O objetivo deste trabalho foi avaliar o status de ferro (Fe) em pacientes hospitalizados por insuficiência cardíaca avançada. Participaram do estudo 50 pacientes, sendo que 24 foram diagnosticados com anemia e desses 8 apresentam anemia por deficiência de ferro. Foram incluídos no estudo indivíduos do sexo masculino, com idade entre 30 e 60 anos e fração de ejeção do ventrículo esquerdo (FEVE) <0,45. Para análise dos níveis séricos de hepcidina, interleucina 6 (IL-6), fator de necrose tumoral-alfa (TNF-&#945;) e eritropoietina os pacientes foram submetidos a coleta de sangue após jejum de 8 horas. Os parâmetros hematológicos e bioquímicos foram avaliados por meio dos resultados de exames laboratoriais rotineiramente realizados e foram verificados em prontuário médico. O consumo alimentar foi avaliado pelo método direto de pesagem dos alimentos. Os resultados entre os grupos foram comparados pelo teste de Mann Whitney e foram feitas correlações de acordo com o teste de Spearman e teste de Pearson. Não foram encontradas diferenças nos níveis séricos de hepcidina entre os anêmicos com e sem deficiência de ferro. Houve correlação negativa entre a concentração de hepcidina e a de ferritina entre os anêmicos com deficiência de ferro e não foi observada correlações da hepcidina com os outros parâmetros inflamatórios. A desnutrição e a baixa ingestão calórica foram frequentes e não foi verificada baixa ingestão alimentar de ferro. Não foi caracterizada anemia de doença crônica com base na concentração sérica de hepcidina. / The aim of this study was to evaluate the iron status in hospitalized with advanced heart failure. 50 patients participated of this study, 24 of them have been diagnosed with anemia and among these 8 were identified with iron deficiency anemia. Males, aged between 30 and 60 years old, with left ventricular ejection fraction (LVEF) <0,45 were include in the study. For analysis of serum levels of hepcidin, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-&#945;) and erythropoietin patients underwent blood collection after 8 hours fasting. Haematological and biochemical parameters were obtained laboratory tests routinely performed and were checked in medical records. Food consumption was evaluated by direct weighing method. The results the groups anemic and nonanemic with or without iron deficiency groups were compared by Mann Whitney test and correlations was made according to the Spearman`s and Pearson`s tests. No differences were found in serum hepcidin levels between anemic patients with or without Fe deficiency. There was a negative correlation between hepcidin and ferritin iron-deficiency patients, and correlations of hepcidin with other inflammatory factors were not significant. Malnutrition and low caloric intake were frequent and dietary intake of iron intake was adequate. Chronic disease anemia was not characterized based on serum hepcidin.

INTRODUÇÃO: As doenças cardiovasculares estão entre as principais causas de óbito no Brasil e no mundo. Dentre as doenças cardiovasculares, a insuficiência cardíaca (IC) participa de maneira importante para morbi-mortalidade por ser via final de todas as entidades que acometem o coração. A internação hospitalar constitui momento crucial no tratamento e sobrevida dos pacientes com IC. Neste momento, em que o estado da doença atinge seu período mais crítico, é de grande importância o conhecimento dos pacientes com maior risco, que necessitam de cuidados mais intensos. No entanto, a apuração dos custos hospitalares é tarefa difícil, principalmente nas situações de alta complexidade, onde a utilização de recursos nos diversos setores do hospital, materiais e medicamentos, é muito heterogênea. Assim, a busca de variáveis clínicas capazes de ajudar a identificar os pacientes com maior risco, morbidade hospitalar (e conseqüente maior tempo de internação), e o custo destas internações foram o escopo deste estudo. OBJETIVO: primariamente, identificar variáveis clínicas capazes de predizer prognóstico de sobrevida e custos de internação numa população de pacientes internados por IC. Secundariamente, determinar custo mediano destas internações, correlacionando os as variáveis clínicas, de etiologia da cardiopatia de base, e com o perfil hemodinâmico na admissão hospitalar. Visamos ainda projetar os dados da Instituição no modelo de regressão por árvore de decisão proposto pelo estudo ADHERE. MÉTODOS: Realizamos um estudo retrospectivo na qual foram analisados dados consecutivos referentes a internações de pacientes que chegaram ao Pronto Socorro do InCor e permaneceram no Hospital por mais de 24 horas, sendo internados nos anos de 2006 e 2007. Foram avaliados dados clínicos na chegada ao pronto atendimento e evolutivos durante a internação. Foi realizada avaliação de custo da doença durante internação hospitalar através de modelo misto de análises de custos diretos contabilizados por absorção total e rateio dos setores de apoio. Análises estatísticas incluíram modelos de: regressão de proporcional de Cox para variáveis de morbidade-permanência hospitalar, regressão logística para variáveis de mortalidade hospitalar, e regressão através de árvores de decisão para definição de variáveis prioritárias. RESULTADOS: Foram avaliadas 577 internações de pacientes diferentes, sendo 60% do sexo masculino, e idade mediana de 69 anos (57-77). As principais variáveis clínicas preditoras de tempo de internação para nossa população foram: perfil hemodinâmico C, necessidade de dobutamina, ventilação mecânica, ou antibióticos. As principais variáveis clínicas preditoras de mortalidade foram: fração de ejeção, pressão arterial sistólica, clearence estimado de creatinina, ocorrência de infecção hospitalar, e a necessidade de dobutamina, noradrenalina, ou cateteres centrais. Todas estas variáveis compuseram os modelos de regressão. O custo mediano das internações foi de R$ 4.450 (1.353 - 13.432), sendo o fator independente na análise multivariada, o tempo de internação hospitalar, que teve mediana de 5 dias (2-13). A mortalidade hospitalar geral foi de 132 pacientes (23%). CONCLUSÃO: As variáveis clínicas preditoras de tempo de internação para nossa população foram: perfil hemodinâmico, necessidade de dobutamina, ventilação mecânica, ou antibióticos. As variáveis clínicas preditoras de mortalidade foram a fração de ejeção, a pressão arterial sistólica, o clearence estimado de creatinina, a ocorrência de infecção hospitalar, e a necessidade de dobutamina, noradrenalina, ou cateteres centrais. Estas variáveis foram diferentes daquelas apontadas por outros estudos. A etiologia chagásica se correlacionou à maior incidência de choque cardiogênico, caracterizando assim maiores taxas de mortalidade, tempo de permanência, e custos frente às outras etiologias. A presença de choque cardiogênico na entrada se correlacionou a altas taxas de mortalidade, internações mais prolongadas, e maiores de custos de internação. O modelo descrito pelo estudo ADHERE pôde ser aplicado em nossa população, porém, propusemos outro modelo de árvore de decisão composto pelas variáveis: presença de choque cardiogênico uréia sérica, e pressão arterial sistólica, que apresentou maior acurácia em relação ao desfecho mortalidade hospitalar. O custo das internações variou muito de acordo com a evolução clínica dos pacientes, e conseqüentemente, seu tempo de internação hospitalar. No caso de pacientes atendidos pelo SUS, menos de um terço das internações tiveram custos inferiores ao valor médio das AIHs pagas por internações de pacientes com IC. / BACKGROUND: Heart diseases are the main mortality cause in Brazil and the rest of the world. Among those diseases, heart failure (HF) is utmost importance because it is the final pathway for overall heart diseases. Acute decompensate HF is a crucial situation while treating this disease because of its severity. At this critical time, stratification of risk is imperative in order to determine care. Hospital costs determination, however, is difficult in high complexity situations that use resources in a heterogeneity manner. The look for the clinical variables that could identify patients at higher risk for morbidity (and length of stay), mortality, and costs were the main aims of this study. OBJECTIVES: primarily to identify clinical variable able to predict survive and costs in a population of patients admitted by HF. Secondarily, determine median costs for the admissions, correlating these values to clinical variables, etiologies of HF, and hemodynamic profile at entrance. We aimed also to run our data in the tree regression model previously proposed by the ADHERE registry. METHODS: we reviewed consecutively 577 admissions records of different patients admitted by acute decompensated heart failure that stayed for more than 24 hours at the hospital during 2006 and 2007. Clinical data at the admissions and in-hospital follow-up data were analyzed. Costs analysis was performed through a mix model of microcosting (for direct resources) and average costing (for indirect resources). Statistical analysis included regression models as follows: Cox proportional for length of stay variables, logistic for hospital mortality, and classification and regression tree for defining priority variables. RESULTS: among the 577 patients, 60% were men; median age was 69 years (57- 77). The main predictor variables for length of stay were as follows: C hemodynamic profile, need for dobutamine, mechanic ventilation, or antibiotics. The main predictor variables for mortality were as follows: ejection fraction, systolic blood pressure, estimated creatinine clearance, occurrence of hospital infections, and need for dobutamine, norepinephrine, or central catheters. All these variables composed the regression models. Median admission cost was R$ 4.450 (1.353 13.432). Length of stay was an independent factor for predicting costs, with median of 5 days (2-13). Inhospital mortality rate was 23% (132 patients). CONCLUSION: The main predictor variables for length of stay were as follows: hemodynamic profile, need for dobutamine, mechanic ventilation, or antibiotics. The main predictor variables for mortality were as follows: ejection fraction, systolic blood pressure, estimated creatinine clearance, occurrence of hospital infections, and need for dobutamine, norepinephrine, or central catheters. These variables differ from other studies that evaluated similar outcomes. Chagas heart disease etiology was correlated to higher rates of cardiogenic shock, mortality rates, length of stay, and costs. The model used in the ADHERE registry could be used in our population; however, we proposed another variables integrating the regression and classification tree (systolic blood pressure, blood urea nitrogen, and hemodynamic profile C). This model presented greater accuracy for hospital mortality in our population. The cost of admissions ranged according to clinical evolution of the patients, and as consequence of length of stay. Less than a third of the admissions reimbursed by the government had their costs below the mean estimated value for reimbursement

Objetivos: Comparar as distribuições das medidas dos instrumentos DUFS, DEFS e Pictograma de Fadiga de acordo com a gravidade da insuficiência cardíaca (IC) avaliada pela Classe Funcional da New York Heart Association (CF-NYHA) e a avaliar sua relação com a fração de ejeção do ventrículo esquerdo (FEVE). Método: Estudo metodológico, de corte transversal, cuja amostra foi composta por adultos com IC atendidos em um hospital universitário do Estado de São Paulo, de setembro de 2014 a março de 2015. O DUFS avalia a fadiga relacionada à cardiopatia (8 itens, intervalo total de 8 a 40; quanto maior o valor, maior a intensidade da fadiga) e o DEFS avalia a fadiga relacionada às atividades físicas e aos esforços (9 itens, intervalo de nove a 45; maiores valores indicando maior intensidade da fadiga). O Pictograma de Fadiga avalia a intensidade (item A) e o impacto (item B) da fadiga relacionada às atividades da vida diária, quanto maior a pontuação em cada item, maior a sensação e o impacto da fadiga. Os dados foram coletados por entrevistas e consulta aos prontuários. Para testar se as médias dos grupos eram diferentes, fizemos uma Análise de Variância com o valor da escala como variável resposta e CF-NYHA grupo como variável explanatória. Quando o fator grupo era estatisticamente significante, fizemos o teste de comparação múltipla de médias (método post hoc de Bonferroni). Para verificar a correlação entre as medidas obtidas pelos instrumentos DUFS e DEFS e a FEVE, foi utilizado o teste de Correlação de Pearson. A associação entre as distribuições das respostas aos itens do Pictograma de Fadiga e a FEVE, categorizada em preservada (>= 55) ou reduzida (<55), foi analisada pelo teste Exato de Fisher. O nível de significância adotado foi de 0,05. Resultados: Participaram 118 pacientes, com média de idade de 63 (D.P.=13) anos, 62% do sexo masculino, 86% não desempenhavam atividades remuneradas, com média de 6 (D.P.=5) anos de estudo. Observamos aumento nas médias das medidas obtidas por DUFS ou DEFS entre os pacientes de acordo com a progressão da doença medida pela CF-NYHA (p<0,001, para os dois instrumentos). Não constatamos diferenças entre a fadiga (avaliada pelo DUFS) dos pacientes da CF-NYHA III com os das II e IV. Ao analisarmos as diferenças da fadiga, avaliada pelo DEFS, não observamos diferenças entre as médias dos pacientes da CF-NYHA II com os das I e III, e os da III, com os pacientes da IV. As correlações entre a FEVE com as medidas de fadiga foram de positiva e fraca magnitude para o DEFS (r=0,18; p=0,05) e para o DUFS (r=0,16; p=0,08). Somente o item A do Pictograma de Fadiga teve associação com os grupos de CF-NYHA (p<0,001). Conclusão: Os três instrumentos demonstraram piora nos níveis de fadiga de acordo com a gravidade da doença avaliada pela CF-NYHA, entretanto, não houve discriminação entre os grupos de maior gravidade, pois houve grande variação dentro de cada grupo funcional / Objectives: Compare the distributions of the measures of the Dutch Fatigue Scale (DUFS), Dutch Exertion Fatigue Scale (DEFS) and Fatigue Pictogram according to the severity of heart failure (HF), assessed by the New York Heart Association Functional Class (NYHA-FC) and to assess its relationship with the left ventricle ejection fraction (LVEF). Method: Methodological, cross-sectional study with a sample composed of adults with HF cared for by a university hospital in the state of São Paulo, Brazil from September 2014 to March 2015. The DUFS assesses fatigue related to heart disease (8 items, total interval from 8 to 40; the higher the score, the more intense the fatigue) and the DEFS assesses fatigue related to physical exertion (9 items, interval from nine to 45; higher scores indicate more intense fatigue). The Fatigue Pictogram assesses the intensity (item A) and impact (item B) of fatigue related to daily living activities; the higher each item\"s score, the greater the intensity and impact of fatigue. Data were collected using interviews and by consulting medical files. To test whether the groups\" means were different, an analysis of variance was performed with the scale\"s score as the response variable and the group\"s FC-NYHA as the explanatory variable. When the group factor was statistically significant, a multiple comparison test (Bonferroni\"s post-hoc method) was used. Person\"s Correlation test was used to verify correlation between the measures obtained by the DUFS, DEFS and LVFE. Association between the distributions of responses to the Fatigue Pictogram\"s items and LVEF, categorized in preserved (>= 55) or reduced (<55), was analyzed by the Fisher\"s exact test. The level of significance adopted was 0.05. Results: A total of 118 patients aged 63 (SD=13) years old on average participated; 62% were males, 86% did not have a paid job, with 6 (SD=5) years of education, on average. The means of the measures obtained by the DUFS or DEFS increased among patients as the disease progressed, as measure by the NYHA-FC (p<0.001 for both instruments). No differences were found between the fatigue (assessed by the DUFS) of patients classified in NYHA-FC III with those classified in NYHA-FC II and IV. When analyzing means of fatigue, measured by the DEFS, no differences were found between the means of patients in NYHA-FC II with those in functional classes I or III, or between those in NYHA-FC III with patients in IV. Correlations between LVEF and fatigue measures were of a positive and weak magnitude for the DEFS (r=0.18; p=0.05) and for the DUFS (r=0.16; p=0.08). Only item A of the Fatigue Pictogram was associated with NYHA- FC groups (p<0.001). Conclusion: The three instruments showed worse levels of fatigue according to the severity of the disease assessed by NYHA-FC, however, there was no discrimination between the groups with greater severity, as there was a large variation within each functional group

A redução do consumo de alimentos é freqüente durante a descompensação da insuficiência cardíaca, quando há um aumento do gasto energético basal. Os triglicérides de cadeia média, utilizados como suplementação energética, aumentam a densidade calórica dos alimentos, contribuindo para o metabolismo energético dos pacientes com insuficiência cardíaca. O objetivo foi avaliar o efeito da suplementação de triglicérides de cadeia média sobre o quoeficiente respiratório, na insuficiência cardíaca congestiva e na baixa ingestão alimentar. Foi realizado um estudo randomizado aberto com 45 pacientes de 18 a 70 anos com insuficiência cardíaca congestiva descompensada, fração de ejeção < 0,45, sem drogas vasoativas, dieta oral, IMC < 25kg/m2 para adultos e < 27 kg/m2 para idosos. Foram alocados aleatoriamente para grupo com suplementação de TCM e grupo controle. Os grupos realizaram duas medidas de VCO2 e VO2, por calorimetria indireta. O QR foi avaliado pela análise de variância com medidas repetidas. Foi considerado significante P < 0,05. 75% dos pacientes foram identificados em eutrofia pelo IMC, porém destes, 67% foram diagnosticados com desnutrição calórica e 65% com desnutrição protéico calórica quando analisados e classificados os indicadores de dobras cutâneas. A proporção de lipídeos aumentou de 9,5% para 57% das recomendações com 236,7 ± 95,0 kcal/d do triglicérides de cadeia média (P <0,001). A ingestão de calorias aumentou de 1966,3 ± 643,3 kcal /d para 2202,7 ± 708,4 kcal /d no grupo intervenção e manteve 1960,7 ± 702,6 kcal /d no grupo controle. Não houve variação significativa quoeficiente respiratório (grupo triglicérides de cadeia média +0,4%; grupo controle: +2,5%, P = 0,458). Quatro pacientes apresentaram efeitos adversos ao suplemento, no entanto, sem necessidade de suspensão. O triglicéride de cadeia média não reduziu o quoeficiente respiratório, no entanto melhorou a proporção de carboidratos e lipídios, contribuindo para a melhora do aproveitamento energético. / Food intake reduction is frequent during decompensation of heart failure, when basal energy expenditure increases. In addition, medium chain triglycerides are used as energy supplementation increases caloric density of food, contributing to energy metabolism of patients with heart failure. The objective was to evaluate the effect of supplementation of medium chain triglycerides on the respiratory coefficient in congestive heart failure and low food intake. We conducted a randomized open label study with 45 patients from 18 to 70 years old with decompensated congestive heart failure, ejection fraction < 0,45, without intravenous inotropic drugs, oral diet and body mass index < 25 kg/m2 for adults and <27 kg/m2 for the elderly Patients were randomly allocated to supplementation with medium chain triglycerides or control group. They were submitted to two measurements of VCO2 and VO2 by indirect calorimetry. Analysis of variance with repeated measures analyzes respiratory coefficient change and two-sided. P< 0,05 was significant. 75% of patients were identified in eutrophic by body mass index, but these, 67% were diagnosed with calorie malnutrition and 65% with protein calorie malnutrition when analyzed and classified by skinfolds measures. Adequate proportion of carbohydrates and lipids increased from 9,5% to 57% of patients with 236,7 ± 95,0 kcal/d of medium chain triglycerides (P<0,001). Caloric intake increased from 1966,3 ± 643,3 kcal/d to 2202,7 ± 708,4 kcal/d in the medium chain triglycerides group and remained 1960,7 ± 702,6 kcal/d in control group. There was not a significant respiratory coefficient variation (medium chain triglycerides group +0,4%; control group: +2,5%; P=0,458). Four patients presented adverse effects with medium chain triglycerides; however, without requirement of withdrawal. Medium chain triglycerides did not reduce respiratory coefficient, however they improved carbohydrates and lipids proportion, contributing to improvement of energy utilization.

O objetivo desta tese é avaliar a expressão do miRNA-423-5p, em diferentes sítios, em modelo experimental de remodelamento cardíaco após insulto isquêmico em ratos. Os animais foram randomizados em grupos SHAM (cirurgia sem oclusão da artéria coronária descendente anterior esquerda) ou IAM (cirurgia com ligadura da artéria coronária descendente anterior esquerda) e acompanhados por 1, 7, 28 e 90 dias. Após o tempo de seguimento, os animais foram submetidos ao ecocardiograma e eutanasiados. Foi retirado sangue do plexo retroorbital, sangue venoso e arterial e coletado tecido do músculo gastrocnêmio e do ventrículo esquerdo separando as áreas remota (REM), infartada (INF) e peri-infartada (PERI). A partir da homogeneização dos tecidos, foi realizada a extração de miRNA e sua expressão quantificada pelo método de PCR em tempo real. Também foi mensurado os níveis plasmáticos do peptídeo natriurético cerebral (BNP). Os dados foram analisados pela teste de ANOVA de uma e duas vias e correlações através do programa estatístico SPSS 21.0. Quanto a caracterização do modelo utilizado, podemos verificar que a fração de ejeção do ventrículo esquerdo dos ratos IAM foram menores que os do grupo SHAM e os percentuais de área acinética foram iguais em todos os grupos IAM, como esperado. Também observamos que o miRNA-423-5p é expresso no coração, nos diferentes segmentos analisados, apresentando variação significativa nos tempos avaliados, correlacionado-se positivamente com o tamanho do infarto e negativamente com a fração de ejeção do ventrículo esquerdo. Diante deste cenário, nossos achados solidificam o conceito de que a expressão do miRNA-423-p se altera ao longo do tempo após insulto isquêmico e pode ter papel relevante no remodelamento cardíaco de origem isquêmica. / The objective of this project was to evaluate the expression of miRNA-423-5p in an experimental model of cardiac remodeling after ischemic injury in rats. Animals were randomized to SHAM group (surgery without occlusion of the left anterior descending coronary artery) or acute myocardial infaction (AMI) group (surgery with ligation of the left anterior descending coronary artery) and followed for 1, 7, 28 and 90 days. After the follow-up period, the animals were submitted to echocardiography and euthanized. Blood from the retroorbital plexus, venous and arterial blood was collected; and gastrocnemius and left ventricle tissue was collected, separating the remote (REM), infarcted (INF) and peri-infarcted (PERI) areas. From the homogenization of tissues, miRNA was extracted and its expression quantified by real-time PCR. Plasma levels of brain natriuretic peptide (BNP) were also measured by ELISA. Data were analyzed by one-way and two-way ANOVA and coefficient correlations were calculated using the statistical package SPSS 21.0. Regarding the experimental model, we could verify that the left ventricular ejection fraction of the AMI rats were reduced compared to the SHAM group and the percentages of akinetic area were the same in all AMI groups, as expected. We also observed that miRNA-423-5p is expressed in the heart in the different segments analyzed, showing significant variation in the different periodos that were evaluated, is positively correlated with infarct size and negatively with left ventricular ejection fraction. In this scenario, our findings solidify the concept that miRNA-423-p expression changes over time after an ischemic insult and may play a relevant role in the cardiac remodeling of ischemic origin.

Background: The burden of non-communicable diseases including cardiovascular diseases such as heart failure in Africa is rising rapidly, and they are now recognised as a significant cause of morbidity and mortality in the continent. Heart failure causes significant multidimensional impact (physical, social, psychological and spiritual), even with the advent of medicines that offer mortality benefit. Comprehensive care for heart failure must include palliative care that addresses multidimensional needs in line with patient-centered care. However, most research on heart failure in Africa has not explored these multidimensional needs from the patients’ perspective, and palliative care is still seen as being for those with cancer and HIV/AIDS. Aims: To understand the multidimensional experiences, needs, and use of services by patients with heart failure during their disease trajectory. To understand health care professionals’ perceptions of patients’ needs, the care required and the availability of services for patients with advanced heart failure in Uganda. Methods: A total of 48 face to face qualitative longitudinal interviews (36-patient alone, 4 paired-patient and family carer, 8 with bereaved carers), were conducted with 21 patients with stage 3 or 4 heart failure being treated in Mulago Hospital and some of their family carers. Patient interviews were followed by the administration of the African Palliative Care Association African Palliative Outcome Scale supplemented with the broader symptom assessment tool the POS-S. Patients were interviewed during the time of hospitalisation when the researcher first made contact with them, and were followed up monthly by phone. Longitudinal interviews were conducted at 3 and 6 months after the first interview if their clinical condition remained stable, and earlier if there were major concerns or changes in their multidimensional experiences. Eight single interviews were conducted with health professionals (5 doctors, 2 nurses and 1 social worker) involved in the care of the patients. All interviews were audio recorded, and those of the health professionals transcribed verbatim, those of the patients were first translated to English and transcribed and all were exported into QSR Nvivo software version 10 for analysis. Principles from Charmaz’s grounded theory (line by line coding, focused coding, constant comparison and theoretical coding) were employed for analysis. Findings: The patients’ experience was that of learning to live with the unknown in a life dominated by symptoms despite, and because of, treatments. The impact of the various symptoms limited physical performance leading to multiple losses. Presence of a high level of health illiteracy, lack of information on their illness coupled with a high reliance on local cultural beliefs to make health decisions, led to the following: delayed recognition of illness and seeking of care; inappropriate self- care and poor adherence to medications; poor understanding of illness and its prognosis; unrealistic expectations of treatment; and inappropriate choices of where to seek care. Patients were often faced with health system challenges that contributed to late diagnosis and exacerbated the problem of poor adherence to treatment because of lack of medicines and lack of information. The illness impact was also observed in the social, psychological and spiritual domains of patients’ lives causing anxiety and worry, isolation, rejection and stigma, spiritual pain and spiritual growth. Patients expressed the need for normal functioning, information, to be in control and to be facilitated to cope and adapt to the unknown. Patients employed different mechanisms of coping and adaptation, with hope being central in coping as they tried to live with the unknown. Patients suggested changes to the health system and in the conduct of health professionals to improve future care. Health professionals were able to recognise the multidimensional impact of the illness on the patients, but the details of the concerns tended to differ for the patients and health professionals. Health professionals’ proposals on improving care tended to emphasise interventions that would improve physical care as opposed to the other dimensions. Conclusion: This is the first qualitative longitudinal research in Uganda that has explored the experiences of patients with advanced heart failure to gain an understanding of their needs and concerns from their perspective over the course of their illness. Many concerns such as a lack of information, challenges with coping, the symptom experience and its impact on function and the psychological, social and spiritual aspects of their lives are enduring in literature. However, this study also identified other concerns less common in the literature that could have led to a unique illness experience. These included: health system challenges; the impact of culture; beliefs and poverty; and a high level of health illiteracy.

Background: Cardiovascular disease continues to remain a leading cause of morbidity and mortality in both developing and developed worlds. The sirtuin and urocortin systems are novel hormone systems in humans with an emerging role in cardiovascular physiology and pathophysiology. Through a series of studies, this thesis examines the cardiovascular effects of SRT2104 (a novel small molecule SIRT1 activator) in otherwise healthy cigarette smokers and in patients with type 2 diabetes mellitus, and of urocortins 2 and 3 in healthy volunteers and in patients with heart failure. Methods: Twenty-four otherwise healthy cigarette smokers and 15 subjects with stable type 2 diabetes participated in a randomised, double blind, placebo controlled, crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, markers of platelet and monocyte activation and pulse wave analysis and velocity were measured at baseline and the end of each treatment period together with an assessment of forearm blood flow during intra-arterial bradykinin, acetylcholine and sodium nitroprusside infusions. The pharmacodynamic profile of urocortins 2 and 3 were assessed in 18 healthy male volunteers recruited into a series of randomised, double blind, placebo controlled, crossover studies. Bilateral forearm venous occlusion plethysmography was performed during incremental intra-arterial infusions of urocortin 2 (3.6-120 pmol/min), urocortin 3 (1.2-36 nmol/min) and substance P (2-8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole) and nitric oxide synthase (L-NG-monomethyl-arginine (L-NMMA)). Finally, 12 patients with stable heart failure (New York Heart Association (NYHA) II-IV) and 10 age- and sex-matched healthy volunteers were recruited to attend once each. Bilateral forearm arterial blood flow was measured using forearm venous occlusion plethysmography during incremental intra-arterial infusions of urocortin 2 (3.6-36 pmol/min), urocortin 3 (360-3600 pmol/min) and substance P (2-8 pmol/min). Results: SRT2104 was safe and well tolerated in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus. There were no significant differences in fibrinolytic or blood flow parameters between placebo and SRT2014. Treatment with SRT2104 was associated with a significant reduction in augmentation pressure (P=0.0273) and a trend towards improvement in the augmentation index (AIx) and corrected augmentation index (0.10 > P > 0.05 for both) without significant changes in pulse wave velocity (PWV) and time to wave reflection (Tr) (P > 0.05). Administration of SRT2104 had a favourable effect on lipid profile in otherwise healthy cigarette smokers in comparison to placebo. Urocortins 2 and 3 evoked arterial vasodilatation (P < 0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L-NMMA reduced vasodilatation to substance P and urocortin 2 (P≤0.001 for both) but had little effect on urocortin 3 (P > 0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P > 0.05 for all). In the presence of all three inhibitors, urocortin 2- and urocortin 3-induced vasodilatation were attenuated (P < 0.001 for all) to a greater extent than with L-NMMA alone (P≤0.005). The vasodilatory effects of urocortins 2 and 3 were preserved in patients with heart failure. Conclusion: Activation of SIRT1 through SRT2104 improved lipid profile but did not produce demonstrable differences in vascular or platelet function with some effect on measures of arterial stiffness. Urocortins 2 and 3 appear to be potent arterial vasodilators whose vasomotor responses remained preserved in patients with heart failure and were at least partly mediated via the endothelium. Both hormone systems hold potential in their role in cardiovascular disease in man but require further studies to help translate findings of this thesis to clinical practice.

Identifying people with advanced illnesses whose health is deteriorating, assessing their needs and planning care proactively with them are healthcare priorities given the demographic trend of ageing populations in the UK and internationally. Over the past 10 years (2004-2014), I have led a series of research studies that have made an important academic contribution to improving palliative care services for patients with heart disease and advanced multimorbidity. My first paper reported secondary analysis of data generated from a qualitative study of the illness and care experiences of patients with advanced heart failure. This work used innovative, qualitative research methods to explore and understand patient, carer and health professional perspectives over time. My second study then evaluated whether health and social care services were configured and delivered in response to the needs of people with heart failure and their families. This led me to recommend an anticipatory care framework which integrated a palliative care approach with other aspects of treatment and care. Around this time, advance care planning (planning ahead to facilitate end-of-life care aligned with people’s goals and preferences) was being strongly advocated by NHS health policy makers despite limited research in the UK. For my third study, I evaluated an evidence-based, educational intervention for general practitioners while also exploring barriers and facilitators to advance care planning in primary care for patients with cancer or other advanced conditions. It was becoming increasingly clear that failure to identify people with deteriorating health and a high risk of dying in a timely way was a major barrier to more effective palliative care. The problem was greatest for patients with non-malignant conditions whose illness trajectory is much less easy to predict than in cancer populations. I therefore started to research and develop a new clinical tool designed to prompt early, proactive patient identification in routine clinical practice – the Supportive and Palliative Care Indicators Tool (SPICT). My fourth research paper reported an evaluation of the SPICT in a mixed-methods study in a large tertiary care hospital. The SPICT was then used to identify people with multimorbidity for my fifth study, a longitudinal exploration of patient and carer experiences of hospital admission and ongoing community care. In my final paper, I drew on my previous research and combined this with well-developed approaches to timely identification and effective communication. I described the design of a successful pilot randomised trial of future care planning with people who had advanced heart disease and their carers. This thesis presents a critical review of these six research studies setting them in context and demonstrating the impact they have had in ensuring that high quality research evidence informs current and future developments in palliative care policy and clinical practice.

The development and function of the heart is governed by a conserved set of transcription factors (TFs) that regulate gene expression in a cell-type, time point and stimulus driven manner. Of these core cardiac TFs, the most ubiquitously expressed is the zinc finger protein GATA4. In cardiomyocytes, GATA4 is central to proliferation, differentiation, hypertrophy and induction of pro-survival pathways. In cardiac endothelial cells, it is required for valve and septal development, although the exact mechanisms remain unclear. To regulate such a wide array of functions in a spatially and temporally controlled manner, GATA4 interacts with specific protein partners, the majority of whom have been identified in cardiomyocytes. However, a complete understanding of the protein interactome of GATA4, particularly in cardiac endothelial cells, has not yet been achieved. Using a mass spectrometry-based approach, we have identified a series of novel GATA4 interacting partners in cardiac endothelial cells. 3xFlag GATA4 was stably overexpressed via retroviral transduction in the TC13 cardiac endothelial precursor cell line, immunoprecipitated from nuclear protein extracts and sent for HPLC-ESI-MS/MS. Several novel GATA4 interacting partners were identified including the chaperone protein Heat Shock Protein 70 (HSP70), the inducible orphan nuclear receptor Nerve Growth Factor 1β (NGFIβ, NUR77) and the Drosophila-Binding/Human Splicing protein family members Non-POU Domain Containing Octamer Binding Protein (NONO) and Paraspeckle 1 (PSPC1). Chapter 1 discusses the interaction between GATA4 and HSP70 and its role in cardiomyocyte survival upon exposure to chemotherapeutic agent Doxorubicin (DOX). HSP70 binds directly to GATA4, preventing DOX-mediated cleavage and degradation by Caspase-1, cardiomyocyte cell death and heart failure. Chapter 2 focuses on the cooperative interaction between GATA4 and NUR77 in cardiac microvascular endothelial cells and its central role in myocardial angiogenesis in response to pressure overload. The GATA4-NUR77 complex transactivates the promoter of Angiopoietin-Like 7 (ANGPTL7), a secreted pro-angiogenic chemotactic factor, triggering endothelial cell proliferation and tube formation in cultured cardiac endothelial cells and increasing myocardial capillary density in vivo. Chapter 3 discusses the interaction between GATA4 and the DBHS proteins NONO and PSPC1 in the regulation of cardiac development. These proteins play opposing roles when bound to GATA4 as PSPC1 enhances GATA4 activation of critical cardiac promoter targets and NONO acts as a rheostat to repress GATA4 activity. In vivo, loss of NONO results in left ventricular non-compaction consistent with humans with loss-of-function mutations. However, simultaneous Gata4 haploinsufficiency partially rescues this phenotype. Together, this data identifies multiple novel cell type and time point specific GATA4 protein partners and sheds light on GATA4 regulatory mechanisms in cardiac development and disease.

The pathogenesis of heart failure (HF) involves compensatory left ventricular hypertrophy. Reactive oxygen species (ROS) are elevated in HF and mediate myocardial hypertrophy. ROS also mediate formation of lipid peroxidation byproducts, yet little is known about their role in promoting hypertrophy. One lipid peroxidation byproduct, 4-hydroxy-trans-2-nonenal (HNE) is a reactive aldehyde that forms covalent adducts on proteins. HNE levels are also elevated in HF and may mediate hypertrophy via HNE-adduct formation. LKB1 - a tumor suppressor protein - regulates cellular growth through activation of the downstream kinase AMPK. Activation of AMPK suppresses functions that consume ATP and simultaneously activates processes to generate energy. The LKB1 protein is inhibited by oxidants, but whether this results in myocardial hypertrophy is unclear. I hypothesized that HNE can directly promote cardiac hypertrophy via the modification of LKB1. In HEK293T cells I observed that HNE adducts inhibit activity of LKB1 through direct oxidative modification. Mutation of LKB1 Lys-96 or Lys-97 resulted in less HNE-LKB1 adduct formation. Mutation of LKB1 Lys-97 prevented the inhibitory effect of HNE, suggesting that HNE-adduction at this residue is sufficient to inhibit LKB1. In cardiomyocytes HNE inhibited both LKB1 and AMPK, increased phosphorylation of mTOR, p70S6K, and S6K, and increased protein synthesis. HNE also activated Erk1/2, which contributed to S6K activation but was not required for cellular growth. Hypertrophic S6K activation was dependent on mTOR. Mice fed a high-fat high-sucrose (HFHS) diet have myocardial hypertrophy that can be prevented by antioxidants. Hearts of HFHS mice have HNE-LKB1 adducts, inhibited LKB1 activity, yet no change in AMPK activation. Mice lacking aldehyde dehydrogenase 2 (ALDH2), an enzyme involved in HNE detoxification, have increased myocardial hypertrophy when fed HFHS diet yet have increased LKB1 activity. In summary HNE directly causes hypertrophy in cardiomyocytes. This occurs through inhibition of LKB1 and in part through Erk1/2 activation. In HFHS-fed mice HNE-LKB1 adduct formation is associated with decreased LKB1 activity. Impairing detoxification of reactive aldehydes in the ALDH2-KO mice is sufficient to increase myocardial hypertrophy, but this appears to be independent of LKB1. This study demonstrates a novel mechanism of cardiac hypertrophy caused by reactive aldehydes.