Dissertations / Theses on the topic 'Cardiovascular Disease Mortality'

Louise evaluated the utility of risk score models for predicting cardiovascular mortality in Australian women. She found that most risk models do not diagnose “at risk” women well. Currently published predicted risk levels used for screening and recommending treatment are ineffective. Lower treatment thresholds are recommended. Central obesity and ethnicity have been identified for inclusion in future models. Her study has important implications for improving the accuracy of identifying “at risk” women for preventive treatment.

The purpose of this study was to compare between ethnicities if there is a difference in survival and treatment when it comes to cardiovascular diseases in the Middle East. To find out if there is a difference 28 articles was selected for inclusion, both qualitative and quantitative studies. Searches were made in the databases Medline, PubMed, Google and Google Scholar.The results showed that it is possible that there are differences in mortality and morbidity between ethnicities affected by cardiovascular disease. These may be due to differences in abdominal obesity, insulin resistance in diabetes and other risks such as C-reactive protein in the blood plasma which is normally excreted in inflammation in the body and also adiponectin, which is a hormone found in fat tissue whose secretion is diminished in people who have diabetes. But studies saying that a difference does exist are too few and the need for more and larger studies is needed. It may also be that not all ethnicities are as benefited from current treatments available against cardiovascular diseases for example beta-blockers. The conclusion of this study is that more research in this area is needed as well as more comprehensive studies regarding public health in the Middle East.
Syftet med denna studie var att jämföra mellan etniska grupper om det finns en skillnad i överlevnad och behandling när det gäller hjärt-och kärlsjukdomar i Mellanöstern. För att ta reda på det har 28 artiklar valts ut efter inklusionskriterierna, både kvalitativa och kvantitativa studier. Sökningar gjordes i databaserna Medline, Pubmed, Google and Google Scholar.Resultatet visade på att det sannolikt finns skillnader i dödlighet samt sjuklighet mellan etniciteter som drabbats av hjärt- och kärlsjukdomar. Dessa kan bero på skillnader i abdominal fetma, insulin resistens vid diabetes och andra risker så som C-reaktivt protein som finns i blodplasman och i vanliga fall utsöndras vid inflammationer i kroppen och adiponectin som är ett hormon som finns i fettvävnaden vars utsöndring är sämre hos personer som har diabetes. Dock är studierna som visar på skillnader alldeles för få, det behövs fler och större undersökningar inom detta område. Denna litteratur översikt visar också att det även kan vara så att inte alla etniciteter gynnas av dagens behandlingar som finns mot hjärt- och kärlsjukdomar som t ex Betablockerare. Slutsatsen i denna studie är att mer forskning inom ämnet behövs samt fler övergripande studier gällande folkhälsan i Mellanöstern.

Les malalties cardiovasculars (CV) són una de les primeres causes de morbimortalitat a tot el món. Aquestes malalties, en gran mesura, es podrien prevenir. La Dieta Mediterrània ha estat reconeguda com un dels patrons alimentaris més saludables. Fins el moment, existeix una forta evidència científica que demostra els beneficis de la dieta Mediterrània en la prevenció i el tractament de la malaltia cardiovascular. Aquesta tesi ha estat realitzada en el context de l’estudi PREDIMED, un estudi clínic paral•lel, multi cèntric i aleatoritzat que avaluava l’efecte de la dieta Mediterrània, en comparació a una dieta baixa en greix, en la prevenció primària de la malaltia cardiovascular. L’objectiu va ser determinar l’efecte dels fruits secs, l'oli d’oliva i les seves varietats, i el magnesi en el risc cardiovascular, mortalitat per causa específica i mortalitat per totes les causes en una població Mediterrània amb alt risc cardiovascular. Tots els aliments avaluats són components claus del patró de dieta Mediterrània i són consumits en altes quantitats en la nostra població. Els resultats del nostre treball demostren que consumir fruits secs amb més freqüència estava inversament relacionat amb la mortalitat cardiovascular, mortalitat per càncer i mortalitat total després de seguir als participants durant una mitja de 4.8 anys. L’oli d’oliva, concretament la varietat extra verge, s’associava a un risc reduït de malaltia cardiovascular i mortalitat cardiovascular després de 4.8 anys de mitja de seguiment. També vam observar que el magnesi dietètic s’associava inversament a la mort cardiovascular, per càncer i mortalitat total. En conclusió, els resultats d’aquesta tesi corroboren els efectes beneficiosos dels components de la dieta Mediterrània en la prevenció de malaltia cardiovascular i mort.
Las enfermedades cardiovasculares (CV) son una de las primeras causas de morbi-mortalidad en todo el mundo. Estas enfermedades, en gran medida, se podrían prevenir. La Dieta Mediterránea ha sido reconocida como uno de los patrones alimentarios más saludables. Hasta el momento, existe una fuerte evidencia científica que demuestra los beneficios de la dieta Mediterránea en la prevención y el tratamiento de la enfermedad cardiovascular. Esta tesis ha sido realizada en el contexto del estudio PREDIMED, un estudio clínico paralelo, multicéntrico y aleatorizado que evalúa el efecto de la dieta mediterránea, en comparación a una dieta baja en grasa, en la prevención primaria de la enfermedad cardiovascular. El objetivo fue determinar el efecto de los frutos secos, aceite de oliva y magnesio en el riesgo cardiovascular, mortalidad por causa específica y mortalidad por todas las causas en una población Mediterráneo con alto riesgo cardiovascular. Todos los alimentos evaluados son componentes claves del patrón de dieta Mediterránea y son consumidos en altas cantidades en nuestra población. Los resultados del presente trabajo demostraron que consumir frutos secos con más frecuencia estaba inversamente relacionado con la mortalidad cardiovascular, mortalidad por cáncer y mortalidad total tras seguir a los participantes durante una media de 4.8 años. Observamos también que el aceite de oliva, concretamente la variedad extra virgen, se asociaba a un riesgo reducido de enfermedad cardiovascular y mortalidad cardiovascular después de 4.8 años de media de seguimiento. También observamos que el magnesio dietético se asociaba inversamente a la muerte cardiovascular, por cáncer y mortalidad total. En conclusión, los resultados corroboran los efectos beneficiosos de los componentes de la dieta Mediterránea en la prevención de enfermedad cardiovascular y muerte.
Cardiovascular disease (CVD) is one of the main causes of disability and death worldwide. Importantly, in a large extent, CVD are preventable. The Mediterranean Diet (MedDiet) is recognized as one of the healthier dietary patterns. To date, strong evidence exists supporting the benefits of the MedDiet for the prevention and management of CVD. This thesis has been conducted in the framework of the PREDIMED Study, a parallel-group, multicenter randomized nutrition trial evaluating the efficacy of a MedDiet compared to a low-fat control diet on the primary prevention of CVD. We aimed to asses the associations between nuts, olive oil and its varieties, and magnesium on the risk of CVD, cause-specific and all-cause mortality on an elderly Mediterranean population at high cardiovascular risk. All of these foods are key components of the MedDiet pattern and are highly consumed in our population. The results of the present work demonstrate that the frequency of nut consumption was inversely related to cardiovascular, cancer and total mortality after 4.8 years of follow-up. We found that olive oil consumption, specifically the extra-virgin variety, was associated with reduced risk of cardiovascular disease and cardiovascular mortality after 4.8 years of follow-up. We have also observed that dietary magnesium intake was inversely associated with cardiovascular, cancer and total mortality risk after 4.8 years of follow-up. In conclusion, the findings of this thesis support the healthy benefits of the components of a MedDiet on the primary prevention of cardiovascular disease and mortality.

Background Low aerobic fitness and obesity are associated with atherosclerosis, and thereforegreatly increase the risk of cardiovascular disease (CVD) and early death. It has long been known that atherosclerosis my begin early in life. Despite this fact, it remains unknown how obesity and aerobic fitness early in life influence the risks of atherosclerosis, CVD and death. Furthermore, it is unknown whether high aerobic fitness can compensate for the risks associated with obesity, and how genetic confounding affects the relationshipsof aerobic fitness with CVD and all-cause mortality. Thus, the main aims of this thesis were to investigate the associations of aerobic fitness in late adolescence with myocardial infarction (Study I), stroke (Study II) and all-cause mortality (Study III), and how genetic confounding influences the relationshipsof aerobic fitness with CVD, diabetes and death (Study IV). Methods The study population comprised up to1.3 million men who participated in mandatory Swedish military conscription. During conscription, all conscripts underwent highly standardized tests to assess aerobic fitness, body mass index, blood pressure and cognitive function. A physician also examined all conscripts. Data on subjects’ diagnoses, death and socioeconomic status during follow-up were retrieved using record linkage. Subjects were subsequently followed until the study endpoint, date of death or date of any outcome of interest. Associations between baseline variables and the risks of adverse outcomes were assessed using Cox’s proportional hazard models. Genetic confounding of the relationships between aerobic fitness and diabetes, CVD and death was assessed using a twin population and a paired logistic regression model. Results In Study I, low aerobic fitness at conscription was associated with an increased risk of myocardial infarction (MI) during follow-up (hazard ratio [HR] 0.82 per standard deviation increase). Similarly, in Study II, high aerobic fitness reduced the risk of stroke (HR 0.84 for ischemic stroke, HR 0.82 for hemorrhagic stroke; P < 0.001 for all), and obesity was associated with an increased risk of stroke (HR 1.15 for ischemic stroke, HR 1.18 for hemorrhagic stroke; P < 0.001 for all). In Study III, high aerobic fitness was also associated with reduced all-cause mortality later in life (HR 0.49, P < 0.001). High aerobic fitness exerted the strongest protection against death from substance and alcohol abuse, suicide and trauma (HRs 0.20, 0.41 and 0.52, respectively; P < 0.001 for all). Obese individuals with aerobic fitness were at higher risk of MI and all-cause mortality than were normal-weight individuals with low fitness (Studies I and III). In Study IV, fit twins had no reduced risk of CVD or death during follow-up compared with their unfit twin siblings (odds ratio 1.11, 95% confidence interval 0.88–1.40), regardless of how large the difference in fitness was. However, the fitter twins were protected against diabetes during follow-up. Conclusions Already early in life, aerobic fitness is a strong predictor of CVD and all-cause mortality later in life. In contrast to the “fat but fit” hypothesis, it seems that high aerobic fitness cannot fully compensate for the risks associated with obesity. The associationsof aerobic fitness with CVD and all-cause mortality appear to be mediated by genetic factors. Together, these findings have implications for the view of aerobic fitness as a causal risk factor for CVD and early death.

Cardiovascular disease (CVD) is one of the major health issues of our time. The prevalence of CVD is increasing, both in industrialized and in developing countries, and causes suffering and a decreased quality of life for millions of people worldwide. CVD can have multiple etiologies, but the main underlying cause is atherosclerosis, which causes blood clot formation and obstructs vital arteries. Multiple risk factors of atherosclerosis have been identified, and body fatness is one of the most important ones.  The main aims of this thesis were to investigate the relation between body fatness and: CVD risk factors (paper I), incident stroke (paper II), and overall mortality (paper III). The results showed that abdominal obesity is strongly associated with both CVD risk factors and stroke incidence (papers I-II). The results also suggested that a substantial part of the association between increased body fat and stroke can be explained by an increase in traditional stroke risk factors associated with increased body fat (paper II). A gynoid fat distribution, with a high share of fat located around the hip, is, on the other hand, associated with lower risk factor levels in both men and women, and with a decreased risk of stroke in women (papers I-II). This illustrates the importance of assessing the overall distribution of body fat rather, than solely focusing on total body fatness. In elderly women, total body fat was found to be associated with increased survival, while abdominal fat moderately increased mortality risk (paper III). Lean mass (fat-free mass) was strongly associated with increased survival among elderly men and women (paper III). Erythrocyte sedimentation rate (ESR) is an indicator of inflammation and, possibly, an indicator of atherosclerotic disease. In paper IV, the relationship between ESR in young adulthood and the later risk of myocardial infarction (MI) was studied. Results showed that higher levels of ESR were associated with a higher MI risk, in a dose-responsive manner, and was independent of other well-established risk factors. In summary, both total and regional fat distribution are associated with CVD risk factors and stroke, but do not seem to correspond to an increase in mortality risk among the elderly. Also, inflammation, detected as an increase in ESR, is associated with long term MI risk in young men.

Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer. The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations. This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial. In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol. Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations.

Rheumatoid arthritis (RA) is a chronic disabling disease that is associated with a shortened life span. Cardiovascular disease (CVD) contributes to this increased mortality, and also to a great extent to the co-morbidity observed in patients with RA. This thesis aimed to investigate these issues further. The incidence of, and prognosis after an acute myocardial infarction (AMI) /or stroke in a cohort of RA patients was compared with that in the general population within the northern Sweden MONICA register. The standard incidence ratio (SIR) for AMI was 2.9 and for stroke 2.7 in RA patients compared with the general population (p<0.05 for both). During the first 10 years following an event, RA patients had a higher overall case fatality (CF) compared with controls (HR for AMI=1.67, 95%CI [1.02, 2.71], HR for stroke=1.65, 95%CI [1.03, 2.66]). An elevated level of homocysteine is regarded to be a risk marker for CVD. The effects of treatment with B vitamins on the homocysteine level in patients with RA were studied in a consecutive cohort of patients with RA. Sixty-two patients with RA having a homocysteine level of 12 mol were randomized to receive either a placebo or a combination of the vitamins B6, B12 and folic acid. The patients were treated and evaluated in a double-blind manner over 12 months. The homocysteine level was found to be significantly decreased in the B-vitamin treated patients compared with the placebo group (p<0.0001). To evaluate the progression of sub-clinical atherosclerosis in patients with very early RA compared with controls, all patients from the three most northern counties of Sweden newly diagnosed with RA and aged ≤60 years were consecutively recruited. Age and sex matched controls from the general population were also included. Intima media thickness (IMT) of the common carotid artery and endothelium dependent flow mediated dilation (ED-FMD) of the brachial artery were measured using ultrasonography. After 18 months the same measurements were undertaken in a sub-group of the patients with early RA and the relevant controls. There were no differences between patients with early RA and controls in terms of IMT or ED-FMD at inclusion into the study. However, after 18 months there was a significant increase in the IMT among the patients with early RA (p<0.05); no such increase occurred in the control group. Biomarkers of endothelial activation that may reflect the early atherosclerosis that occurs in RA were also evaluated. At inclusion, both IMT and ED-FMD among the patients with early RA related significantly to several of the biomarkers of endothelial activation. Furthermore, markers of inflammation (e.g., DAS28) were significantly related to biomarkers of endothelial activation. In conclusion, RA patients had a higher incidence of CVD and a higher CF after a CV event. The increased homocysteine level among patients with RA was as easy to decrease as in the general population. At the time of diagnosis of RA there were no differences in atherosclerosis between patients and controls, however the patients with RA had a more rapid progression of atherosclerosis than the control subjects. Moreover, there were implications of endothelial activation already in patients with very early RA. Taken together, these results emphasize the necessity of optimizing the preventive, diagnostic and caring strategies for CVD in patients with RA.

Patients with rheumatoid arthritis (RA) have a shorter life span than the general population. An increased death due to cardiovascular disease (CVD) has been reported. RA is characterized by synovitis and joint destruction accompanied by an acute phase reaction and systemic features. The present work investigates the epidemiology of CVD in patients with RA in the county of Västerbotten and the influence of inflammation on lipid metabolism and haemostasis. In a retrospective cohort study on 606 RA patients, the overall mortality was significantly higher than in the general population, with an excess death rate for CVD and for ishemic heart diseae (IHD) in both sexes. Multiple Cox regression, showed that male sex, higher age at disease onset and cardiovascular event increased the risk for death. Male sex, high age at disease onset and hypertension increased the risk for cardiovascular event. Diabetes mellitus, treatment with corticosteroids, disease modifying antirheumatic drugs and postmenopausal estrogen neither influenced survival nor the risk of cardiovascular event. In 93 patients with active RA, the levels of cholesterol, high density- (HDL) and low density (LDL) lipoprotein cholesterol were significantly lower, and Lipoprotein(a) was significantly higher compared to controls. In a follow-up on 53 patients, a relation between the change of Lp(a) and acute phase proteins was found only in patients with high levels of Lp(a). Preheparin lipoprotein lipase (LPL) activity and mass were significantly decreased in 17 postmenopausal women with active RA. Preheparin LPL mass correlated inversely to several acute phase proteins and interleukin-6. Low levels of LPL mass may implicate increased hepatic clearence but also increased macrophage ingestion of lipoproteins via the LDL receptor-related protein (LRP). Haemostasis of the circulation was investigated in 74 of the 93 patients with active RA. In patients with extraarticular disease, the release of tissue plasminogen activator (tPA) was significantly decreased, and its inhibitor (PAI-1) was significantly increased compared to patients with nonsystemic disease, implicating hypofibrinolysis. In a two year follow-up, patients with thromboembolic events had significantly elevated levels of von Willebrand factor, PAI-1, triglycerides and haptoglobin compared to event-free patients. In 29 RA patients and 18 spondylarthropathy patients with gonarthritis, radiological joint destruction correlated to PAI-1 antigen in synovial fluid and, inversely, to plasminogen. A relationship between activation of fibrin degrading proteolytic enzymes and joint destruction was implicated. In conclusion, several processes involved in lipid metabolism and haemostasis are influenced in active RA. In view of the increased death rate due to CVD, an efficient control of inflammation should be important, not only for reducing joint destruction, but also for reducing systemical atherogenic and thrombogenic effects.

s. 1-54: sammanfattning, s. 55-133: 6 uppsatser

digitalisering@umu.se

Human population-based studies of longitudinal design observe that higher intelligence in youth confers protection from premature mortality in adulthood. This field of study (“cognitive epidemiology”; Deary & Batty, 2007) has firmly established associations between intelligence and health outcomes, and has begun to address the likely mechanisms involved. The present thesis assessed some social, educational, and lifestyle factors that potentially confound and/or mediate the intelligence-mortality link. First, I carried out a systematic review of longitudinal cohort studies reporting intelligence differences in youth in relation to adult mortality risk, and in meta-analysis I aggregated the effect sizes from 16. A one SD advantage in intelligence scores was associated with 24% (95% CI 23% to 25%) lower risk of death, during 17- to 69-year follow-up; this magnitude showed no sex differential. Socioeconomic status in early life did not explain the effect. Rather, the person’s own occupational status in adulthood and educational attainment explained a third and a half of the association, respectively. One issue in controlling for education, in such models, is its strong correlation with intelligence test performance, which could lead to statistical overadjustment. A second aspect of this thesis, therefore, addressed the nature of the intelligence-education covariance in two behaviour-genetic studies of large general population-based samples of schoolchildren from England and The Netherlands. Previous studies that reported intelligence—education genetic covariances were potentially biased in their use of twin self-selection or pre-selection sampling. Moreover, the analysis in this thesis used a novel statistical approach, and included non-twin data to represent fully the variance in performance scores of a population. Analysis of the English cohort confirmed the top end of estimates from previous studies: 76% to 88% of the phenotypic correlation was due to heritability. The Dutch cohort showed greater variance for equivalent estimates (33% to 100%). The results indicate a limit to the extent to which education and intelligence might be causative of one another suggesting caution in interpreting some of the substantive attenuation effects by education reported in the literature. Third, I investigated pathways from intelligence to cardiovascular disease risk factors, given the consistent and robust finding that an advantage in intelligence relates to lower cardiovascular disease-outcomes. I used data from the 1958 National Child Development Study to investigate age-11 intelligence in association with inflammatory and haemostatic biomarker status at age 46 years. The results replicated inverse associations previously reported in an older age sample, and a one SD advantage in intelligence related to a 1.1mg/L decrease in C-reactive protein. The effect was largely mediated by lifestyle factors, including smoking, occupational status and abdominal obesity. In two further studies I used the west of Scotland Twenty-07 cohort, to investigate processing speeds among 16, 36 and 56 year-olds in relation to: (1) Inflammation, and (2) metabolic-risk, after 20 years. The advantage of experimental rather than psychometric measures of cognitive ability is their reduced cultural and social bias. Faster reaction time predicted lower systemic inflammation in the youngest male cohort, which appeared to be partially confounded by baseline smoking and socioeconomic status. Furthermore, advantage in reaction time performance in the young and middle-aged cohorts significantly predicted reduced metabolic risk. This was partially explained by occupational status, but retained statistical significance in some fully-adjusted models. A one SD advantage in age 16 simple reaction time variability, related to the 21% (95% CI 12% to 30%) reduced odds of metabolic syndrome by age 36 in the basic model, and this effect remained unchanged after controlling for all covariates. The growing evidence for specific social and behavioural factors that mediate intelligence-to-mortality pathways are discussed, in respect of indirect evidence that underlying system integrity or early life confounding may contribute incrementally to the effect.

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Cardiovascular diseases are among the leading causes of death in the world and in Brazil. Women of childbearing age have been affected by these events in increasingly significant numbers, since it modifies the expected pattern of deaths in this age group. This dissertation aimed to outline the epidemiological profile of cardiovascular disease mortality in women of childbearing age, in the state of Goiás, from 2000 to 2014. It is a retrospective study with a quantitative approach. The data corresponding to the deaths of women of childbearing age, from 10 to 49 years, for cardiovascular diseases (Chapter IX of ICD-10), in the state of Goiás, were digitally accessed at the Mortality Information Service (SIM) in the period of 2000 To 2014. Cardiovascular diseases ranked third in the number of deaths in the study group. The most prevalent diseases that led to women of childbearing age were, respectively, cerebrovascular diseases, ischemic heart diseases and other forms of heart disease. Mortality declined in the group of women between the ages of 20 and 49, with a more pronounced decline in the age group of 40 to 49 years. In relation to marital status, there was a decrease in the number of deaths of married and widowed women and an increase among women in a stable union. In terms of schooling, there was a decrease in the number of deaths among women with uninformed or ignored education and without any education, whereas among women with four years or more of education there was an increase in the number of deaths. There was an increase in the number of deaths among women of brown color and fall among white women. In the majority of cases, women died, especially in the hospital environment, with deaths occurring at home in the second place. It is concluded that, over the years, women of childbearing age have presented better responses regarding the modification of risk factors for cardiovascular diseases, as well as adherence to guiding principles for the reduction of these risk factors. Although health and education policies have followed this trend, they still lack epidemiological evidence for their better targeting and implementation.
As doenças cardiovasculares estão entre as principais causas de óbito no mundo e no Brasil. As mulheres em idade fértil têm sido acometidas por esses eventos em números cada vez mais expressivos, dado que modifica o padrão esperado dos óbitos nesta faixa etária. A presente dissertação teve por objetivo delinear o perfil epidemiológico da mortalidade por doenças cardiovasculares em mulheres em idade fértil, no estado de Goiás, no período de 2000 a 2014. Trata-se de um estudo retrospectivo com abordagem quantitativa. Foram acessados digitalmente no Serviço de Informação de Mortalidade (SIM) os dados correspondentes às mortes de mulheres em idade fértil, entre 10 e 49 anos, por doenças cardiovasculares (Capítulo IX do CID-10), no estado de Goiás, no período de 2000 a 2014. As doenças cardiovasculares ocuparam a terceira colocação no número de óbitos no grupo estudado. As doenças mais prevalentes que levaram as mulheres em idade fértil a óbito foram, respectivamente, as doenças cerebrovasculares, as doenças isquêmicas do coração e outras formas de doenças do coração. Houve queda da mortalidade no grupo de mulheres entre 20 e 49 anos, com declínio mais acentuado na faixa etária de 40 a 49 anos. Em relação ao estado civil, observou-se queda no número de óbitos de mulheres casadas e viúvas e aumento entre mulheres em união estável. Em se tratando de escolaridade, houve diminuição do número de óbitos entre as mulheres com instrução não informada ou ignorada e sem nenhuma instrução, enquanto entre as mulheres com quatro anos ou mais de instrução registrou-se aumento do número de óbitos. Foram identificados aumento do número de óbitos entre mulheres de cor parda e queda entre mulheres brancas. Em sua maioria, as mulheres vieram a óbito especialmente em ambiente hospitalar, ficando em segundo lugar os óbitos em seus domicílios. Conclui-se que, ao longo dos anos, as mulheres em idade fértil têm apresentado melhores respostas quanto à modificação dos fatores de risco das doenças cardiovasculares, assim como em relação à adesão aos princípios norteadores para a diminuição destes fatores de risco. Embora as políticas de saúde e educação venham acompanhando tal tendência, ainda carecem de evidências epidemiológicas para seu melhor direcionamento e implementação.

Great apes housed in zoological collections have an important role to play in conservation. A sound understanding about their health and welfare forms a critical part of their custodianship. Chapter 1 of this thesis outlines a systematic review of 189 published articles relating to the topic of great ape morbidity and mortality (Strong et al. 2016). It concluded that there was a critical need for an up-to-date review of zoo-housed great ape mortality, especially among the European population, to be carried out. Such a review of data relating to 681 great ape deaths was therefore performed and is outlined in Chapter 2 of this thesis. This mortality review identified the main causes of death within each taxa and age group, and allowed for a series of recommendations about future disease investigation and monitoring to be generated. Diseases of the cardiovascular system specifically, were identified as being associated with significant proportional mortality. Despite this, however, understanding about the epidemiology, pathogenesis and diagnosis of cardiovascular disorders among great apes remains poor. The remainder of the thesis therefore outlines a series of further projects and studies designed to confront this lack of knowledge and understanding: Chapter 3 focuses on cardiovascular disease epidemiology and identifies similarities and differences in disease risk between the taxa, highlighting age and male sex as potential risk factors. Chapter 4 is dedicated to the development of two protocols designed to standardise both the ante- and post-mortem investigation of cardiovascular disease in great apes. Chapter 5 addresses the controversial topic of carrying out cardiovascular disease screening in immobilised animals by comparing the effects of two anaesthetic protocols. Finally, Chapter 6 outlines a detailed study of great ape cardiovascular pathology and specifically idiopathic myocardial fibrosis in chimpanzees. The findings of each of the studies outlined in this thesis are informative, not only for the day-to-day management of zoo-housed great apes, but also for future research into their health, disease and therefore welfare.

The main purpose of this study was to determine the impact of depression and anxiety on mortality, CHD incidence, and quality-of-life in patients hospitalised for an acute myocardial infarction (MI). Questionnaires, including the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory were completed during hospitalisation by 288 MI patients, and four months and 12 months after discharge among survivors. Quality-of-life was assessed at both follow-up points using the Dartmouth COOP charts. Twenty-five (8.7%) patients died, 22 of cardiac causes, during the four month follow-up. Six further fatalities occurred between four and 12 months following MI. Symptoms of depression and anxiety did not predict either cardiac or all-cause mortality, or CHD incidence at either follow-up point. Indices of disease severity predicted both four month and 12 month mortality and CHD incidence. In a subset of seven patients who died prior to discharge, depressive symptoms did predict mortality, but the association did not withstand correction for severity of infarction. Multiple regression analyses revealed that baseline depression and state anxiety, as well as severity of infarction, predicted both four and 12 month quality-of-life. In addition, partner status and living alone also predicted four and 12 month quality-of-life, respectively. Attendance at rehabilitation was positively associated with quality-of-life at both four and 12 months, and negatively associated with 12 month CHD morbidity. In conclusion, depression and anxiety were not significant predictors of mortality, or CHD incidence, during the first year following MI but they were predictive of four and 12 month quality-of-life among survivors.

O transtorno de humor bipolar (THB) é uma condição incapacitante e caracterizada pela presença de episódios de humor associados a alterações de cognição e de comportamento. Indivíduos com diagnóstico de THB estão particularmente propensos a múltiplas condições metabólicas. Em uma parcela dos pacientes acometidos pela doença observa-se a neuroprogressão do quadro, com alterações no campo da neuroimagem e de biomarcadores – citocinas inflamatórias, estresse oxidativo e neurotrofinas. Tais fatores parecem também relacionar-se ao aumento do risco cardiovascular (RCV) observado nessa população, visto que a doença cardiovascular (DCV) constitui a principal causa de morte em pacientes com THB. Mesmo conhecendo tal estatística, há escassez de literatura científica abordando avaliação cardiovascular em pacientes bipolares. Dessa forma, a presente tese tem o objetivo de melhorar o entendimento da associação entre neuroprogressão e doença cardiovascular. Para tal, inicialmente conduzimos uma revisão da literatura englobando variáveis associadas ao estadiamento e à neuroprogressão, sobretudo aspectos que se referem a biomarcadores, neuroimagem, cognição, funcionalidade e resposta ao tratamento. Em seguida, foi realizado estudo clínico com o objetivo de avaliar a prevalência de doença aterosclerótica coronariana através do uso do escore de cálcio coronariano (ECC) em pacientes ambulatoriais bipolares tipo 1. Os pacientes incluídos eram bipolares tipo 1, todos eutímicos e tendo assinado o termo de consentimento. Os escores de cálcio foram adquiridos utilizando um scanner Aquilion 64 CXL (Toshiba Medical Systems) e a quantificação realizada através do método de Agatston. Em nosso estudo verificou-se que pacientes com ECC positivo eram mais velhos (média 55.2 anos; p=0.001) e tinham uma média maior de internações psiquiátricas prévias (media 4.7; p=0.04) quando comparados ao grupo com ECC negativo, além de também haver uma associação positiva entre ECC e número de internações psiquiátricas prévias entre toda a amostra do estudo (p<0.001). Nossos resultados sugerem a associação entre idade e maiores escores coronarianos, além da relação entre cálcio coronariano e número de internacões psiquiátricas prévias. É possível que este achado relacione-se ao fato de que pacientes em estágios mais avançados da doença tenham maior carga inflamatória que, juntamente com os fatores de risco para DCV, justificaria o aumento do RCV, sugerindo um possível link entre neuroprogressão no THB e aterosclerose coronariana acelerada.
Bipolar disorder (BD) is a disabling condition characterized by the presence of mood episodes associated with changes in cognition and behavior. Individuals diagnosed with BD are particularly prone to multiple metabolic conditions. In a portion of the patients affected by the disease the neuroprogression is observed, with alterations in the field of neuroimaging and of biomarkers - inflammatory cytokines, oxidative stress and neurotrophins. These factors also seem to be related to the increased cardiovascular risk (CVR) observed in this population, since cardiovascular disease (CVD) is the main cause of death in patients with BD. Even knowing this statistic, there is a paucity of scientific literature addressing cardiovascular evaluation in bipolar patients. Thus, the present thesis aims to improve the understanding of the association between neuroprogression and cardiovascular disease. To this objective, we initially conducted a literature review encompassing variables associated with staging and neuroprogression, especially aspects that refer to biomarkers, neuroimaging, cognition, functionality and response to treatment. Afterwards, a clinical study was performed to evaluate the prevalence of coronary atherosclerotic disease through the use of coronary calcium score (CCS) in outpatient bipolar type 1 patients. The patients included were diagnosed as BD type 1, all of them euthymic and signed the consent form. Calcium scores were acquired using an Aquilion 64 CXL scanner (Toshiba Medical Systems) and quantification performed using the Agatston method. In our study, patients with CCS positive were older (mean 55.2 years; p = 0.001) and had a higher mean of previous psychiatric hospitalizations (mean 4.7, p = 0.04) when compared to the CCS negative group, and there was also a positive association between CCS and number of previous psychiatric hospitalizations among the entire study sample (p<0.001). Our results suggest the association between age and higher coronary scores, as well as the relationship between coronary calcium and the number of previous psychiatric hospitalizations. It is possible that this finding is related to the fact that patients in more advanced stages of the disease have a higher inflammatory load that, together with the risk factors for CVD, would justify the increase of CVR, suggesting a possible link between neuroprogression in BD and accelerated coronary atherosclerosis.

For over a century, there have been suggestions of a link between what is currently called bipolar disorder and cardiovascular mortality. In the contemporary epidemiological literature, this risk has been confirmed and approximates twice that expected based on age and gender. To date, however, this information has come primarily from clinical samples, which carry considerable risk of selection bias. The studies contained in this dissertation sought to assess this relationship using methods less vulnerable to selection bias and to determine the role that course of illness and treatments for illness may play in the development of vascular disease. In a nationally representative sample, we confirmed a link between mood disorders and vascular disease, which was particularly pronounced in women with bipolar disorder. In subsequent studies, a dose-response relationship between the duration of clinically significant hypomanic or manic symptoms and both cardiovascular mortality and endothelial function was seen. While medication exposure did not appear related to mortality or endothelial function, first generation antipsychotics were associated with arterial stiffness, an effect apparently mediated by elevations in blood pressure. In cross-sectional samples, our data suggests that vasculopathy is not present early in the course of bipolar disorder although is much greater than expected later in the course of illness. This dissertation purports that vasculopathy develops over the long-term course of bipolar disorder, is proportional to symptom burden, and is influenced by health behaviors and treatments. These findings may provide opportunities for clinicians and those afflicted to intervene to address this excess risk of vascular morbidity and mortality.

Background: Systemic sclerosis (SSc) is an autoimmune disease associated with significant mortality and morbidity. Cardiovascular causes are the single largest contributor to premature death. To date, much of the focus on managing the care of SSc patients has concentrated on traditional risk factors related to fibrotic and microvascular dysfunction. There is, however, evidence of a strong cardiovascular component to the disease and points to macrovascular dysfunction as being a key contributor to the premature mortality associated with SSc. This thesis reports on the conduct of a multi-centre, randomised, placebo-controlled clinical trial (the SSTEP Study). The aim of the study was to assess whether oral Iloprost was more effective than placebo in reducing cardiovascular events and disease progression in SSc. Methods: Two hundred and sixteen patients with systemic sclerosis were recruited, between February 2002 and February 2005, at nine centres in the UK and Ireland. After one month placebo run-in, participants were randomised to either oral Iloprost (50-200mcg daily) or matched placebo. Baseline demographics, disease characteristics and organ screening data were collected, and participants were reviewed annually for endpoint measurements; CV events, SSc disease progression and mortality, with regular safety reviews between these annual visits. Participants were followed up for a period of 4 to 7 years. Results: Data analysis of the combination of the two measures (survival free from death or a cardiovascular event) demonstrated a trend towards favouring Iloprost over placebo but the difference was not statistically significant (Logrank test: Chi square=0.75, p=0.39). When time to a confirmed cardiovascular endpoint alone was examined there was a suggestion of a benefit from Iloprost, but the difference was again not statistically significant (Logrank test, Chi square =0.82, p=0.37). There was no statistically significant change in the rate at which organ screening endpoints occurred throughout follow-up, and for each endpoint there was no statistically significant difference between results in patients randomised to Iloprost compared to those randomised to placebo. Withdrawal from the treatment to which the patient was randomised was frequent with 97 (45%) of the total participants discontinuing study medication. ‘On treatment’ analysis, undertaken using the endpoint of death or confirmed cardiovascular endpoint, just failed to show statistical significance at the 5% level (p=0.054). Conclusion: The results of the SSTEP study showed that there was a trend towards favouring oral Iloprost over placebo in systemic sclerosis, though there was no statistically significant evidence to recommend its use to prevent disease progression. The high rate of withdrawal from both Iloprost and placebo hindered the possibility of demonstrating that Iloprost was effective in this study. It cannot be concluded that it is a useful therapy that may prevent premature mortality or progression to cardiovascular disease in this patient group.

Objective: Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality. Design: Prospective cohort study with a 4.5-year follow-up period. Methods: From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality. Results: At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m2. No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2–Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2–Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33–0.74; adjusted HR 0.62, 95% CI 0.42–0.939; CV events: Q2–Q5 versus Q1: crude HR 0.54, 95% CI 0.38–0.77; adjusted HR 0.68, 95% CI 0.48–0.97). Kaplan–Meier curves revealed similar data. Conclusions: Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors.

Background. The incidence of starting renal replacement therapy (RRT) among young people (< 20 years of age) in 2013 in Scotland was 7.7 per million (age-related) population. Little knowledge exists about cardiovascular risk factors (CVRFs), long-term survival and cardiovascular disease (CVD) outcomes in patients who initiated RRT in childhood. The main source of routine data for these patients is available from the European Society of Paediatric Nephrology/European Renal Association- European Dialysis and Transplant Association (ESPN/ERA-EDTA) registry. In Scotland nationally comprehensive data on patients receiving RRT is available from the Scottish Renal Registry (SRR). Aim and objectives. The overall aim of the thesis is to review relevant literature and conduct retrospective cohort studies describing CVRF prevalence, all-cause mortality and incidence of CVD outcomes in patients who initiated RRT in childhood. ESPN/ERA-EDTA registry data were used to describe the prevalence of anaemia, hypertension, dyslipidaemia and BMI categories and their association with all-cause and CV mortality. SRR data were used to describe all-cause mortality and CVD incidence and their association with age at start of RRT, sex, primary renal disease (PRD), type of RRT and period of start of RRT. Methods. Systematic searches were performed to identify relevant literature. For the ESPN/ERA-EDTA analyses patients who started RRT between 0 and 20 years of age and who had CVRF data were included. Patients were followed from date of first CVRF measurement until the earliest of death, loss to follow-up, reaching 20 years of age or the end of follow-up (December 31st 2012). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality, comparing patients with and without each CVRF. For the SRR analyses, patients who started RRT under 18 years of age in the period from 1963 to 2013 were included in the analyses. To describe CVD incidence the SRR data were linked to national registers for death and CVD hospital admissions available from 1981 onwards. These analyses, therefore, included patients who started RRT between 1981 and 2013 with follow-up until first CVD event after start of RRT, end of follow-up period or censoring at death. Cox proportional hazard models were used to examine the association of age at initiation of RRT, sex, PRD, type of RRT and period of initiation of RRT with all-cause mortality and CVD incidence. Results. The systematic reviews revealed a gap in current knowledge about CVD incidence and the association of CVRFs with CVD outcomes in patients who initiated RRT in childhood. In total, 7,845 patients were included in the ESPN/ERA-EDTA registry analysis. The mean age of the patients was 9.5 (SE 0.06) years, 58.9% were male, and the most common PRD was congenital anomalies of kidney and urinary tract (CAKUT). The prevalence of dyslipidaemia, hypertension, anaemia overweight/obesity and underweight was 87.5%, 79.3%, 36.0%, 29.9% and 4.3%, respectively. During median follow-up of 3.7 (IQR 1.7-6.8) years 357 patients died. HRs for anaemia were 2.19 (95% CI 1.64-2.93) and 2.55 (95% CI 1.27-5.12) for all-cause and CVD mortality, respectively. The HR for all-cause mortality for underweight was 1.81 (95% CI 1.30-2.53). No other studied CVRFs were statistically significantly associated with all-cause and CVD mortality. In total, 479 patients were included in the SRR analyses of all-cause mortality. The most common PRD was CAKUT and 55.3% of patients were male. During a median follow-up of 18.3 (IQR 8.7-27.0 years) years 126 patients died. Twenty-year survival among patients initiated RRT in childhood was 77.6% (95% CI 73.8-81.3). Age at start of RRT, PRD and type of RRT were significantly associated with all-cause mortality. HR for all-cause mortality for patients who started RRT under 2 years of age was 2.50 (95% CI 1.19-5.25) compared to patients who started RRT at 12 to 18 years old. HR for all-cause mortality for patients with PRD other than CAKUT or glomerulonephritis (GN) was 1.58 (95% CI 1.05-2.39) compared to patients with CAKUT. HRs for all-cause mortality for patients who only received either HD or PD during follow-up were 19.4 (95% CI 10.4-36.4 and 19.5 (9.65-39.7), respectively, compared to patients who received a renal transplant. In total, 381 patients were included in the SRR analyses of CVD incidence. During a median of 12.9 (IQR 5.6-21.5) years of follow-up after initiation of RRT 134 patients (35.2%) developed CVD. The overall crude CVD incidence was 2.6 (95% CI 2.2-3.0) per 100 person-years. HRs for CVD were 1.69 (95% CI 1.05-2.74) for males compared to females, 1.72 (95% CI 1.02-2.91) for PRD other than CAKUT or GN compared to CAKUT and 8.38 (95% CI 3.31-21.23) and 7.30 (95% CI 2.30-23.16) for patients who only received either HD or PD during follow-up, respectively, compared to patients who received a renal transplant. Conclusions. This thesis has contributed to knowledge about CVRF prevalence, longer-term survival and CVD outcomes in patients who initiated RRT in childhood by identifying high prevalence of CVRFs and that CVD is a common complication. This study did not investigate whether anaemia, hypertension, dyslipidaemia and obesity are associated with a higher risk of developing CVD after start of RRT. Future research is needed to study whether treatment of anaemia, hypertension, dyslipidaemia and controlling body weight will reduce the risk of CVD and mortality in patients who initiated RRT in childhood.

Background: This study explored the differences between the seasonal mortality rates (by age and gender) between the two jurisdictions (the Republic of Ireland (RoI) and Northern Ireland (NI)). The study assessed the relationship between cold temperatures and daily mortality, and assessed for effect modification of the cold weather-mortality relationship by age and gender. Methods: Mortality rates were calculated for each cause-specific mortality group during various seasons in both jurisdictions. A time-stratified case-crossover approach was applied to examine the cold weather-mortality relationship, 1984-2007. The daily mortality risk was explored in association with exposure to daily maximum temperatures on the same day and up to 6 weeks preceding death, during the winter months and extended cold period (October-March), using distributed lag models. Model stratification by age and gender assessed for modification of the cold weather-mortality relationship. Results: The winter mortality rates were significantly greater than the summer rates. NI experienced higher mortality from cardiovascular disease, respiratory disease and stroke. The impact of cold weather in the winter months persisted up to 35 days in the RoI, with a cumulative mortality increase for all-cause of 6.4% (95%CI: 4.8%-7.9%) with regards to every 1oC drop in the daily maximum temperature with similar associations for cardiovascular disease and stroke with twice as much for respiratory diseases. The associations were less pronounced and less persistent in NI. Conclusions: The study observed excess winter mortality. The cold weather-mortality associations increased with age with some suggestion of gender differences. There were strong cold weather-mortality associations in both jurisdictions, with suggestive differences in associations by age and gender. The findings suggest the potential contribution of societal differences, and require further exploration. These findings will hopefully contribute to the current efforts to modify fuel policy and reduce winter mortality in both jurisdictions.

Studies carried out in a number of countries have revealed statistically significant negative correlations between death rates from cardiovascular disease (CVD) or ischaemic heart disease (IHD), and the hardness of local water supplies, a phenomenon which is known as the "water story". These findings have not, however, been universal and it was decided that a study carried out in South Africa with its high CVD and IHD death rates, might yield meaningful results to contradict or support existing findings. In 1983 a pilot study was thus initiated using a spatial model and a more detailed study began in 1984. This study ultimately involved the correlation of standardized mortality ratios (SMRs) for CVD and IHD with total water hardness and with a number of contributory and associated water quality factors. The study supported the hypothesised "water story", showing the existence of negative correlations between standardized mortality ratios (SMRs) for both CVD and IHD, and the hardness of potable water, whether measured as total hardness or as its two major contributory cations, calcium and magnesium. The level of statistical significance at which this correlation occurred, however, varied with differences in methodological approach. A "population-unweighted" methodology, which was applied to enable comparison with a number of previously published studies, pointed to potassium (a known hypertension normalisor) in permanently hard water as being an important factor. Problems inherent to each methodological approach have been discussed as has the need for improved data. In this regard, the need for a National water quality data bank has been emphasised.

Thesis (PhD)--Stellenbosch University, 2012.
ENGLISH ABSTRACT: Left ventricular hypertrophy (LVH) is a strong independent predictor of cardiovascular morbidity and mortality, while its regression is associated with an improved clinical prognosis. It is, therefore, vital to elucidate and fully comprehend the mechanisms that contribute to LVH development and to identify markers that indicate a strong predisposition to the development of severe cardiac hypertrophy, before its occurrence. Hypertrophic cardiomyopathy (HCM) serves as a model to investigate LVH development. This primary cardiac disease is characterised by LVH in the absence of increased external loading conditions and is caused by defective sarcomeric proteins, as a result of mutations within the genes encoding these proteins. However, the hypertrophic phenotype of HCM is largely complex, as we see strong variability in the extent and distribution of LVH in HCM, even in individuals with the same disease-causing mutation from the same family; this points toward the involvement of additional genetic and environmental modifiers. Components of the renin-angiotensin-aldosterone system (RAAS) influence LVH indirectly, through their key role in blood pressure regulation, but also directly, due to the direct cellular hypertrophic effects of some RAAS components. Previous genetic association studies aimed at investigating the contribution of RAAS variants to LVH were largely centred on a subset of polymorphisms within the genes encoding the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor genes, while the renin section and RAAS components downstream from ACE remained largely neglected. In addition, most previous studies have reported relatively small individual effects for a small subset of RAAS variants on LVH. In the present study we, therefore, employ a family-based genetic association analysis approach to investigate the contribution of the entire RAAS to this complex hypertrophic phenotype by exploring both the individual as well as the compound effects of 84 variants within 22 RAAS genes, in a cohort of 388 individuals from 27 HCM families, in which either of three HCM-founder mutations segregate. During the course of this explorative study, we identified a number of RAAS variants that had significant effects on hypertrophy in HCM, whether alone or within the context of a multi-variant haplotype. Through single variant association analyses, we identified variants within the genes encoding angiotensinogen, renin-binding protein, the mannose-6-phosphate receptor, ACE, ACE2, angiotensin receptors 1 and 2, the mineralocorticoid receptor, as well as the epithelial sodium channel and the Na+/K+-ATPase β-subunits, that contribute to hypertrophy in HCM. Using haplotype-based association analyses, we were able to identify haplotypes within the genes encoding for renin, the mannose-6-phosphate receptor, angiotensin receptor 1, the mineralocorticoid receptor, epithelial sodium channel and Na+/K+-ATPase α- and β subunits, as well as the CYP11B1/B2 locus, that contribute significantly to LVH. In addition, we found that some RAAS variants and haplotypes had statistically significantly different effects in the three HCM founder mutation groups. Finally, we used stepwise selection to identify a set of nine risk-alleles that together predicted a 127.80 g increase in left ventricular mass, as well as a 13.97 mm increase in maximum interventricular septal thickness and a 14.67 mm increase in maximum left ventricular wall thickness in the present cohort. In contrast, we show that a set of previously identified “pro-LVH” polymorphisms rather poorly predicted LVH in the present South African cohort. This is the first RAAS investigation, to our knowledge, to provide clear quantitative effects for a subset of RAAS variants indicative of a risk for LVH development that are representative of the entire pathway. Our findings suggest that the eventual hypertrophic phenotype of HCM is modulated by the compound effect of a number of RAAS modifier loci, where each polymorphism makes a modest contribution towards the eventual phenotype. Research such as that presented here provides a basis on which future studies can build improved risk profiles for LVH development within the context of HCM, and ultimately in all patients with a risk of cardiac hypertrophy.
AFRIKAANSE OPSOMMING: Linker ventrikulêre hipertrofie (LVH) is 'n sterk onafhanklike voorspeller van kardiovaskulêre morbiditeit en mortaliteit, terwyl LVH regressie verband hou met ‘n verbeterde kliniese voorspelling. Dit is dus noodsaaklik om die meganismes wat bydra to LVH ontwikkeling ten volle te verstaan en merkers wat 'n sterk geneigdheid tot die ontwikkeling van ernstige kardiale hipertrofie te identifiseer, voordat dit voorkom. Hipertrofiese kardiomiopatie (HKM) dien as 'n model om LVH ontwikkeling te ondersoek. Hierdie primêre hartsiekte word gekenmerk deur LVH en word meestal veroorsaak deur foutiewe sarkomeer proteïene as gevolg van mutasies binne die gene wat kodeer vir hierdie proteïene. Die hipertrofiese fenotipe van HKM is egter grootliks kompleks; ons sien, by voorbeeld, sterk veranderlikheid in die omvang en die verspreiding van LVH in HKM, selfs in individue met dieselfde siekte-veroorsakende mutasie binne dieselfde gesin, wat dui op die betrokkenheid van addisionele genetiese en omgewing modifiseerders. Komponente van die renien-angiotensien-aldosteroon sisteem (RAAS) beïnvloed LVH indirek, deur middel van hul belangrike rol in bloeddruk regulasie, maar ook direk, as gevolg van die direkte sellulêre hipertrofiese gevolge van sommige RAAS komponente. Vorige genetiese assosiasie studies wat daarop gemik was om die bydrae van RAAS variante LVH te ondersoek, was hoofsaaklik gesentreer op 'n groepie polimorfismes binne die gene wat kodeer vir die “angiotensin converting enzyme” (ACE) en angiotensien II tipe 1-reseptor gene, terwyl die renien gedeelte en RAAS komponente stroomaf van ACE meestal nie ondersoek was nie. Daarbenewens het die meeste vorige studies relatief klein individuele gevolge gerapporteer vir 'n klein groepie RAAS variante op LVH. In die huidige studie het ons dus 'n familie-gebaseerde genetiese assosiasie-analise benadering gebruik om die bydrae van die hele RAAS tot hierdie komplekse hipertrofiese fenotipe te ondersoek deur 'n studie van die individuele-, sowel as die saamgestelde effekte van 84 variante binne 22 RAAS gene, in 'n groep van 388 individue vanaf 27 HKM families, waarin een van drie HCM-stigter mutasies seggregeer. Gedurende die loop van hierdie studie het ons 'n aantal RAAS variante wat ‘n beduidende uitwerking op HKM hipertrofie geïdentifiseer, hetsy alleen of binne die konteks van' n multi-variant haplotipe. Deur middel van enkele variant assosiasie toetsing het ons variante geïdentifiseer binne die gene wat kodeer vir angiotensinogen, renien-bindende proteïen, die mannose-6-fosfaat reseptor, ACE, ACE2, angiotensien reseptore 1 en 2, die mineralokortikoïd reseptor, sowel as die epiteel natrium kanaal en Na+/ K+-ATPase β-subeenhede, wat bydra tot HKM hipertrofie. Deur die gebruik van haplotipe-gebaseerde assosiasie ontleding was ons in staat om haplotipes te identifiseer binne die gene wat kodeer vir renien, die mannose-6-fosfaat reseptor angiotensien reseptor 1, die mineralokortikoïd reseptor, epiteel natrium kanaal en die Na+/ K+-ATPase α-en β subeenhede, sowel as die CYP11B1/B2 lokus, wat aansienlik bydra tot LVH. Verder het ons bevind dat sommige RAAS variante en haplotipes statisties beduidende verskillende effekte gehad het in die drie HKM stigter mutasie groepe. Laastens, het ons stapsgewyse seleksie gebruik om 'n stel van nege risiko-allele wat saam' n toename van 127.80 g in linker ventrikulêre massa, sowel as 'n 13.97 mm toename in maksimum ventrikulêre septale dikte, en' n 14.67 mm verhoging in maksimum linker ventrikulêre wanddikte voorspel, te identifiseer in die huidige kohort. In teenstelling hiermee wys ons dat 'n stel van voorheen geïdentifiseerde "pro-LVH" polimorfismes swakker gevaar het as LVH-voorspellers in die huidige Suid-Afrikaanse kohort. Hierdie is die eerste RAAS ondersoek, tot ons kennis, wat ‘n duidelike kwantitatiewe gevolge vir 'n stel RAAS variante wat ‘n verhoogde risiko tot LVH ontwikkeling aandui, wat verteenwoordigend is van die hele RAAS. Ons bevindinge dui daarop dat die uiteindelike hipertrofiese fenotipe van HKM gemoduleer word deur die saamgestelde effek van 'n aantal RAAS wysiger loki, waar elke polimorfisme ' n beskeie bydrae maak tot die uiteindelike fenotipe. Navorsing soos dié wat hier aangebied word dien as 'n basis waarop toekomstige studies kan bou vir ‘n verbeterde risiko-profiel vir LVH ontwikkeling binne die konteks van die HKM, en uiteindelik in alle pasiënte met' n verhoogde risiko vir kardiale hipertrofie.

Objective: Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality. Design: Prospective cohort study with a 4.5-year follow-up period. Methods: From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality. Results: At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m2. No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2–Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2–Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33–0.74; adjusted HR 0.62, 95% CI 0.42–0.939; CV events: Q2–Q5 versus Q1: crude HR 0.54, 95% CI 0.38–0.77; adjusted HR 0.68, 95% CI 0.48–0.97). Kaplan–Meier curves revealed similar data. Conclusions: Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors.

Background: Acute myocardial infarction (AMI) is a major public health concern. There are limited recent national-level population-based epidemiological data on AMI in England. As a result, the current burden of disease is difficult to quantify. Aim: This thesis addresses gaps in knowledge on AMI in England. It aims to provide a comprehensive analysis of AMI epidemiology over the last decade. Methods: This is a population-based study using person-linked routine hospital and mortality data for England for the period from 1 April 1998 to 31 March 2008. Main outcome measures include: trends in event rate, case fatality, and mortality for AMI, as well as trends in characteristics of, and hospital care for, the AMI patient population between 1999 and 2007; rates of occurrence and case fatality for first and recurrent AMI in 2007; and five-year survival and risk of a second AMI for 2003 to 2007. Results: Total age-standardised AMI mortality rate fell by around half, while the age-standardised event rate and case fatality rate each declined by around one third between 1999 and 2007. Approximately half of the decline in AMI mortality was attributed to a decline in event rate and half to improved survival. During the 2000s, the hospitalised AMI patient population became increasingly elderly, presented with more comorbidities, underwent more revascularisation procedures, and spent less time in hospital. In 2007, approximately 90,000 AMIs occurred in England, of which around one third were fatal, one in seven were reinfarctions, and three quarters were AMIs in those aged 65 years and older. Among 30-day survivors of a first AMI, around one in three men and one in four women died within five years, and about one in eight men and one in six women experienced a second AMI in the same time period. Conclusions: There have been substantial improvements in AMI occurrence, survival, and mortality over the last decade in England. This was driven by improvements in prevention and acute medical treatment. The results in this thesis emphasise the importance of both.

This thesis consists of three prospective studies, examining whether leisure time physical activity may compensate for the adverse association between diabetes and risk of death from cardiovascular disease and risk of acute myocardial infarction (AMI). We have used data from the HUNT Study, linked with the Cause of Death Registry as well as hospital admissions due to acute myocardial infarction at the two hospitals in Nord- Trøndelag County. Diabetes was associated with almost threefold higher risk of death from cardiovascular disease among the physically inactive. People with diabetes who reported ≥ 3 hours of light physical activity had similar risk as inactive people without diabetes. We also found that the favourable effect of physical activity were largest among those with most severe diabetes, measured as medical treatment status. Finally, we found an increased risk of first acute myocardial infarction among people with diabetes, and that this excess risk was cancelled out among those who reported a high physical activity level. Moreover, a normal body weight was associated with lower risk of first AMI, especially when combined with a moderate or high level of physical activity. Our results suggests that the favourable effect of physical activity should be within reach for most people with diabetes and should be more strongly encouraged as a therapeutic measure additional to medical treatment.
Denne avhandlingen består av tre prospektive studier som undersøker hvorvidt fysisk aktivitet kan kompensere for den uheldige sammenhengen mellom diabetes og risiko for kardiovaskulær død og risiko for hjerteinfarkt. Vi har benyttet data fra Helseundersøkelsen i Nord-Trøndelag koblet til Dødsårsaksregisteret, samt informasjon om sykehusinnleggelser grunnet hjerteinfarkt ved de to sykehusene i Nord-Trøndelag. Diabetes var assosiert med nesten tre ganger så høy risiko for å dø av kardiovaskulær sykdom hos de fysisk inaktive. Personer med diabetes som rapporterte ≥ 3 timer med lett fysisk aktivitet per uke, hadde tilsvarende risiko som inaktive personer uten diabetes. Videre fant vi at den gunstige effekten av fysisk aktivitet var størst for de med alvorligst grad av diabetes, målt som medikamentell behandling. Vi fant også en økt risiko for hjerteinfarkt blant personer med diabetes, og at denne forhøyete risikoen ble kansellert blant de som rapporterte et høyt fysisk aktivitetsnivå. En normal kroppsvekt var også assosiert med lavere risiko for hjerteinfarkt, særlig i kombinasjon med fysisk aktivitet. Våre resultater tyder på at den gunstige effekten av fysisk aktivitet er innen rekkevidde for de fleste med diabetes og i enda større grad bør vektlegges som et ledd i behandlingen av personer med diabetes, i tillegg til medisinering.

Doença cardiovascular é uma causa importante de morte em pacientes em diálise. Doença arterial obstrutiva periférica (DAOP) é um fator prognóstico de doença cardiovascular. Índice de pressão tornozelo-braquial (ITB) é um método não invasivo usado para o diagnóstico de DAOP. A diferença entre ITB pré e pós diálise ainda não foi formalmente testada e foi um dos objetivos deste estudo. Além disso, nós avaliamos o ITB como marcador de mortalidade em pacientes incidentes em hemodiálise. ITB foi obtido por método oscilométrico automático em uma população de pacientes incidentes em hemodiálise. Este estudo foi desenhado para testar a aplicabilidade da determinação do ITB com o uso de 2 aparelhos oscilométricos simultâneos de pressão arterial (Omron Corp 705 CP Corp, Tokyo, Japan) comparando pré e pós diálise assim como lados direito e esquerdo. 123 pacientes (85 homens e 38 mulheres) idade 53±19 anos foram incluídos. Medidas de pressão arterial do lado direito e do lado esquerdo apresentaram médias semelhantes (p=0,565), assim como em 3 sessões consecutivas de diálise, tempo 1, 2 e 3 (coeficiente de variação menor que 5). Nenhuma diferença foi encontrada entre ITB pré e pós diálise, tanto no lado direito quanto no lado esquerdo, assim como nos tempos 1, 2 e 3. Em pacientes com história de DAOP, o ITB pré vs. pós diálise teve uma tendência a ser significante no lado direito (p=0,088). Durante o período de acompanhamento, 31 pacientes morreram. Estes pacientes eram mais velhos e apresentaram maiores níveis de cálcio. Diabetes, hipertensão e qualquer outro fator de risco cardiovascular não estiveram associados com mortalidade. Pacientes com ITB baixo (<0,9) e alto (>1,3) apresentaram maior mortalidade que pacientes com ITB normal (0.9-1.3). Foi concluído que medidas de ITB pré e pós diálise mostraram baixa variabilidade. O ITB em pacientes com história de DAOP deve ser avaliado com mais atenção. A presente técnica usada neste estudo pode ser usada como marcador de mortalidade em pacientes incidentes em hemodiálise
Cardiovascular disease is an important cause of death in patients on dialysis. Peripheral arterial disease (PAD) is a prognostic factor for cardiovascular disease. Ankle-brachial index (ABI) is a non-invasive method used for the diagnosis of PAD. The difference between ABI pre and post dialysis was not yet formally tested, and it was one objective of this study. In addition, we evaluate the ABI in predict mortality in incident patients on hemodialysis. ABI was assessed by automated oscillometric device in incident patients on hemodialysis. This study was designed to assess the applicability of ABI determination with the employment of two automated oscillometric blood pressure devices simultaneously (Omron Corp 705 CP Corp, Tokyo, Japan), comparing pre and post dialysis as well right and left side. The measurements were done by using two oscillometric devices simultaneously to measure blood pressure in upper and lower extremities. 123 patients (85 men and 35 women), age 53±19 years were enrolled. Blood pressure measurements on the right side and on the left side presented similar means (p=0,565), as well in the consecutive sessions, times 1, 2 and 3, (coefficient of variation lower than 5). We found no difference in ABI pre and post dialysis, either on the right or left side, as well in times 1, 2 and 3. In patients with history of PAD, the ABI pre vs. post dialysis was of borderline significance on the right side (p=0.088). During the follow-up period, 31 patients died. These patients were older and presented higher calcium level. Diabetes, hypertension and any other cardiovascular risk factor were not associated with mortality. Patients with either low ABI or high ABI (<0.9 and >1.3, respectively) presented higher mortality than patients with normal ABI (0.9-1.3). We concluded that ABI measured pre and post dialysis offered low variability. The ABI in patients with history of PAD should be evaluating with caution. The current method applied in this study can predict mortality among incident patients on hemodialysis

Introduction: Diagnosed adrenal incidentalomas (AI) are increasing and dexamethasonesuppression test (DST) is gold standard for detection of excess cortisol production. Patients canbe categorized into three groups based on the DST level; non-functional adrenal adenomas(NFAA), possible autonomous cortisol secretion (PACS) and autonomous cortisol secretion(ACS), the latter two associated with increased risk of cardiovascular morbidity and mortality. Aim: The aim of this study was to compare cardiovascular morbidity and mortality in patientswith adrenal incidentalomas with and without hypercortisolemia defined by the EuropeanSociety of Endocrinology (2016) guidelines. Method: Retrospectively 160 consecutive patient charts between 2008 and 2015 were reviewedand 59 included. They were further categorized in NFAA (n = 37) or PACS (n = 22). Patientswith signs and symptoms of hormonal overproduction or AI found during malignancyinvestigations were excluded. Due to strict adherence to inclusion and exclusion criteria, onlyone case of ACS was found and excluded due to ethical reason. Results: Increased prevalence of type 2 diabetes in PACS group at baseline. No difference incardiovascular disease or mortality between the groups could be seen after mean follow up of7 years. Three (8%) patients in the NFAA group deceased, all of malignancy. In the PACSgroup, five (23%) deceased. Cause of death was cerebral infarction (n = 2), malignancy (n =1)and other causes (n =2). Conclusion: No significant difference of cardiovascular morbidity and mortality could be seenbetween NFAA and PACS during follow up. A prospective multicentre study is needed toidentify the long-term outcomes.

The aim of this PhD thesis was to expand the current knowledge of “traditional Sami” diet and lifestyle, and to test aspects of the Sami diet and lifestyle, specifically dietary pattern, macronutrient distribution and coffee consumption, in population-based epidemiological studies of mortality and incident cardiovascular disease and cancer in a general population. In Paper I, semi-structured interviews were conducted with 20 elderly Sami concerning their parent’s lifestyle and diet 50-70 years ago. Questionnaire data from 397 Sami and 1842 matched non-Sami were also analyzed, using non-parametric tests and partial least square methodology.  In Papers II-IV, mortality data and incident cancer data for participants in the Västerbotten Intervention Program (VIP) cohort were used for calculations of hazard ratios by Cox regression. In Paper II, a Sami diet score (0-8 points) was constructed by adding one point for each intake above the median for red meat, fatty fish, total fat, berries and boiled coffee, and one point for each intake below the median for vegetables, bread and fibre. In Paper III, deciles of energy-adjusted carbohydrate (descending) and protein (ascending) intake were added to create a Low-Carbohydrate, High-Protein (LCHP) score (2-20 points). In Paper IV, filtered and boiled coffee consumption was studied in relation to incident cancer. In Paper V, a nested case-control study of filtered and boiled coffee consumption and acute myocardial infarction, risk estimates were calculated by conditional logistic regression. Surprisingly, fatty fish may have been more important than reindeer meat for the Sami of southern Lapland in the 1930’s to 1950’s, and it is still consumed more frequently by reindeer-herding Sami than other Sami and non-Sami. Other dietary characteristics of the Sami 50-70 years ago and present-day reindeer-herding Sami were high intakes of fat, blood, and boiled coffee, and low intakes of bread, fibre and cultivated vegetables (Paper I). Stronger adherence to a “traditional Sami” diet, i.e. a higher Sami diet score, was associated with a weak increase in all-cause mortality, particulary apparent in men (Paper II). A diet relatively low in carbohydrates and high in protein, i.e. a high LCHP score, did not predict all-cause mortality compared with low LCHP score, after accounting for saturated fat intake and established risk factors (Paper III).  Neither filtered nor boiled coffee consumption was associated with cancer for all cancer sites combined, or for prostate or colorectal cancer. For breast cancer, consumption of boiled coffee ≥4 versus <1 occasions/day was associated with a reduced risk. An increased risk of premenopausal and a reduced risk of postmenopausal breast cancer were found for both total and filtered coffee. Boiled coffee was positively associated with the risk of respiratory tract cancer, a finding limited to men (Paper IV). A positive association was found between consumption of filtered coffee and the risk of acute myocardial infarction in men (Paper V). In conclusion, the findings of Paper I, in particular the relative importance of fatty fish compared to reindeer meat in the “traditional Sami” diet of the 1930’s-1950’s, suggest that aspects of cultural importance may not always be of most objective importance. The findings of Papers II-V generally did not support health benefits for the factors studied. The relatively good health status of the Sami population is therefore probably not attributable to the studied aspects of the “traditional Sami” lifestyle, but further investigation of cohorts with more detailed information on dietary and lifestyle items relevant for “traditional Sami” culture is warranted.
Syftet med denna avhandling var att beskriva livsstil och kostvanor hos samer. Det var också att undersöka hur en ”traditionell samisk” livsstil påverkar risken att insjukna av eller dö i cancer och hjärt-/kärlsjukdom i en norrländsk normalbefolkning. En majorietsbefolkning har alltså undersökts ur ett minoritetsperspektiv. Avhandlingen belyser framför allt kostvanor, fördelning av de näringsämnen som innehåller energi (kolhydrat, protein, fett) och konsumtion av kok- och bryggkaffe. Bakgrunden till undersökningarna var att samerna, till skillnad från de flesta andra urfolk i världen, kan förvänta sig ett lika långt liv som majoritetsbefolkningen. När det gäller hjärtkärlsjukdom finns inga stora etniska skillnader, men samiska män, särskilt renskötande, har lägre risk att drabbas av cancer än icke-samer. Det finns ingen entydig förklaring till samernas relativt goda hälsa, men det kan finnas ett samband med kostvanor och livsstil. Delstudie I var en intervjustudie med äldre samer och fungerade som bakgrund för de andra delstudierna. Tjugo äldre samer intervjuades om sina föräldrars livsstil och kostvanor för 50-70 år sedan. Dessutom analyserades kostdata från 81 renskötande och 226 icke-renskötande samer och 1842 matchade icke-samer för att se vilka skillnader som fanns mellan grupperna. Intervjuerna visade överraskande att fet fisk kan ha varit viktigare än renkött för samerna i södra Lappland under 1930-1950-talen. Fet fisk äts fortfarande i högre utsträckning av renskötande samer än av andra samer och icke-samer. Saker som har hög kulturell betydelse (i detta fall renkött) behöver alltså inte alltid ha lika stor betydelse ur ett objektivt, vetenskapligt perspektiv. Andra typiska särdrag hos den samiska kosten var en hög andel av fett, blod och kokkaffe och en låg andel av bröd, fibrer och odlade grönsaker. Det dagliga livet hos samerna på 1930-1950-talen präglades också mycket mer av fysisk aktivitet än vad det gör idag. De samiska männen arbetade oftast långt hemifrån, medan kvinnorna hade ansvaret hemmavid för fiske, jordbruk och trädgårdsskötsel (som introducerades under 1930-1950-talen). Kvinnorna tog även hand om hushållsarbetet och barnen. Delstudierna II-V handlade om olika aspekter av samisk kost i relation till dödlighet och sjuklighet. Till dessa användes huvudsakligen data från Västerbottens hälsoundersökningar, men i delstudie V även från MONICA-projektet, som är en del av ett multinationell forskningsprojekt om hjärt-/kärlsjukdom.  Totalt ingick på så sätt data från mer än 80 000 unika individer från en allmän, till största delen icke-samisk, normalbefolkning. Delstudie II byggde på en modell liknande den som använts för att undersöka hälsoeffekter av så kallad Medelhavsdiet.  En poängskala från 0-8 poäng, en så kallad ”Sami diet score”, skapades för att spegla likheter med ”traditionell samisk” kost. Den hälft av deltagarna som åt mest rött kött, fet fisk, fett, bär respektive kokkaffe, fick 1 poäng var, sammanlagt maximalt 5 poäng. Den hälft av deltagarna som åt minst grönsaker, bröd respektive fibrer fick också 1 poäng var, sammanlagt maximalt 3 poäng. Stora likheter med en ”traditionell samisk” kost, det vill säga höga ”Sami diet score” poäng, var förknippade med en svagt ökad dödlighet, särskilt hos männen. Det verkar därför osannolikt att den samiska kosten i sig förklarar den relativt goda hälsan hos samer. Denna fråga är dock mycket svår att undersöka, eftersom kostvanorna kan ha skiljt sig mellan olika samegrupper och över tid. Dessutom äter dagens västerbottningar mycket mindre av vissa livsmedel, jämfört med vad samerna gjorde förr i tiden. Det gäller till exempel fet fisk och bär.  För sådana livsmedel kan det därför vara extra svårt att påvisa samband med dödlighet. Syftet med kostenkäten i Västerbottens hälsoundersökningar är inte heller att spegla en ”traditionell samisk” kost. Det finns till exempel inga frågor om renkött och vilt, utan sådant kött räknas som en del av övrigt rött kött. Det här är första gången som någon undersökt betydelsen av ett ”traditionellt samiskt” kostmönster för hälsan på detta sätt. Fler liknande undersökningar i material med mer detaljerade frågor, som bättre fångar en samisk kost, är önskvärda. Lågkolhydratdieter, som har vissa likheter med den ”traditionella samiska” kosten, är både populära och kontroversiella. Eventuella långtidseffekter för hälsan är till stor del okända. I delstudie III speglades förhållandet mellan kolhydrater och protein i kosten med hjälp av så kallade LCHP (låg-kolhydrat, hög-protein) poäng. Högsta LCHP poäng fick de deltagare som åt minst kolhydrater och mest protein. Höga LCHP poäng påverkade inte risken att dö, eller att dö i cancer eller hjärt-/kärlsjukdom, efter att statistisk hänsyn tagits till intaget av mättat fett och de vanligaste riskfaktorerna. LCHP score användes i denna studie, istället för exempelvis en LCHF (low carbohydrate, high fat) variant. På så sätt kunde betydelsen av total fettmängd och av mättat fett också vägas in i analyserna. Dessutom innehåller kolhydrater och protein samma mängd energi per gram, vilket gör det lättare att byta ut dem mot varandra i en poängskala. Fett innehåller nästan dubbelt så mycket energi per gram som proteiner och kolhydrater. Inte bara olika sorters fett, utan även olika sorters protein och kolhydrater, kan spela roll för hälsan. Det är därför mycket svårt att skilja ut effekterna av mängd och kvalitet av kolhydrater, protein och fett i kosten. I delstudierna IV och V undersöktes risken att bli sjuk i cancer eller få en akut hjärtinfarkt hos västerbottningar som dricker mer respektive mindre kok- och bryggkaffe. De som drack mycket kaffe hade varken ökad generell cancerrisk, eller ökad risk för prostata- eller tjocktarmscancer. Kvinnor som drack kokkaffe ≥ 4 ggr/dag hade minskad risk för bröstcancer jämfört med kvinnor som drack <1 gång/dag.  Både totalt kaffeintag och intag av bryggkaffe var kopplade till ökad risk för bröstcancer hos yngre kvinnor och minskad risk hos äldre. Män som drack mycket kokkaffe hade ökad risk för cancer i luftvägarna. Dessa resultat visar att de som dricker olika sorters kaffe kan ha olika stor risk att drabbas av olika sorters cancer. I tidigare studier har inga starka samband hittats mellan kaffedrickande och cancer. Denna studie var den första att undersöka hur cancerriskerna ser ut hos människor som dricker olika sorters kaffe. När det gäller hjärtinfarkt, hade män som drack mycket bryggkaffe ökad risk, medan inga entydiga resultat kunde visas bland män som drack mycket kokkaffe. Tidigare studier har visat motstridiga resultat när det gäller kaffe och hjärt-/kärlsjukdom, även om kaffekonsumtion är vedertaget förknippat med en del faktorer som kan öka risken att drabbas av hjärtinfarkt, till exempel ökade halter av blodfetter. Betydelsen av kokkaffe har aldrig undersökts tidigare i en studie där uppgifter om kaffedrickande samlats in i förväg. Delstudierna II-V är alla så kallade observationsstudier. I sådana studier följer deltagarna ingen bestämd forskningsplan, utan lever sina normala liv och jämförs sedan med varandra.  I observationsstudier är det mycket svårt att ta hänsyn till alla möjliga störande faktorer som kan finnas i omgivningen. Därför är det i princip omöjligt att bevisa direkta samband mellan orsak och verkan i en observationsstudie. Delstudierna II-V hade emellertid den starkaste design som en observationsstudie kan ha. De byggde på en representativ normalbefolkning (= en befolkningsbaserad kohort), där data samlats in från ett stort antal personer (> 80 000 unika individer) medan de ännu var friska (= en prospektiv kohort).  Resultaten av enstaka observationsstudier har störst betydelse som underlag för att planera nya liknande, eller andra typer av mer riktade undersökningar. De är med andra ord hypotesgrundande. Om däremot flera observationsstudier visar på liknande resultat brukar man utgå från att resultaten är sanna, eller åtminstone sannolika.
(Nordsamiska) Guorahallama ulbmil lea muitalit sámi biepmu ja eallinvuogi birra ja iskat got árbevirolaš sámi borranvierut, makrobiebmama juogustus ja gáffegolaheapmi  váikkuhit jámolašvuođa  ja riskka oažžut borasdávdda dehe váibmo-/ suotnadávdda dábálaš davvi-ruoŧŧelaš ássiid luhtte. Guoktelogi sámi vuorrasa ledje jearahallon daid vánhemiid eallinvuogi  ja borramuša birra 50-70 jagi áigi (Oassedutkan 1). Dasa lassin  397 sámi ja 1842 ruoŧŧelačča biebmandata guorahallojuvvo eahpe-paramehtarlaš iskamiid ja partialalaš unnimus kvadráhta metoda (PLS) mielde. Dát golbma čuovvovaš oassedutkama, gait kohortdutkamat, isket jápminsiva dehe borasdávdabuohccivuođa oaseváldiid luhtte  Västerbottenis dearvas-vuohŧaiskkademiid hárrái (64 603-77 319 iskama) ja riskkaluoitimat leat rehkenaston Cox regrešuvnna  mielde. Oassedutkamis  2  árbevirolaš sámi biebman  lea speadjalaston čuokkesskála vuostá   0 rájes gitta 8 čuoggá.  Dát bealli oaseváldiin geat leat eanemus rukses bierggu, buoiddes guoli, buoiddi, murjiid ja vuoššangáfe borran, lea ožžon 1 čuoggá juohke áidna biebmanelemeanta ovddas, oktiibuot eanemus 5 čuoggá. Vel 3 čuoggá dát bealli oaseváldiin lea ožžon geat lea unnimus šattuid, láibbi ja fiberiid borran, eanemus oktiibuot 3 čuoggá. Oassedutkamis 3 speadjalastá oktavuođa kolhydráhtaid ja proteiinnaid gaskkas  biebmamis  LCHP (vuolit-kolhydráhta, alit-proteiidna) čuoggáid bokte. Alimus LHCP čuoggát (=20) dát oasseváldit leat ožžon geat leat borran unnimus kolhydráhtaid ja eanemus proteiinnaid  ja vuolimus čuoggát (=2)  dát oasseváldit leat ožžon geat leat borran eanemus kolhydráhtaid ja unnimus proteiinnaid. Oassedutkamis 4 riska borasdávdabuohccivuođa ektui guorahallojuvvo brygg- ja vuoššangáffejuhkkiid  luhtte. Oassedutkan 5 lei goallostuvvon dárkkástus-dutkan, gos riska fáhkkatlaš healladávdda oažžut gáffejuhkkiid luhtte rehkenasto logistihkalaš eaktuduvvon regrešuvnna bokte. Sáhttá leahkit nu ahte buoiddes guolli lea rievtti mielde leamašan deaŧaleabbo sámiide go boazobiergu lulli Lapplánddas  1930-1950-logus ja badjeolbmot ain dávjábut borret dan go iežá sámiid ja ruoŧŧelaččat. Iežá sierra erenomášvuohta sámi biebmamis lei alit oassi buoiddis, mális ja vuoššangáfes ja vuolit oassi láibbis, fiberiin ja šaddaduvvon  šattuin (Oassedutkan 1). Stuora seammaláganvuođat árbevirolaš sámi biebmamiin, rievtti mielde alit Sami diet score čuoggát, ledje čatnon veahá aliduvvon jámolašvuhtii  dievdduid luhtte muhto ii fal nissoniid luhtte (Oassedutkan 2). Biebman mas vuolit oassi kolhydráhtaid ja alit oassi proteiinnat, rievtti mielde alit LHCP čuoggát, ii váikkuhan riskka jápmit, maŋŋel go lea statistihkalaččat jurddašan ahte buoiddi borrat ja mat dát leat dát sajáiduvvon riskafáktorat (Oassedutkan 3). Gáffejuhkan ii lean čatnon eaneduvvon borasdávdariskii, iige eaneduvvon riskii oažžut prostata- gassačoalleborasdávdda. Nissoniin mat juhke vuoššangáfe ≥ 4 geardde/beaivái lei geahpeduvvon riska oažžut čižžeborasdávdda go nissonat mat juhke <1 geardde/beaivái.  Ollesgáffe ja brygg-gáffe ledje čatnon eaneduvvon riskii oažžut čižžeborasdávddá nuorat nissoniid luhtte ja geahpeduvvon riskii vuorrasiin luhtte. Dievdduin mat juhke ollu vuoššangáfe lei eaneduvvon riska oažžut borasdávdda (Oassedutkan 4). Dievdduin mat juhke olu brygg-gáfe lei eaneduvvon riska oažžut healladávdda (Oassedutkan 5). Vuorrasit sámiid muitalusat man olu guoli sin vánhemat leat borran boazobierggu ektui 1930-1950-logus, čujuhit ahte bealit main alit kultuvrralaš mearkkašupmi eai dárbbaš seamma nanu objektivalš mearkkašumi atnit. Oassedutkamiid 2-5 bohtosat čujuhit ahte guorahallon bealit árbevirolaš sámi biebmamis ja eallinvuogis eai váikkut gárrasit dearvvašvuođa ja buohccivuođa dábálaš davviruoŧŧelaš ássiid luhtte.
(Lulesamiska) Dán guoradallama ájggom lij sáme biebmov ja viessomvuogev tsuojgodit, ja åtsådit gåk árbbedábak sáme bårråmdábe, stuoräládusebna juohkem ja káffajuhkam nuorttalándak álmmugin, bájnná jábmemav ja bårredávddabalov ja tsåhke-/ varravárredávddabalov. Guoktalågev sáme gatjádaláduvvin sijá äjgádij viessomvuoge ja biebmo birra 50-70 jage dán åvddåla (Oasseåtsålvis 1). Biebbmodáhtá 397 sámes ja 1842 láttes guoradaláduvvin parametragahtes gähttjalimij ja muhtem miere unnemus kvadráhta vuoge (PLS) viehkijn. Gålmmå tjuovvo oasseåtsådime, gájkka kohorttaåtsådime, vuolggin Västerbottena varresvuohtaåtsådimj oassálasstij jábmemårijs jali bårredávddaskihpudagájs (64 603-77 319). Ballamoarremerustallamav dahkin Cox regressionijn.  Oasseåtsådibme 2 spiedjildij avtaárvojt árbbedábak sáme biebmon tjuokkesmåhtajn nållå rájes gávtse tjuoggáj. Dat lahkke oassálasstijs gudi bårrin ienemus ruoppsis biergov, buojdes guolev, buojdev, muorjijt ja máleskáfav, oattjoj avtav tjuoggáv juohkka avta bårråmoases, aktan 5 tjuoggá ienemusát.  Ájn 3 tjuoggá oattjoj dat lahkke oassálasstijs mij båråj binnemus ruonudisájt, lájbijt ja fiberijt, aktan ienemusát 3 tjuoggá. Oasseåtsådibme 3 spiedjilt vidjurijt kolhydráhtaj ja proteijnaj gaskan biebmon nåv gåhtjodum LCHP (vuolle-kolhydráhta, alla-proteijna) tjuoggáj viehkijn.  Alemus LCHP tjuoggájt (=20) oadtjun oassálasste gudi binnemus kolhydráhtajt ja ienemus proteinajt bårrin ja vuolemus LCHP tjuoggájt (=2) oassálasste gudi ienemus kolhydráhtajt ja binnemus proteijnajt bårrin.  Oasseåtsådimen 4 åtsådaláduváj bårredávddaballo brygga- ja máleskáffajuhkkijn. Oasseåtsådibme 5 lij aktijdum guoradim-åtsådibme, gånnå káffajuhkkij tsåhkedávddaballo merustaláduváj aktijdam vihkemáhtsadime baktu. Vuordedahtek lij buojdes guolle ájnnasabbo gå boatsojbierggo sámijda oarjje Lapplándan 1930-1950-lågojn ja ájn vilá ällosáme guolev ienebut bårri gå ietjá sáme ja látte. Ietjá sierra merka sáme biebmon lij alep oasse buojdes, máles ja máleskáfas ja unnep oasse lájbes, fiberis ja sáddjidum ruonudisájs (Oasseåtsådibme 1). Árbbedábak sáme biebmo muoduk biebbmo, alep Sami diet score tjuoggáj, aktijaneduváj lasse jábmemijn sierraláhkáj ålmmåj hárráj (Oasseåtsådibme 2). Biebbmo vuolep kolhydráhttaåsijn ja alep proteijnnaåsijn, alla LCHP tjuoggáj, ittjij jábmembalov bájne, maŋŋel gå statistijkalattjat gehtjadam buojddebårråmijt ja ieme ballovidjurijt (Oasseåtsådibme 3).  Káffajuhkam lij tjanádum juogu de lasse gájkkásasj bårredávddaballuj, jali lasse prostáhta- bahtatjoallebårredávddaj. Kujnajn gudi máleskáfav juhkin ≥ niellji bäjvváj lij binnep njidtjebårredávddaballo gå buohtastahttá kujnaj gudi < akti bäjvváj juhkin. Ålleskáffa ja bryggakáffa tjanáduváj lasse njidtjebårredávddaballuj nuorap kujnaj hárráj ja binnep vuorrasappoj. Ålmmåjn gudi juhkin edna máleskáfav lij lasse bårredávddaballo vuojŋŋamorgánajn (Oasseåtsådibme 4). Ålmmåjn gudi juhkin edna bryggakáfav lij lasse tsåhkedávddaballo (Oasseåtsådibme 5). Vuorrasap sámij tsuojggoma äjgádij guollebårråmis gå buohtastahttá boatsojbierggobårråmijn 1930-1950-lågo, vuosedi biele alla kultuvrak sisanos e agev dárbaha sämmi nanos objektijvak sisanov adnet. Oasseåtsådimij 2-5 båhtusa vuosedi åtsådum biele árbbedábak sámebiebmos ja viessomvuoges e varresvuodav ja skihpudagáv nuorttalándak álmmuga hárráj heva bájne.
(Sydsamiska) Dan goerehtimmien ulmie lea saemien beapmoem jïh jielemevuekiem buerkiestidh jïh dotkedh guktie aerpievuekien saemien beapmoevuekieh, makrobïepmehtimmiej juekeme jïh prïhtjhjovhkeme jaemedem jïh riskem dijpieh vaajmoe-/ jïh soeneskïemtjelassen muhteste noerhtesvöörjen sïejhmi årroji luvnie. Lea göökteluhkie saemien voeresh goerehtamme daej eejtegi jielemevuekien jïh beapmoen dïehre  50-70 jaepiej juassah (Stuhtjedotkeme 1). Dïsse lissine lea beapmoedaatam goerehtamme 397 saemijste jïh 1842 laedtijste ov-parametrihken gïehtjedimmiej jïh partiellen unnemes kvadraaten vuekien mietie (PLS).  Dah golme båetien stuhtjedotkemh, gaajhkh kohortdotkemh, leah dotkeme man gaavhtan jaameme jallh mïetskeåedtjieskïemtjelassh daej luvnie gïeh meatan Västerbottenen healsoedotkemi muhteste (64 603-77 319 dotkemh) jïh riskeryøknemh  dorjeme Cox  regresjovnen viehkine. Stuhtjedotkemisnie 2 lea mohtedamme guktie aerpievuekien saemien beapmoe vaestede låhkoeraajterasse 0 raejeste 8 raajan. Daate bielie daejstie gïeh meatan gïeh jeenemes rööpses bearkoem, buajtehks gueliem, buejtiem, muerjieh jïh voessjemeprïhtjegem byöpmedamme, leah aktem låhkoem åådtjeme fïere guhte beapmoeelementen åvteste, jeenemes 5 låhkoeh. Dïsse lissine 3 låhkoeh åådtje daate bielie daejstie gïeh meatan gïeh unnemes kruanesaath, laejpiem jïh fiberh byöpmedamme, jeenemes 3 låhkoeh. Stuhtjedotkemisnie 3 daelie mohtede kolhydraath jïh proteinh beapmosne LHCP (vuelehks-kolhydraath, jïlle-proteine) låhkoej viehkine. Jillemes LHCP låhkoem åådtjeme (=20) dah gïeh meatan gïeh vaenemes kolhydraath jïh jeenemes proteinh byöpmedamme jïh vueliehkommes LHCP låhkoem (=2) åådtjeme dah gïeh meatan gïeh jeenemes kolhydraath jïh vaenemes proteinh byöpmedamme. Stuhtjedotkemisnie 4 riskem goerehtamme mietskeåedtjieskïemtjelassem åadtjodh brygg- jïh voessjemeprïhtjegejovhkiji luvnie. Stuhjtedotkeme 5 lïj tjetskeme-dotkeme gusnie riskem ryöknoe logistihken regresjovnen baaktoe jis maahta  faahketji vaajmoedåeriesmoerh åadtjodh prïhtjhjovhkiji luvnie. Buajtehks guelie meehti vihkielåbpoe årrodh båatsoesaemide goh bovtsebearkoe åarjel Lapplaantesne 1930-1950-låhkosne jïh daamhtah båatsoesaemieh daam byöpmedieh jeenebe goh jeatjah saemieh jïh laedtieh. Jeatjah sïejhmi sjïere vuekieh saemien beapmosne lea jïlle stuhtje buejteste,  maeleste jïh voessjemeprïhtjegistie jïh vuelie stuhtje laejpeste, fiberistie jïh kruanesaatijste (Stuhtjedotkeme 1). Jeenh saemien aerpievuekien beapmoe, jïlle Sami diet score låhkoeh, provhki vuesiehtidh vaenie jeananamme jaemede ålmaj gaskemsh bene ij nyjsenæjjaj gaskemsh (Stuhtjedotkeme 2). Beapmoe man vuelehks stuhtje kolhydraath jïh stoerre stuhtje proteijnh, jeenh LCHP låhkoeh, ij leah dïjpeme riskem jaemedh, dan mænggan goh lea ussjedamme statistihken muhteste man jeene buejtiem byöpmedidh jïh sijjiedahteme riskefaktovrh ussjedamme. (Stuhtjedotkeme 3). Prïhtjhjovhkeme ij leah tjoelmesovveme jeananamme mïetskeåedtjieriskese, jallh jeananamme riskese prostaate-voeresbuejtiemïetskeåedtjiem åadtjodh. Nyjsenæjjah gïeh voessjemeprïhtjegem jovhkeme ≥ 4 aejkien/biejjesne unnemes riskem utnin njammamïetskeåedtjiem åadtjodh nyjsenæjjaj muhteste gïeh jovhkeme <1 aejkien/biejjesne. Ellies prïhtjege jïh bryggeprïhtjege lea tjoelmesovveme jeananamme riskese njammamïestkeåedtjiem åadtjodh noere nyjsenæjjah luvnie jïh unniedamme riskem voeresi luvnie. Ålmah gïeh jeenh voessjemeprïhtjegem juvhkieh jeananamme riskem utnieh mïetskeåedtjiem åadtjodh girsesne (Stuhtjedotkeme 4). Ålmah gïeh jeenh bryggeprïhtjegem jovhkeme jeananamme riskem utnieh vaajmoedåeriesmoerem åadjtodh (Stuhtjedotkeme 5). Dah saemien voeresi soptsestimmieh man jeeneh gueliem daej eejtegh leah byöpmedamme bovtsebearkoem muhteste 1930-1950-låhkosne, vuesehte ahte daate bielie man vihkeles kultuvren sisvege ij eejnegen seamma objektiven sisvegem utnieh. Illeldahkh stuhtjedotkemijstie 2-5 vuesiehtieh ahte  dah bielieh mejtie lea goerehtamme saemien aerpienvuekien beapmoen jïh jielemevuekien muhteste eah healsoem jïh skïemtjelassem dïjph jeenebe goh sïejme noerhtesvöörjen årrojh.
(Umesamiska) Dahte guoreteme suptseste saamien beäpmoen jah jielemevuökien  biire jah giehtjedie guktie aarpievuökien saamien beäpmoeh, oajviebeäpmoeh jah kaavoeh mietete jaameke vahkake jah  cancerenne jah vajmoen/ virreveättennea nuorthen  allmetjeih luunie. Guökteluhke saamieih boariesh gihtjedihke lie elltie eihtegeh jielemevuökien jah beäpmoen biire dann baelie 50-70 jaapieh (Oasie 1). Jieneh beäpmoe-dataede dahkedihke lie 397 saamieiheste jah 1842 ruotseiheste dennake viehketihenne ieh parmetriske giehtjedemeh jah  partiellen unnemes kvadraten vuökien miete (PLS). Dah gullme oasieh boatien kohort- luhkemeh, allkemme lie jaamemeste jall canceremeste mieteih Västerbottenen varaasgiehtjemeih luunie (64603-77319 ollu) vahkake-tsiehkesjeme dahkedihke Cox-enne regressione. Oasienne 2 vuöjnedihke leh akte laakatjenne aarpievuökien saamien beäpmoeh vuösstede akte tsiehkesjerairoe 0 – 8. Dahte bielie deistie gieh jienemes ruöpses beärrkoede, buöjteks guöliede, buöjtiede borrein jah vuossjeme kaavoede juukein, akte tsiehkie fierte beäpmoih outeste otjoin, jienemes 5 tsiehkieh.Vielie 3 tsiehkieh dahte bielie otjoin gieh unnemes jaamoede jah urhtsede, laipiede jah fiberede borrein, jienemes 3 tsiehkeh. Oasienne 3 vuöjnedihke aktevuotta gasske kolhydrateh jah proteieneh beäpmoenne LCHP-esne (vuöleke kolhydrateh, jylloeke-proteineh) tsiehkie. Jyllemes LCHP tsiehkieh (=20) dainie mietenne unnemes kolhydrateh jah ollomes proteineh borrein jah unnemes LCHP tsiehkieh (2) dainie mietenne ollomes kolhydrateh jah unnemes proteineh borrein. Oasienne 4 giehtjedihke vahkake cancerede brygg- jah vuossjeme kaavoe juukejenne. Oasie 5 tjohkenne lin kontrolle- giehtjedeme vahkake hiehke vaajmoe-narrenne kaavoe-juukejenne tsiehkiesjdihke logistiske regressionenne. Buöjteke guölieh borretdihke mahtein vieliebe buutsebeärrkoeste saamieihesne oarrjel  saamien eätname 1930-1950 jaapienne jah vieliebe borretdihke buutsesaamieiheste guh jeätja saamieh jah ruotse-allmetjeh. Jeätja siejhme sierreme saamien beäpmoesne lin akte jylloeke oasie buöjtie-, viire-, jah vuossjeme kaavoeste jah akte vuöleke oasie laipie-, fibere-, joamoe jah urhtseste (Oasie 1). Ollu aktelaaka aarpievuökien saamien beäpmoeh, ollu Sami diet score tsiehkieh tjohkan lin vieliebe jaameme ollmaihenne sierrelaaka (oasie 2). Beäpmoihenne unne kolhydrateh jah ollu proteineh, ollu LCHP tsiehkie, ieh vahkake lasste jaamet, dann mingjelen guh statistiske ussjede valltedihke leh borremmiean gallane buöjtieste jah vihties vahkake faktoreiheste (oasie 3). Kaavoejuukeminne lin ieh vielebe aarpievuökien cancer-vahkake tjohkenne, jall vielebe vahkake prostate-kolorektale-cancere. Nyesenejah guh vuossjeme kaavoe juukein ≥4  aikieh/biejvie  unnebe vahkake nitje-cancereb lin muhteste nyesenejanneh gieh  <1 aikie/biejvie juukein. Gaihkekaavoe jah brygg-kaavoe lie tjoahkan vielebe nitje cancereb nyesenejanne jah unnebe vahkake boariesh nyesenejaihenne. Ollma guh ollu vuossjeme kaavoeb juukein cancereste gonkelmesenne vieliebe vahkake otjoin (oasie 4). Ollma guh ollu brygg-kaavoe vajmoe-narreme vieleb vahkake otjoin (oasie 5). Dah boariesh saamieh suptsestemeh man jingje guöliede elltie eihtegeh buutsebeärrkoeh borrein 1930-1950-aikie, vuösiete dahte bielie veäksekes kulture miele ieh gaihke aikie darpesjedennake veäksekes objektive miele leh. Oasie 2-5 vuösiete dah giehtjedemes dahte bielie aarpievuökien saamien beäpmoen jah jielemen vuökien ieh varaas jah skieptjeme mietete ieh nuorthen almetejeh ollu.

The term sedentary refers to a distinct class of activities which involve sitting or reclining and which do not cause an increase in energy expenditure above resting levels. Observational studies have reported positive associations between both sedentary time and the number of hours spent sitting per day, with risk for a number of health outcomes that are independent of moderate to vigorous physical activity (MVPA). The total time spent sitting can be amassed in different patterns (long and short bouts) and different types (watching TV, driving, working at a computer) that may have differential associations with health outcomes as well as different confounders that have yet to be properly explored. Further, limitations in current measures used to quantify sedentary behaviour and the possibility of residual confounding, mean that it is unclear whether the posture of sitting itself represents a risk to health or whether sitting is actually a proxy for low energy expenditure. This thesis aimed to examine; the associations between five separate sitting types with health risk, the prevalence of sitting behaviour in England, and the biological mechanisms which might underpin the observed negative health consequences of sitting. Using data from the Whitehall II cohort study the first four studies of this thesis examined prospective associations between sitting at work, TV viewing, non-TV leisure time sitting, total leisure time sitting (TV and non-TV leisure sitting combined) and total sitting from work and leisure, with four health outcomes; mortality, cardiovascular disease, type II diabetes and obesity. No association between any of the sitting indicators with risk for mortality or incident cardiovascular disease was found. TV viewing and total sitting were associated with an increase in risk for type II diabetes following adjustment for sociodemographic covariates and MVPA, but were attenuated following further adjustment for body mass index. None of the five sitting indicators were associated with incident obesity but being obese prior to the measurement of sitting was associated with the number of reported hours of daily TV viewing. The final study of this thesis examined the acute effect of sustained versus interrupted sitting on glucose and insulin metabolism. Interrupting sitting with repeated short bouts of light intensity walking significantly improved insulin sensitivity while repeated short bouts of standing did not. Sitting is a prevalent behaviour in English adults and varies by socio-demographic characteristics. Previously reported associations between sitting time and health risk may be confounded by light intensity physical activity and obesity. The absence of an effect of repeated standing bouts (a change in posture without a change in energy expenditure) suggests that promoting reductions in sitting without also promoting increases in movement are not likely to lead to improvements in metabolic health. New measures of sedentary behaviour are required that can be used in population studies, and can discriminate between the posture of sitting, standing and very low levels of physical activity of a light intensity. This would permit further studies that are needed to clarify the precise nature of the association between sitting and health.

Aquesta tesi es va plantejar per a millorar el coneixement de l’ epidemiologia de l’arteriopatia perifèrica, estudiar els factors implicats en la seva aparició i la repercussió en la morbimortalitat cardiovascular en el nostre entorn. A través del seguiment durant 5 anys d’ una cohort poblacional d'edat superior a 49 anys (cohort ARTPER), es van realitzar 3 estudis relacionats. En el primer estudi es va valorar la incidència d’arteriopatia perifèrica als 5 anys de seguiment de la cohort poblacional ARTPER i els factors associats a la seva aparició. En el segon estudi es va valorar la contribució de l’índex turmell-braç en la reclassificació del risc cardiovascular segons les funcions de risc Framingham i REGICOR i en el tercer estudi es va valorar l’evolució i el grau de control dels factors de risc cardiovascular clàssics, després de 5 anys de seguiment de la cohort i la seva relació amb la incidència d’arteriopatia perifèrica. La cohort ARTPER va ser creada entre octubre de 2006 i juny de 2008 per a estudiar la prevalença d’ arteriopatia perifèrica reclutant 3.786 individus >49 anys procedents de 24 centres de salut de l’àrea metropolitana de Barcelona i del Barcelonès Nord-Maresme. Posteriorment es va realitzar seguiment telefònic i revisió de la història clínica cada 6 mesos des de la inclusió dels participants fins 2016. Entre 2011- 2012 es van reexaminar els participants en una segona visita presencial per tal d’ avaluar la incidència d’ arteriopatia perifèrica. La participació va ser del 77%. Com a resultats d’ aquesta tesi s’ han publicat els següents articles: Alzamora MT, Forés R, Pera G, Baena-Díez JM, Heras A, Sorribes M, Valverde M, Muñoz L, Mundet X, Torán P. Incidence of peripheral arterial disease in the ARTPER population cohort after 5 years of follow-up. BMC Cardiovasc Disord. 2016; 16: 8. FI: 1,832. Q3. Forés R, Alzamora MT, Pera G, Baena-Díez JM, Mundet-Tuduri X, Torán P. Contribution of the ankle-brachial index to improve the prediction of coronary risk: the ARTPER cohort. PLoS One. 2018; 13(1): e0191283. FI: 2,806 Q1. Forés R, Alzamora MT, Pera G, Valverde M, Angla M, Baena-Díez JM, Mundet-Tuduri X. Evolución y grado de control de los factores de riesgo cardiovascular tras 5 años de seguimiento y su relación con la incidencia de arteriopatía periférica: cohorte poblacional ARTPER. Med Clin (Barc). 2017;148(3):107–113. FI: 1,125. Q3. Conclusions: La incidència d’ arteriopatia perifèrica en la cohort poblacional ARTPER després de 5 anys de seguiment es de 8,6 casos /1.000 persones-any. En persones < 65 anys és major en homes, igualant-se a partir dels 75 anys en ambdós sexes. Els factors associats al descens de l’índex turmell-braç i a la incidència d’arteriopatia perifèrica són: el tabaquisme, l’ edat i la limitació per realitzar exercici físic. Afegir l’índex turmell-braç al càlcul del risc cardiovascular (REGICOR) produeix una millora en la reclassificació a risc elevat del 7%. L’índex turmell-braç < 0,9 s’associa a una major incidència d’esdeveniments coronaris i cerebrovasculars en la cohort poblacional, de baix risc cardiovascular, ARTPER. La prevalença dels factors de risc clàssics i el seu tractament augmenten als 5 anys de seguiment però, només s’ obté un control òptim en el 7% dels pacients. El risc de presentar AP es multiplica per 2 en pacients amb HTA mal controlada i per 5 en persones fumadores.
This thesis was designed to improve the knowledge of peripheral arterial disease epidemiology , to study the involved factors in its onset and the cardiovascular morbidity and mortality impact in our environment. After 5 years of follow - up of a population cohort aged over 49 years (ARTPER cohort), 3 related studies were conducted. The first study evaluated the incidence of peripheral arterial disease at 5 years of follow-up of the ARTPER population cohort and the factors associated with its onset. The second study evaluated the contribution of the ankle-brachial index in the reclassification of cardiovascular risk according to Framingham and REGICOR the risk scores. The third study evaluated the evolution and the degree of control of the classics cardiovascular risk factors, after 5 years of cohort monitoring and its relation to the incidence of peripheral arterial disease. The ARTPER cohort was created between October 2006 and June 2008 to study the prevalence of peripheral arterial disease recruiting 3,786 individuals > 49 years old from 24 health centers in the metropolitan area of ​​Barcelona and the Barcelonès Nord-Maresme. Subsequently, a telephone tracking and review of the medical history was carried out every 6 months from the inclusion of the participants until 2016. Between 2011-2012 the participants were re-examined in a second face-to-face visit to evaluate the incidence of peripheral arterial disease. The participation was 77%. As a result of this thesis the following articles have been published: Alzamora MT, Forés R, Pera G, Baena-Díez JM, Heras A, Sorribes M, Valverde M, Muñoz L, Mundet X, Torán P. Incidence of peripheral arterial disease in the ARTPER population cohort after 5 years of follow-up. BMC Cardiovasc Disord. 2016; 16: 8. FI: 1,832. Q3. Forés R, Alzamora MT, Pera G, Baena-Díez JM, Mundet-Tuduri X, Torán P. Contribution of the ankle-brachial index to improve the prediction of coronary risk: the ARTPER cohort. PLoS One. 2018; 13(1): e0191283. FI: 2,806 Q1. Forés R, Alzamora MT, Pera G, Valverde M, Angla M, Baena-Díez JM, Mundet-Tuduri X. Evolución y grado de control de los factores de riesgo cardiovascular tras 5 años de seguimiento y su relación con la incidencia de arteriopatía periférica: cohorte poblacional ARTPER. Med Clin (Barc). 2017;148(3):107–113. FI: 1,125. Q3. Concusions: The peripheral arterial disease incidence in the ARTPER cohort after 5 years of follow-up was 8.6 cases / 1,000 person-years. In people <65 years old, it is higher in men, equaling> 75 years in both sexes. Smoking, age and limitation for physical exercise are the associated factors with decreased ankle-brachial index and the appearance of peripheral arterial disease. Adding the ankle-brachial index to the REGICOR score improves the reclassification at high risk cardiovascular about 7%. An ankle-brachial index <0.9 is associated with a higher incidence of coronary and cerebrovascular events in the population cohort, with low cardiovascular risk, ARTPER. The classic cardiovascular risk factors prevalence and its treatment increase after 5 years of follow-up, but only optimal control is achieved in 7% of patients. Poorly controlled hypertension doubles the risk of having peripheral arterial disease and smoking fivefold.

The aim was to contribute to the optimal use of the resting ECG by exploring, in middle-aged and elderly men, the development and regression of ECG abnormalities; the prognostic value of the ECG for cardiovascular disease compared to conventional risk factors; and the impact of age at baseline and follow-up time for prediction of cardiovascular disease.

It was based on the Uppsala Study of Adult Men cohort that was started in 1970. Participants were examined at ages 50, 70, 77, and 82, with annual updates on mortality and in-hospital morbidity using national registries.

The studies indicated that the prevalence of silent MI and frequency of regression of major Q/QS patterns may be higher than previously believed. Considering that persistent T wave abnormalities and ST segment depression carried twice as high a risk for future cardiovascular disease (CVD) mortality as new or reverted abnormalities, the results suggested that serial electrocardiograms (ECG) would contribute to proper risk assessment. Also, the inclusion of ischemic ECG findings significantly increased the predictive power of the Framingham score at age 70 for CVD.

While hypertension and dyslipidemia were consistent long-term risk factors for myocardial infarction at ages 50 and 70, the length of follow-up period and age at baseline affected the predictive power of ECG abnormalities, fasting insulin, BMI, and smoking.

For stroke, midlife values for blood pressure and ECG abnormalities retained prognostic value over long follow-up periods, even though they improved when re-measured in elderly participants. ApoB/apoA1 ratio, driven by apoA1, was associated with stroke in elderly but not middle-aged men. Hyperinsulinemia and diabetes mellitus were more specifically associated with ischemic stroke than with any-cause stroke.

In summary, the resting ECG carried prognostic information beyond conventional risk factors. Even though the low prevalence of ECG abnormalities at the age of 50 calls into question the role of the ECG as a screening tool, the additional risk information it carries with it justifies its regular and repeated registration above the age of 50.

Sepsis remains the second largest killer in the Intensive Care Unit (ICU), giving rise to a significant economic burden ($17b per annum in the US, 0.3% of the gross domestic product). The aim of the work described in this thesis is to improve the estimation of severity in this population, with a view to improving the allocation of resources. A cohort of 2,143 adult patients with sepsis and hypotension was identified from the MIMIC-II database (v2.26). The implementation of state-of-the-art models confirms the superiority of the APACHE-IV model (AUC=73.3%) for mortality prediction using ICU admission data. Using the same subset of features, state-of-the art machine learning techniques (Support Vector Machines and Random Forests) give equivalent results. More recent mortality prediction models are also implemented and offer an improvement in discriminatory power (AUC=76.16%). A shift from expert-driven selection of variables to objective feature selection techniques using all available covariates leads to a major gain in performance (AUC=80.4%). A framework allowing simultaneous feature selection and parameter pruning is developed, using a genetic algorithm, and this offers similar performance. The model derived from the first 24 hours in the ICU is then compared with a “dynamic” model derived over the same time period, and this leads to a significant improvement in performance (AUC=82.7%). The study is then repeated using data surrounding the hypotensive episode in an attempt to capture the physiological response to hypotension and the effects of treatment. A significant increase in performance (AUC=85.3%) is obtained with the static model incorporating data both before and after the hypotensive episode. The equivalent dynamic model does not demonstrate a statistically significant improvement (AUC=85.6%). Testing on other ICU populations with sepsis is needed to validate the findings of this thesis, but the results presented in it highlight the role that data mining will increasingly play in clinical knowledge generation.

BACKGROUND Vascular calcification is a major risk factor for cardiovascular morbidity and mortality in patients with end stage renal disease (ESRD). In Western countries, Blacks with ESRD appear to have lesser degrees of vascular calcification compared to non-Blacks. However, there is no published data on the association of ethnic differences in vascular calcification and survival in ESRD from Sub-Saharan Africa. METHODS This study assessed the 5-year change in vascular calcification and mortality in a previously published cohort of patients with ESRD. Vascular calcification was assessed by abdominal aortic calcification score (lateral abdominal radiograph) and vascular stiffness by pulse wave velocity. RESULTS Sixty-six of the original 74 participants, studied a baseline, were identified. The median age was 46.6 years (37.6-59.2) and 57.6% were women. Abdominal aortic calcification showed no progression among Blacks [baseline range 0-5, follow up range 0-8 (p=1.00)], but a nonsignificant trend to progression among non-Blacks [baseline range 0-19, follow up range 0-22 (p=0.066)]. Black participants did not display a survival advantage (p=0.870). Overall, sepsis was the most common cause of mortality (64% of those with an identifiable cause of death). Non-Blacks had higher parathyroidectomy rates than Blacks with 9/30 cases compared to 2/36 (p=0.036). After adjustment for parathyroidectomy at follow up, the odds ratio of having abdominal vascular calcification score of ≥1 amongst non-Blacks was 8.6-fold greater compared to Blacks (p= 0.03). Central aortic systolic pressures (CASP) and pulse wave velocities (PWV) were higher in the study population than age matched normative values. At follow up, a positive correlation (r=0.3) was observed between PWV and abdominal aortic calcification (p=0.04). Elevated baseline coronary artery calcification score and FGF-23 level at baseline were not associated with a difference in mortality. CONCLUSION There was no significant progression in vascular calcification among Blacks. After adjusting for increased parathyroidectomy rates, there was a greater progression of vascular calcification amongst non-Blacks compared to Blacks highlighting possible ethnic differences in calcium phosphate metabolism in patients with ESRD. The lack of vascular calcification progression in Blacks was not however associated with improved survival, but the sample size was small.

Objective: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and post discharge mortality and treatment of patients hospitalized with ADHF according to COPD status. Methods: The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 4 study years: 1995, 2000, 2002, and 2004. Results: Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and ACE inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 (adjusted RR 1.10; 95% CI 1.06, 1.14) and 5-years (adjusted RR 1.40; 95% CI 1.28, 1.42) after hospital discharge than patients who were not previously diagnosed with COPD. Conclusions: COPD is a common co-morbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and to ensure that patients with ADHF and COPD receive optimal treatment modalities.

Objective: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and post discharge mortality and treatment of patients hospitalized with ADHF according to COPD status. Methods: The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 4 study years: 1995, 2000, 2002, and 2004. Results: Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and ACE inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 (adjusted RR 1.10; 95% CI 1.06, 1.14) and 5-years (adjusted RR 1.40; 95% CI 1.28, 1.42) after hospital discharge than patients who were not previously diagnosed with COPD. Conclusions: COPD is a common co-morbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and to ensure that patients with ADHF and COPD receive optimal treatment modalities.