängige Unterschied in der Auswirkung der ß-Zellspezifischen GC-A-Deletion auf die Glukose-stimulierte Insulinsekretion. Weibliche, aber nicht männliche ß GC-A KO-Mäuse zeigten erhöhte Nüchtern-Insulinspiegel und eine signifikant erhöhte Glukose-stimulierte Insulinsekretion, was zu einer deutlich verbesserten Glukosetoleranz führte. Der postulierte und untersuchte Mechanismus beinhaltet eine Interaktion von Östrogenen und NPs, welche die Expression des mitochondrialen Uncoupling Protein 2 beeinflussen. Diese Arbeit erweitert das derzeitige Wissen über die metabolischen Effekte des NP/GC-A-Systems. Insbesondere zeigen die Ergebnisse, dass Natriuretische Peptide zu einer gesteigerten ß-Zellfunktion und Vitalität in frühen Stadien eines erhöhten Insulinbedarfs, d.h. bei Diabetes Typ 2, beitragen. Da die Studien eine wesentliche Rolle dieser kardialen Hormone im endokrinen Pankreas aufdecken, ist es umso wichtiger die pleiotropen Eigenschaften von NPs und ihre möglichen therapeutischen Anwendungen bei kardio-metabolischen Erkrankungen weiter zu untersuchen. / The cardiac hormones atrial (ANP) and B-type (BNP) natriuretic peptide exert well-known renal and cardiovascular actions which are mediated by their shared cGMP-forming guanylyl cyclase A receptor (GC-A). These actions are critically involved in the physiological maintenance of arterial blood pressure and intravascular volume homeostasis. In addition, recent studies indicate that NPs can increase fatty acid mobilization from adipose tissue and their oxidation by skeletal muscles and activate a thermogenic program in brown and white fat. Thereby NPs increase energy expenditure and improve insulin sensitivity. Moreover, obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic insulin/glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells (ß GC-A KO). In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Interestingly, the ablation of the GC-A receptor under basal conditions had no effect on physiological and metabolic parameters in vivo. Both male and female ß GC-A KO animals showed no differences in basal insulin and glucose homeostasis, as they have similar fasting blood glucose and insulin levels (after overnight fasting) as the control mice. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation. Apart from that, the most consistent result of the in vivo studies was the gender dependent difference in the impact of ß-cell GC-A deletion on glucose-stimulated insulin secretion. Female, but not male, ß GC-A KO mice showed enhanced fasted insulin levels and a markedly enhanced glucose-stimulated insulin secretion resulting in a distinctly improved glucose tolerance. The postulated and investigated mechanism involves an interaction of estrogens and NPs affecting expression levels of mitochondrial uncoupling protein 2. This thesis extends the current knowledge of the metabolic actions of the NP/GC-A system. Specifically the results indicate that natriuretic peptides contribute to enhanced ß-cell function and vitality during early stages of increased insulin demand, i.e. in type 2 diabetes. Since the studies show an essential role of these cardiac hormones in the endocrine pancreas, it becomes even more important to further investigate the pleiotropic actions of NPs and their potential therapeutic applications in cardio-metabolic diseases.