<p>Kidney dysfunction increases cardiovascular disease (CVD) risk. The mechanisms for the risk increase seem to involve a combination of traditional and non-traditional CVD risk factors.</p><p>We studied renal dysfunction as CVD and mortality risk factor in middle-aged men free from diabetes and CVD. The risk for myocardial infarction (MI) and CVD mortality was increased by ~40% in the 16.5% of men with worse renal function, independent of other CVD risk factors.</p><p>Renal transplant dysfunction as CVD and mortality risk factor was also studied. Renal transplant dysfunction was a risk factor for mortality and for combined CVD endpoint. The risk by renal transplant dysfunction was independent of traditional CVD risk factors as well as transplantation-specific risk factors. Only moderate increase in serum creatinine resulted in mortality and CVD risk comparable to diabetes, older age and higher low density lipoprotein levels.</p><p>In haemodialysis patients, the effects of a dialysis session on non-traditional CVD risk factors were studied. A HD session reduced asymmetric dimethylarginine (ADMA) and homocysteine levels, as well as augmentation index (AIx). The change in AIx was related to ADMA plasma level change.</p><p>In patients with stage 3-5 chronic kidney disease (CKD), endothelium dependent vasodilation (EDV) was studied together with markers of oxidative stress and C-reactive protein (CRP). CRP was related to lipid peroxidation, while EDV was related to intracellular antioxidative capacity measured by reduced glutathione levels.</p><p>These studies demonstrate that mild to moderate renal dysfunction is independently associated with increased CVD risk in apparently healthy people, as well as in renal transplant recipients. The mechanisms by which renal dysfunction increases CVD risk are yet to be elucidated. We suggest that arterial stiffness could be reduced in haemodialysis patients by increasing nitric oxide bioavailability. In stage 3-5 CKD patients, improving intracellular antioxidative capacity may result in endothelial function improvement.</p>

Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2007.

Thesis (Ph.D. (Electronical Engineering))--North-West University, Potchefstroom Campus, 2008.

Kidney dysfunction increases cardiovascular disease (CVD) risk. The mechanisms for the risk increase seem to involve a combination of traditional and non-traditional CVD risk factors. We studied renal dysfunction as CVD and mortality risk factor in middle-aged men free from diabetes and CVD. The risk for myocardial infarction (MI) and CVD mortality was increased by ~40% in the 16.5% of men with worse renal function, independent of other CVD risk factors. Renal transplant dysfunction as CVD and mortality risk factor was also studied. Renal transplant dysfunction was a risk factor for mortality and for combined CVD endpoint. The risk by renal transplant dysfunction was independent of traditional CVD risk factors as well as transplantation-specific risk factors. Only moderate increase in serum creatinine resulted in mortality and CVD risk comparable to diabetes, older age and higher low density lipoprotein levels. In haemodialysis patients, the effects of a dialysis session on non-traditional CVD risk factors were studied. A HD session reduced asymmetric dimethylarginine (ADMA) and homocysteine levels, as well as augmentation index (AIx). The change in AIx was related to ADMA plasma level change. In patients with stage 3-5 chronic kidney disease (CKD), endothelium dependent vasodilation (EDV) was studied together with markers of oxidative stress and C-reactive protein (CRP). CRP was related to lipid peroxidation, while EDV was related to intracellular antioxidative capacity measured by reduced glutathione levels. These studies demonstrate that mild to moderate renal dysfunction is independently associated with increased CVD risk in apparently healthy people, as well as in renal transplant recipients. The mechanisms by which renal dysfunction increases CVD risk are yet to be elucidated. We suggest that arterial stiffness could be reduced in haemodialysis patients by increasing nitric oxide bioavailability. In stage 3-5 CKD patients, improving intracellular antioxidative capacity may result in endothelial function improvement.

Objective: Insulin-like growth factor-I (IGF-I) has been suggested to be a prognostic marker for the development of cancer and, more recently, cardiovascular disease. These diseases are closely linked to obesity, but reports of the association of IGF-I with measures of obesity are divergent. In this study, we assessed the association of age-dependent IGF-I standard deviation scores with body mass index (BMI) and intra-abdominal fat accumulation in a large population. Design: A cross-sectional, epidemiological study. Methods: IGF-I levels were measured with an automated chemiluminescence assay system in 6282 patients from the DETECT study. Weight, height, and waist and hip circumference were measured according to the written instructions. Standard deviation scores (SDS), correcting IGF-I levels for age, were calculated and were used for further analyses. Results: An inverse U-shaped association of IGF-I SDS with BMI, waist circumference, and the ratio of waist circumference to height was found. BMI was positively associated with IGF-I SDS in normal weight subjects, and negatively associated in obese subjects. The highest mean IGF-I SDS were seen at a BMI of 22.5–25 kg/m2 in men (+0.08), and at a BMI of 27.5–30 kg/m2 in women (+0.21). Multiple linear regression models, controlling for different diseases, medications and risk conditions, revealed a significant negative association of BMI with IGF-I SDS. BMI contributed most to the additional explained variance to the other health conditions. Conclusions: IGF-I standard deviation scores are decreased in obesity and underweight subjects. These interactions should be taken into account when analyzing the association of IGF-I with diseases and risk conditions.

In cardiovascular medicine, the assessment of blood flow is fundamental to the understanding and detection of disease. Many pharmaceutical, interventional, and surgical treatments impact the flow. The primary purpose of the cardiovascular system is to drive, control and maintain blood flow to all parts of the body. In the normal cardiovascular system, fluid transport is maintained at high efficiency and the blood flow is essentially laminar. Disturbed and turbulent blood flow, on the other hand, appears to be present in many cardiovascular diseases and may contribute to their initiation and progression. Despite strong indications of an important interrelationship between flow and cardiovascular disease, medical imaging has lacked a non-invasive tool for the in vivo assessment of disturbed and turbulent flow. As a result, the extent and role of turbulence in the blood flow of humans have not yet been fully investigated. Magnetic resonance imaging (MRI) is a versatile tool for the non-invasive assessment of flow and has several important clinical and research applications, but might not yet have reached its full potential. Conventional MRI techniques for the assessment of flow are based on measurements of the mean velocity within an image voxel. The mean velocity corresponds to the first raw moment of the distribution of velocities within a voxel. An MRI framework for the quantification of any moment (mean, standard deviation, skew, etc.) of arbitrary velocity distributions is presented in this thesis. Disturbed and turbulent flows are characterized by velocity fluctuations that are superimposed on the mean velocity. The intensity of these velocity fluctuations can be quantified by their standard deviation, which is a commonly used measure of turbulence intensity. This thesis focuses on the development of a novel MRI method for the quantification of turbulence intensity. This method is mathematically derived and experimentally validated. Limitations and sources of error are investigated and guidelines for adequate application of MRI measurements of turbulence intensity are outlined. Furthermore, the method is adapted to the quantification of turbulence intensity in the pulsatile blood flow of humans and applied to a wide range of cardiovascular diseases. In these applications, elevated turbulence intensity was consistently detected in regions where highly disturbed flow was anticipated, and the effects of potential sources of errors were small. Diseased heart valves are often replaced with prosthetic heart valves, which, in spite of improved benefits and durability, continue to fall short of matching native flow patterns. In an in vitro setting, MRI was used to visualize and quantify turbulence intensity in the flow downstream from four common designs of prosthetic heart valves. Marked differences in the extent and degree of turbulence intensity were detected between the different valves. Mitral valve regurgitation is a common valve lesion associated with progressive left atrial and left ventricular remodelling, which may often require surgical correction to avoid irreversible ventricular dysfunction. The spatiotemporal dynamics of flow disturbances in mitral regurgitation were assessed based on measurements of flow patterns and turbulence intensity in a group of patients with significant regurgitation arising from similar valve lesions. Peak turbulence intensity occurred at the same time in all patients and the total turbulence intensity in the left atrium appeared closely related to the severity of regurgitation. MRI quantification of turbulence intensity has the potential to become a valuable tool in investigating the extent, timing and role of disturbed blood flow in the human cardiovascular system, as well as in the assessment of the effects of different therapeutic options in patients with vascular or valvular disorders.

La present tesi avalua els efectes de certs factors ambientals sobre la paraoxonasa1 (PON1), enzim antioxidant, possiblement protector enfront les malalties cardiovasculars, a través de dos estudis d'intervenció i un de transversal. En primer lloc, el tractament amb simvastatina dels pacients amb hipercolesterolèmia familiar, que presentaven una activitat paraoxonasa baixa, s'associava a un increment de l'activitat fins a valors similars als d'individus normolipèmics, independentment dels polimorfismes PON1-55 o PON1-192. En segon lloc, l'entrenament físic s'associava a un augment de l'activitat paraoxonasa en els individus QQ i una disminució de la mateixa en els portadors de l'al·lel R pel polimorfisme PON1-192. L'increment de l'activitat paraoxonasa immediatament després de l'exercici físic agut era seguit per una disminució subseqüent de l'activitat. La recuperació dels nivells basals d'activitat paraoxonasa a les 24h de l'exercici físic agut es donava en els individus QQ independentment del seu estat d'entrenament, i en els individus portadors de l'al·lel R només quan estan entrenats. En tercer lloc, el consum elevat d'àcid oleic comportava un augment de la concentració de c-HDL i de l'activitat paraoxonasa en els homes portadors dels genotips QR i RR del polimorfisme PON1-192, respectivament.Paraules claus: paraoxonasa, PON1, genotips, simvastatina, hipercolesterolèmia familiar, interacció gen-dieta, lipoproteïna d'alta densitat (HDL), exercici físic agut, entrenament físic, estrès oxidatiu, àcid oleic, oli d'oliva, peròxids lipídics, malaltia cardiovascular. / The present thesis evaluates some environmental factor effects on paraoxonase1 (PON1), an possibly protective against cardiovascular disease antioxidant enzyme, through two intervention studies and a cross-sectional one. First, treatment with simvastatin of the familial hypercholesterolemic patients, which had low paraoxonase activity, was associated with an increase in the activity to values similar to the normolipemic ones, regardless of the PON1-55 or PON1-192 polymorphisms. Second, Regular exercise was associated with an increase in PON1 activity in QQ subjects and with a decrease in R carriers. Increased PON1 activity immediately after a bout of exercise was subsequently followed by a decrease of activity. The recovery of the basal PON1 activity levels at 24 h was found in QQ subjects regardless of their training status and in trained R carriers, but not in untrained R carriers. Third, high oleic acid intake was associated with increased HDL cholesterol and PON1 activity levels only in men who were QR and RR of the PON1-192 polymorphism, respectively.

<p>Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most notably asthma. Recently, leukotriene-based inflammation has also been implicated in atherosclerosis: ALOX5AP and LTA4H, two genes in the leukotriene biosynthesis pathway, have been associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a non-familial data set of early onset coronary artery disease. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility. Motivated by this need, we investigated the statistical properties of a class of matrix-based statistics to assess epistasis. We simulated multiple two-variant disease models with haplotypes to gain an understanding of pathway interactions in terms of correlation patterns. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequlibrium (LD) patterns with other haplotype markers. The simulated models can be summarized into three categories: 1. No epistasis in the presence of marginal effects and LD; 2. Epistasis in the presence of LD and no marginal effects; and 3. Epistasis in the presence marginal effects and LD. We then assessed previously introduced single-gene methods that compare whole matrices of Single Nucleotide Polymorphism (SNP) LD between two samples. These methods include comparing two sets of principal components, a sum-of-squared-differences comparing pairwise LD, and a contrast test that controls for background LD. We also considered a partial least-square (PLS) approach for modeling gene-gene interactions. Our results indicate that these measures can be used to assess epistasis as well as marginal effects under certain disease models. Understanding and quantifying whole-gene variation and association to disease using multiple SNPs remains a difficult task. Providing a single statistical measure per gene will facilitate combining multiple types of genomic data at a gene-level and will serve as an alternative approach to assess epistasis in genome-wide association studies. The matrix-based measures can also be used in pathway ascertainment tools that require scores on a gene-level.</p> / Dissertation

The overall aim of this thesis was to study the influence of physical activity on health. Risks and benefits of physical activity is of particular interest since there is a global trend of less physical activity among youths and adults. In order to investigate this aim we used a database from a large cross country ski race, Vasaloppet, with participants with a wide age range, and with both elite athletes and ordinary people who exercise and promote their health. The most serious risk of strenuous exercise is sudden death and it is challenging to identify preventive effects of major endemic diseases. Using epidemiological methodology we studied 200 000 Vasaloppet skiers and compared them with the general population. Based on personal identification numbers we added data from Swedish national personal and health registers, clinical registers as the cancer register, Swedeheart, or Swedish stroke register, and socioeconomic information from Statistics Sweden. In the Vasaloppet database we collected data on age, gender, finish time and number of races during the period 1989 to 2010. We evaluated risk of death during the race in two papers (I,II). During 90 years of annual races, cardiac arrest occurred in 20 skiers, of which five survived. The death rate is in average two per 100 000 skiers. We also studied the association with cancer incidence (paper III). The overall reduction of cancer was modest among skiers compared with the general population, but for cancers related to lifestyle the risks were markedly lower. We investigated the risk for recurrent myocardial infarction and found a 30% reduction among skiers (paper IV). In paper V we showed that skiers with a first stroke have a lower incidence of all-cause death. The skiers had a higher frequency of atrial fibrillation but had less severe stroke and no increased risk of recurrent stroke. Thus our data suggest that a lifestyle with a high level of physical activity may work as a protection after a cardiovascular event. Summary: The short excess mortality in endurance physical activity is by far outweighed by the long term protective effect of exercise in cardiovascular diseases and cancer.

At present there is a reliance on behavioral interventions that have been limited in their effectiveness to reduce the public health burden of chronic disease, partly because the effects of social context on the initiation and maintenance of health behaviors is not incorporated into public health policy and practice. Yet current research indicates that there are macro-level structural and contextual influences on population health that cannot be reduced to individual or compositional effects. This study investigated the associations between social structural factors, community social context, individual characteristics, and self-reported correlates of disease. Distal influences included social structural inequalities such as income inequality and absolute deprivation or poverty. Pertinent mechanisms through which these influences might have operated on disease included social contextual factors, such as social capital. Both political economy and the ecosocial perspective were selected to inform this study and to provide the theoretical framework from which hypotheses were derived.The design was a multilevel, retrospective, nonexperimental study using secondary data. The study linked three data sources (2001 Behavioral Risk Factor Surveillance System, Social Capital Community Benchmark Study, and U.S. Census) by Federal Information Processing Standards codes in order for individuals to be placed in their community or state contexts. Results provided mixed evidence of the direct role of structural and contextual inequalities on self-rated health. Any direct effects of social structural inequalities on the health outcomes disappeared once individual factors were included in the models. Findings demonstrated that one dimension of social capital, organizational activism, retained its significant direct effect on general health status, once individual characteristics were considered. Conclusions suggested indirect associations whereby the negative influence of social structural inequalities on health was mediated by the erosion of social trust, which in turn was associated with engaging in risk behavior, thus increasing the odds of reporting hypertension, fair/poor general health, and mental distress. Although results were inconsistent, this study contributed to advancing Healthy People 2010 goals of increasing quality of life and reducing health disparities by advancing understanding of the multilevel nature of perceived health and the chronic diseases they predict.