Class of 2015 Abstract / Objectives: Assess the impact of hydralazine in contributing to the risk of heart transplant rejection. Our primary working hypothesis is that patients who have undergone heart transplantation and have taken hydralazine have an increased risk of transplant rejection and ultimately have worse outcomes. Methods: A retrospective cohort study on data extracted from a patient’s medical chart at a local hospital. Data was collected using a paper data extraction form consisting of gender, race, age, panel reactive antibody scores, co-morbidities, white blood cell count, type of immunosuppression therapy and any other medications. The proportion of patients with rejections will then be compared and analyzed using a chi square test. Results: This study obtained 340 patient cases that involved heart transplantation. From the 340 patients that were extracted, 42 of them were recorded as having taken hydralazine. Of the 42 patients, 7 had stopped hydralazine before transplantation. The mean +/- S.D. age of the 35 patients analyzed was 54 +/- 20.5 years, and 69% were men. Approximately 14% of the 42 patients were found to have had a heart transplant rejection. Conclusions: Heart transplant patients at this institution who received hydralazine post surgery were on it about an average of 21 months. Most patients were placed on ACE inhibitors. ACE inhibitors have a theoretical benefit of immunosuppression, and this therapy is usually pursued in transplant patients. Further research must be done to determine the clinical significance of hydralazine use in heart transplant rejection.

No description available.

No description available.

A síndrome hipertensiva gestacional (SHG) afeta três milhões de mulheres por ano no mundo e pode resultar em inúmeras perdas fetais e perinatais, além de ser responsável pela morte de uma mulher a cada 6 minutos em todo o mundo. Durante uma crise hipertensiva na gestação ocorre vasoconstrição arteriolar generalizada e diminuição do fluxo útero placentário. A diminuição de fluxo na artéria uterina ocasiona déficit do aporte de oxigênio nas áreas de troca materno fetal submetendo o feto à regime de hipóxia transitória comprováveis na avaliação hemodinâmica. O labetalol e a hidralazina são anti hipertensivos de primeira escolha na gravidez, uma vez que aumentam o fluxo útero-placentário em decorrência da redução da resistência vascular uterina. Objetivos Avaliar as condições hemodinâmicas materno/fetais durante o período da crise hipertensiva e após seu tratamento com labetalol e/ou hidralazina. Pacientes e métodos Foram avaliadas 18 pacientes com quadro de crise hipertensiva com pressão arterial maior que 160x110mmHg, sem sintomas de eminência de eclâmpsia. Realizou-se estudo dopplervelocimétrico das artérias uterinas direita e esquerda materna, umbilical e cerebral média fetal. A avaliação hemodinâmica materno/fetal foi realizada no momento da crise hipertensiva e após o tratamento com labetalol e/ou hidralazina. A análise pós tratamento foi realizada após estabilização da pressão arterial < 150/100mmHg. Resultados A média de idade das pacientes foi de 29,11 anos e a idade gestacional média do estudo de 34,5 semanas. O valor médio da pressão arterial sistólica e diastólica durante a crise hipertensiva foi de 174,71 e 112,35mmHg, respectivamente. Os parâmetros dopplervelocimétricos avaliados na crise hipertensiva foram: IP da artéria uterina direita 1,24+-0,42; IP da artéria uterina esquerda 1,29+-0,40; IR da artéria cerebral média de 0,78+-0,06 e IR da artéria umbilical de 0,65+-0,12. Após o tratamento da crise hipertensiva a pressão arterial sistólica média foi de 146,47mmHg e a pressão arterial diastólica média de 87,06mmHg. Após o tratamento da crise hipertensiva, os parâmetros avaliados foram: IP da artéria uterina direita 1,26+-0,37; IP da artéria uterina esquerda 1,37+-0,36; IR da artéria cerebral média de 0,78+-0,09 e IR da artéria umbilical de 0,67+-0,09. Não houve diferenças estatísticas significativas nos parâmetros Doppler quando comprados os valores na crise hipertensiva e após o controle da pressão arterial. Conclusão As gestações de pacientes com síndromes hipertensivas são consideradas de alto risco e, devem ser alvo de observação rigorosa durante o pré-natal. A análise dopplervelocimétrica fetal (artéria cerebral média e umbilical) e materna (artérias uterinas) deve ser realizada para avaliação da vitalidade fetal nestas pacientes, inclusive durante de crise hipertensiva. Este estudo demonstrou não haver diferença na avaliação dos parâmetros dopplervelocimétricos materno e fetal, durante ou após a crise hipertensiva tratada com hidralazina/labetalol. / Introduction The gestational hypertension syndrome affects three million women a year worldwide and can result in a number of fetal losses and perinatal deaths, and was responsible for the death of one woman every 6 minutes throughout the world. During a hypertensive crisis in pregnancy is widespread arteriolar vasoconstriction and decreased placental flow uterus. The decrease in flow in the uterine artery causes deficit of oxygen supply in the areas of maternal fetal exchange subjecting the fetus to the regime of transient hypoxia in comparable hemodynamic evaluation. Labetalol and hydralazine are antihypertensive drugs of choice in pregnancy, they increase the uteroplacental flow due to the reduction of uterine vascular resistance. Objectives To evaluate the conditions maternal-fetal hemodynamics during the hypertensive crisis and after treatment with labetalol and/or hydralazine. Patients and methods Eighteen pregnant women with acute hypertensive were evaluated (blood pressure (BP) > 160x110mmHg, without imminent eclampsia symptoms). This study was performed by Doppler velocimetry of right and left uterine arteries, umbilical artery and fetal middle cerebral artery. Maternal-fetal hemodynamic assessment was performed at the time of hypertensive crisis and after treatment with labetalol and/ or hydralazine. Post treatment analysis was performed after blood pressure stabilization (BP< 150x100mmHg). Results Mean patients age was 29,11 years old and mean gestational age was 34.5 weeks. Mean systolic and diastolic blood pressure during hypertensive crisis was 174.71 and 112.35 mmHg, respectively. Doppler parameters evaluated in hypertensive crisis were: right uterine artery PI 1.24 ± 0.42; left uterine artery PI 1.29 ± 0.40; middle cerebral artery RI 0.78 ± 0,06 and umbilical artery RI 0.65 ± 0.12. After the hypertensive crisis treatment mean systolic blood pressure was 146.47 mmHg and diastolic 87.06 mmHg. Doppler parameters evaluated after hypertensive crisis were: right uterine artery PI 1.26 ± 0.37; left uterine artery PI 1.37 ± 0.36; middle cerebral artery RI 0.78 ± 0,09 and umbilical artery RI 0.67 ± 0.09. No statistical difference was observed in Doppler parameters during hypertensive crisis or after blood pressure control. Conclusion Hypertensive pregnancy disorders are considered high risk to disfavorable perinatal outcome and should be subject to close observation during prenatal by fetal Doppler velocimetry analysis (middle cerebral artery and umbilical cord) and maternal Doppler velocimetry analysis (uterine artery) to assess fetal well being. This study demonstrated no difference in maternal fetal Doppler parameters during or after hypertensive crisis treated with hydralazine/labetalol.

A síndrome hipertensiva gestacional (SHG) afeta três milhões de mulheres por ano no mundo e pode resultar em inúmeras perdas fetais e perinatais, além de ser responsável pela morte de uma mulher a cada 6 minutos em todo o mundo. Durante uma crise hipertensiva na gestação ocorre vasoconstrição arteriolar generalizada e diminuição do fluxo útero placentário. A diminuição de fluxo na artéria uterina ocasiona déficit do aporte de oxigênio nas áreas de troca materno fetal submetendo o feto à regime de hipóxia transitória comprováveis na avaliação hemodinâmica. O labetalol e a hidralazina são anti hipertensivos de primeira escolha na gravidez, uma vez que aumentam o fluxo útero-placentário em decorrência da redução da resistência vascular uterina. Objetivos Avaliar as condições hemodinâmicas materno/fetais durante o período da crise hipertensiva e após seu tratamento com labetalol e/ou hidralazina. Pacientes e métodos Foram avaliadas 18 pacientes com quadro de crise hipertensiva com pressão arterial maior que 160x110mmHg, sem sintomas de eminência de eclâmpsia. Realizou-se estudo dopplervelocimétrico das artérias uterinas direita e esquerda materna, umbilical e cerebral média fetal. A avaliação hemodinâmica materno/fetal foi realizada no momento da crise hipertensiva e após o tratamento com labetalol e/ou hidralazina. A análise pós tratamento foi realizada após estabilização da pressão arterial < 150/100mmHg. Resultados A média de idade das pacientes foi de 29,11 anos e a idade gestacional média do estudo de 34,5 semanas. O valor médio da pressão arterial sistólica e diastólica durante a crise hipertensiva foi de 174,71 e 112,35mmHg, respectivamente. Os parâmetros dopplervelocimétricos avaliados na crise hipertensiva foram: IP da artéria uterina direita 1,24+-0,42; IP da artéria uterina esquerda 1,29+-0,40; IR da artéria cerebral média de 0,78+-0,06 e IR da artéria umbilical de 0,65+-0,12. Após o tratamento da crise hipertensiva a pressão arterial sistólica média foi de 146,47mmHg e a pressão arterial diastólica média de 87,06mmHg. Após o tratamento da crise hipertensiva, os parâmetros avaliados foram: IP da artéria uterina direita 1,26+-0,37; IP da artéria uterina esquerda 1,37+-0,36; IR da artéria cerebral média de 0,78+-0,09 e IR da artéria umbilical de 0,67+-0,09. Não houve diferenças estatísticas significativas nos parâmetros Doppler quando comprados os valores na crise hipertensiva e após o controle da pressão arterial. Conclusão As gestações de pacientes com síndromes hipertensivas são consideradas de alto risco e, devem ser alvo de observação rigorosa durante o pré-natal. A análise dopplervelocimétrica fetal (artéria cerebral média e umbilical) e materna (artérias uterinas) deve ser realizada para avaliação da vitalidade fetal nestas pacientes, inclusive durante de crise hipertensiva. Este estudo demonstrou não haver diferença na avaliação dos parâmetros dopplervelocimétricos materno e fetal, durante ou após a crise hipertensiva tratada com hidralazina/labetalol. / Introduction The gestational hypertension syndrome affects three million women a year worldwide and can result in a number of fetal losses and perinatal deaths, and was responsible for the death of one woman every 6 minutes throughout the world. During a hypertensive crisis in pregnancy is widespread arteriolar vasoconstriction and decreased placental flow uterus. The decrease in flow in the uterine artery causes deficit of oxygen supply in the areas of maternal fetal exchange subjecting the fetus to the regime of transient hypoxia in comparable hemodynamic evaluation. Labetalol and hydralazine are antihypertensive drugs of choice in pregnancy, they increase the uteroplacental flow due to the reduction of uterine vascular resistance. Objectives To evaluate the conditions maternal-fetal hemodynamics during the hypertensive crisis and after treatment with labetalol and/or hydralazine. Patients and methods Eighteen pregnant women with acute hypertensive were evaluated (blood pressure (BP) > 160x110mmHg, without imminent eclampsia symptoms). This study was performed by Doppler velocimetry of right and left uterine arteries, umbilical artery and fetal middle cerebral artery. Maternal-fetal hemodynamic assessment was performed at the time of hypertensive crisis and after treatment with labetalol and/ or hydralazine. Post treatment analysis was performed after blood pressure stabilization (BP< 150x100mmHg). Results Mean patients age was 29,11 years old and mean gestational age was 34.5 weeks. Mean systolic and diastolic blood pressure during hypertensive crisis was 174.71 and 112.35 mmHg, respectively. Doppler parameters evaluated in hypertensive crisis were: right uterine artery PI 1.24 ± 0.42; left uterine artery PI 1.29 ± 0.40; middle cerebral artery RI 0.78 ± 0,06 and umbilical artery RI 0.65 ± 0.12. After the hypertensive crisis treatment mean systolic blood pressure was 146.47 mmHg and diastolic 87.06 mmHg. Doppler parameters evaluated after hypertensive crisis were: right uterine artery PI 1.26 ± 0.37; left uterine artery PI 1.37 ± 0.36; middle cerebral artery RI 0.78 ± 0,09 and umbilical artery RI 0.67 ± 0.09. No statistical difference was observed in Doppler parameters during hypertensive crisis or after blood pressure control. Conclusion Hypertensive pregnancy disorders are considered high risk to disfavorable perinatal outcome and should be subject to close observation during prenatal by fetal Doppler velocimetry analysis (middle cerebral artery and umbilical cord) and maternal Doppler velocimetry analysis (uterine artery) to assess fetal well being. This study demonstrated no difference in maternal fetal Doppler parameters during or after hypertensive crisis treated with hydralazine/labetalol.

La barrière hémato-encéphalique (BHE) est la structure essentielle au système nerveux central (SNC), localisée au sein des capillaires cérébraux. Elle est responsable du maintien de l’homéostasie cérébrale ainsi que de sa protection. En effet, les pathologies affectant le SNC sont souvent associées à une altération au niveau de la BHE. L’un des nombreux facteurs, pouvant altérer l’homéostasie du SNC, est l’hypoxie puisque le cerveau est le premier consommateur d’oxygène. De nombreuses études ont démontré qu’une hypoxie aigüe (modélisation de l’ischémie cérébrale transitoire ou l’AVC), altère la perméabilité de cette barrière. Cependant, certaines pathologies sont liées à une hypoxie intermittente, notamment les troubles respiratoires associés au sommeil, comme le syndrome d’apnées du sommeil. Cette hypoxie intermittente ne semble pas être sans conséquence sur la structure et la fonction du cerveau, car des études menées chez l’Homme ont démontré que ces patients souffraient de troubles cognitifs. L’enjeu dans l’étude de ces pathologies est d’avoir une meilleure compréhension des mécanismes amenant à l’altération de la BHE, afin de développer des stratégies thérapeutiques adéquates. Toutefois, peu d’études à ce jour se sont intéressées à l’impact de l’hypoxie intermittente sur la BHE en raison de la complexité du cerveau. De ce fait, les modèles in vitro de BHE semblent être des outils adéquats à l’étude de la BHE en conditions pathologiques. L’objectif de ce travail de thèse a été de mettre en place un modèle in vitro de BHE permettant l’étude de l’impact de stress hypoxiques répétés sur l’intégrité de cette barrière.Le modèle mis en place est un modèle de co-culture « contact » mettant en jeu des cellules endothéliales cérébrales immortalisées de souris et des astrocytes immortalisés de rat. En effet, de nombreuses études ont montré l’importance des interactions entre les astrocytes et les cellules endothéliales, dans la mise en place du phénotype de barrière de la BHE. Nous avons fait le choix de développer un modèle murin afin d’être en adéquation avec les études menées, chez le petit animal, au laboratoire. Ce modèle a été caractérisé en termes de résistance électrique transendothelial (TEER), de perméabilité membranaire, de jonctions serrées et de transporteurs d’efflux. Ce modèle répond aux critères attendus pour un modèle in vitro de BHE et est rapide à mettre en place.L’impact cellulaire de l’hypoxie intermittente est difficile à étudier in vitro en raison de la rapidité du phénomène. De ce fait, nous avons mis en place une méthode alternative d’induction de stress hypoxique par un agent chimique, l’hydralazine, qui soit reproductible, contrôlable et réversible, afin d’étudier les mécanismes cellulaires et moléculaires induits au niveau de cette BHE. / The blood-brain barrier (BBB) is the essential structure of the central nervous system (CNS), located at the level of brain capillaries. The BBB is responsible for the maintenance of cerebral homeostasis and its protection. Indeed, diseases affecting the CNS are often related to a disorder at the BBB’s site. One of the several factors which can alter the homeostasis of the CNS, is hypoxia because the brain is one of the the first consumer of oxygen of the body. Several studies showed that acute hypoxia (mimic transient brain ischemia or stroke), could alter BBB permeability. However, some disorders are related to intermittent hypoxia, particularly sleep related breathing disorders, such as sleep apnea syndrome. This intermittent hypoxia does not seem to be innocent on the brain structure and function, since studies in humans have demonstrated that these patients suffer from cognitive disorders. The challenge in the study of such pathologies is represented by a better understanding of mechanisms leading to this alteration, in order to develop adequate therapeutic strategies. Nevertheless, few studies have focused, to date, on the impact of intermittent hypoxia on the BBB, due to the complexity of the brain structure in vivo. In this regard, in vitro BBB model appear to be suitable tools for the study of BBB in pathologies conditions. The aim of this thesis was to set up an in vitro BBB model suitable for the study of BBB’s integrity after repeated hypoxic stress exposure.

<p>Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde-products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs).</p><p>This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes. From studies on mice, it was also found that an SSAO inhibitor potently reduces the incorporation of methylamine-metabolite in the tissues. By quantifying SSAO-gene expression in alloxan-induced diabetes, increased transcription could be ruled out as a cause for the increased enzyme activity, thereby opening up for the possibility that the activity is regulated post-translationally. In fact, increased enzyme activity in adipose tissue was accompanied by decreased mRNA-levels, suggesting that the gene expression could be negatively controlled by the enzyme activity.</p>

Plasma activity of the enzyme semicarbazide-sensitive amine oxidase (SSAO; EC.1.4.3.6) has been reported to be high in disorders such as diabetes mellitus, chronic congestive heart failure and liver cirrhosis. Little is known of how the activity is regulated and, consequently, the cause for these findings is not well understood. Due to the early occurrence of increased enzyme activity in diabetes, in conjunction with the production of highly cytotoxic substances in SSAO-catalysed reactions, it has been speculated that there could be a causal relationship between high SSAO activity and vascular damage. Aminoacetone and methylamine are the best currently known endogenous substrates for human SSAO and the resulting aldehyde-products are methylglyoxal and formaldehyde, respectively. Both of these aldehydes have been shown to be implicated in the formation of advanced glycation end products (AGEs). This thesis is based on studies exploring the regulation of SSAO activity and its possible involvement in the development of vascular damage. The results further strengthen the connection between high SSAO activity and the occurrence of vascular damage, since type 2 diabetic patients with retinopathy were found to have higher plasma activities of SSAO and lower urinary concentrations of methylamine than patients with uncomplicated diabetes. From studies on mice, it was also found that an SSAO inhibitor potently reduces the incorporation of methylamine-metabolite in the tissues. By quantifying SSAO-gene expression in alloxan-induced diabetes, increased transcription could be ruled out as a cause for the increased enzyme activity, thereby opening up for the possibility that the activity is regulated post-translationally. In fact, increased enzyme activity in adipose tissue was accompanied by decreased mRNA-levels, suggesting that the gene expression could be negatively controlled by the enzyme activity.

No description available.

As doenças cardiovasculares são a maior causa de morte no mundo e entre essas doenças, a hipertrofia cardíaca (HC) tem se destacado especialmente por ser um fator de risco de insuficiência cardíaca. A HC é um fenômeno que acompanha a hipertensão arterial e no qual se observa aumento de proteínas estruturais e contráteis dos cardiomiócitos, havendo muitas vezes concomitantemente aumento do colágeno intersticial. Fatores independentes da pressão arterial também podem contribuir para o desenvolvimento da hipertrofia cardíaca. Dentre estes fatores, a sobrecarga de sal na dieta tem se destacado. Diversos estudos comprovam o efeito hipertrófico do sal. Em modelos animais onde se estudou sobrecarga de sal, não foi detectado aumento da atividade de renina plasmática, sugerindo que o sistema renina-angiotensina aldosterona (SRA) circulante pode não estar envolvido no desenvolvimento da hipertrofia cardíaca. Apesar de alguns estudos tentarem elucidar o papel do sal no desenvolvimento da hipertrofia ventricular esquerda, os mecanismos pelo qual o sal atua ainda não estão totalmente esclarecidos. Neste contexto, o objetivo do presente estudo é observar os fenômenos que ocorrem no ventrículo esquerdo em resposta a sobrecarga de sal na dieta na tentativa de elucidar sua fisiopatologia. Para tanto, ratos Wistar machos foram divididos em cinco grupos de acordo com a dieta (normossódica 1,26% e hipersódica 8% de NaCl) e com o tratamento (losartan, cloridrato de hidralazina ou N-acetilcisteína). Foi avaliada a evolução ponderal, pressão arterial caudal, medida do diâmetro transverso do cardiomiócito, fibrose intersticial, expressão gênica e proteica dos componentes do SRA, dosagem de aldosterona sérica e cardíaca, dosagem de TBARS cardíaco, concentração de angiotensina II e estado conformacional dos receptores AT1 e AT2. Os principais resultados observados foram: o aumento do consumo de ração (com elevada concentração de NaCl) do grupo HS+NAC e consequente aumento na pressão arterial e peso corpóreo; o desenvolvimento de HC independente do incremento da pressão arterial no grupo HS+HZ e a prevenção total ou parcial dessa hipertrofia através dos tratamentos com losartan e N-acetilcisteína, respectivamente e prevenção da fibrose intersticial nos grupos tratados com hidralazina, losartan e N-acetilcisteína / Cardiovascular diseases are the leading cause of death worldwide and among these diseases, the cardiac hypertrophy (CH) has been highlighted, especially as an important risk factor for developing heart failure. The CH is a phenomenon that accompanies hypertension and in which there is increased structural and contractile proteins in cardiomyocytes, with often concomitant increase of interstitial collagen. Blood pressure independent risk factors can also contribute to the development of cardiac hypertrophy. Among these factors, the high salt intake has been outstanding. Several studies confirm the hypertrophic effect of salt. In animal models submitted to salt overload, no increase in plasma renin activity was observed, suggesting that the renin-angiotensin (RAS) circulating system may not be involved in the development of cardiac hypertrophy. Although some studies attempting to elucidate the role of salt in the development of left ventricular hypertrophy, the mechanisms by which salt acts are not yet fully understood. In this context, the objective of this study is to observe the phenomena occurring in the left ventricle in response to dietary salt overload in an attempt to elucidate its pathophysiology.Male Wistar rats were divided into five groups according to their diet (1.26% and 8% NaCl) and treatment (losartan, hydralazine or N-acetylcysteine). We evaluated the body weight, tail-cuff blood pressure, the transverse diameter of the cardiomyocyte, interstitial fibrosis, gene and protein expression of RAAS components, serum and cardiac aldosterone dosage, cardiac TBARS, angiotensin II concentration and binding of conformation-specific anti-AT1 and anti-AT2 antibodies. The main results were: increased food intake (with high NaCl content) in the HS + NAC group and consequent increase in blood pressure and body weight; developing blood pressure-independent CH in the HS + HZ group partial or total prevention of such hypertrophy by treatment with losartan and N-acetylcysteine, respectively, and prevention of interstitial fibrosis in groups treated with hydralazine, losartan and N-acetylcysteine