Cardiovascular disease (CVD) is highly prevalent in chronic kidney disease (CKD) patients. Whilst this can in part be explained by the high incidence of traditional CVD risk factors such as hypertension and diabetes evident in CKD patients, recent focus has been on non-traditional risk factors and their role in CVD progression. These include endothelial dysfunction, arterial stiffness, inflammation and oxidative stress. The potent vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of CKD and the CVD associated with it. Further understanding of the mechanisms by which it contributes to CKD and CVD pathogenesis, specifically its interactions with non-traditional risk factors are still required. Additionally, the potential applications of ET antagonists in renal disease have not been fully explored. This thesis aims to investigate the role of ET-1 in the development of renal disease and the associated inflammation, hypertension and vascular dysfunction through a series of in vitro, in vivo and clinical studies. I have demonstrated using in vitro techniques that murine macrophages (Mϕ) express both endothelin A (ETA) and endothelin B (ETB) receptors but that ET-1 does not elicit either a classical pro-inflammatory or alternative anti-inflammatory phenotype in Mϕ. I was however, able to show that M display chemokinesis towards ET-1 and M ETB receptors provide a novel clearance mechanism for ET-1 through receptor mediated dynamin-dependent endocytosis In an in vivo study I investigated whether ET-1 mediates the progressive renal injury after renal ischaemia reperfusion injury (IRI) that leads to the development of CKD. I demonstrated that endothelin A receptor antagonism provided long term beneficial effects reducing blood pressure and preventing progressive kidney injury, inflammation, and the development of fibrosis resulting from an episode of acute kidney injury (AKI). Similar benefits were observed with calcium channel blockade, suggesting hypertension may mediate some of the long term effects of renal IRI and anti-hypertensive treatments could prevent the development of CKD after AKI. Finally, in a clinical study I showed for the first time that CKD patients lack the diurnal variation in arterial stiffness that is seen in matched subjects without CKD. Alteration in the circadian variation of the ET-1 system may contribute to this. In summary, my studies have furthered our understanding of the role of ET-1 in CKD progression and the cardiovascular risk associated with it. Mϕ were shown to express both ET receptors and a novel mechanism of ET-1 clearance was observed in Mϕ. Using an in vivo model of AKI I was able to identify ETA receptor antagonism as a novel therapeutic agent in preventing the development of CKD caused by AKI where data are limited. Finally, alterations in the circadian rhythm of the cardiovascular system is emerging as an important factor in disease pathogenesis. Here the diurnal variation in arterial stiffness was described for the first time in a group of CKD patients and matched controls.

Regular aerobic exercise may reduce cardiovascular disease (CVD) risk in part by lowering the concentration of inflammatory markers such as C-reactive protein (CRP). While studies in diseased populations have shown significant decreases in CRP concentrations with regular aerobic training, little has been conclusively determined regarding the effects of aerobic training on CRP concentrations in apparently healthy, untrained populations who may not be adequately screened for CVD risk by traditional methods. PURPOSE: To examine the effects of a 17-wk half marathon training program (TP) on CRP concentrations, aerobic fitness, and body composition in apparently healthy, untrained men. METHODS: Twenty men (29.3 ± 1.0 yr, 37.0 ± 1.6 mL•kg-1•min-1 VO2max, 29.1 ± 1.8% body fat) registered as training subjects (TRN) in a 17-wk half marathon TP. An additional 22 men (27.8 ± 1.4 yr, 38.8 ± 1.0 mL•kg-1•min-1 VO2max, 26.8 ± 1.4% BF) served as controls (CON). Fasting blood samples were taken at four time points over the TP and were analyzed for CRP and interleukin-6 (IL-6) concentrations. Aerobic capacity (VO2max) and body fat (BF%) were measured before and after the TP. RESULTS: No significant changes in CRP (P=0.69) or IL-6 concentrations (P=0.73) were seen in TRN as a result of the TP despite significant improvements in VO2max (42.2 ± 1.9 ml•kg-1•min-1, P<0.0001), resting heart rate (P =0.004), BF% (P =0.03) and BMI (P =0.05). No significant changes in CRP, aerobic fitness, BMI or BF% were detected in CON over time. CONCLUSION: Moderate, long-term aerobic training does not appear to affect CRP concentrations in apparently healthy, untrained men despite significant improvements in BW, BF%, BMI, and VO2max.

Background: Cardiovascular disease (CVD) is becoming one of the leading causes of death in middle and low income countries, with ischaemic heart disease specifically being predicted to be the 4th and 5th causes respectively. The numerous risk factors for the development of CVD have been extensively researched; however, the same wealth of data is not available for the black South African population as there is for Caucasians. Although the same risk factors that are present in Caucasians have been seen to be present in the black South Africans, there are questions regarding the contributory roles of the individual risk factors, particularly within the context of urbanisation. The role of diet in CVD has been widely studied and it is known that with urbanisation there are dietary changes which are thought to add the development of CVD. With urbanisation, however, there are numerous other lifestyle changes taking place within a population, making it difficult to isolate and make conclusions of the individual role of diet. Added to this is the complex issue of assessing dietary intake. Assessing only nutrient or food intake does not give a holistic picture of dietary habits. The main aim of this study was to determine the association between dietary intake and CVD risk in black South Africans in the context of urbanisation. Methods: The first study that forms part of this thesis was a case-control study aimed at exploring the risk factor profile and clinical presentation of black South African patients with coronary artery disease (CAD). In this study clinical, biochemical and nutrient intakes were compared with a black South African control group that were matched for age and body composition. The second study to form part of this thesis aimed to relate the dietary intakes of the Prospective Urban and Rural Epidemiological (PURE) study population to CVD risk associated with urbanisation, by using both nutrient intake and predefined diet quality scores (DQS). The Healthy Diet Indicator (HDI) and the Deficiency and Excess Score were carefully selected from the large number of available scores and adapted as best as possible for the black South African population. The third study aimed to investigate the role of dietary intake by using nutrients as well as food group consumption patterns as a risk factor in urbanised black South African CAD patients. The dietary habits of the coronary artery disease (CAD) patients were compared to that of an apparently healthy reference group of volunteers selected from the PURE study population. This urbanised reference group was from a similar socio- demographic background and was selected according to their risk for CVD. The Reynolds Risk score which includes C-reactive protein as factor was used to stratify the PURE population into CVD risk categories, in order to select the reference group, which had a low risk (<5%) of developing CVD within the next 10 years. Dietary intake was assessed by comparing nutrient and food group intake (including the ultra-processed food group category). Results and discussion: Black South African CAD patients had increased levels of the same risk factors that are seen in Caucasians with insulin resistance and LDL size being particularly significant in their contribution. Apart from a lower vitamin C intake, no differences in dietary intake and physical activity were observed between the CAD and control group. When comparing the dietary intake of the rural and urban group, the urban group, who had an increased CVD risk, had higher intakes of macro- and micronutrients as well as higher DQS. The DQS must however be interpreted with caution, as when looking at the absolute intakes of individual components of the scores, the urban group was still deficient in a numerous vital micronutrients. A similar picture was seen in the third study, in that the CAD patients also consumed more saturated fatty acids and ultra-processed foods than the reference group, as well as more of the “protective” foods such as fruit and vegetables. However, although their dietary habits could be considered prudent, they were still inadequate in numerous important micronutrients. Conclusion and recommendation: This thesis therefore shows that there are two sides of the story regarding the role of diet in CVD in black South Africans. Although it is important to follow prudent dietary guidelines so as to control the intake of nutrients and foods known to play a role in the development of CVD, it is just as important to ensure adequate intake of the foods rich in micronutrients known to protect against CVD. Dietary advice and prevention programs should also focus on the adequacy aspect of the diet, such as increasing fruit and vegetable and low fat dairy intake, not only on the prudent diet aspect. Additionally, nutrient intake alone does not adequately explain the link between diet and CVD and additional analyses such food consumption patterns are required. / Thesis (PhD (Dietetics))--North-West University, Potchefstroom Campus, 2013

Background: Cardiovascular disease (CVD) is becoming one of the leading causes of death in middle and low income countries, with ischaemic heart disease specifically being predicted to be the 4th and 5th causes respectively. The numerous risk factors for the development of CVD have been extensively researched; however, the same wealth of data is not available for the black South African population as there is for Caucasians. Although the same risk factors that are present in Caucasians have been seen to be present in the black South Africans, there are questions regarding the contributory roles of the individual risk factors, particularly within the context of urbanisation. The role of diet in CVD has been widely studied and it is known that with urbanisation there are dietary changes which are thought to add the development of CVD. With urbanisation, however, there are numerous other lifestyle changes taking place within a population, making it difficult to isolate and make conclusions of the individual role of diet. Added to this is the complex issue of assessing dietary intake. Assessing only nutrient or food intake does not give a holistic picture of dietary habits. The main aim of this study was to determine the association between dietary intake and CVD risk in black South Africans in the context of urbanisation. Methods: The first study that forms part of this thesis was a case-control study aimed at exploring the risk factor profile and clinical presentation of black South African patients with coronary artery disease (CAD). In this study clinical, biochemical and nutrient intakes were compared with a black South African control group that were matched for age and body composition. The second study to form part of this thesis aimed to relate the dietary intakes of the Prospective Urban and Rural Epidemiological (PURE) study population to CVD risk associated with urbanisation, by using both nutrient intake and predefined diet quality scores (DQS). The Healthy Diet Indicator (HDI) and the Deficiency and Excess Score were carefully selected from the large number of available scores and adapted as best as possible for the black South African population. The third study aimed to investigate the role of dietary intake by using nutrients as well as food group consumption patterns as a risk factor in urbanised black South African CAD patients. The dietary habits of the coronary artery disease (CAD) patients were compared to that of an apparently healthy reference group of volunteers selected from the PURE study population. This urbanised reference group was from a similar socio- demographic background and was selected according to their risk for CVD. The Reynolds Risk score which includes C-reactive protein as factor was used to stratify the PURE population into CVD risk categories, in order to select the reference group, which had a low risk (<5%) of developing CVD within the next 10 years. Dietary intake was assessed by comparing nutrient and food group intake (including the ultra-processed food group category). Results and discussion: Black South African CAD patients had increased levels of the same risk factors that are seen in Caucasians with insulin resistance and LDL size being particularly significant in their contribution. Apart from a lower vitamin C intake, no differences in dietary intake and physical activity were observed between the CAD and control group. When comparing the dietary intake of the rural and urban group, the urban group, who had an increased CVD risk, had higher intakes of macro- and micronutrients as well as higher DQS. The DQS must however be interpreted with caution, as when looking at the absolute intakes of individual components of the scores, the urban group was still deficient in a numerous vital micronutrients. A similar picture was seen in the third study, in that the CAD patients also consumed more saturated fatty acids and ultra-processed foods than the reference group, as well as more of the “protective” foods such as fruit and vegetables. However, although their dietary habits could be considered prudent, they were still inadequate in numerous important micronutrients. Conclusion and recommendation: This thesis therefore shows that there are two sides of the story regarding the role of diet in CVD in black South Africans. Although it is important to follow prudent dietary guidelines so as to control the intake of nutrients and foods known to play a role in the development of CVD, it is just as important to ensure adequate intake of the foods rich in micronutrients known to protect against CVD. Dietary advice and prevention programs should also focus on the adequacy aspect of the diet, such as increasing fruit and vegetable and low fat dairy intake, not only on the prudent diet aspect. Additionally, nutrient intake alone does not adequately explain the link between diet and CVD and additional analyses such food consumption patterns are required. / Thesis (PhD (Dietetics))--North-West University, Potchefstroom Campus, 2013

Inflammation contributes to the etiology of type 2 diabetes (T2D) and cardiovascular disease (CVD). Therefore, it is of interest to investigate how diet relates to plasma inflammatory proteins, particularly whole grain and fibre intakes, as these factors have been associated with lower CVD and T2D risk. Only a limited number of observational studies have examined these relationships. The objective of this study was to investigate the cross-sectional relationships of whole and refined grain and dietary fibre intakes with plasma inflammatory proteins. There was a strong inverse relationship between whole grain intake and plasminogen activator inhibitor type 1 (PAI-1) (β =-0.102; SE=0.038; p=0.0077), and a positive relationship between refined grain intake and PAI-1 (β=0.076; SE=0.034; p=0.0251). Additionally, dietary fibre was related to lower concentrations of C-reactive protein (β=-0.034; SE=0.010; p=0.0008) and fibrinogen (β=-1.207; SE=0.505; p=0.0171). This research suggests that whole and refined grain and fibre intakes may influence inflammatory protein concentrations.

Inflammation contributes to the etiology of type 2 diabetes (T2D) and cardiovascular disease (CVD). Therefore, it is of interest to investigate how diet relates to plasma inflammatory proteins, particularly whole grain and fibre intakes, as these factors have been associated with lower CVD and T2D risk. Only a limited number of observational studies have examined these relationships. The objective of this study was to investigate the cross-sectional relationships of whole and refined grain and dietary fibre intakes with plasma inflammatory proteins. There was a strong inverse relationship between whole grain intake and plasminogen activator inhibitor type 1 (PAI-1) (β =-0.102; SE=0.038; p=0.0077), and a positive relationship between refined grain intake and PAI-1 (β=0.076; SE=0.034; p=0.0251). Additionally, dietary fibre was related to lower concentrations of C-reactive protein (β=-0.034; SE=0.010; p=0.0008) and fibrinogen (β=-1.207; SE=0.505; p=0.0171). This research suggests that whole and refined grain and fibre intakes may influence inflammatory protein concentrations.

<b>Background</b> Cardiovascular risk scores are used to estimate absolute risk of disease and identify patients who will benefit most from treatments to lower risk. As a key risk factor for cardiovascular disease, blood pressure is accounted for in many risk scores, but is inherently variable and may be influenced by both biological and measurement factors. This thesis aims to determine how routinely collected blood pressure measurements should best be used for accurate estimation of cardiovascular risk. <b>Methods</b> This thesis describes four main studies. A patient survey and prospective study establish the current practice of blood pressure measurement. Secondary analyses of data from blood pressure monitoring trials determine how risk estimates may be affected by the use of different summary measures of blood pressure. A systematic review evaluates the evidence of an association between blood pressure variability and cardiovascular risk. Finally, a cohort study in the Clinical Practice Research Datalink determines if inclusion of blood pressure variability in cardiovascular risk scores may improve risk estimation. <b>Results</b> Current practice of blood pressure measurement may differ from that in risk score derivation studies. However, these differences have limited effects on cardiovascular risk estimates with few patients reclassified across risk thresholds. Increased long-term variability in blood pressure is in itself a risk factor for cardiovascular disease over and above mean blood pressure but its inclusion in a cardiovascular risk score does not materially improve the accuracy of risk estimates. <b>Conclusions</b> Healthcare professionals should continue to estimate risk for primary prevention of cardiovascular disease using the blood pressure measurements available to them, whether measured at home or in the clinic. There is also no additional benefit of considering measures of long-term blood pressure variability in risk estimation.

Philosophiae Doctor - PhD / Background: Obesity is increasing worldwide, and cultural perception of body image is considered an important contributor to the obesity epidemic among black Africans. Aim: To explore the association between body image perceptions and perceived obesity threat, change in adiposity, and total cardiovascular disease (CVD) mortality risk. Study Design: This is a mixed-methods study embedded in the PURE longitudinal cohort study involving adults aged 35-78 years in South Africa. Data Collection/Analysis: This included analysis of baseline cross-sectional data, the conduct of a qualitative study and a cross-sectional follow-up survey. Sex-specific logistic regression models of excessive adiposity were determined. Body image perception indexes were obtained based on 'Feel- Ideal' difference (FID) and 'Feel-Actual' discordance (FAD). Bivariate analyses and analysis of variance were used to determine the relationships between body image and adiposity, annual changes in weight and adiposity. The correlations between body image indexes (FID and FAD) and total 10- year CVD risk score were determined – controlling for possible confounders. Qualitative data was managed with ATLAS-ti software and analysed thematically. Results: The prevalence of excessive body fat at baseline and at 5-year follow-up based on body fat percent were 96.0% and 79.6% for women, and 44.3% and 62.2% for men respectively. The majority of the obese (85%) and overweight (79%) participants underestimated their weight, and weight discordance status was inversely associated with the willingness to lose weight. Mean total 10-year CVD risk score was 18.7%, and 61% of men and 26% of women with body mass index (BMI) ≥ 25 kg/m2 had CVD risk scores ≥ 20%. Bivariate analyses indicated that FID and FAD were significantly associated with annual changes in weight and adiposity. FAD index had a significant but weak correlation with total CVD risk score (r = 0.13, p-value = 0.001) when adjusted for covariates. Conclusion: Body image discordance was associated with an annual change in adiposity, total 10- year CVD risk scores, and there was poor obesity risk perception, and low motivation towards weight loss among predominantly obese black adults with negative body image. Interventions to reduce obesity need to address negative body image, poor obesity risk perception, self-efficacy and motivation towards weight loss. / National Research Foundation; Chromnic Disease Initiative for Africa (CDIA); National Institute of Health (NIH)

Osteoarthritis (OA) is a prevalent and progressive musculoskeletal condition characterized by the degradation of the cartilage and bone and is often comorbid with cardiovascular disease (CVD), with both disease prevalence’s increasing with age. Several factors, such as the site of OA and the menopause transition, are known to independently influence both conditions. OA and CVD share overlapping risk factors and proposed mechanisms, though it is not well understood how these mechanisms influence the risk of comorbidity. This thesis examines the relationship of CVD risk factors, sites of OA, and menopausal variables on CVD risk in individuals with OA. The first aim of this thesis was to examine preclinical markers of CVD risk, namely the carotid intima-media thickness (cIMT) and cardiovascular risk scores, the Framingham risk score (FRS) and the InterHeart risk score (IHRS), in individuals with and without OA to examine differences in CVD risk profiles. Additional considerations were given to the site of OA, as well as non-specific CVD risk factors (such as social disadvantage and frailty). Risk factors were compared between age- and sex-matched individuals with and without OA and between weight-bearing and non-weight bearing OA. Individuals with OA had significantly greater cIMT, FRS, and IHRS, though no differences were found when comparing the site of OA. Unadjusted and multivariate adjusted odds ratios (OR) calculated odds of CVD at 3-year follow-up in the same cohorts. There was a significantly unadjusted (p<0.001, OR:1.70) and adjusted (p<0.001, OR ranging from 1.67-1.70) influence of OA diagnosis on odds of CVD at 3-year follow-up. There was no significant unadjusted or adjusted difference in odds of CVD at 3-year follow-up when comparing different sites of OA (p ranging from 0.24-0.75, OR ranging from 0.69-0.71). The second aim of this thesis was to study CVD risk in post-menopausal women. CVD risk factors and the IHRS were used to calculate differences between age-matched post-menopausal women. Unadjusted and multivariable adjusted ORs calculated odds of CVD at 3-year follow-up. There was a significant unadjusted influence of OA diagnosis (p=0.03, OR:1.34) on CVD outcomes, though the effect of OA diagnosis became non-significant after adjusting for the IHRS (p=0.25, OR:1.36) and the IHRS with menopausal variables (p=0.22, OR:1.40). Although OA is a multifaceted condition, it has often been viewed as a joint-centric disease. The elevated risk of CVD individuals with OA suggests that additional aspects of the OA pathology, such as inflammation and frailty, may drive the increase in risk of CVD independent of age, sex, or menopausal status. / Thesis / Master of Science (MSc) / Osteoarthritis (OA) and cardiovascular disease (CVD) are two of the most prevalent comorbidities that affect the aging population. Surrogate measures of CVD, such as CVD risk scores and carotid intima-media thickness, have rarely been examined in individuals with OA despite studies showing elevated CVD risk in individuals with OA. We used baseline and 3-year follow-up data collected by the Canadian Longitudinal Study on Aging to study CVD risk factors in older individuals with and without OA, with considerations given to the site of OA and to menopause, which are additional non-modifiable factors known to influence vascular outcomes. We hypothesized that individuals with OA have greater CVD risk and odds of developing CVD compared to individuals without OA. We found that individuals with OA have greater CVD risk and odds of developing CVD at 3-year follow-up, with no influence of OA site on CVD outcomes, and post-menopausal women with OA have greater odds of developing CVD than post-menopausal women without OA. Our findings suggests that aspects of the OA pathology play a role in increasing CVD risk, which are partially explained through shared risk factors and etiology.

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.