A hipertensão pulmonar como consequência de lúpus na gravidez : caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy

OBJECTIVES We sought to determine if a hypertensive response to exercise (HRE) is associated with myocardial changes consistent with early hypertensive heart disease. BACKGROUND An HRE predicts the development of chronic hypertension (HT) and may reflect a preclinical stage of HT. METHODS Patients with a normal left ventricular (LV) ejection fraction and a negative stress test were recruited into three matched groups: 41 patients (age 56 +/- 10 years) with HRE (210/105 mm Hg in men; > 190/105 in women), comprising 22 patients with (HT+) and 19 without resting hypertension (HT-); and 17 matched control subjects without HRE. Long-axis function was determined by measurement of the strain rate (SR), peak systolic strain, and cyclic variation (CV) of integrated backscatter in three apical views. RESULTS An HRE was not associated with significant differences in LV mass index. Exercise performance and diastolic function were reduced in HRE(HT+) patients, but similar in HRE(HT-) patients and controls. Systolic dysfunction (peak systolic strain, SR, and CV) was significantly reduced in HRE patients (p < 0.001 for all). These reductions were equally apparent in patients with and without a history of resting HT (p = NS) and were independent of LV mass index and blood pressure (p < 0.01). CONCLUSIONS An HRE is associated with subtle systolic dysfunction, even in the absence of resting HT. These changes occur before the development of LV hypertrophy or detectable diastolic dysfunction and likely represent early hypertensive heart disease. (C) 2004 by the American College of Cardiology Foundation.

Factors determining disease duration in Alzheimer's disease:a postmortem study of 103 cases using the Kaplan-Meier estimator and Cox regression

Factors associated with duration of dementia in a consecutive series of 103 Alzheimer's disease (AD) cases were studied using the Kaplan-Meier estimator and Cox regression analysis (proportional hazard model). Mean disease duration was 7.1 years (range: 6 weeks-30 years, standard deviation = 5.18); 25% of cases died within four years, 50% within 6.9 years, and 75% within 10 years. Familial AD cases (FAD) had a longer duration than sporadic cases (SAD), especially cases linked to presenilin (PSEN) genes. No significant differences in duration were associated with age, sex, or apolipoprotein E (Apo E) genotype. Duration was reduced in cases with arterial hypertension. Cox regression analysis suggested longer duration was associated with an earlier disease onset and increased senile plaque (SP) and neurofibrillary tangle (NFT) pathology in the orbital gyrus (OrG), CA1 sector of the hippocampus, and nucleus basalis of Meynert (NBM). The data suggest shorter disease duration in SAD and in cases with hypertensive comorbidity. In addition, degree of neuropathology did not influence survival, but spread of SP/NFT pathology into the frontal lobe, hippocampus, and basal forebrain was associated with longer disease duration. © 2014 R. A. Armstrong.

Evidências de validade do Millon Behavioral Medicine Diagnostic: avaliação de indicadores de adesão ao tratamento em pacientes com hipertensão

Systemic Arterial Hypertension – SAH – is defined as the syndrome which its main feature is the presence of high tensional levels, associated with alterations of functional or structural levels in the organs that it strikes. Its specific causes are not very well bounded and have an asymptomatic character. Due to its chronicity it requires adherence to the treatment plan in a systematic and permanent manner, implicating in lifestyle changes, combined or not with the use of medication. The personality inventories have been largely used in the lineation of indicative traits of difficulties with the adherence to the treatment. In this sense, developed by Theodore Millon, the Millon Behavioural Medicine Diagnostic – MBMD is an instrument made from the consensus among healthcare professionals, aiming at identifying psychological factors that may compromise medical treatment so that they can be conducted in a way to enable a better adherence. Objective: evaluation of the evidence of validity of the Millon Behavioural Medicine Diagnostic – MBMD for a public of patients with hypertension, aiming at investigating the indicators implicated in the adherence or not to the anti-hypertensive treatment. Method: there was a group of 200 participants in a university hospital in the city of Natal/RN, males and females, ranging from 20 to 70 years old. An interview protocol was administered in order to obtain information about socio-demographic data, clinical history, healthcare habits and way of conducting treatment, and after, the administration of the MBMD followed. Results: by means of Factor Analysis it was verified that the organization proposed by the factors is favorable and it adjusts to the theory, allowing the visualization of other underlying constructs to the scales, with adequate adjustment indexes and satisfactory Cronbach’s alpha indicators. Besides, the MBMD revealed itself sensitive to the intragroup differences relative to the sex, age, schooling, marital status, profession, income, SAH history, diagnostic time, medication use, comorbidity presence, hyposodic diet, social support and adherence criteria variables. The utilization of such instrument in the evaluation of the adherence to the anti-hypertensive treatment show, therefore, indicators of validity.

Investigating the Role of PDE4D1/2 in Vascular Smooth Muscle Cell Desensitization

Vascular smooth muscle cell (VSMC) behaviour and phenotypic modulation is critical to vessel repair following damage, and the progression of various cardiovascular diseases. The second messenger cyclic adenosine monophosphosphate (cAMP) plays a key role in VSMC function under the synthetic/activated phenotype, which is typically associated with unhealthy cell behaviour. Consequently, cAMP signaling is often targeted in attempts to impact several pathological diseases, including atherosclerosis, restenosis, and pulmonary arterial hypertension (PAH). The cyclic nucleotide phosphodiesterases (PDEs) catalyze hydrolysis of cAMP to an inactive form, and therefore directly regulate cAMP signaling. The PDE4D family dominates in synthetic VSMCs, and there is considerable interest in determining how distinct PDE4D isoforms affect cell function. Specifically, we are interested in the potential link between short isoforms of PDE4D and VSMC desensitization to pharmacological agents that impact cardiovascular disease via cAMP signaling. This study extends on previous work that assessed the expression of PDE4D splice variants in rat aortic VSMCs following prolonged challenge with cAMP-elevating agents. It was determined that PDE4D1 and PDE4D2 were uniquely expressed in synthetic VSMCs incubated with these agents, and that this upregulation impacted PDE activity and cAMP accumulation in these cells. Here, we report that PDE4D1 and PDE4D2 are markedly upregulated in synthetic human aortic smooth muscle cells (HASMCs) following prolonged challenge with cAMP-elevating agents. Using a combination of RNAi-based and pharmacological approaches, we establish that this upregulation is reflected in levels of cAMP PDE activity, and restricted to the cytosolic sub-cellular compartment. Our results suggest a role for localized PDE4D1 and PDE4D2 activity in regulating cAMP-mediated desensitization in HASMCs, and highlight their therapeutic potential in treating various cardiovascular diseases.

Irregularidade do ciclo menstrual no Menacme como marcador para fatores de risco cardiovasculares na pós-menopausa

A associação entre fatores de risco cardiovascular (FRCV) na pósmenopausa e o antecedente de irregularidade menstrual no menacme foi avaliado em estudo caso-controle envolvendo 414 mulheres na pósmenopausa com idade de 60,4 ± 5,5 anos e IMC de 25,3 ± 4,7 kg/m2. As variáveis consideradas foram: caracterização do ciclo menstrual entre 20 e 35 anos (independente) e relato atual sobre ocorrência de hipertensão arterial, dislipidemia, diabetes mellitus e doença arterial coronariana (dependentes). Utilizou-se o teste qui-quadrado e modelos de regressão logística, ajustados para outras variáveis implicadas no risco para doenças CV, com nível de significância 5%. Observou-se que mulheres que relataram irregularidade menstrual prévia estiveram associadas com risco aumentado para ocorrência de algum FRCV [odds ratio ajustado (OR)= 2,14; IC-95%= 1,02–4,48], quando comparadas àquelas com ciclos regulares. Análise estratificada demonstrou as seguintes associações significativas com o antecedente de irregularidade menstrual: hipertensão arterial (OR= 2,4; 95% IC= 1,39–5,41), hipercolesterolemia (OR= 2,32; 95% IC= 1,17–4,59), hipertrigliceridemia (OR= 2,09; 95% IC= 1,10–4,33) e angioplastia coronariana (OR= 6,82; 95% IC= 1,44–32,18). Os dados sugerem que o antecedente de irregularidade menstrual, indicativo da ocorrência da síndrome dos ovários policísticos na idade reprodutiva, pode estar relacionado com aumento do risco para doenças CV na pós-menopausa __________________________________________________ABSTRACT Menstrual Cycle Irregularity as a Marker of Cardiovascular Risk Factors at Postmenopausal Years.To evaluate the association between cardiovascular risk factors (CVRF)during postmenopausal years and previous menstrual irregularity during reproductive years, we performed a case-control study in 414 postmenopausal women (mean age 60.4 ± 5.5 years; BMI 25.3 ± 4.7 kg/m2). The variables assessed were: menstrual cycle characteristics at age 20–35y (independent) and records of arterial hypertension, dyslipidemia, diabetes mellitus, and coronary heart disease (dependent). Statistical analysis used the chi-square test and logistic regression, adjusting for potential confounders for cardiovascular risk, with significance set at 5%. Women reporting previous menstrual irregularity were associated with increased risk for some CVRF [adjusted odds ratio (OR) 2.14; CI-95%= 1.02–4.48], when compared with those reporting regular menstrual cycles. Stratified analysis demonstrated significant associations of previous menstrual irregularity with: arterial hypertension [OR= 2.74; CI-95%= 1.39–5.41), hypercholesterolemia (OR= 2.32; CI-95%= 1.17–4.59), hypertriglyceridemia (OR= 2.09; CI-95%=1.10–4.33), and coronary angioplasty (OR= 6.82; CI-95%= 1.44–32.18). These data suggest that a prior history of menstrual irregularity, as indicative of polycystic ovary syndrome, may be related to increased risk for CVD during postmenopausal years

Irregularidade do ciclo menstrual no Menacme como marcador para fatores de risco cardiovasculares na pós-menopausa

A associação entre fatores de risco cardiovascular (FRCV) na pósmenopausa e o antecedente de irregularidade menstrual no menacme foi avaliado em estudo caso-controle envolvendo 414 mulheres na pósmenopausa com idade de 60,4 ± 5,5 anos e IMC de 25,3 ± 4,7 kg/m2. As variáveis consideradas foram: caracterização do ciclo menstrual entre 20 e 35 anos (independente) e relato atual sobre ocorrência de hipertensão arterial, dislipidemia, diabetes mellitus e doença arterial coronariana (dependentes). Utilizou-se o teste qui-quadrado e modelos de regressão logística, ajustados para outras variáveis implicadas no risco para doenças CV, com nível de significância 5%. Observou-se que mulheres que relataram irregularidade menstrual prévia estiveram associadas com risco aumentado para ocorrência de algum FRCV [odds ratio ajustado (OR)= 2,14; IC-95%= 1,02–4,48], quando comparadas àquelas com ciclos regulares. Análise estratificada demonstrou as seguintes associações significativas com o antecedente de irregularidade menstrual: hipertensão arterial (OR= 2,4; 95% IC= 1,39–5,41), hipercolesterolemia (OR= 2,32; 95% IC= 1,17–4,59), hipertrigliceridemia (OR= 2,09; 95% IC= 1,10–4,33) e angioplastia coronariana (OR= 6,82; 95% IC= 1,44–32,18). Os dados sugerem que o antecedente de irregularidade menstrual, indicativo da ocorrência da síndrome dos ovários policísticos na idade reprodutiva, pode estar relacionado com aumento do risco para doenças CV na pós-menopausa __________________________________________________ABSTRACT Menstrual Cycle Irregularity as a Marker of Cardiovascular Risk Factors at Postmenopausal Years.To evaluate the association between cardiovascular risk factors (CVRF)during postmenopausal years and previous menstrual irregularity during reproductive years, we performed a case-control study in 414 postmenopausal women (mean age 60.4 ± 5.5 years; BMI 25.3 ± 4.7 kg/m2). The variables assessed were: menstrual cycle characteristics at age 20–35y (independent) and records of arterial hypertension, dyslipidemia, diabetes mellitus, and coronary heart disease (dependent). Statistical analysis used the chi-square test and logistic regression, adjusting for potential confounders for cardiovascular risk, with significance set at 5%. Women reporting previous menstrual irregularity were associated with increased risk for some CVRF [adjusted odds ratio (OR) 2.14; CI-95%= 1.02–4.48], when compared with those reporting regular menstrual cycles. Stratified analysis demonstrated significant associations of previous menstrual irregularity with: arterial hypertension [OR= 2.74; CI-95%= 1.39–5.41), hypercholesterolemia (OR= 2.32; CI-95%= 1.17–4.59), hypertriglyceridemia (OR= 2.09; CI-95%=1.10–4.33), and coronary angioplasty (OR= 6.82; CI-95%= 1.44–32.18). These data suggest that a prior history of menstrual irregularity, as indicative of polycystic ovary syndrome, may be related to increased risk for CVD during postmenopausal years

Idosos em atendimento ambulatorial: adesão á terapêutica medicamentosa e fatores relacionados.

A adesão à terapêutica medicamentosa por idosos é um fenômeno dependente de fatores diversificados. Defende-se como tese: A adesão aos medicamentos prescritos em idosos em atendimento ambulatorial apresenta-se relacionada aos fatores referentes às características: demográficas, socioeconômicas; dos serviços de saúde, dos profissionais de saúde; das condições de saúde; da terapêutica medicamentosa; comportamentais. Esses fatores estão relacionados aos principais motivos referidos pelos idosos para aderirem ou não aos medicamentos prescritos. Foram objetivos: identificar na literatura brasileira e estrangeira a prevalência de adesão à terapêutica medicamentosa e os fatores relacionados em idosos; caracterizar os idosos em atendimento ambulatorial em um hospital universitário no Rio Grande/RS, Brasil, quanto às características demográficas, socioeconômicas, condições de saúde e uso de medicamentos; identificar os motivos referidos por estes idosos que levavam à adesão/não adesão à terapêutica medicamentosa; verificar a prevalência de adesão à terapêutica medicamentosa nestes idosos; verificar se há associação entre adesão à terapêutica medicamentosa e fatores demográficos, socioeconômicos, condições de saúde, terapêutica medicamentosa e fatores comportamentais destes idosos. Pesquisa realizada por meio de uma revisão integrativa da literatura e de um estudo quantitativo. Na revisão integrativa selecionaram-se 49 artigos e os fatores identificados foram organizados nas categorias: demográficas e socioeconômicas; sistema e profissionais de saúde; condições de saúde; terapêutica medicamentosa; comportamentais. O estudo quantitativo foi exploratório, descritivo, transversal, realizado em um serviço ambulatorial de um hospital universitário no Rio Grande/RS, Brasil. Participaram 107 idosos que responderam ao instrumento para caracterização do idoso e dos fatores relacionados à adesão à terapêutica medicamentosa; ao Miniexame do Estado Mental; à Escala de Medida de Adesão aos Tratamentos. A coleta de dados foi realizada em novembro de 2013. Realizou-se análise estatística descritiva e inferencial. Verificaram-se mais idosos do sexo feminino, na faixa etária entre 60-69 anos. A doença mais prevalente foi a Hipertensão Arterial e a média de uso de medicamentos por dia foi de 4,8. Querer sentir-se bem/manter a saúde e querer controlar a doença e os sintomas foram os motivos para aderir à terapêutica medicamentosa prescrita. A ocorrência de reação adversa e falta de condições financeiras foram os motivos para não aderir. A prevalência de adesão à terapêutica medicamentosa foi de 86,9%. Houve associação entre a adesão e receber orientações do médico sobre como tomar os medicamentos, ter reação adversa, acreditar que os medicamentos são importantes para manutenção da saúde e ter vontade de não tomar os medicamentos. A tese é confirmada em parte: a adesão aos medicamentos prescritos em idosos em atendimento ambulatorial apresenta-se relacionada aos fatores referentes às características: dos profissionais de saúde; das condições de saúde; da terapêutica medicamentosa; comportamentais. Esses fatores estiveram relacionados aos principais motivos referidos pelos idosos para aderirem ou não aos medicamentos prescritos. Por outro lado, a adesão não apresentou relação com os fatores demográficos e socioeconômicos, embora as condições financeiras tenham sido referidas pelos idosos como um motivo que leva à não adesão.

Role of membrane lipids in the regulation of erythrocytic oxygen-transport function in cardiovascular diseases

The composition and condition of membrane lipids, the morphology of erythrocytes, and hemoglobin distribution were explored with the help of laser interference microscopy (LIM) and Raman spectroscopy. It is shown that patients with cardiovascular diseases (CVD) have significant changes in the composition of their phospholipids and the fatty acids of membrane lipids. Furthermore, the microviscosity of the membranes and morphology of the erythrocytes are altered causing disordered oxygen transport by hemoglobin. Basic therapy carried out with the use of antiaggregants, statins, antianginals, beta-blockers, and calcium antagonists does not help to recover themorphofunctional properties of erythrocytes. Based on the results the authors assume that, for the relief of the ischemic crisis and further therapeutic treatment, it is necessary to include, in addition to cardiovascular disease medicines, medication that increases the ability of erythrocytes’ hemoglobin to transport oxygen to the tissues. We assume that the use of LIM and Raman spectroscopy is advisable for early diagnosis of changes in the structure and functional state of erythrocytes when cardiovascular diseases develop.

Relatório de estágio: Enfermagem Comunitária

O envelhecimento demográfico em Portugal é uma realidade, sendo o Alentejo a região mais afetada. Este facto torna-se um desafio para a área da saúde, não sendo a enfermagem uma exceção. É importante capacitar os nossos idosos para um envelhecimento ativo, através da adoção de estilos de vida saudáveis. O presente relatório resultou do estágio em Enfermagem Comunitária realizado na freguesia de Santo Amaro, concelho de Sousel, no período compreendido entre 14/02/2011 e 26/06/2011 e tem como objetivo descrever e analisar as atividades desenvolvidas. Foi efetuado previamente um diagnóstico de saúde para aferir as reais necessidades da população idosa desta freguesia e definir as áreas de intervenção prioritárias. O Projeto 65 + Saúde surgiu como resposta às prioridades identificadas, sendo direcionado à população idosa e seu cuidadores formais. As sessões e atividades realizadas relacionaram-se com a adoção de estilos de vida saudáveis, direcionados à hipertensão arterial, à diabetes mellitus, à inclusão social e ao exercício físico. Em todas as etapas foi utilizada a metodologia do planeamento em saúde. As sessões de educação para a saúde realizadas tiveram por base a Teoria da Aprendizagem Social de Bandura. Pretendeu-se com o estágio a aquisição da maioria das competências específicas do Enfermeiro Especialista em Enfermagem Comunitária e de Saúde Pública.

Factores asociados al perfil de lípidos sanguíneos en los pacientes del área de salud de Montes de Oca, Costa Rica

En este estudio se analiza la asociación entre la exposición a diversos factores —de biotipo, socioeconómicos y patológicos— y la alteración del perfil de lípidos sanguíneos (dislipidemia) en pacientes adscritos al Área de Salud de Montes de Oca. Se realizó un estudio de caso-control, con un total de 135 casos e igual cantidad de controles, entre 20 y 65 años, a los que se les hizo un perfil de lípidos sanguíneos durante el año 2006. Las variables estudiadas fueron: edad, sexo, índice de masa corporal, tipo de aseguramiento, estado de portador de hipertensión arterial, de diabetes mellitus o de ambas patologías crónicas a la vez. Se realizó un análisis univariado, seguido de un análisis multivariado, mediante un modelo logístico múltiple. La única variable asociada con la dislipidemia fue el índice de masa corporal, tanto en el análisis univariado como en el multivariado; las variables restantes no mostraron asociación estadística. Aquellos pacientes con mayor índice de masa corporal presentan un mayor riesgo de tener un perfil alterado de lípidos sanguíneos.

Investigating the Role of PDE4D1/2 in Vascular Smooth Muscle Cell Desensitization

Thesis (Master, Biochemistry) -- Queen's University, 2016-10-14 02:44:01.604

The role of inflammation in vascular function and pregnancy outcome in the pregnant stroke prone spontaneously hypertensive rat

During pregnancy, the maternal cardiovascular system undergoes major adaptation. One of these changes is a 40-50 % increase in circulating blood volume which requires a systemic remodelling of the vasculature in order to regulate maternal blood pressure and maximise blood supply to the developing placenta and fetus. These changes are broadly conserved between humans and rats making them an appropriate pre-clinical model in which to study the underlying mechanisms of pregnancy-dependent cardiovascular remodelling. Whilst women are normally protected against cardiovascular disease; pregnancy marks a period of time where women are susceptible to cardiovascular complications. Cardiovascular disease is the leading cause of maternal mortality in the United Kingdom; in particular hypertensive conditions are among the most common complications of pregnancy. One of the main underlying pathologies of these pregnancy complications is thought to be a failure of the maternal cardiovascular system to adapt. The remodelling of the uterine arteries, which directly supply the maternal-fetal interface, is paramount to a healthy pregnancy. Failure of the uterine arteries to remodel sufficiently can result in a number of obstetric complications such as preeclampsia, fetal growth restriction and spontaneous pregnancy loss. At present, it is poorly understood whether this deficient vascular response is due to a predisposition from existing maternal cardiovascular risk factors, the physiological changes that occur during pregnancy or a combination of both. Previous work in our group employed the stroke prone spontaneously hypertensive rat (SHRSP) as a model to investigate pregnancy-dependent remodelling of the uterine arteries. The SHRSP develops hypertension from 6 weeks of age and can be contrasted with the control strain, the Wistar Kyoto (WKY) rat. The phenotype of the SHRSP is therefore reflective of the clinical situation of maternal chronic hypertension during pregnancy. We showed that the SHRSP exhibited a deficient uterine artery remodelling response with respect to both structure and function accompanied by a reduction in litter size relative to the WKY at gestational day (GD) 18. A previous intervention study using nifedipine in the SHRSP achieved successful blood pressure reduction from 6 weeks of age and throughout pregnancy; however uterine artery remodelling and litter size at GD18 was not improved. We concluded that the abnormal uterine artery remodelling present in the SHRSP was independent of chronic hypertension. From these findings, we hypothesised that the SHRSP could be a novel model of spontaneously deficient uterine artery remodelling in response to pregnancy which was underpinned by other as yet unidentified cardiovascular risk factors. In Chapter 1 of this thesis, I have characterised the maternal, placental and fetal phenotype in pregnant (GD18) SHRSP and WKY. The pregnant SHRSP exhibit features of left ventricular hypertrophy in response to pregnancy and altered expression of maternal plasma biomarkers which have been previously associated with hypertension in human pregnancy. I developed a protocol for accurate dissection of the rat uteroplacental unit using qPCR probes specific for each layer. This allowed me to make an accurate and specific statement about gene expression in the SHRSP GD18 placenta; where oxidative stress related gene markers were increased in the vascular compartments. The majority of SHRSP placenta presented at GD18 with a blackened ring which encircled the tissue. Further investigation of the placenta using western blot for caspase 3 cleavage determined that this was likely due to increased cell death in the SHRSP placenta. The SHRSP also presented with a loss of one particular placental cell type at GD18: the glycogen cells. These cells could have been the target of cell death in the SHRSP placenta or were utilised early in pregnancy as a source of energy due to the deficient uterine artery blood supply. Blastocyst implantation was not altered but resorption rate was increased between SHRSP and WKY; indicating that the reduction in litter size in the SHRSP was primarily due to late (>GD14) pregnancy loss. Fetal growth was not restricted in SHRSP which led to the conclusion that SHRSP sacrifice part of their litter to deliver a smaller number of healthier pups. Activation of the immune system is a common pathway that has been implicated in the development of both hypertension and adverse pregnancy outcome. In Chapter 2, I proposed that this may be a mechanism of interest in SHRSP pregnancy and measured the pro-inflammatory cytokine, TNFα, as a marker of inflammation in pregnant SHRSP and WKY and in the placentas from these animals. TNFα was up-regulated in maternal plasma and urine from the GD18 SHRSP. In addition, TNFα release was increased from the GD18 SHRSP placenta as was the expression of the pro-inflammatory TNFα receptor 1 (Tnfr1). In order to investigate whether this excess TNFα was detrimental to SHRSP pregnancy, a vehicle-controlled intervention study using etanercept (a monoclonal antibody which works as a TNFα antagonist) was carried out. Etanercept treatment at GD0, 6, 12 and 18 resulted in an improvement in pregnancy outcome in the SHRSP with an increased litter size and reduced resorption rate. Furthermore, there was an improved uterine artery function in GD18 SHRSP treated with etanercept which was associated with an improved uterine artery blood flow over the course of gestation. In Chapter 3, I sought to identify the source of this detrimental excess of TNFα by designing a panel for maternal leukocytes in the blood and placenta at GD18. A population of CD3- CD161+ cells, which are defined as rat natural killer (NK) cells, were increased in number in the SHRSP. Intracellular flow cytometry also identified this cell type as a source of excess TNFα in blood and placenta from pregnant SHRSP. I then went on to evaluate the effects of etanercept treatment on these CD3- CD161+ cells and showed that etanercept reduced the expression of CD161 and the cytotoxic molecule, granzyme B, in the NK cells. Thus, etanercept limits the cytotoxicity and potential damaging effect of these NK cells in the SHRSP placenta. Analysing the urinary peptidome has clinical potential to identify novel pathways involved with disease and/or to develop biomarker panels to aid and stratify diagnosis. In Chapter 4, I utilised the SHRSP as a pre-clinical model to identify novel urinary peptides associated with hypertensive pregnancy. Firstly, a characterisation study was carried out in the kidney of the WKY and SHRSP. Urine samples from WKY and SHRSP taken at pre-pregnancy, mid-pregnancy (GD12) and late pregnancy (GD18) were used in the peptidomic screen. In order to capture peptides which were markers of hypertensive pregnancy from the urinary peptidomic data, I focussed on those that were only changed in a strain dependent manner at GD12 and 18 and not pre-pregnancy. Peptide fragments from the uromodulin protein were identified from this analysis to be increased in pregnant SHRSP relative to pregnant WKY. This increase in uromodulin was validated at the SHRSP kidney level using qPCR. Uromodulin has previously been identified to be a candidate molecule involved in systemic arterial hypertension but not in hypertensive pregnancy thus is a promising target for further study. In summary, we have characterised the SHRSP as the first model of maternal chronic hypertension during pregnancy and identified that inflammation mediated by TNFα and NK cells plays a key role in the pathology. The evidence presented in this thesis establishes the SHRSP as a pre-clinical model for pregnancy research and can be continued into clinical studies in pregnant women with chronic hypertension which remains an area of unmet research need.

Síndrome desequilibrio esfuerzo-recompensa y enfermedades cardiovasculares : revisión de la literatura 2006-2016

Introducción El modelo desequilibrio esfuerzo – recompensa es un importante predictor de estrés laboral y por consiguiente de alteraciones en la salud cardiovascular, por ello en los últimos 10 años se ha encontrado importante evidencia y estudios respecto al tema; las publicaciones científicas se han enfocado en establecer relación entre factores psicosociales en el trabajo y consecuencias sobre la salud dándole relevancia a los factores biológicos principalmente los cardiovasculares. Objetivo Se evaluó la evidencia entre el desequilibrio esfuerzo recompensa y las alteraciones cardiovasculares en los trabajadores. Metodología Se realizó una revisión de la literatura en principales bases de datos como son pubmed, ovid y revistas electrónicas, en idioma inglés – español durante los últimos 10 años, usando palabras de búsqueda como desequilibrio esfuerzo recompensa, alteraciones cardiovasculares, trabajadores. Resultados Se encontró fuerte evidencia entre el desequilibrio esfuerzo recompensa con enfermedades cardiovasculares en los trabajadores, principalmente con las alteraciones en la tensión arterial en los trabajadores más expuestos, al igual que una relación mayor en mujeres que hombres que aumentaba con la edad. Se evidenció que después de haber sufrido un evento coronario agudo los trabajadores que continuaban expuestos a altas cargas de tensión laboral eran más propensos a desarrollar enfermedad coronaria recurrente. El sobrecompromiso (PR 1,91, IC 95% 1,35-2,69) y el desequilibrio esfuerzo recompensa (PR 2,47, IC 95% 1,62-3,75) se asociaron con riesgo de hipertensión arterial después de ajustar las variables de confusión. Se encontró asociación entre el desequilibrio esfuerzo recompensa e hipertensión arterial (OR 1,53-3,71 IC 95%). La ERI alta y la baja recompensa se asociaron con enfermedad coronaria recurrente (RR = 1,75, intervalo de confianza del 95% [IC] = 0,99 - 3,08 y HR = 1,77, IC del 95% = 1,16 - 2,71). Hubo una interacción de género que mostró efectos más fuertes entre las mujeres (HR respectivamente ajustadas para ERI alta y baja recompensa: HR = 3,95, IC del 95% = 0,93- 16,79, y HR = 9,53, IC del 95% = 1,15- 78,68). Conclusiones Se encontró una relación entre el desequilibrio esfuerzo recompensa con enfermedades cardiovasculares, principalmente con las alteraciones en la tensión arterial y eventos coronarios