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Master of Health Sciences in Cardiovascular Physiology, North-West University, Potchefstroom Campus Motivation - African populations are more prone to the development of left ventricular structure abnormalities and dysfunction, however limited information exists on potential metabolic pathways contributing to early left ventricular structural changes. Consequently, the importance of identifying possible metabolomic markers in association with left ventricular mass in the youth is vital for future prediction and prevention of hypertension-related organ damage. To the best of our knowledge, no studies have been done to determine the relationship of left ventricular mass with urinary metabolomics in 20-30 year-old black and white populations from South Africa. Aim - We aimed to investigate the metabolomic profiles and identify possible metabolites associated with left ventricular mass index in young black and white South African adults. Methodology - This cross-sectional study formed part of the larger African prospective study on early detection and identification of cardiovascular disease and hypertension (African-PREDICT). We included 20-30 year-old normotensive black (N=80) and white (N=80) participants from the African-PREDICT study, with complete data on urinary metabolomics and echocardiography. This substudy was approved by the Health Research Ethics Committee of the North-West University (NWU-00029-18-S1) and adhered to all applicable requirements according to the revised Declaration of Helsinki for investigation on human participants. Questionnaires included a General Health and Demographic Questionnaire and a 24-hour dietary recall questionnaire. Anthropometric measurements included body height and weight to calculate body mass index, as well as waist circumference. Body surface area was additionally calculated. Twenty-four-hour ambulatory blood pressure (ABPM) was determined with a 24-hour ABPM and electrocardiogram (ECG) apparatus (CardXplore, Meditech, Budapest, Hungary). An appropriately sized cuff was used on the non-dominant arm to measure blood pressure in 30-minute intervals during the day, and hourly during night-time. A standard transthoracic echocardiogram was performed by a clinical technologist using the General Electric Vivid E9 device (GE Vingmed Ultrasound A/S, Horten, Norway) to determine left ventricular dimensions for calculating left ventricular mass. Basic biochemical analyses included serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, high sensitivity C-reactive protein, total serum protein, creatinine and sodium fluoride plasma glucose. Cotinine, total glutathione and creatine kinase-MB (muscle/brain) analyses were also included. Urinary metabolites were measured using nuclear magnetic resonance spectroscopy, liquid chromatography tandem mass spectrometry and gas chromatography time-of-flight mass spectrometry. We performed univariate statistical analysis, which included independent t-tests (adjusted for multiple comparisons), effect size (d≥0.3) and single regression analysis to identify the most prominent urinary metabolites. Multivariate adjusted analyses were performed to test for independent associations of left ventricular mass index with identified metabolites. Results - When comparing the black and white groups, the black group had lower body weight (p

PhD (Science with Physiology), North-West University, Potchefstroom Campus Motivation - The accurate measurement of blood pressure remains the most essential technique for the diagnosis and management of hypertension. In addition, there is increasing evidence that the measurement of clinic blood pressure may yield incorrect estimates of a patient’s true blood pressure status. This is due to blood pressure fluctuations throughout the day-night period, with reported higher blood pressure during the day and lower at night, reflecting the physiological dipping pattern of night-time blood pressure. Furthermore, studies indicated the occurrence of cardiovascular events such as stroke, myocardial infarction and sudden cardiac death more frequently during the morning hours after waking up, due to increased blood pressure. The morning blood pressure surge (MBPS) is a normal physiological response to changes in the activity of the sympathetic nervous system associated with the process of awakening and other factors (including age, ethnicity, sex, hypertensive status, health behaviours, or dipping status). A MBPS up to 37 mmHg is considered physiological, while an exaggerated MBPS above 37 mmHg is pathological, and associated with cardiovascular events, mainly in hypertensive and elderly individuals. A majority of previous studies focusing on exaggerated MBPS were conducted in elderly and hypertensive individuals, but there is scant knowledge on ethnic differences, prevalence and effects of an exaggerated MBPS on subclinical hypertension-mediated organ damage in young healthy individuals. This study therefore investigated MBPS in young black and white normotensive adults, and the relationships between the MBPS, measures of arterial function and autonomic function in healthy black and white South African men and women, aged between 20 and 30 years. Aim - The overarching aim of this Ph.D. thesis was to obtain a better understanding regarding the MBPS and how it relates to arterial function and subclinical hypertension-mediated organ damage in a healthy bi-ethnic South African population, aged between 20 and 30 years. Methodology - This thesis used data (presented in Chapter 3, 4 and 5) collected from the African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension (African-PREDICT). We included the first consecutive 845 black and white men and women in total. Groups were stratified by gender and ethnicity, and dipping status as specified by statistical interaction terms. Cardiovascular measurements included ambulatory blood pressure measurements, MBPS (sleep-trough and dynamic morning surge) and pulse wave velocity. Using fundoscopy, we also included measurements of the microvasculature, namely retinal vessel calibres. As part of ambulatory blood pressure and electrocardiogram monitoring, we measured 24-hour heart rate variability. Baroreceptor sensitivity was determined using the validated cross-correlation baroreflex sensitivity (xBRS) method. Using accelerometery, we were able to measure total energy expenditure and activity energy expenditure. Results and conclusions of each manuscript. The first manuscript (Chapter 3) aimed to determine interactions of sex and black and white ethnicity across increasing quartiles of MBPS. This manuscript also aimed to explore whether differences in cardiovascular-related measures and specific health behaviours exist across increasing MBPS quartiles. We also aimed to determine if an exaggerated MBPS already occurs in young black and white adults. We found an interaction of ethnicity on the relationship between sleep-trough surge with cardiovascular markers and health behaviours (p

MHSc (Cardiovascular Physiology), North-West University, Potchefstroom Campus Motivation - Cardiovascular disease was responsible for 17.5 million deaths in 2014, which made it the main cause of mortality among non-communicable diseases. Statistics from low- and middleincome countries demonstrated that South Africa had the highest prevalence of hypertension (78%), obesity (45%), and physical inactivity (59%) among individuals who are older than 50 years, compared to countries such as China, Ghana, India, Mexico, and Russia. These figures are a cause for concern, considering that there is a dose-dependent relationship between physical inactivity and cardiovascular disease. A sedentary lifestyle may for instance cause endothelial dysfunction by means of increased oxidative stress and inflammation, as well as a subsequent decrease in nitric oxide bioavailability. Physical inactivity also contributes to increases in arterial stiffness (arteriosclerosis) and the development of atherosclerosis. Pharmacological treatments for cardiovascular disease have potential side effects and can be a financial burden, which limits the use of this treatment in low- and middle-income countries such as South Africa. Physical activity has been shown to be a cost-effective preventative, alternative, and conjoining therapy, which is associated with lower cardiovascular disease mortality, independent of other cardiovascular disease risk factors. In fact, the therapeutic effects of physical activity were shown to be as effective as drug treatment for cardiovascular disease, highlighting the necessity for research in this regard. Previous research demonstrated that high intensity physical activity is required to obtain optimal cardiovascular risk-lowering benefits. However, this physical activity prescription may be difficult to adhere to, especially in older populations. Limited research is available that explores the relationship between physical inactivity and vascular dysfunction, along with these associative factors in a South African population. Further, research on physical inactivity and cardiovascular disease is generally obtained with subjective measures such as self-reported questionnaires, therefore emphasising the need for more objective research obtained by physical activity measuring devices. Aim - The aim of this study was to investigate the interplay of vascular function measures, including twenty-four hour blood pressure, total peripheral resistance, and Windkessel compliance, with oxidative stress, inflammation, and nitric oxide synthesis capacity markers in physically active and inactive South Africans. Methodology - This cross-sectional study formed part of the second phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans study. This phase of the study was conducted between February 2011 and May 2012, and included 359 black and white school teachers, between the ages of 25 and 65 years, from the Dr Kenneth Kaunda Educational District, North West Province, South Africa. After the exclusion criteria were met, a total of 216 black and white men and women were included. Exclusion criteria included an ear temperature >37.5°C, α- and β- blocker/psychotropic substance users, pregnant/lactating women, and individuals vaccinated/donated blood within three months prior to participation. Additional exclusion criteria for our study are participants with physical activity recordings that did not last the entire seven days, or recordings with more than 40 minutes daily lost time. Standardised methods were used to capture data, which included physical activity measurements with a validated Actiheart® (CamNtech Ltd., Cambridge, UK), anthropometric measurements, and questionnaires. Cardiovascular measurements comprised Windkessel compliance and total peripheral resistance measured with a validated Finometer device (Finapres Medical Systems®, Amsterdam, Netherlands). Twenty-four hour blood pressure, including systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure were also measured with a validated Meditech Cardiotens CE120® apparatus (Budapest, Hungary). Biochemical analyses included markers of oxidative stress such as glutathione reductase, glutathione peroxidase, total glutathione, gamma-glutamyltransferase, and thiobarbituric acid reactive substances. Inflammatory markers such as interleukin-6, Creactive protein, monocytes, and eutrophil/lymphocyte ratio, as well as nitric oxide synthesis capacity markers such as L-homoarginine, asymmetric dimethylarginine, and symmetric dimethylarginine were also measured. Participants were divided into physically active (n=84) and physically inactive (n=132) groups according to the 2008 United States Physical Activity Guidelines. Means between groups were compared with the use of analyses of covariance whereas proportions were compared with Chi-square tests. Relationships of cardiovascular variables with markers of oxidative stress, inflammation and nitric oxide synthesis capacity were investigated by means of partial and multiple regression analyses. Results and conclusions The physically active group consisted of 84 (38.9%) participants, of whom only 3 (3.57%) participants achieved high intensity physical activity levels. The physically active group included 18.3% fewer black participants (p=0.009) than the inactive group, but sex distribution was similar. Despite higher total energy expenditure and activity-related energy expenditure levels (both p≤0.001) in the physically active group, body mass index was higher (p=0.046) than in the physically inactive group. Physically active participants had higher Windkessel compliance (p=0.041) and Lhomoarginine (p=0.006) while gamma-glutamyltransferase was lower (p=0.034) when compared to the inactive group. Unexpectedly, thiobarbituric acid reactive substances (p=0.043) were higher in the physically active group. Both partial and multiple regression analyses revealed associations between twenty-four hour diastolic blood pressure and total glutathione (β=0.18; p=0.037), as well as L-homoarginine (β=0.21; p=0.028) in the physically active group. Additionally, in multiple regression analyses, twenty-four hour systolic blood pressure (β=0.18; p=0.04) and twenty-four hour mean arterial pressure (β=0.20; p=0.025) correlated with L-homoarginine. In both analyses, the physically inactive group showed relationships of twenty-four hour systolic blood pressure (β=0.25; p=0.001), twenty-four hour diastolic blood pressure (β=0.20; p=0.013), twenty-four hour mean arterial pressure (β=0.23; p=0.003), and twenty-four hour pulse pressure (β=0.21; p=0.012) with symmetric dimethylarginine. In further analyses, since cardiovascular variables did not associate with markers of inflammation in multiple regression analyses, we repeated the above analyses, with additional inclusion of C-reactive protein to the models. Associations remained unchanged, indicating that the results are independent of inflammation. In conclusion, even moderate physical activity alters vascular risk, possibly by means of modifications in nitric oxide synthesis capacity. These results suggest that increased nitric oxide synthesis capacity due to physical activity may mitigate the development of cardiovascular disease in a South African population. Masters

Background and aims Increased left ventricular mass is an independent predictor for cardiovascular events, and shown to be higher in black than white populations. To gain a better understanding of early factors contributing to increased left ventricular mass in young black adults, we investigated metabolomic profiles, identified and compared metabolites that associated with left ventricular mass index in healthy black and white adults. Methods and results We included normotensive black and white participants from the African-PREDICT study, with data on urinary metabolomics and echocardiography. Urinary metabolites were measured using three different analytical platforms. Univariate statistical analyses, including independent t-test (adjusted for multiple comparisons), effect size (d ≥ 0.3) and single regression analyses were used to identify metabolites. When comparing the black and white groups, the black group had higher central systolic blood pressure (p > 0.005), whereas left ventricular mass index was similar between the groups (p = 0.97). Three from a total of 192 metabolites were identified to be more abundant (p < 0.046) and inversely associated with left ventricular mass index in the black group only: hydroxyproline (β = −0.22; p = 0.045), glycine (β = −0.20; p = 0.049) and trimethylamine (β = −0.21; p = 0.037). Conclusion Higher urinary levels of hydroxyproline, glycine and trimethylamine were inversely associated with left ventricular mass index in the black adults only. Hydroxyproline and glycine are important in maintaining healthy collagen turnover and stability in the heart. Our results may reflect an increase in collagen biosynthesis and collagen deposition in the left ventricle due to higher central systolic blood pressure in the black population

Background and aims The L-arginine derivatives asymmetric (ADMA) and symmetric dimethylarginine (SDMA), as well as L-homoarginine may have opposing effects in the pathogenesis of atherosclerosis. We aimed to investigate (i) 5-year changes in arginine derivatives, and (ii) the association between baseline arginine derivatives and follow-up measures of carotid wall thickness in South Africans. Methods and results This study included men (n = 187) and women (n = 396) who took part in the 2010 and 2015 data collections of the South African arm of the Prospective Urban and Rural Epidemiology (PURE) study. Arginine derivatives were determined in plasma with liquid chromatography-tandem mass spectrometry. Carotid intima-media thickness (cIMT) and cross-sectional wall area (CSWA) were determined with B-mode ultrasonography. Results Mean values of arginine derivatives did not change over time. In the study group, follow-up cIMT (β = − 0.10 p = 0.018) and CSWA (β = − 0.12; p = 0.004) inversely associated with baseline L-homoarginine, and cIMT inversely associated with ADMA (β = − 0.09; p = 0.033). In women, CSWA inversely associated with both ADMA (β = − 0.11; p = 0.034) and L-homoarginine (β = − 0.11; p = 0.024). No such associations were found in men. Conclusion These results suggest that higher levels of L-homoarginine may play a protective role against vascular injury and delay progression of carotid wall thickening in this cohort. The role of ADMA in atherosclerosis deserves further investigation in this population

Mounting evidence supports the central role of oxidative stress and inflammation in obesity and the development of hypertension. However, most studies focusing on the non-enzymatic antioxidants, such as uric acid and bilirubin, and their relationship with obesity and hypertension were done in older populations with overt cardiovascular disease. The aim of this study was therefore to compare measures of cardiovascular function (blood pressure and arterial stiffness) and non-enzymatic antioxidants (uric acid and bilirubin) between young healthy lean and overweight/obese men and women and to investigate the link between these variables. We grouped 967 men and women (aged 20–30 years) according to body mass index (BMI) categories (lean BMI

Oxidative stress is implicated in hypertension, carotid wall thickening, and renal dysfunction. Oxidative stress is linked to cardiovascular pathology in the black South African individuals who have a high prevalence of hypertension and early vascular aging. However, there are limited data relating changes in oxidative stress with vascular and renal deterioration over time. We aimed to investigate whether changes in oxidative stress over 3 years are associated with target organ damage in black (N = 89) and white (N = 91) men. Carotid intima-media thickness was measured using the SonoSite Micromaxx ultrasound system, and cross-sectional wall area (CSWA) was calculated. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. The percentage change (%∆) in oxidative stress markers was calculated and included reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR). Over 3 years, black men exhibited decreased ROS, SOD, and GR, while white men revealed decreased SOD and GPx. Black men displayed positive associations of CSWA with %∆ ROS (β = 0.28; p = 0.017) and %∆ SOD (β = 0.24; p = 0.047). White men displayed a negative association of CSWA with %∆ SOD (β = −0.22; p = 0.042) and positive associations of eGFR with %∆ GPx (β = 0.33; p = 0.001) and %∆ GR (β = 0.39; p

Background: Oxidative stress and increased cardiovascular reactivity are associated with endothelial dysfunction and cardiovascular disease development. These factors along with early vascular compromise are more pronounced in black populations. We aimed to compare cardiovascular reactivity and investigate associations thereof with oxidative stress in two bi-ethnic cohorts (younger: 25.0 ± 3.19yrs; older: 44.7 ± 9.61yrs). Methods: Cardiovascular reactivity using the color-word conflict test was measured with the Finometer device. Oxidative stress markers included superoxide dismutase (SOD), γ-glutamyl transferase (γ-GT) and reactive oxygen species (ROS). Results: Black groups displayed greater cardiovascular responses to stress than white groups. In younger white participants, diastolic blood pressure (DBP) (β = 0.31; p = 0.001) and mean arterial blood pressure (MAP) (β = 0.28; p = 0.002) associated with ROS. In older black participants, DBP (β = 0.23; p = 0.009), MAP (β = 0.18; p = 0.033), stroke volume (β = −0.20; p = 0.023) and arterial compliance (β = −0.25; p = 0.005) associated with γ-GT. In older white participants, systolic blood pressure (β = −0.20; p = 0.006) and MAP (β = −0.19; p = 0.009) associated with SOD. Conclusions: In the older black group, cardiovascular reactivity associated with markers of glutathione metabolism, suggesting a possible compensatory up-regulation thereof in order to correct their heightened responses to stress. Independent of age, findings in the white groups support a regulatory role of ROS to maintain vascular tone during stress

Objective: Selenium plays an important physiological role as component for antioxidant selenoproteins such as glutathione peroxidase (GPx). Since oxidative stress contributes to hypertension development, it is likely that selenium deficiency may contribute to the burden of cardiovascular disease. To better understand the involvement of selenium and GPx in the early development of cardiovascular disease, we investigated in young, healthy black and white African men and women whether measures of the micro- and macrovasculature are related to selenium and GPx activity. Methods: In young adults (N = 394; aged 20–30 years) we determined serum selenium, GPx activity, microvascular measures (central retinal artery equivalent, central retinal vein equivalent, arteriolar-to-venular ratio [AVR], and estimated glomerular filtration rate [eGFR]), and macrovascular measures (pulse wave velocity, 24-hour pulse pressure [PP] and augmentation index [Aix]). Results: In multivariable-adjusted regression analyses, there were vasculoprotective associations between serum selenium and a microvascular measure (AVR [β = 0.23; p = 0.036]) in black African women and with a macrovascular measure (24-hour PP [β = −0.15; p = 0.048]) in white African women. In turn, GPx activity also showed a protective association with a microvascular measure (eGFR) in white African men (β = 0.23; p = 0.035), as well as with macrovascular measures (AIx, PP) in the black (β = −0.25; p = 0.027) and white African men (β = −0.22; p = 0.035), and black African women (β = −0.32; p = 0.001). Conclusions: Collectively the findings suggest a protective role for the micronutrient selenium and GPx on both the micro- and macrovasculature in a young, healthy bi-ethnic population

PhD (Physiology), North-West University, Potchefstroom Campus Motivation - The human immunodeficiency virus (HIV) continues to be a global health concern, with an estimation of 38 million people living with HIV. Out of these 38 million people living with HIV, 70% are residing in Sub-Saharan Africa (SSA) countries. Alongside the high burden of HIV infection, cardiovascular diseases (CVD) are also an important health concern in this region. The introduction of antiretroviral therapy (ART) has increased the life expectancy of HIV-infected individuals with consequential exposure to comorbidities such as hypertension, dyslipidaemia and diabetes mellitus as well as liver and renal disease – all known to be associated with an increased risk for the development of CVD. With 90% of South Africans living with HIV expected to be on ART by 2030, the prevalence of CVD risk factors is also expected to increase. Hence, it is vital to fully understand the impact of HIV, ART and conventional cardiovascular risk factors in the development of CVD in HIV-infected individuals. This understanding is currently limited by available evidence from longitudinal studies, especially in the SSA region. To better understand the long-term risk of developing CVD in people living with HIV, the cardiovascular health transition of HIV-infected Africans who are at risk of developing CVD was investigated for this study. Aim - The central aim of this study was to investigate the longitudinal cardiovascular health of a black South African cohort infected with HIV and a literature review based on studies conducted in the SSA region. Methods - The narrative review included a synthesis of studies done in SSA reporting on blood pressure (BP) and hypertension in HIV. PubMed and EBSCO Discovery Service were searched for manuscripts published up to May 2020. Ultimately, 19 studies were included that reported on estimates of BP and/or hypertension prevalence in treated HIV-infected individuals versus untreated HIV-infected individuals and uninfected controls, residing in SSA countries. The original papers of this study are based on the South Africa leg of the Prospective Urban and Rural Epidemiology (PURE) study, North West Province. Manuscript two and three, which form part of the PURE study, included 117 HIV-infected individuals and 131 uninfected controls and 126 HIV-infected and 126 uninfected controls, respectively. The study participants comprised of African men and women older than 35 years. Participation in the PURE study was voluntary and written informed consent was obtained from each participant. Standard protocols and methods were used to gather all data and consisted of questionnaire data (demographic, lifestyle and medical history). Other data included HIV-related factors (ART use and duration, CD4 cell count), body composition and cardiovascular measurements (blood pressure, carotid femora pulse wave velocity, carotid intima-media thickness), as well as biochemical analyses of all relevant biomarkers used in the study. Regarding statistical analyses, variables that were not normally distributed were log-transformed. Means and proportions were compared using the independent t-tests, dependent t-tests, Chi-square test, McNemar test or analysis of variance or covariance and repeated measure analysis. With manuscript three, partial and multiple regression analyses were used to investigate associations between the main dependent (cfPWV and cIMT) and independent (endothelial activation ad cardiovascular risk markers) variables of interest. In all cases, p≤0.05 was used to indicate statistical significance. Results of each manuscript - Manuscript one - A narrative review synthesis was conducted to determine the estimates of raised BP and hypertension in HIV-infected patients compared to untreated and HIV-uninfected controls from SSA. A total of 19 eligible studies that compared treated HIV-infected with untreated and/or HIV-uninfected controls were included. In studies comparing treated HIV-infected patients to uninfected controls, a large proportion of studies, reported lower BP 6,882 (56.30%) and hypertension prevalence 21,819 (79.2%) respectively, in the treated HIV-infected individuals than in HIV-uninfected controls. On the other hand, studies including 753 (6.16%) and 3,553 (12.9%) participants showed a higher BP and hypertension prevalence. Lastly, 4,588 (37.54%) and 2,180 (7.91%) participants showed no difference in BP and the prevalence of hypertension between the treated HIV-infected individuals and HIV-uninfected controls. Estimates of BP and hypertension prevalence were further compared for of treated versus untreated HIV-infected individuals. Studies including 5,757 (44.2%) and 4,547 (74.5%) participants reported lower BP and hypertension, respectively in treated compared to untreated HIV-infected individuals. On the other hand, studies including 200 (1.53%) and 598 (9.80%) participants showed higher BP and hypertension prevalence. Similar BP and hypertension prevalence was reported 7,073 (54.28%) and 959 (15.7%) participants respectively in the treated and untreated HIV-infected individuals. Manuscript two - This manuscript profiled the demographic and cardiometabolic factors, indicators of inflammation and oxidative stress as well as liver and renal function of HIV-infected Africans and uninfected controls over 10 years. The HIV-infected individuals living with HIV for over 10 years presented with longitudinal increases in C-reactive protein (p=0.002), alanine transaminase (p=0.006) and gamma-glutamyl transferase (p=0.046) levels as well as estimated glomerular filtration rate (eGFR) (p

Purpose Despite selenium’s beneficial effects in counteracting oxidative stress, inflammation, and vascular endothelial dysfunction, controversial results exist regarding the long-term associations between selenium and atherosclerosis, arterial stiffness, and hypertension. We investigated in normal and selenium-deficient groups (and the total group), whether serum selenium relates to measures of large artery structure and function over 10 years. Methods This longitudinal study included black adults from rural and urban areas in South Africa. Serum selenium and blood pressure were measured at baseline (N = 987). At follow-up, carotid intima media thickness (IMT), cross-sectional wall area (CSWA), carotid-femoral pulse wave velocity (c-fPWV), and blood pressure were measured (N = 718). Selenium deficiency was classified as serum levels

Background and Aims: Black boys (6–8 years of age) were shown to have higher pulse wave velocity with potential early vascular compromise. We aimed to compare predefined urinary metabolites in black and white boys to explore associations of pulse wave velocity with these metabolites. Methods and Results: We included 40 white and 40 black apparently healthy boys between the ages of 6 and 8 years. Femoral pulse wave velocity was measured along with various metabolites using liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS) methods. Pulse wave velocity and diastolic blood pressure were higher in the black compared to the white boys (both p ≤ 0.002). Isovalerylcarnitine was lower and 1-metylhistidine tended to be lower (p = 0.002 and p = 0.073, respectively), whereas L-proline levels tended to be higher (p = 0.079) in the black compared to the white boys. In single, partial, and multiple regression analyses, pulse wave velocity correlated inversely with β-alanine (β = –0.414; p = 0.008) and 1-methylhistidine (β = –0.347; p = 0.032) and positively with L-proline (β = 0.420; p = 0.008), threonic acid (β = 0.977; p = 0.033), and malonic acid (β = 0.348; p = 0.030) in black boys only. Conclusion: Our study is the first to discover the associations of pulse wave velocity with β-alanine, 1-methylhistidine, and L-proline in children from South Africa, which may suggest potential early compromise in cardiac protective metabolic pathways in black boys as young as 6 years of age.

Consistent reports indicate that hypertension is a particularly common finding in black populations. Hypertension occurs at younger ages and is often more severe in terms of blood pressure levels and organ damage than in whites, resulting in a higher incidence of cardiovascular disease and mortality. This review provides an outline of recent advances in the pathophysiological understanding of blood pressure elevation and the consequences thereof in black populations in Africa. This is set against the backdrop of populations undergoing demanding and rapid demographic transition, where infection with the human immunodeficiency virus predominates, and where under and over-nutrition coexist. Collectively, recent findings from Africa illustrate an increased lifetime risk to hypertension from foetal life onwards. From young ages black populations display early endothelial dysfunction, increased vascular tone and reactivity, microvascular structural adaptions as well as increased aortic stiffness resulting in elevated central and brachial blood pressures during the day and night, when compared to whites. Together with knowledge on the contributions of sympathetic activation and abnormal renal sodium handling, these pathophysiological adaptations result in subclinical and clinical organ damage at younger ages. This overall enhanced understanding on the determinants of blood pressure elevation in blacks encourages (a) novel approaches to assess and manage hypertension in Africa better, (b) further scientific discovery to develop more effective prevention and treatment strategies and (c) policymakers and health advocates to collectively contribute in creating health-promoting environments in Africa.

M Health Science (Cardiovascular Physiology), North-West University, Potchefstroom Campus Background and motivation: Myeloperoxidase (MPO) is an enzyme with both pro-inflammatory and pro-oxidative functions. Previous studies in the United States have found MPO levels to be higher in African American than in white groups, but studies examining MPO levels in South Africa are scant. Recent findings indicated that increased circulating levels of MPO are linked to hypertension and stroke, especially in older populations. Early microvascular changes may aid in the prediction of cardiovascular disease (CVD). The retina is a unique site to investigate microvascular changes with non-invasive techniques, such as the Retinal Vessel Analyzer. Retinal vessel calibres can be determined from retinal fundus images to determine the central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE). In South African populations, CRVE was found to be wider and CRAE narrower in black adults when compared with white adults. Arterial narrowing is commonly associated with hypertension, whereas venular widening is associated with incident stroke. Retinal arterial narrowing is a difficult measure to estimate precisely and therefore a summary measure, the ratio of CRAE and CRVE, the arterio-to-venous ratio (AVR) was proposed. Arterio-to-venous ratio can be used as an index of the severity of arteriolar narrowing. Whether there are potential associations between MPO levels and the microvasculature among young black and white individuals with no apparent CVD still needs to be investigated. The African Prospective study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT) allows us to investigate the association between the microvasculature and MPO in young participants. Aim: To determine whether measures of the retinal microvasculature associate with MPO in young, bi-ethnic South African adults. Methods: We included the first 577 participants of the African-PREDICT study, aged 20-30 years, with complete retinal vessel calibre data at baseline, namely black (n=284) and white (n=285) men and women. Participants who presented with missing data for MPO (n=5) and those using anti-inflammatory medication (n=3) were excluded from this study. The final group consisted of 569 participants. Data on anthropometric measures including body height, weight, and waist circumference were collected, and body mass index was calculated. Clinic blood pressure was measured on the left arm in duplicate while participants remained in a rested seated position. The Retinal Vessel Analyzer was used to capture retinal images. The images were analysed to calculate CRAE and CRVE. Biochemical analyses included MPO, the lipid profile (triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol), gamma-glutamyltransferase (GGT), cotinine, high sensitivity C-reactive protein (CRP), white blood cell count, creatinine and serum peroxides, as an indicator of reactive oxygen species (ROS). Statistical analyses included independent T-tests and Chi-square tests to compare means and proportions. Single, partial and multiple regression analyses were performed to investigate the associations between the retinal vessel calibres and MPO while adjusting for age, waist circumference, systolic blood pressure, total energy expenditure (TEE), white blood cell count, GGT, HDL-C, cotinine and glucose. Results: Groups were divided based on interactions found for sex on the associations between CRVE and MPO (p=0.027) and between AVR and MPO (p=0.027), along with evidence in the literature reporting on different MPO levels and retinal microvascular calibres; found in black and white groups. No significant differences were found between black and white men (p=0.71) or women (p=0.95) when comparing MPO levels between the groups. When comparing black and white groups, CRAE and AVR (all p

Background: The impact of a sedentary and unhealthy lifestyle on cardiovascular health is well documented, however the current obesity and hypertension trends among children is concerning. The ExAMIN Youth SA study aims to investigate the impact of lifestyle behaviors (physical fitness/activity, dietary intake and psychosocial factors) involved in early vascular aging among South African children. Methods: This study is an analytical, multidisciplinary, observational cohort study in a school-based setting. We aim to phenotype a cohort of approximately 1000 primary school children (black and white boys and girls between ages 5–9 years) based on current clinical childhood conditions including hypertension and obesity. The primary phenotype is large artery stiffness and retinal microvascular diameters, both biomarkers of early vascular aging. The risk factors and mediators of early vascular ageing and also responsible for the clinical conditions include physical inactivity, unhealthy diet, and life stress. Additionally, urinalysis and salivary analyses will be performed to identify biomarkers related to the pathophysiology of early vascular aging. Discussion: In line with the growing prevalence of obesity and hypertension responsible for the development of early vascular ageing from childhood to adulthood, this study will address the critical areas in which we observe unfavorable arterial modulation related to dietary behaviors, physical inactivity and early life stress. Implementation of novel biological markers may further contribute to our understanding of early cardiovascular adaptations in childhood, and aid in the development of primary prevention programs. Trial registration: The study was retrospectively registered on ClinicalTrials.gov on 15 August 2019 (NCT04056377).

PhD (Sciences Physiology), North-West University, Potchefstroom Campus Background and motivation: The global burden of cardiovascular disease (CVD) including hypertension is ever-increasing, especially in the South African context. Nitric oxide (NO) plays a vital role in normal vascular endothelial function with considerable evidence of imbalanced NO bioavailability in the elderly and diseased states such as hypertension. Endothelial dysfunction with attenuated NO bioavailability is central to the pathogenesis of CVD and has been implicated as a possible mechanism in the premature development of hypertension. Due to the prevalence of hypertension being the highest in Sub-Saharan Africa, the need for early identification and risk stratification of vascular abnormalities in arterial hypertension is paramount, especially in understudied black populations. Due to the nature of NO, measuring markers involved in its bioavailability as possible indicators of a NO profile is warranted. Moreover, further understanding the interactions of NO-related markers with endothelial function may impact the progression of CVD. Conversely, there is limited data surrounding the NO profile and the possible pathophysiological roles thereof in young healthy black and white populations respectively. Therefore, exploring whether an unfavourable NO profile plays a pivotal role in the development of CVD is warranted, especially in the black population who seem to be predisposed to CVD. Aim: The aim of this study was to explore the associations of NO-related markers with cardiovascular structure and function in apparently healthy children and young adults. The study also aimed to determine whether the NO profile differed among groups stratified by age, sex and ethnicity and if there are any associations of plasma and urinary NO-related markers with blood pressure (BP), arterial structure and endothelial function in black and white South Africans. Methodology: This thesis included data from the Arterial Stiffness in Offspring Study (ASOS) and the African Prospective study on the Early Detection and Identification of Cardiovascular Disease and Hypertension (African-PREDICT). These studies were cross-sectional and included black and white children (ASOS: n=81) and young adults (African-PREDICT n=1202). Anthropometric procedures included body height (cm), body weight (kg), waist and hip circumference (cm). Additionally, body mass index (BMI) was calculated. Biochemical analyses were performed where urinary arginine, homoarginine, asymmetric (ADMA) and symmetric dimethylarginine (SDMA) as well as ornithine/citrulline, malondialdehyde (MDA), creatinine, nitrite and nitrate were determined in both the ASOS and African-PREDICT studies (gas chromatography-mass spectrometry (GC-MS)). The urinary nitrate-to-nitrite ratio (UNOxR) was additionally calculated. Plasma arginine, homoarginine, ADMA and SDMA were determined in the African-PREDICT study only (liquid chromatography-tandem mass spectrometry (LC-MS/MS)). Additional biochemical analyses were performed in the African-PREDICT study which included the lipid profile (total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglycerides), gamma glutamyltransferase, creatinine and high sensitivity C-reactive protein (Cobas Integra 400 plus Roche, Basel Switzerland). Serum cotinine levels were determined with a chemiluminescence method on the Immulite (Siemens, Erlangen, Germany). Creatine kinase (CK) was determined with electrochemiluminescence method on the E411 (Roche, Basel Switzerland). Sodium fluoride plasma glucose (Siemens, Erlangen, Germany) and EDTA whole blood glycated haemoglobin was determined (Cobas Integra 400 plus Roche, Basel Switzerland). Urinary albumin (mg/L) and creatinine (mmol/L) were determined (Cobras Integra® 400plus, Roche, Basel, Switzerland) and the urinary albumin-to-creatinine ratio (uACR) was calculated. Furthermore, the Chronic Kidney Disease Epidemiology (CKD-EPI) formula was utilised to calculate the estimated glomerular filtration rate (eGFR) from serum creatinine values. Cardiovascular measures in the ASOS study included brachial office BP using the Omron HEM-759-E (750IT) device (Omron Healthcare, Tokyo, Japan) and carotid intima media thickness (cIMT) using B mode ultrasonography (SonoSite MicroMaxx, Bothell, WA). Likewise, the cardiovascular measures in the African-PREDICT study included brachial office BP (Dinamap® ProCare 100 Vital Signs Monitor (GE Medical Systems, Milwaukee, USA)), 24-hour ambulatory BP (CardioXplore, Meditech, Budapest, Hungary, British Hypertension Society (BHS) validated), cIMT (General Electric Vivid E9 device; GE Vingmed Ultrasound A/S, Horten, Norway), central BP (central systolic blood pressure (cSBP)) and pulse wave velocity (PWV) (SphygmoCor XCEL device (AtCor Medical Pty. Ltd., Sydney, New South Wales, Australia). Statistical analyses included independent T-tests to compare means and chi-square to compare proportions between the groups. Pearson, partial and multiple regression analyses were performed and adjusted for potential confounders to investigate the associations of both plasma and urinary NO-related markers with cardiovascular and biochemical markers according to the specified focus of each research manuscript. Doctoral

Nitric oxide plays an important role in maintaining endothelial function, while increased oxidative stress may lead to nitric oxide inactivation and cardiovascular disease. If nitric oxide biosynthesis/bioavailability is already suppressed early in life, it may potentially predispose an individual to the early development of cardiovascular disease. We therefore aimed to identify differences in nitric oxide-related markers (urinary nitrate, nitrite and the nitrate-to-nitrite ratio (UNOxR)) between young black and white individuals, and whether these markers are associated with blood pressure and carotid intima media thickness. We included black and white healthy boys (n = 80; aged 6–8 years) and men (n = 510; 20–30 years) and measured blood pressure and carotid intima media thickness, along with urinary biochemical markers including nitrate and nitrite. The black boys and men had lower nitrate and UNOxR (all p ≤ 0.003) than their white counterparts. In single and multiple regression analyses, we found an inverse association of diastolic blood pressure in the black boys (adj. R2 = 0.27; β = –0.32; p = 0.030), and systolic blood pressure in black men (adj. R2 = 0.07; β = –0.13; p = 0.036) with nitrate. Carotid intima media thickness associated inversely with UNOxR in the black men (adj. R2 = 0.02; β = –0.14; p = 0.023), but not in the boys. Lower urinary nitrate in black boys and young men was associated negatively with blood pressure, suggesting that potentially lower nitric oxide bioavailability in young black individuals may contribute to hypertension development in later life.

Purpose: Elevated blood pressure is a well‐documented risk factor for cardiovascular disease and mortality in Sub‐Saharan Africa (SSA). With SSA also affected by high Human Immunodeficiency Virus (HIV) infection rates, it remains controversial whether the HIV‐infected population has a higher cardiovascular risk than the general population. We, therefore reviewed the literature comparing blood pressure estimates in treated HIV‐infected populations against untreated and/or uninfected controls from SSA. Methods: We conducted a narrative review through PubMed and EBSCO Discovery Service (EDS) to determine the estimates of raised blood pressure and hypertension in the HIV‐infected individuals versus uninfected controls (01 January 2005 to 11 November 2018). Results: After review, we included 14 eligible studies from six countries including 26,302 participants that compared treated HIV‐infected, versus untreated and uninfected controls. Studies involving 24,696 participants reported lower blood pressure and/or prevalence of hypertension in treated HIV‐infected patients compared to uninfected controls. Studies comprising of 3,536 participants reported higher blood pressure and hypertension prevalence in the treated HIV‐infected group than uninfected counterparts, whereas studies with 6,379 participants showed no difference in blood pressure and/or prevalence of hypertension. When comparing HIV patients with and without antiretroviral treatment, studies with 10,304 patients showed treated patients to have lower blood pressure and/or prevalence of hypertension, one study indicated higher blood pressure and/or prevalence of hypertension and studies with 5,806 patients showed no difference in blood pressure and/or prevalence of hypertension than untreated infected patients. Conclusion: The majority of the findings in this review indicate lower or similar blood pressure and/or prevalence of hypertension in treated HIV‐infected individuals compared to untreated and uninfected controls from SSA. It is imperative to further clarify these findings to provide reliable tools for screening and monitoring raised blood pressure in HIV‐infected patients