<b><u>Introduction:</b></u> Some cancer survivors are known to have an elevated risk of morbidity and mortality from cardiovascular disease. An important cause of this elevated risk is recognised to be irradiation of normal tissues during radiotherapy received as part of cancer therapy. There are substantial difficulties in studying radiation-related cardiovascular disease (RRCD). The reasons for this include the complexities of measuring radiation normal tissue doses retrospectively and the prolonged latencies of many of the cardiovascular endpoints. A variety of complimentary research methodologies can help provide additional knowledge to guide the appropriate management of patients treated in the past and of new patients in the future. <b><u>Methods:</b></u> 1) A cohort study of mortality from circulatory disease in the nationwide British Childhood Cancer Survivor Study (BCCSS). 2) A case-control study of valvular heart disease (VHD) in Dutch Hodgkin lymphoma (HL) survivors, including retrospective radiation dosimetry to estimate the radiation dose to heart valves. 3) A dosimetric study of cardiovascular radiation doses in patients entered into the UK NCRI Lymphoma Study Group RAPID trial, including predictions of 15-year cardiac mortality using innovative methods. 4) A modelling study to predict mean whole heart dose (MWHD) from involved field radiotherapy (IFRT) for HL using anatomical measures. 5) A prospective study using cardiovascular magnetic resonance (CMR) imaging to characterise the heart in women receiving radiotherapy for breast cancer. <b><u>Results:</b></u> 1) The risks of all types of circulatory mortality are elevated in survivors of childhood cancer. The absolute excess risks continue to increase 40+ years following diagnosis. The risk of death from cardiomyopathy and heart failure increased substantially with the introduction of anthracycline chemotherapy. There is no evidence of a reduction in risk of circulatory mortality in more recent eras of diagnosis. 2) There is a strong relationship between estimated radiation dose to the affected heart valve and the risk of subsequent VHD (p<0.001). This effect was modelled to allow prediction of the risk of VHD. 3) A proportion of patients treated with IFRT received a substantial cardiac radiation dose (MWHD = 8.8 Gy, SD = 5.6) but, on average, the predicted 15-year cardiac mortality following treatment is low (absolute risk 0.2%, range 0.0 to 2.7%). 4) It is possible to estimate the mean whole heart dose from IFRT prior to detailed radiotherapy planning based on pre-treatment diagnostic imaging to an accuracy of 5-6% of the prescribed dose. 5) Although women received low cardiac doses (MWHD = 1.5 Gy, SD = 0.8) and have a low predicted risk of cardiac radiation-related morbidity and mortality, there is some evidence of subclinical effects on strain and strain rate imaging of the anterior portions of the left ventricle that receive the highest radiation dose. <b><u>Conclusions:</b></u> Using a variety of methods these studies have all succeeded in adding to knowledge about the nature, magnitude and timing of RRCD. This knowledge can be used to help the future management of cancer patients. In addition, each of the studies has natural and planned extensions and will continue to contribute further knowledge into the future.

This thesis develops biophysically-based data-driven mathematical models of intracellular calciumdynamics in ventricularmyocytes for both normal and genetically modified mouse hearts, based on species- and temperature-consistent experimental data. The models were subsequently applied to quantitatively examine the changes in calcium dynamics in mice with cardiomyocyte-specific knockout (KO) of the cardiac sarco/endoplasmic reticulum ATPase (SERCA2) gene, to determine the contributing mechanisms which underlie the ultimate development of heart failure in these animals. In Chapter 1, with emphasis on calcium dynamics and calcium regulation in heart failure, an overview of cardiac electrophysiology, excitation-contraction coupling and mathematical models of cardiac electrophysiology is provided. In Chapter 2, models of calcium dynamics in the ventricular myocytes from the C57BL/6 mouse heart at a physiological temperature is developed and validated based on species- and temperature-consistent measurements. In Chapter 3, the C57BL/6 model framework is re-parameterised to experimental data from the control and SERCA2 KO mice at 4 weeks after gene deletion. The models are then used to quantitatively characterise changes in calcium dynamics in the KO animals and the role of the compensatory mechanisms. In Chapter 4, the model framework is extended to include differential distributions of ion channels in the sarcolemma and the calcium dynamics in the sub-sarcolemmal space, with parameters in these sub-components fitted to experimentally measured calcium dynamics from the control and KO cardiomyocytes at 7-week after gene deletion. Finally in Chapter 5, conclusions are drawn, the limitations of this study are discussed, and the future extensions to this study are described.

Next-generation sequencing methods now allow rapid and cost-effective sequencing of DNA on a scale not previously possible. This offers great opportunities for the research of Mendelian disorders, but also significant challenges. The sequencing of exomes, or whole genomes, has emerged as a powerful clinical research tool, with targeted gene analyses generally being preferred in the clinical diagnostic setting. These methods have been employed here with the aim of identifying novel genetic causes of inherited heart disorders and to gain insights into the utility and limitations of these techniques for clinical diagnosis in these disorders. Data produced from the introduction of a targeted multi-gene next-generation sequencing test into clinical practice has been studied. Variation within the mitochondrial genome has been analysed to assess the importance of mitochondrial DNA variants in patients with hypertrophic cardiomyopathy. The m.4300A>G mutation is identified as an important cause of this disorder, with other previously cardiomyopathy-associated and novel variants also identified. Such multi-gene tests can facilitate interpretable and phenotype-relevant results, but at the expense of limiting more extensive data acquisition. Whole-genome sequencing has been performed in five families with different autosomal dominant inherited heart disease phenotypes of unknown genetic aetiology. In two of these likely pathogenic variants were identified, one in the gene encoding titin (TTN) and the other in the calcium channel subunit gene CACNA1C. In vitro studies were undertaken to support the pathogenicity of the TTN variant and understand the functional effects of this. In the other three families either multiple candidate gene variants were identified or no clear candidate variant was identified. This highlights the difficulties in interpreting these results, even in carefully selected families. Overall, although the research benefits of exome or genome studies are evident, the interpretation and validation of genetic variant data produced remains highly challenging for clinical diagnosis.

Cardiovascular disease is the leading cause of death in the United States. Chronic short sleep duration is also a significant public health problem and has been linked to several markers and outcomes of cardiovascular disease. To date, inconsistency of assessments of sleep duration and insufficiency, use of covariates, and cardiovascular disease measurement across studies limits strong conclusions about the relationship between sleep duration, sleep insufficiency, and cardiovascular disease. The current study examined the association between sleep duration, sleep insufficiency, and a marker of preclinical coronary heart disease (i.e., carotid intima-media thickness) in a community sample using a cross-sectional design. Some evidence for a relationship between sleep duration and cIMT was found, with longer sleep duration predicting higher cIMT in some segments. Additionally, the interaction between sleep duration and sleep insufficiency was significant. However, neither of these effects were significant after adjusting for age and in some cases race/ethnicity, suggesting demographics may explain this association. Actigraphy and sleep diary duration assessments demonstrated significantly different correlations with cIMT in some segments, suggesting the nature of the assessment method may impact the strength or direction of the relationship between sleep duration and cIMT. Limitations and future directions are discussed.

Cardiovascular disease (CVD) worldwide has grown exponentially in the last two decades and while sub-Saharan Africa (SSA) has been grappling with the crippling effects of epidemic infectious diseases such as HIV/AIDS and malaria, cardiovascular disease is now emerging as a grievous concern. Research and resources have largely been directed toward understanding and curtailing infectious diseases in the African continent. But as the risk of cardiovascular disease reaching endemic proportions in sub-Saharan Africa becomes more evident, research is critically needed in order to understand how to manage it and more importantly to direct the development and implementations of culturally relevant prevention strategies. The risks and effects of CVD are present in both men and women across the globe, but there are differences in their occurrence based on gender that are worth considering. Women in sub-Saharan Africa, who are already burdened with the disadvantage of access to health care by virtue of their gender alone, are likely to be most adversely affected by CVD. Socioeconomic status (SES), epidemiologic transition and urbanization, lifestyle changes, and gender-based violence are all factors implicated in the compounded risk for CVD among women in this region. To understand how women in a sub-Saharan region perceive CVD and its risk factors, this descriptive phenomenological study set out to answer the following research question: How do Kenyan women perceive the modifiable risk factors for CVD? Furthermore, how do they perceive its effects on their lives and their families? Two samples from central Kenya representing an urban and rural area were selected and interviewed in a focus group setting. A number of themes were extrapolated from the interviews. The modifiable risk factors were perceived to be independent of CVD. Diet modification and physical activity were found to be helpful in controlling these diseases but clear understanding on their effects on overall cardiovascular health was lacking. Cigarette smoking generated the least discussion because none of the women were smokers. The effects of having either hypertension or type two diabetes included financial cost, emotional burden on the women and their families, and the concern of losing a breadwinner from disease or illness. These results have implications in nursing practice, public health, primary care provision, and national and global policies. They also shed light on areas of potential consideration in prevention program design and implementation. Awareness, though felt by the women to be slowly gaining in Kenya, is key to disease prevention. There is limited research on this subject matter in SSA and more studies are needed to understand the scope and effects of CVD in this region.

D. Tech. (Food Service Management, Dept. of Hospitality, Faculty of Human Sciences)|cVaal University of Technology / Main Purpose of the study: To evaluate the impact of soy protein feeding intervention over a period of six months on the nutritional status of an elderly (≥60 years old) community of Sharpeville, in which poverty, household food security and malnutrition were prevalent. Methods: An experimental design that had no control group but a comparison between hypercholesterolaemic (HC) and normocholesterolaemic (NC) groups was used with 134 randomly selected elderly respondents. The first stage involved a baseline survey which determined the prevalence of risk factors for cardiovascular disease (CVD) and nutritional status among participants. Measurements included biochemical indices (serum lipids, vitamin B12, folate and homocysteine), anthropometry (weight, height and waist circumference) and dietary intake using 24h-recall and 7-day dietary diversity questionnaire. Socio-demographic information gathered from previous studies on the same subjects was used. The second stage was the preparation, formulation, and implementation of a nutrition education programme to assess its impact on nutrition knowledge after the nutrition education intervention. The nutrition education was conducted in two sections, namely an exploratory study and an experimental study. An exploratory study was conducted to assess the nutrition education needs of the elderly and was followed by the experimental study, which assessed nutrition knowledge before and after the intervention. The third stage was the implementation of the 10 grams soy protein daily feeding intervention for a period of six months and evaluation of its impact on risk factors for cardiovascular disease and on nutritional status. Sensory tests, compliance and the same measurements conducted at baseline were used at follow-up (feeding intervention). A comparison of the findings of the baseline study and follow-up study was conducted. Also to provide deeper insight into the effect of soy on the risk factors for CVD and nutritional status, respondents were further stratified into HC and NC groups based on their LDL-C levels at baseline study and results were also presented as such. The data analyses included descriptive statistics and t-tests on SPSS version 21.0. Results: From the baseline study, the dietary intake results revealed a poor dietary intake which contributed to inadequate estimated average requirements (EAR) and adequate intakes (AI) of nutrients. A mainly carbohydrate-based diet was consumed with minimal intake of dairy and legumes despite a medium dietary diversity score. The anthropometric indices at baseline indicated over-nutrition based on the reported waist circumference 97.32±10.32 (80.6%) above substantial risk of CDL, obesity (75.3%) and hypertension (56.7%), with the highest percentages for both waist circumference of substantial risk and overweight/obesity found among the women (80.9% and 79.9% respectively) and for hypertension among the men (79.1%). For the biochemical results at baseline, the prevalence of risk factors for CVD was observed as abnormal mean serum lipids such as LDL-cholesterol (3.6±1.1), HDL-cholesterol (0.73±0.4), total cholesterol:HDL-cholesterol ratio (7.9±2.9), triglyceride:HDL-cholesterol ratio (2.7±2.1) and homocysteine (17.1±9.2) in the total group. The women had high TC (5.2±1.1) indicating borderline risk of CVD as compared with men who had lower TC (4.5±0.8) and this was significantly different (p=0.049). The nutrition education programme was effective in increasing knowledge with an improvement of 14.5 percent from pre- (62.3%) to post-test (76.8%) for the total group which was statistically significant (p=0.000). The results for the soy protein feeding intervention, the dietary intake for the total group indicated a statistically significant decrease in energy intake (p=0.001), by about 20.4 percent form baseline to follow-up, while energy intake at baseline was already below the EAR. Also a statistically significant decrease was seen from baseline to follow-up for total dietary fat (p=0.004), cholesterol (p=0.008) and animal protein (p=0.000), with a statistically significant increase only on dietary folate (p=0.001) and iron (0.001). These dietary changes were also observed for the HC and NC groups after the intervention with only fat not decreasing significantly for the HC group. For the anthropometry indices, and hypertension no significant impact after the intervention for the total group and also for the HC and NC groups was observed. The biochemical results indicated a beneficial effect of the soy-based products on the following serum lipids: a significant improvement in LDL-C (p=0.000), HDL-C (p=0.000) and TC:HDL ratio (p=0.000) for the HC group while only TC:HDL ratio showed a significant improvement for the NC group after the intervention. However, high risk factors for CVD in this elderly group were still observed, with a significant decrease after the intervention of serum folate (p=0.000) below the recommended level and a significant increase in homocysteine (p=0.000) above the recommended level. Significant differences between the HC and NC groups were seen in TC, LDL-C, LDL:HDL-C ratio and TC:HDL-C ratio at the beginning of the intervention (baseline). However, at the end of the intervention (follow-up), significant differences were observed only in TC, LDL-C and homocysteine. Conclusion: Although the energy intake reduced significantly, only three of the micro-nutrients (pantothenate, Niacin and selenium) had a significant decrease between baseline and follow-up. Therefore the nutritional status of these elderly was not affected as it was also observed that there was no significant impact on anthropometric indices that took place. However this intervention had a significant impact on iron intake, which was one of the deficiencies identified amongst this elderly people from previous study. Also the nutrition education and a daily consumption of at least 10g of soy had a significant beneficial effect on LDL-C, HDL-C and TC:HDL ratio for the HC groups, thus reducing risk of CVD. Although soy had a beneficial effect on blood lipid profile no effect on hypertension was observed. The guideline of a 25g intake of soy should be encouraged as recommended by FDA as an effective cholesterol-lowering food item.

Introdução: O aumento na prevalência das doenças cardiovasculares alerta para a necessidade de estratégias eficazes e de baixo custo como medidas preventivas na redução dos fatores de risco, morbidades e óbitos decorrentes de eventos coronarianos. As modificações no estilo de vida são as primeiras alternativas a serem adotadas. Nesse contexto, a dieta ocupa lugar de destaque e os benefícios dos ácidos graxos poli-insaturados ômega-3 na saúde cardiovascular são amplamente reconhecidos. As doenças cardiovasculares são influenciadas por diversos fatores de risco e o desequilíbrio na concentração plasmática das lipoproteínas é um fator de risco independente no desenvolvimento da doença cardiovascular aterosclerótica. Entretanto, há evidências de que as subfrações lipoproteicas podem influenciar o risco cardiovascular de maneira diferenciada, dependendo das características físico-químicas e funcionalidade de cada partícula. O desenvolvimento de novas técnicas, capazes de identificar esses parâmetros, tem sido foco de grande interesse científico. Objetivo: Avaliar o papel do ômega-3 sobre as características físico-químicas da LDL e HDL e possível associação entre medidas Z-scan e marcadores cardiometabólicos em indivíduos adultos. Metodologia: A partir de uma subamostra do estudo CARDIONUTRI (estudo clínico, randomizado, controlado e duplo cego com seguimento de 8 semanas) foram selecionados 36 indivíduos do Grupo Ômega-3 (3,0g/dia de óleo de peixe - 1,11g de EPA + 0,69g de DHA) e 27 do Grupo Placebo (3,0g/dia de óleo mineral). Foram monitorados o perfil clínico, antecedentes familiares, consumo alimentar, atividade física e antropometria. Amostras de sangue foram coletadas após 12 horas de jejum para avaliação das concentrações plasmáticas de CT, TAG, HDL-C, LDL-C, APOAI, APOB, PON1 e glicose. O tamanho da HDL e LDL foi analisado pelo método padronizado Lipoprint®. O conteúdo de LDL(-) foi determinado por ELISA. As medidas Z-scan foram determinadas por meio da difusividade térmica e absorção linear da LDL (1,0 mg/dL de proteína), isolada por ultracentrifugação. Todos as variáveis do estudo foram avaliadas no momento basal e após 8 semanas de intervenção. A adesão à intervenção foi monitorada pela contagem de cápsulas e percentual dos ácidos graxos plasmáticos. Para avaliar a associação das medidas Z-Scan aos marcadores cardiometabólicos, os dados obtidos no momento basal foram submetidos à Análise de Componentes Principais. Resultados: A idade média dos participantes do estudo foi de 51,5 (10,5) anos. A suplementação com ômega-3 promoveu redução significativa de CT, TAG, não-HDL, HDLPEQUENA e LDL(-), além de aumento significativo de HDL-C e HDLGRANDE. O ômega-3 foi mais eficaz na redução dos TAG (29,2 por cento ) quando comparado ao placebo (2,9 por cento ). O Grupo Ômega-3 apresentou aumento de HDLGRANDE (16,9 por cento ) e redução de HDLPEQUENA (-16,3 por cento ) ao final da intervenção, com diferença significativa quando comparado ao Grupo Placebo que apresentou redução de HDLGRANDE (-4,8 por cento ) e aumento de HDLPEQUENA (17,7 por cento ). Não foram observadas diferenças nas medidas Z-scan após a intervenção, porém as medidas se associaram positivamente a Componentes Principais com padrões cardioprotetores da amostra e negativamente a padrões aterogênicos. Conclusão: O ômega-3 demonstrou efeito positivo no perfil lipídico e propriedades aterogênicas das subfrações lipoproteicas. A suplementação com ômega-3 não modificou as medidas Z-scan, no entanto, a técnica demonstrou ser uma ferramenta capaz de se associar a padrões aterogênicos e antiaterogênicos monitorados no presente estudo / Introduction: The increased of cardiovascular disease prevalence draws attention to the need to adopt effective and inexpensive strategies as preventive measures to reduce risk factors, morbidity and deaths from coronary events. Lifestyle modification is indicated as first alternative to be adopted. In this context the diet stands out and omega-3 polyunsaturated fatty acids benefits on cardiovascular health are largely recognized. Cardiovascular diseases are influenced by several risk factors and the plasma imbalance lipoprotein is considered a crucial independent risk factor. However, there is evidence of the influence of lipoprotein subfractions in cardiovascular risk, based on the physicochemical characteristics of these particles. The development of new techniques able to identify those parameters has been the focus of great scientific interest. Objective: To evaluate the role of omega-3 on HDL and LDL physicochemical characteristics and possible association between Z-scan measurements and cardiometabolic markers in adults. Methods: From a subsample of the study CARDIONUTRI (clinical, randomized, controlled, double blind study with 8-week follow-up) were selected 36 individuals from the Omega-3 Group (3.0g/day of fish oil - 1,11g EPA + 0.69g DHA) and 27 individuals from the Placebo Group (3.0g/day of mineral oil). The clinical profile, family history, dietary intake, physical activity and anthropometry were monitored. Blood samples were collected after 12 hours of fasting to evaluate plasma concentrations of TC, TAG, HDL-C, LDL-C, APOAI, APOB, PON1 and glucose. The HDL and LDL size was analyzed by the standard method Lipoprint®. The levels of LDL (-) was determined by ELISA. The Z-scan measurements were determined by thermal diffusivity and linear absorption of LDL (1.0 mg / dL protein) isolated by ultracentrifugation. All study variables were evaluated at baseline and after 8 weeks of intervention. The intervention accession was monitored by capsule count and percentage of plasma fatty acids. To evaluate the association of the Z-Scan measurements to cardiometabolic markers, the data collected at baseline were subjected to Principal Component Analysis. Results: The average age of individuals were 51.5 (10.5) years. The omega-3 supplementation promoted a significant decreased of TC, TAG, non-HDL, small HDL and LDL(-), and significantly increased HDL-C and large HDL. The omega-3 was more effective in reducing the TAG (29.2 per cent ) when compared to placebo (2.9 per cent ). The Omega-3 Group increased large HDL (16.9 per cent ) and decreased small HDL (-16.3 per cent ) after the intervention, with significant difference when compared to the Placebo Group that decreased large HDL (-4.8 per cent ) and increased small HDL (17.7 per cent ). There were no differences in Z-scan measurements with the interventions, but were observed positively associated the Z-scan measurements with the anti-atherogenic sample patterns and negatively associated with atherogenic sample patterns when the sample was standardized from the Principal Components Analysis. Conclusion: The omega-3 demonstrated positive effect on the lipid profile and atherogenic lipoprotein subfractions. Supplementation with omega-3 did not modify the Z-scan measurements, however, the technique proved to be a tool that can be associated with atherogenic and anti-atherogenic sample patterns monitored in this study.

Introdução: A doença cardiovascular é a maior causa de mortalidade no mundo e o Brasil está entre os 10 países com maiores índices, principalmente entre homens com idade inferior a 70 anos. A alimentação é um fator de risco modificável, que pode influenciar a expressão gênica e a concentração de biomarcadores inflamatórios relacionados à obesidade e à aterosclerose. Objetivo: Este subestudo avaliou se uma intervenção nutricional baseada na alimentação habitual brasileira modifica a expressão de genes envolvidos com aterosclerose e a concentração plasmática de biomarcadores inflamatórios, na prevenção secundária para doença cardiovascular. Métodos: Foram selecionados seis pacientes do sexo masculino, idade igual ou superior a 45 anos, obesos e com circunferência abdominal elevada, em acompanhamento do plano alimentar quali-quantitativo por 6 meses, para determinação da concentração plasmática de biomarcadores inflamatórios (interleucina (IL)-1, IL-6, IL-8, IL-10, IL-12, fator de necrose tumoral alfa, proteína C reativa e adiponectina) e expressão de 84 genes relacionados à aterosclerose em células totais do sangue periférico, bem como perfil lipídico, glicemia, insulinemia, ácidos graxos plasmáticos, dados sobre ingestão alimentar (recordatório de 24 horas) e antropometria (peso, estatura e circunferência da cintura), nas visitas inicial e final. Resultados: Após a intervenção nutricional, os pacientes reduziram o peso, a circunferência abdominal, o índice Homeostasis Model Assessment para resistência à insulina (p= 0,046) e a contagem global de leucócitos (p= 0,046) e de neutrófilos (p= 0,028). Não houve alteração significativa na concentração plasmática dos biomarcadores inflamatórios, contudo, verificou-se aumento significativo na expressão dos genes Apo A1 (p= 0,011), ELN (p= 0,017) e IL4 (p= 0,037). Conclusão: Assim, o plano alimentar quali-quantitativo, composto de alimentos habituais brasileiros, não reduziu a concentração de biomarcadores inflamatórios, mas aumentou a expressão de três genes envolvidos com aterosclerose, em pacientes obesos, na prevenção secundária para doença cardiovascular / Introduction: Cardiovascular disease is the largest cause of mortality in the world and Brazil is among the 10 countries with the highest rates, especially among men under 70 years of age. Diet is a modifiable risk factor, which may influence the gene expression and concentration of inflammatory biomarkers related to obesity and atherosclerosis. Objective: This substudy evaluated whether a nutritional intervention based on the usual Brazilian diet modifies the expression of genes involved with atherosclerosis and the plasma concentration of inflammatory biomarkers in the secondary prevention for cardiovascular disease. Methods: Six male patients, aged 45 years or older, obese and with high waist circumference were selected, to follow a qualitative-quantitative food plan for 6 months, in order to determine the plasma concentration of inflammatory biomarkers (interleukin (IL) -1), IL-6, IL-8, IL-10, IL-12, tumor necrosis factor alpha, C-reactive protein and adiponectin) and expression of 84 atherosclerosis-related genes in total peripheral blood cells, as well as lipid profile, glycemia, insulinemia, plasma fatty acids, food intake data (24-hour recall) and anthropometry (weight, height and waist circumference) at the initial and final visits. Results: After nutritional intervention, patients reduced weight, waist circumference, Homeostasis Model Assessment index for insulin resistance (p = 0.046) and overall leukocyte count (p = 0.046) and neutrophils (p = 0.028). There was no significant modification in the plasma concentration of the inflammatory biomarkers. However, there was a significant increase in the expression of Apo A1 (p = 0.011), ELN (p = 0.017) and IL4 (p = 0.037) genes. Conclusion: Thus, the qualitative-quantitative food plan, composed of Brazilian usual foods, did not reduce the concentration of inflammatory biomarkers, but increased the expression of three genes involved with atherosclerosis in obese patients, in secondary prevention for cardiovascular disease

Introdução: A obesidade pode se constituir como fator de risco para o uso de contraceptivos hormonais, especialmente aqueles contendo estrogênios, devido a possíveis efeitos metabólicos indesejados. As alterações metabólicas decorrentes do uso do sistema intrauterino liberador de levonorgestrel (SIU-LNG) foram bem descritas em mulheres com peso normal, mas não em mulheres obesas. Objetivo: Avaliar o efeito do sistema intrauterino liberador de levonorgestrel (SIU-LNG) sobre marcadores ultrassonográficos e laboratoriais de risco metabólico e doença cardiovascular em mulheres obesas. Casuística e Métodos: Estudo clínico randomizado aberto avaliando 106 mulheres obesas (30,0 Kg/m2 e <40 Kg/m2), com idade entre 18 e 40 anos, sem outras comorbidades. As pacientes foram avaliadas antes do início da contracepção e após um ano, sendo realizada randomização simples, para uso de SIU-LNG ou método não hormonal (a paciente poderia escolher entre dispositivo intrauterino de cobre ou preservativo). Foram avaliados: evolução ponderal; circunferência da cintura; volume uterino e ovariano; insulinemia e glicemia de jejum; perfil lipídico; testosterona; sex hormone binding globulin (SHBG); hemograma; aspartato aminotransferase (AST), a alanina aminotransferase (ALT), a fosfatase alcalina e gama glutamil transferase; índice de rigidez da carótida e espessura íntima-média (EIM); dilatação mediada por fluxo da artéria braquial (DMF) e doença hepática gordurosa não alcoólica (DHGNA). Resultados: Nenhuma diferença estatística foi observada na dilatação mediada por fluxo da artéria braquial entre as mulheres em uso de SIU-LNG e métodos não hormonais em um ano de observação. Observou-se uma redução do volume ovariano (-0,5&177;2,6 vs. 0,7&177;2,6 cm3, p=0,03). A hemoglobina aumentou nas usuárias de SIU-LNG (0,4&177;0,8 vs. -0,1&177;0,8 g/dL, p=0,00) juntamente com o hematocrito (1,8&177;2,2 vs. -0,0&177;2,3 %, p=0,00). Não houve alteração do perfil lipídico, glicêmico, da função hepática e doença hepática gordurosa não alcoolica no grupo das usuárias de SIU-LNG e nem das usuárias de métodos não hormonal. Conclusão: Concluiu-se que o SIU-LNG não apresentou efeito metabólico desfavorável comparado a métodos não hormonais após um ano, em mulheres obesas grau I e II, sem outras comorbidades. / Background: Obesity may be a risk factor for the use of hormonal contraceptives, especially those containing estrogens, due to possible unwanted metabolic effects. The metabolic effects of levonorgestrel-releasing intrauterine system (LNG-IUS) have been studied in normal-weight women but not in obese women. Objective: To evaluate the effect of levonorgestrel-releasing intrauterine system on multiple ultrasonographic and laboratorial markers of metabolic and cardiovascular disease risk in obese women. Methods: A randomized clinical trial study evaluating 106 obese women ( 30.0 kg/m2 and <40 kg/m2), aged between 18 and 40 years with desire contraception, without other co-morbidities. Patients were evaluated before the start of contraception and after a year, made simple randomization to use of LNG-IUS or nonhormonal method (the patient could choose between copper intrauterine device or condom). Were evaluated: weight gain; waist circumference; uterine and ovarian volumes; insulinemia and fasting glucose; lipid profile; testosterone; sex hormone binding globulin (SHBG); hemogram; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and gamma glutamyl transferase; stiffness index and carotid intima-media thickness (IMT); flow-mediated brachial artery dilatation (FMD) and nonalcoholic fatty liver disease (NAFLD). Results: No statistical difference was observed in flow-mediated brachial artery among women using the LNG-IUS and non-hormonal methods in one year of observation dilation. There was a volume reduction (-0.5 &177; 2.6 vs. 0.7 &177; 2.6 cm3, p=0.03). Hemoglobin increased in users of LNG-IUS (0.4 &177; 0.8 vs. -0.1 &177; 0.8 g/dL, p=0.00) together with the hematocrit (1.8 &177; 2.2 vs. -0.0 &177; 2.3%, p=0.00). There was no change in lipid profile, glucose, liver function and nonalcoholic fatty liver disease in the group of users of the LNG-IUS or the users of non-hormonal methods. Conclusion: We conclude that the LNG-IUS showed no adverse metabolic effect compared to non-hormonal methods after one year in grade I and II obese women without other comorbidities.

Introdução: As doenças cardiovasculares são a principal causa de morte no Brasil e no mundo e apresentam importante contribuição para a carga global de doenças. A dieta tem sido considerada um dos determinantes primários do estado de saúde dos indivíduos, atuando na modulação dos fatores de risco metabólicos para doença cardiovascular. Objetivos: Desenvolver um modelo conceitual para a relação entre fatores de risco metabólicos e investigar sua associação com padrões de dieta de adultos e idosos residentes no município de São Paulo. Métodos: Estudo transversal de base populacional com amostra probabilística de adultos e idosos, residentes em área urbana do município de São Paulo, que participaram do Inquérito de Saúde do Município de São Paulo, realizado em duas fases entre os anos de 2008 e 2011 (estudo ISA Capital 2008). Na primeira fase do estudo, 1.102 adultos e idosos, de ambos os sexos, foram entrevistados no domicílio, por meio da aplicação de questionário estruturado e do recordatório alimentar de 24 horas. Na segunda fase, 642 indivíduos adultos e idosos foram reavaliados quanto ao consumo alimentar por meio da aplicação, por telefone, do segundo recordatório alimentar, e, destes, 592 participaram da coleta domiciliar de amostras de sangue venoso, da medição antropométrica e da aferição da pressão arterial por técnico de enfermagem. Os alimentos relatados em ambos os recordatórios foram agrupados segundo a similaridade do valor nutricional e hábitos alimentares da população, e corrigidos pela variância intrapessoal da ingestão por procedimentos estatísticos da plataforma online Multiple Source Method. Os grupos de alimentos foram analisados por meio de análise fatorial exploratória e confirmatória (manuscrito 1) e por modelos de equações estruturais exploratórios (manuscrito 3), a fim de obter os padrões de dieta. O modelo conceitual da relação entre os fatores de risco metabólicos (leptina sérica, proteína C-reativa de alta sensibilidade sérica, pressão arterial sistólica e diastólica, razão colesterol total/lipoproteína de alta densidade, razão triacilglicerol/lipoproteína de alta densidade, glicemia de jejum plasmática, circunferência da cintura e peso corporal) foi obtido por modelos de equações estruturais estratificados por sexo (manuscrito 2). Por fim, a associação dos padrões de dieta com o modelo conceitual proposto (manuscrito 3) foi investigada por modelos de equações estruturais exploratórios. Índices de qualidade de ajuste foram estimados para avaliar a adequação de todos os modelos. As análises foram realizadas no programa Mplus versão 6.12. Resultados: No manuscrito 1, a análise fatorial exploratória revelou a existência de dois padrões de dieta, os quais apresentaram boa qualidade de ajuste na análise fatorial confirmatória quando aplicados os pontos de corte de cargas fatoriais |0,25| na rotação oblíqua Promax. No manuscrito 2, a relação entre os fatores de risco metabólicos foi diferente entre os sexos. Nas mulheres, a leptina sérica apresentou efeitos indiretos e positivos, mediados pelo peso corporal e pela circunferência da cintura, em todos os fatores de risco avaliados. Já nos homens, a leptina sérica apresentou efeitos diretos e positivos sobre a proteína C-reativa de alta sensibilidade e efeitos indiretos e positivos (mediados pelo peso corporal e pela circunferência da cintura) sobre a razão triacilglicerol/lipoproteína de alta densidade, colesterol total/lipoproteína de alta densidade e glicemia de jejum plasmática. No manuscrito 3, foram obtidos três padrões de dieta, dos quais o Tradicional apresentou relação direta e negativa com a leptina sérica e relação indireta e negativa com o peso corporal e a circunferência da cintura, bem como com os demais fatores de risco metabólicos. Já o padrão Prudente apresentou relação direta e negativa com a pressão arterial sistólica, enquanto o padrão Moderno não se associou aos fatores de risco metabólicos investigados. Conclusão: Diferenças nos padrões de dieta de acordo com o tipo de rotação fatorial empregada foram observadas. A relação entre os fatores de risco metabólicos para doença cardiovascular foi distinta entre homens e mulheres, sendo a leptina um dos possíveis hormônios envolvidos. Os padrões de dieta Tradicional e Prudente associaram-se inversamente com os fatores de risco metabólicos, desempenhando uma importante estratégia de prevenção e controle às doenças cardiovasculares no país. / Introduction: The cardiovascular diseases are the main causes of death in Brazil and worldwide, presenting an important contribution to the global burden of diseases. The diet has been considered one of the primary determinants of the population health, by modulating metabolic risk factors for cardiovascular diseases. Objectives: To develop a conceptual model for the relationship between metabolic cardiovascular disease risk factors and investigate its association with dietary patterns of adults and elderly residents in the city of São Paulo. Methods: This is a population-based cross-sectional study with a probabilistic sample of adults and elderly living in the city of São Paulo, Brazil, whom participated in the Health Survey of São Paulo (HS-SP): a study performed in two stages between 2008 and 2011. In the first stage, a total of 1,102 adults and elderly, both sexes, were interviewed at home by trained interviewers, who applied a structured questionnaire and collected a 24-hour dietary recall. In the second stage, a total of 642 adults and elderly were re-evaluated by the application of the second 24-hour dietary recall by telephone. Of these individuals, a total of 592 underwent a household collection of blood samples, anthropometric measurements, and blood pressure assessment by a nurse assistant. The foods reported in both 24-hour recalls were collapsed into food groups according to nutritional composition and dietary habits of the population, and adjusted for the within-person variation of intake by statistical procedures of the web-based platform Multiple Source Method. The food groups were analyzed by exploratory and confirmatory factorial analysis (manuscript 1) and by exploratory structural equation model (manuscript 3) in order to extract the dietary patterns. The conceptual model for the relationship of the metabolic cardiovascular disease risk factors (serum leptin, serum high-sensitivity C-reactive protein, systolic blood pressure, diastolic blood pressure, total cholesterol/HDL-cholesterol ratio, triacylglycerol/HDL-cholesterol ratio, fasting plasma glucose, waist circumference and body weight) was obtained by a structural equation model stratified by sex (manuscript 2). Finally, the association of dietary patterns with the proposed model (manuscript 3) was investigated by exploratory structural equation model. Goodness-of-fit indexes were estimated to evaluate model fit. All analyzes were executed in Mplus software, version 6.12. Results: In manuscript 1, the exploratory factor analysis extracted two dietary patterns. These patterns exhibited a good model fit in the confirmatory factor analysis with the oblique Promax rotation and the factor loading cut-off |0,25|. In manuscript 2, sex differences in the relationship between metabolic cardiovascular disease risk factors were observed. Among women, serum leptin showed positive and indirect effects by mediation of body weight and waist circumference on all metabolic risk factors evaluated. Differently, among men, serum leptin showed positive and direct effects on high-sensitivity C-reactive protein and positive indirect effects (mediated by body weight and waist circumference) on triacylglycerol/HDL-cholesterol ratio, total cholesterol/HDL-cholesterol ratio and fasting plasma glucose. In manuscript 3, three dietary patterns were extracted, with the Traditional one showing negative and direct association with serum leptin and negative indirect effects on the other metabolic risk factors. The Prudent pattern showed a negative and direct association with systolic blood pressure, while the Modern pattern was not associated with any metabolic risk factors investigated. Conclusion: Differences in dietary patterns were observed according to the factor rotation method applied. The relationship between metabolic cardiovascular disease risk factors was distinct between men and women, with leptin emerging as one of the possible hormones involved. The dietary patterns labeled Traditional and Prudent were inversely associated with metabolic risk factors, playing an important strategy for prevention and control of cardiovascular diseases in this country.